REGULATION of PEDIATRIC CANCER DRUG DEVELOPMENT:AN INDUSTRY

REGULATION Of PEDIATRIC CANCER DRUG DEVELOPMENT:AN INDUSTRY

PERSPECTIVE

Penny Wai Ping Ng

A Qualifying Review Submission Presented to the FACULTY OF THE USC SCHOOL OF PHARMACY UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF REGULATORY SCIENCE

September 2019

TABLE OF CONTENTS

TABLE OF CONTENTS ...... 2 LIST OF TABLES ...... 5 LIST OF FIGURES ...... 7 DEDICATION ...... 9 ACKNOWLEDGMENTS ...... 10 ABSTRACT ...... 11 CHAPTER 1. OVERVIEW ...... 12 1.1 Introduction ...... 12 1.2 Statement of the Problem ...... 15 1.3 Purpose of the Study ...... 17 1.4 Importance of the Study ...... 18 1.5 Limitation, Delimitations, Assumptions ...... 19 1.6 Organization of Thesis ...... 20 CHAPTER 2. LITERATURE REVIEW ...... 21 2.1 Pediatric Cancer as a Drug Development Challenge ...... 21 2.1.1 How Are We Doing? Current Pediatric Cancer Development Programs ...... 23 2.1.2 Basic Research: Non-Clinical Models ...... 24 2.1.3 Clinical Research ...... 27 2.1.3.1 Timing of Pediatric Research Relative to Adult Programs ...... 29 2.1.3.2 Current Clinical Study Landscape ...... 35 2.1.3.3 Role of Precision Medicine ...... 37 2.1.3.4 Master Protocol Approach ...... 38 2.2 Pediatric Cancer as a Regulatory Challenge ...... 39 2.2.1 Pediatric Regulatory Framework in the United States (US) ...... 40 2.2.1.1 Early Pediatric Regulations ...... 40 2.2.1.2 Evolution through Legislative Actions ...... 41 2.2.1.3 Effectiveness of PREA, BPCA, and RPDPRV in Pediatric Cancer Drug Development ...... 49 2.2.2 Paediatric (Pediatric) Regulatory Framework in the European Union (EU) ...... 62 2

2.2.3 Key Differences Between the US and EU Pediatric Regulations ... 63 2.2.3.1 Difference in US and EU Pediatric Oncology Study Requirement: Recent Example ...... 67 2.3 Framing the Study of Pediatric Oncology Drug Development ...... 69 CHAPTER 3. METHODOLOGY ...... 74 3.1 Introduction ...... 74 3.2 Survey Development and Focus Group Feedback ...... 74 3.3 Survey Dissemination and Analysis ...... 76 CHAPTER 4. RESULTS ...... 78 4.1 Profiles and Background of Participants ...... 78 4.2 Experience in Pediatric Oncology Development for Drugs/Biologics ...... 80 4.3 Organizational Structure for Pediatric Oncology Development ...... 91 4.4 Experience with FDA and EMA Interactions ...... 101 4.5 Exploratory: Cross Tabulations by Size of Organizations ...... 121 CHAPTER 5. DISCUSSION ...... 123 5.1 Methodological Considerations ...... 123 5.1.1 Delimitations ...... 123 5.1.2 Limitations ...... 125 5.1.2.1 Availability of Representative Participants ...... 125 5.1.2.2 Survey Methodology ...... 127 5.2 Consideration of Results ...... 128 5.2.1 From Exploration to Installation ...... 128 5.2.1.1 Obtaining Information about Regulatory Requirements . 128 5.2.2 From Installation to Implementation ...... 132 5.2.3 Full Implementation ...... 136 5.2.3.1 Challenges in Clinical Programs ...... 136 5.2.3.2 Interactions with Health Authorities ...... 138 5.2.3.3 Current Incentive Structures...... 139 5.2.3.4 Global Collaboration and Knowledge Sharing ...... 141 5.3 Conclusions and Future Directions ...... 143 REFERENCES ...... 144 APPENDIX A...... 154 APPENDIX B...... 155 APPENDIX C...... 162 3

APPENDIX D...... 172 APPENDIX E...... 187

LIST OF TABLES

Table 1: Differences between Blastoma Versus Carcinoma ...... 22 Table 2: PREA Versus BPCA (Under FDAAA) ...... 47 Table 3: Approved Adult Oncology Products with PREA Exemption (January 2016 to September 2017) ...... 50 Table 4: FDA Approved Oncology Drugs Qualified for Disease-Specific Waivers (January 2016 to October 2017) ...... 52 Table 5: Recent Adult Oncology Drugs Approvals Granted with Orphan Drug Designation (January 2016 to October 2017) ...... 53 Table 6: Listing of Rare Pediatric Disease Priority Review Vouchers Awarded (as of October 2017) ...... 57 Table 7: EU Paediatric Regulation: Obligations Versus Incentives ...... 63 Table 8: Differences in Pediatric Regulations: EU Versus US ...... 64 Table 9: Grounds for Waiver Request for Pediatric Studies ...... 65 Table 10: US and EU Pediatric Status of Approved Anti-PD1/L1 Agents (as of October 2017) ...... 68 Table 11: Outline of Implementation Stages: Industry’s Feedback of the Practice-Policy Loop ...... 72 Table 12: List of Focus Group Participants ...... 75 Table 13: Personal Experience in Pediatric Oncology Drug/Biologic Development in the US and in the EU ...... 81 Table 14: Roles in Pediatric Oncology Drug/Biologic Development Within the Organization ...... 83 Table 15: Timing of Pediatric Planning Initiation ...... 92 Table 16: Participation in Meetings and Workshops ...... 93 Table 17: Ranking of Challenges Within the Company/Organization in Pediatric Oncology Development Planning (n =26) ...... 97 Table 18: Ranking of Frequency of Approaches Taken by Organizations for Development Programs ...... 101 Table 19: Experience in Inclusion of New Study Design Elements in Proposals to Health Authorities ...... 102 Table 20: Satisfaction with Current Mechanisms for Development Plan Feedback from the US FDA and/or EU PDCO ...... 106

Table 21: Experience Regarding FDA Discussions on Selected Topics Related to Pediatric Development Plans ...... 109 Table 22: Experience Regarding EMA Discussions on Selected Topics Related to Pediatric Development Plans ...... 111 Table 23: Reasons for Not Receiving 6-Months Pediatric Exclusivity from the US FDA ...... 115 Table 24: Reasons for Not Receiving 6-Months Pediatric Extension from EU CHMP ...... 115 Table 25: Industry’s Perspective on Adequacy of Current Incentives for Pediatric Oncology Drug Development ...... 117 Table 26: Respondents’ Opinion on Key Drivers to Advance Early Pediatric Oncology Drug Development ...... 119 Table 27: Respondents’ Opinion on Key Drivers to Increase Pediatric Stand- Alone Programs Specific for Pediatric Cancers ...... 120 Table 28: Other Experience with Pediatric Oncology Development Programs ...... 121

LIST OF FIGURES

Figure 1: Timing of Pediatric Drug Development Program in Relation to Adult Program ...... 30 Figure 2: Pediatric Drug Development Program with Waiver or Exemption ...... 31 Figure 3: Earlier Pediatric Clinical Program Initiation ...... 33 Figure 4: Pediatric Focused Clinical Program Initiation ...... 35 Figure 5: Timeline of US Laws and Regulations for Pediatric Drug Development ...... 41 Figure 6: Timeline of Dinutuximab Development (Clinical to US BLA Approval) ...... 61 Figure 7: Four Stages of Implementation Framework ...... 71 Figure 8: Feedback Loop: Practice-Policy Communication Cycle ...... 72 Figure 9: Current Job Title of Respondents ...... 78 Figure 10: Functional Areas of Respondents Within the Company ...... 79 Figure 11: Size of Company by Number of Employees ...... 80 Figure 12: Utilization of FDA Guidance Documents ...... 85 Figure 13: Utilization of Other FDA Information and Mechanisms ...... 86 Figure 14: Clarity of FDA Guidance Documents and Information on Pediatric Study Plan Development...... 87 Figure 15: Utilization of EMA Guideline and Information on Pediatric Investigational Plan Development ...... 88 Figure 16: Clarity of EU Guidance Documents and Information ...... 89 Figure 17: Helpfulness of Publicly Available Information ...... 90 Figure 18: Resources Within Organizations for Pediatric Oncology Development ...... 94 Figure 19: Challenges in Pediatric Oncology Development Plan ...... 96 Figure 20: Challenges/Disagreements in Key Elements of Pediatric Oncology Development Plan ...... 98 Figure 21: External Factors Contributing to Challenges in the Implementation of the Pediatric Oncology Development Plan ...... 100 Figure 22: Receptivity of the US FDA to Novel Study Design Elements ...... 103 Figure 23: Receptivity of the EU CHMP to Novel Study Design Elements ...... 104 7

Figure 24: Respondents’ Experience on Timing of PSP and PIP Coordination ...... 108 Figure 25: Experience in Reaching Agreement on PPSR with the FDA within the Estimated Timeframe (N=27) ...... 112 Figure 26: Experience on Timing and Delay in Reaching Agreement with the US FDA or the EU PDCO ...... 113 Figure 27: Experience in Receiving Pediatric Rewards/Incentives ...... 114

DEDICATION

This dissertation is dedicated to my father, Charles Chak Nang Ng, who taught me that learning is a gift and a blessing.

May there be more people working together to free the world from fear, disease, and heartache.

ACKNOWLEDGMENTS

I want to express my deepest appreciation to my advisor, Dr. Frances J. Richmond, for her guidance, supports, and patience over the past 5 years. Dr. Richmond is an excellent researcher, mentor, instructor, and role model. This dissertation would not be possible without her persistent guidance.

I also thank my thesis committee, especially Drs. Nancy Pire-Smerkanich and Neal Storm, my fellow DRSc students, and members of my focus group for all their reviews and invaluable inputs on my research project. And to all who generously shared their time and insights by participating in the survey, making this survey possible, thank you.

Finally, I want to acknowledge with gratitude, the support, and love of my family, my parents

Charles Ng, Maria Ho-Ng (deceased), and Jennifer Au-Ng; my siblings (Kathleen Ng, Susanna

Siu-Ng, Edith Ng, and David Ng); my husband, Tommy Cheng; and my daughter, Cadence

Cheng. They have been very patient with me, keeping me healthy physically, helping me stay focused and sane as I pursued my continuing studies.

ABSTRACT

Drugs for cancer represent perhaps the largest and fastest source of new drug submissions in the last decade, accounting for 21% of new molecular entities (NMEs). Most of these drugs are for adults, for whom cancers are the second leading disease-related cause of death. However, drugs are often unavailable for children, for whom cancers are the leading cause of such deaths. This challenge has led both the Food and Drug Administration (FDA) in the United States (US) and the European Medicines Agency (EMA) to institute new pediatric regulations that include additional incentives and removal of pediatric study-requirement exemptions for companies that develop applicable targeted therapies. Both the US FDA and EMA are also attempting to encourage the earlier conduct of trials focused specifically on pediatric disease. The purpose of this research was to explore current industry views on the challenges and opportunities in pediatric cancer drug development under the existing regulations. Using a survey method, regulatory professionals and consultants with experience in pediatric drug development and/or design were provided with an electronic survey tool through a web-based interface. Data analysis was conducted on responses 46 participants from large and small companies undertaking pediatric oncology drug/biologic development. Results showed that most companies have allocated internal resources for pediatric oncology development and viewed the current pediatric incentives as at least “somewhat adequate”, yet they continued to face challenges with the implementation of pediatric planning and execution of innovative study designs. Factors that appear to inhibit uptake of early or dedicated pediatric oncology programs were difficulties in developing a globally harmonized regulatory plan and knowledge gaps in optimizing pediatric study designs.

CHAPTER 1. OVERVIEW

Introduction

Children are not little adults.

Although children suffer from many of the same diseases as adults and have been treated with the same medications, drug effects and disease pathology can be different because children are still maturing physically and mentally. This is particularly reflected in oncology – the biology of pediatric tumors is different from that of adult malignancy. Hence, therapeutic paradigms are usually not the same (e.g. differ in sensitivity to chemotherapy regimen or choice of targeted therapies to a specific molecular pathway).

Cancer is the leading disease-related cause of death for children aged 1-19. The American

Cancer Society estimated in 2016 that 10,380 new cancer cases were diagnosed and 1,250 cancer deaths occurred in American children aged 0 – 14; 4,280 new cancer cases were diagnosed and

600 cancer deaths occurred among children aged 15 - 19 (ACC, 2016). Similar statistics were also reported in Europe, where 15,000 children are diagnosed with cancer each year, accounting for 1% of all cancers in humans (Vassal, 2009).

The goal of childhood cancer therapy is not only to prolong survival or management as a chronic disease, as is typical for many adult cancer treatment programs but to cure the patients (Raeman,

2015). However, among pediatric survivors, two-thirds are projected to develop long-term and late-term treatment-related complications including a high risk of long term cardiovascular sequelae from chemotherapies, and further risk of developing another cancer from radiotherapies.

Thus, a clear need exists to develop drugs for childhood cancers that currently have no effective

treatment and to provide new drugs with reduced and manageable adverse, including potential late and long-term safety effects.

At the same time, pediatric cancers must compete with adult cancers for attention and resources.

Cancer in American adults is the second most common cause of mortality and the primary health threat for years-of-life lost. The huge health burden caused by adult cancer has driven a dramatic increase in research and development (R&D) over the last decade. This effort resulted in a proliferation of new drugs, as evidenced by the fact that oncologic drugs represent 21% of the total new molecular entities (NMEs) for all diseases over the last 10 years (Milne, 2017).

However, this encouraging record is not also observed in the pediatric sector. Pediatric cancers are typically viewed as relatively rare diseases where commercial returns can be difficult to achieve. As noted by Milne (Milne, 2017), the eight approvals per year for adult cancers from

2013 to 2015 greatly outpaces the introduction of only eight new drugs with a pediatric cancer primary indication in the whole of the last 25 years.

Finding treatments for childhood cancers is complicated not only by the relatively small size of the target markets but also by the heterogeneity of their cancers with respect to those in adults.

Some cancers are seen in both children and adults, but cancers that affect both populations in a similar way are not common. For example, the four most common adult cancers that have been the focus of oncology drug development (lung, breast, prostate, and colorectal) are essentially absent in children. More commonly, the causes of pediatric cancer are specific to children.

When developing targeted agents, it is difficult to repurpose adult drugs for childhood cancers because many of the target signaling pathways that are active in some adult cancers may be essential for normal development in children. Therefore, the R&D programs currently directed at adult cancer are often not applicable to the needs of pediatric indications. Further, childhood

cancer is a collection of “multiple diseases” with varying tumor development/genomic abnormalities. For example, children can have four distinct types of medulloblastoma based on genomic phenotype, each with its own prognosis and therapeutic strategy. A traditional randomized study design with one defined study population is not feasible when populations are substratified until they contain disease groupings with only a small number of patients.

Improving the therapeutic options for pediatric patients has been an important goal for the leading regulatory authorities in the developed world. To this end, the European Medicines Agency

(EMA) developed specific mandatory pediatric regulations and the United States Food and Drug

Administration (US FDA) implemented both the mandatory and voluntary incentive programs to address all indications for drugs that may be used in children. In both constituencies, drugs developed to treat adult indications (US FDA) or adult conditions (EMA) must be tested in children “when appropriate”. Because the biology of cancer is different in adults and children, and hence might be considered “inappropriate”, most drugs targeting adult cancers had, however, been waived or exempted from pediatric testing. To encourage new pediatric drugs for these situations, in 2002, the US FDA put in place a voluntary incentive program linked to the Best

Pharmaceuticals for Children Act (BPCA) that extended patent and statutory market protections by 6 months for pediatric drugs. This incentive proved insufficient to overcome the development and commercial challenges faced by industry when attempting to develop pediatric oncologic drugs. Thus, to encourage drug development for pediatric rare disease, Congress added an additional incentive as part of the Creating Hope Act in 2012. The Act grants the marketing applicant a transferable priority review voucher if the first approved indication of a new molecular entity (NME) or biologic is for a pediatric rare disease. In the EU, the EMA has periodically updated the class waivers list and requesting mechanism of action-driven based pediatric investigational plan instead of based on the adult’s condition. The goal of these 14

regulations is to require sponsors to discuss their strategies for future pediatric development with the respective health authorities early in the overall development program or provide justification for not doing such trials. However, the effectiveness of these regulatory mechanisms to improve drug development for pediatric rare disease is yet to be determined because by the time that the

Creating Hope Act became effective (GAO, 2016), all the products (including the 2 products approved with a pediatric oncology indication) that received the rare pediatric disease priority vouchers to date were already near commercialization.

Statement of the Problem

Pediatric regulations implemented by the US FDA and the EMA have become increasingly complex with the expanding scope of pediatric regulations and more frequent and demanding interactions with regulatory agencies to determine a pediatric investigational plan. The US and the EU pediatric regulatory frameworks and scientific elements of the U.S. Pediatric Study Plan

(PSP) under the Pediatric Research Equity Act (PREA) and EMA Paediatric Investigational Plan

(PIP) are similar, usually referred to as the “stick”. They include assessments of the sponsor’s plan for waiver or deferral, the need for juvenile animal toxicity studies, and the development of a pediatric formulation, for example. Both US PSP and EMA PIP are tied to the adult conditions and indication, respectively. In the US, there is also an incentive mechanism for drugs exempted from PREA, under the Best Pharmaceutical Children Act (BPCA), a sponsor is granted a 6-month pediatric exclusivity award upon completion of pediatric studies in accordance with the FDA’s issued Written Request. Although both US and EU apply a “stick/carrot” program, significant differences exist in other important areas of policy. Different policies can have unintended consequences, limiting the progress of pediatric drug development in some therapeutic areas. A previous survey conducted in 2012 by Premier Research on 55 biotech and pharmaceutical firms

across therapeutic areas (but not limited to rare disease or oncology companies) in both the North

American and European markets noted key problems faced by industry when attempting to comply with pediatric regulations. These include the challenges of recruiting sufficient children that meet the study criteria to participate in clinical trials. They also identify that biopharma companies have a limited understanding of the pediatric regulations, especially with the different recommendations from the FDA Pediatric Review Committee (PeRC) versus the EMA Paediatric

Committee (PDCO) on study designs. The European Federation of Pharmaceutical Industries and

Associations (EFPIA) recently noted that companies are not clear on circumstances under which health authorities may or may not accept extrapolating data rather than new randomized studies, especially in cases of rare disease and oncology, when conducting randomized studies is not often feasible (Sharma, 2018).

At the same time, the Premier Research survey noted the substantial demand that these trials place on the company’s financial resources. About 50% of the survey respondents across both regions indicated that they had to increase their R&D budgets because of PREA requirements, and 9% of EU respondents scaled back new drug development to pay for PIP studies. With regard to their perspective on the use of the 6-month period of pediatric exclusivity as a reward,

60% of both European and US respondents strongly or fairly strongly believed that a longer patent exclusivity extension should be put into place (Premier Research, 2012).

The fact that most information that we have about industry views has been extracted by a single general survey several years ago underlines how sparse is the information available from industry across the spectrum of company sizes in the pediatric cancer subsector. Over the years, occasional workshops have been conducted between industry, health authorities, patient groups, and academia addressing specific aspects of the FDA and EMA pediatric regulations. The

selected few companies chosen to participate in those workshops in order to represent the industry’s perspective were mainly from major pharmaceutical companies. In 2016, the Tufts

Center for the Study of Drug Development held a round table discussion including senior leaders from major drug companies on strategy to maximize efficacy while complying with FDA and

EMA regulations in pediatric oncology drug development. A recent workshop held by the

Friends of Cancer Research included three representatives from the industry to discuss the 2017 change in PREA requirements of new pediatric study requirements for certain cancer drugs.

Aside from these few and limited materials, we know little about the nature and impact of current pediatric regulations when companies attempt to adapt, plan, and implement pediatric oncology drug programs. There is currently no systematic approach to collect the experience from industry across the spectrum of company sizes, and especially from smaller companies, from which many oncolytic drugs emerge.

Purpose of the Study

The research proposed here explored the challenges and opportunities that the current regulations present for companies that are pursuing the development of pediatric oncology drugs. To focus the study, particular attention was directed at the different areas of clinical development that must satisfy both the US and EU pediatric regulations. The study first reviewed literature related to pediatric oncology drug development, so that the reader has a high-level appreciation of the challenges from a scientific and practical perspective. It then reviewed the pediatric regulations in the US and EU to identify what has changed over the last two decades and what some of the challenges with these regulations have been. A survey instrument was used to probe the experience, concerns, and insights of the biopharmaceutical industry regarding the evolving regulatory landscape and its impact on the development and implementation of pediatric cancer

drug programs relative to the overall cancer drug programs for that same product. Of specific interest was the way in which they have implemented changes in their drug development programs based on the relatively new regulations and incentives. Respondents to the survey included regulatory and clinical professionals at middle to senior levels in regulatory and clinical roles, as well as consultants to companies involved in planning and development activities for one or more pediatric oncology drugs.

Importance of the Study

International pediatric drug development has been driven by pediatric legislation in the US and the EU. Although there are many similarities, differences exist between the rules in the two countries. The literature review of this study is an effort to enhance understanding of the pediatric legislation in both regions, to gain insight into the impact and effectiveness of legal and regulatory changes. For companies focusing in oncology drug development, it is important to understand the legislative requirements that must be met along with incentives that exist in the

US and the EU, and also to understand if their experiences when attempting to align those requirements with their drug development program are shared across the industry.

Understanding the experience from the industry’s perspective is helpful to assess if the current process is effective in supporting the goal of facilitating the pediatric cancer drug development in a global setting. By examining differences in survey responses for companies of different types and sizes, it may also be possible to fuel broader discussions among stakeholders to address the gaps and develop actionable strategies to improve the regulatory interactions. In particular, the information may help regulators and legislators to understand where policy or even legislative change might be needed to improve the development, submission, and approval processes essential to bringing new cancer drugs to market. 18

Limitation, Delimitations, Assumptions

This research delimits its exploration to the experience and activities of industry participants who are involved specifically in pediatric oncology clinical development and not that of companies that developing drugs for other types of indications. Further, it did not specifically explore other stages interposed along the drug development path, such as preclinical activities or reimbursement programs. It is not designed to examine specific logistical issues, such as those related to clinical trial management, local health authorities’ feedback in reviewing protocol for study initiation, or informed consent. Because current pediatric regulation is substantially driven by policies set forth by the EMA and the US FDA, the survey delimited its scope to the knowledge, views, and experience of respondents with respect to the impact of regulations developed by the EMA and the US FDA.

The survey results may be limited by the availability of the respondents and their experience with the global pediatric development process as well as their openness in sharing their experiences in addressing the regulatory requirements. Because a new initiative has been signed into US law requiring that companies design their drug development programs around the specific biology of the cancer and the mechanism of action of the drug/biologic rather than target organ (FDA,

2017b), it is possible that many companies with ongoing programs are not aware of these changes and might have found some questions difficult to answer. Because the respondents are assumed to be busy professionals with limited time to allocate to survey participation, the length of the survey must be constrained and this may limit the ability to delve deeper into certain areas of exploration. It is assumed that the participants answered truthfully, but concerns about maintaining the confidentiality of proprietary information may reduce the enthusiasm of

respondents to answer some questions, even if assurances of anonymity and confidentiality are given.

Organization of Thesis

This research study has five main chapters. Chapter 1 presents an overview of the problem and an introduction to the research. Chapter 2 is divided into three main sections. The first section provides a backdrop to provide the reader with foundational information about the current state of pediatric cancer research from a clinical and drug development perspective. The second examines the current regulatory landscape of pediatric cancer drug development, including summaries and analyses from relevant academic and regulatory literature, and a discussion of challenges that can be discerned from the numbers of approvals and feedback from stakeholders so far available in the literature. As part of a description of the current regulatory landscape,

Chapter 2 includes a retrospective analysis of pediatric information made publicly available on the US FDA and EMA websites. The intent of this analysis is to provide information about the current timing of pediatric oncology trials with respect to adult programs. The third part outlines the nature of the research questions and the framework under which this investigation operated.

Chapter 3 describes the methodology used to investigate and analyze the problem, including a description of the survey development, plans for its implementation, and a data analysis plan.

Chapter 4 includes an analysis of the resulting survey data (descriptive statistical analysis), and

Chapter 5 concludes the study with a high-level discussion of these data.

CHAPTER 2. LITERATURE REVIEW

Pediatric Cancer as a Drug Development Challenge

Cancer is one of the most difficult problems facing medicine. Since the 1970s when President

Nixon declared “war on cancer” and signed the National Cancer Act of 1971, much intensive research has been directed at developing cancer cures. Funding for cancer research has averaged nearly five billion dollars each year. Still, as reflected in the launch of the 2016 Cancer

Moonshot national initiative to end cancer, cancer remains one of the top three killers of adults in the US. Thus, it is not surprising that most work has focused on adult cancers.

Treatments for childhood cancer have received less attention compared to those for adults.

Cancers in children account for less than 1% of all diagnosed cancers, and they often differ in etiology from those causing adult malignancy. Adult epithelial malignancies, for example, typically originate from mature tissues that undergo step-wise carcinogenesis. In contrast, pediatric tumors commonly develop as blastomas from stem cells with mutations that never differentiated into mature cells. Thus, many pediatric cancers are not seen in adults (ACC, 2016).

The fact that cancers from blastoma formation are composed of less differentiated cells suggests that they will be more susceptible to therapy than those of adults. Further, the number of genetic mutations in childhood tumors is on average about a hundred-fold lower than is typical for adult tumors. This may present an opportunity to develop targeted treatment for pediatric cancers because their incidence is less likely linked to the multiple possible instigators of carcinogenesis such as long-term exposures to environmental toxins or lifestyle habits, including smoking or dietary preferences. Thus, one might anticipate a better opportunity to correct the mutation with a therapy directed against this mechanism of action (Pearson et al., 2016).

Unlike adult cancers that are typically classified according to the anatomical site of the primary tumor, pediatric cancers are classified by the International Classification of Childhood Cancers schema (ICCC) into 12 major groups related to the histology of a specific tissue type (ACC,

2016). Other biological differences between adult and pediatric tumors are listed in Table 1 below (Toretsky, 2009):

Table 1: Differences between Blastoma Versus Carcinoma

Biological Differences Blastoma Carcinoma Mutation Two-hit hypothesis (e.g. loss of Multiple hits, step-wise tumor suppressor genes) carcinogenesis Link to Etiology Not clear. Does not seem linked Can be related to behavior and to environment environment Response to Chemotherapy Responsive Resistant Cell Differentiation Poorly differentiated Often well differentiated p53 Mutation Not usually involved Often observed

Although some cancers, such as acute myeloid leukemia (AML), Hodgkin and non-Hodgkin lymphoma (HL, NHL), melanoma, and glioblastoma, are seen in both children and adults, those of children often can be differentiated into distinct biological subtypes with different genetic fingerprints; thus, they may exhibit different clinical phenotypes and require a different treatment strategy (ACC, 2016). Health authorities recognize these biological differences when they advise biopharmaceutical companies on specific pediatric programs. For example, in the case of AML, a blood/bone marrow cancer that occurs mostly in elderly patients, the Paediatric Committee of the EMA noted in the standard AML Paediatric Investigational Plan (PIP) that

…not all biologic characteristics are similar (e.g., NPMI mutations)…the therapeutic settings and uses of medicines often cannot be compared across all ages (curative intention pursued with intensive front-line and first relapse treatment in young patients, in contrast to choices for palliation with low- toxicity treatment in the elderly. (EMA, 14 February 2013)

Therapeutic development is complicated further by differences in the same cancer between children of different ages and this makes clinical trial design and implementation more complex.

Differences in prognosis may relate to the presence of different molecular abnormalities and gene mutations as the children grow. In the case of AML, for example, 5-year event-free survival declines as children age, from 54% in young children to 28% in young adults; a similar pattern is also typical for adult lymphoblastic leukaemia (ALL) (EMA, 2013a; ACC, 2016).

How Are We Doing? Current Pediatric Cancer Development Programs

Survival from childhood cancers has improved steadily from 1960 to 2000 (ACC, 2016).

However, such encouraging statistics may be misleading if they are used to suggest that drug treatments for pediatric cancer have improved overall. The increased survival statistics can be attributed primarily to the improved cures of children with ALL, the most common childhood cancer. However, much of this improvement cannot be attributed to the discovery of new drugs even for ALL; about 50% of the drugs used to treat childhood ALL have been on the market since the 1960s. Additionally, the current treatment regimen/approach even for childhood ALL cannot be considered as adequate by most standards. A combination of up to 13 anticancer treatments over 2 to 4 years may be needed to sustain remission, leaving in its wake an array of chronic and disabling morbidities (Vassal et al., 2015; Norris & Adamson, 2012). Children with cancers that do not respond or reoccur quickly after conventional treatment have an overall survival rate below 25%. Other common pediatric cancers, such as neuroblastomas, medulloblastomas, high- grade gliomas, and metastatic sarcomas, have a much bleaker prognosis.

All drugs intended for children will face certain types of challenges. Drug dosage will obviously have to be studied and modified accordingly. Additional pharmacokinetic considerations can come into play if children differ in their rates of absorption, metabolism or excretion. In some cases, a new formulation may be needed specific for pediatric patients, especially those in younger age groups.

However, as noted in Section 2.1above, drugs for oncological applications become more complex to develop because childhood cancers often differ in ways that go beyond their pharmacokinetic differences. Thus, the path for pediatric drug discovery may diverge from the adult model starting even at the preclinical stage. To some extent, the lack of progress in developing new drugs to treat childhood cancer can be attributed to building pediatric programs simply as extensions to adult programs, rather than constructing a more targeted program that builds on a translational and clinical foundation specific to the pediatric disease. Such an approach has had several problems that show themselves at different stages of the drug development path.

Basic Research: Non-Clinical Models

Even at the preclinical stage, the differences between pediatric and adult cancers will affect drug development. In the past, new drugs for children relied on adult tumor models (Adamson,

Houghton, Perlong & Pritchard-Jones, 2014) because well-characterized cell lines and animal models did not exist for all pediatric cancers. However, such approaches may misguide pediatric drug development. The same identified gene or target may have different effects on adult versus childhood tumor development, so that agents that inhibit specific pathways in adult cancers may provide little or no benefit for children. Thus, an understanding of the molecular pathways, disease biology and key permissive factors that contribute to childhood cancer can help researchers create more appropriate drugs. Meaningful preclinical data is particularly important

as a foundation for subsequent drug development because pediatric cancer patients are rare.

Thus, eventual clinical trials can only be justified if there are persuasive non-clinical safety data from developing animals and evaluations of efficacy that can be linked to underlying physiological mechanisms. For drugs intended for a specific pediatric population, little adult experience may exist, so animal studies that identify potential developmental concerns for target organs should be followed by toxicological and developmental studies in juvenile animals before multiple-dose pediatric studies are initiated (FDA, 2010).

A strong preclinical base of knowledge is also fundamental to guide treatment choices based on a tumor’s molecular characteristics (Pearson et al., 2016; ACC, 2016). For example, a research study in which the IKZF1 gene was sequenced from more than 5,000 children with ALL found that most gene variants were linked to the development of leukemia. When the gene variants were introduced into cultured cells, several of these significantly reduced the sensitivity of leukemic cells to the chemotherapeutic agent, dasatinib (ASCO, 2016). It is important to have appropriate biomarkers to evaluate how well-matched and effective the drug will be to different cancers, but few such biomarkers are currently available or identified for pediatric indications.

The choice of an inappropriate biomarker can inadvertently provide misleading signals that might cause the pediatric development team to terminate the program or to point it in the wrong direction.

The National Cancer Institute (NCI) in the US acknowledged the need to expand the mechanistic understanding of pediatric cancers by investing in early-stage research. It has funded a large

Preclinical Pediatric Testing Programme (PPTP) since the mid-2000s to study pediatric cancer pathology and to prioritize cancer drugs provided by more than 50 pharmaceutical companies for early phase clinical studies in children (Vassal, 2009). One of the most important findings from

the PPTP was that many agents efficacious to treat adult cancers have limited activity in pediatric preclinical models. Such information is valuable because it reduces the risk to apply unhelpful drugs in the pediatric clinical setting. Where investigational drugs did show substantial activity in models relevant to pediatric cancers, the risks of pursuing drug development were reduced and companies appeared more willing to advance those development programs. For example, pediatric clinical trials are now underway for two such drugs, the MEK (mitogen-activated protein kinase) inhibitor, selumetinib, for gliomas with mutations in the BRAF (proto-oncogene protein B-raf) gene, and the PARP (poly-ADP ribose polymerase) inhibitor, talazoparib, given in combination with low-dose temozolomide for Ewing sarcoma (NIH, 2015). The outcome of this program is further discussed in Section 2.1.3.3, including a recent successful example described in Section 2.2.1.3.

Using advanced technologies to develop genomically-based biomarkers has advantages beyond the capability to increase the quality of clinical studies in children. By understanding the nature of inherited genetic mutations, it may even be possible to screen family members and to tailor therapies to the particular pathophysiology elicited by that mutation. To advance this cause, the

NCI TARGET initiative to examine childhood cancer genomics was launched in collaboration with St. Jude Children Research Hospital and Washington University Pediatric Cancer Genome

Project. Findings from this work, in which about 4,000 tumor samples were sequenced, confirmed that childhood cancers have fewer gene mutations than adult cancers, many of which are rare or absent in adult cancers.

It is also important to understand the mechanisms of action for pediatric cancers because regulators rely increasingly on knowledge related to the mechanism of action and disease biology when drugs are approved for market. In May 2017, for example, FDA approved KEYTRUDA

(pembrolizumab) for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch-repair- deficient (dMMR) solid tumors that have progressed following prior treatment. The approval of this particular drug relied on the use of a pan-tumor predictive biomarker in both adults and children. As part of its evidence for pediatric approval, the company rationalized that it could predict the potentially positive results in children from the good results in adults with the same biomarker profile as children. It could then rely instead on information about safety and pharmacokinetics gained from the use of the same drug in other pediatric cancer types. Because pediatric oncology clinical trials are so difficult to do, preclinical verification has become particularly important in the drug approval process.

Clinical Research

Preclinical evidence for the safety and efficacy of a drug can never substitute for the additional insight that a well-constructed clinical trial can provide. Such trials of new cancer drugs must demonstrate convincingly that the new drug will have better clinical benefit and/or reduced adverse effects compared to available therapies. However, special hurdles can complicate the design and conduct of pediatric clinical studies. For example, few acceptable/qualified clinical endpoints and validated assessment tools are available for pediatric cancers. Frequent consultations are needed with the clinical experts, health authorities and pediatric oncology cooperative groups/organizations that focus on childhood cancers to select appropriate study- design elements.

Clinical studies in pediatric patients, especially in early phases, differ from conventional drug development in several ways. First, most pediatric studies have significant risks beyond those that would normally be acceptable in a phase 1 adult study to determine the maximum tolerated dose of an agent, where subjects are carefully managed to avoid more than minimal risk. These

risks can be associated not only with the therapeutic agent itself but also from the invasive study procedures often required to assess the effects of the drug. Collection of fluids such as bone marrow, cerebral spinal fluid, or bronchial fluids are often seen as essential to evaluate clinical effects of drugs in children with cancer (e.g. leukemia and lymphoma). These painful and sometimes risky procedures can be particularly hard to carry out in children where the volumes of such fluids are small. Thus, the frequency and volumes must be reduced as much as possible by considering whether the value of the data outweighs the associated risk to the patient.

Second, conventional study design may have to be modified even in the first study. Unlike adult studies, most pediatric oncology studies are “phase 2” studies, carried out in a population with the disease because the drug typically has adverse effects that make the participation of a healthy child problematic from an ethical perspective. Initial studies are usually not randomized against another treatment because the primary goal of the study is to determine response rate and adverse reactions associated with the new agent.

Most phase 2 oncology pediatric studies take a step-wise approach in which the activity of the drug is assessed in a series of cohorts of increasing size and decreasing age. Typically, the drug is given first to a small cohort of subjects older than 12 years of age with about three subjects per dosing group. The design would then extend the testing to more or younger subjects if the observed activity of the drug exceeds a predetermined endpoint and if adverse reactions are manageable. However, it is the difficulty in extrapolating the results of three patients in one age group to a younger group whose responses may differ. This is particularly important for the classes of drugs with potential developmental toxicities that would not have been identified in adults but could be seen in children given the specific molecular targets or signaling pathways affected by the drug (Gore et al., 2017). When genomic differences can be recognized between

children of different ages, pediatric cancer populations may have to be subdivided not only by age but also by stage or additional characteristics that further diminish the size of the already rare disease. The stratification can turn each subgroup into an “ultra-rare/orphan pediatric” indication.

Thus, statistically robust study design may not be available given the small numbers of pediatric patients with certain cancers. The observations from such a small sample size may not support meaningful correlations or conclusions regarding efficacy. They may only provide enough safety information to base future studies if such studies are feasible.

2.1.3.1 Timing of Pediatric Research Relative to Adult Programs

Clinical research exposes its participants to a certain level of risk; the earlier the phase of that research, the greater the risk. According to the International Conference of Harmonization (ICH)

Directive 2001/20/EC, timing of pediatric studies in an overall product development program may vary depending upon whether the target disease is exclusive to the pediatric population.

Figure 1 below shows the typical timings of a typical pediatric development program relative to the regulatory requirements in the EU and the US for a Pediatric Study Plan. When a similar cancer is present in both adults and children, industry usually begins its planning for pediatric development after completing phase 1 or phase 2 adult trials, as required by EMA and FDA respectively. This “follow on” step-wise approach is to take advantage of the lessons provided by adult data on clinical pharmacology, preliminary efficacy and safety data. It may even be the case that pediatric trials will lag the approval of an adult oncology product even further if health authorities agreed to defer requirements for a pediatric trial until after the adult drug has been marketed (Figure 1).

Figure 1: Timing of Pediatric Drug Development Program in Relation to Adult Program

EU PIP=European Paediatric Study Plan; US PSP=United States Pediatric Study Plan; Ph=Phase; Ped.=pediatric; PK/PD=pharmacokinetic/pharmacodynamic

(Adapted from ACC, 2016; Certara, 2016)

Deferring pediatric studies until after the drugs have been approved in adults has been viewed to have a negative impact on a pediatric development program. It can be more difficult to accrue pediatric patients into clinical trials if the adult drug is available off-label for pediatric use. When the drug is used off-label, it is not possible to collect research data systematically.

Off-label use eliminates the opportunity to collect data on safe and effective use of drug products in other children who might potentially benefit or be spared from the toxicity of an ineffective drug. (Gore et al., 2017)

A recent annual report from FDA on the status of postmarketing requirements (PMRs) and postmarking commitments (PMCs) published in the 08 December 2017 Federal Register noted that that 49% (517 of 1,051) of the open (i.e. ongoing) NDA PMRs and 45% (123 of 272) of the open BLA PMRs were pending as of 30 September 2016. The largest category of pending PMRs were the deferred pediatric studies required under the Pediatric Research Equity Act. Notably, drugs do not have to be studied in children at all if they have orphan designations (in the US) or have received pediatric study waivers from the EMA or FDA (Figure 2) unless sponsors conduct them voluntarily, as discussed in more detail below.

Figure 2: Pediatric Drug Development Program with Waiver or Exemption

It is easy to understand why pediatric studies are often delayed with respect to those in adults.

Targeting a pediatric population early in development may pose a significantly greater risk of trial failure for reasons that seem obvious from the challenges described above. Further, the experience gained about the safety and efficacy of a drug from preliminary studies in an adult population can benefit the design of the more vulnerable pediatric clinical program. However, for childhood cancers with poor existing treatment options, clinicians, regulatory authorities, and

parents/patients may want to see earlier trials. Patient advocacy and clinician groups have expressed concerns that much needed drugs for children have not been made available in a timely manner, or worse, have not been studied in children at all because of orphan drug exemptions or waivers. For example, the advocacy group, KIDS vs Cancer (Kids vs Cancer, 2017), advocates that children should be included in all cancer trials unless a scientific or ethical rationale would justify their exclusion. In relapsed or refractory cancers, when the prognosis is dismal and no other options exist, early phase pediatric trials may give hope to families and provide insight into the ways in which promising experimental treatments can be combined with other approved agents in treating advanced disease.

The health authorities, FDA and CHMP, encourage a seamless clinical development approach in which adult and pediatric trials are integrated. As stated in a 2016 interview with Richard Pazdur,

Director of the Oncology Center of Excellence and Office of Hematology and Oncology Products at the FDA’s Center for Drug Evaluation and Research (Ratain, 2016):

…if a trial is evaluating a drug associated with a biomarker, then an expansion cohort might enroll patients with that particular biomarker. A pediatric population could be included in an expansion cohort to more rapidly develop drugs for children. The US FDA would like to see earlier initiation of pediatric studies once an active dose is defined in adults.

As one step in this direction, FDA is currently suggesting that adolescents aged 12-18 years be included in adult clinical trials if their “actionable targets”- their cancers and pharmacological profiles- are similar. This may be the case, for example, in Hodgkin lymphoma. Such an approach would eliminate the delays between development phases and accelerate the addition of pediatric expansion cohorts as described above (Beaver, Ison, & Pazdur, 2017) (Figure 3).

Figure 3: Earlier Pediatric Clinical Program Initiation

EU PIP=European Paediatric Study Plan; US PSP=United States Pediatric Study Plan; Ph=Phase; Ped.=pediatric; MoA= mechanism of action; PK/PD=pharmacokinetic/pharmacodynamic However, enrolling younger patients under 12 years of age when data from toxicity studies are still incomplete remains unacceptable to the Agency because younger children may respond differently than older children (Jenks, 2017).

Industry is often characterized as more cautious than patient groups or governments. This caution is probably justified. Exposing a vulnerable population to drugs with limited understanding of safety profile is a concern. In addition, the negative results in early pediatric clinical trials cannot help but affect the whole strategy for the development of that drug including the adult program.

For example, an early-stage clinical trial in children might uncover adverse events that are unique to children because of their less mature and more vulnerable physiologies. Even if those same safety issues in children are absent or are less frequent or severe in adults, their presence might cause a company to terminate a drug development program in totality, and risk depriving adults

of a useful treatment. Further, if the drug fails to show efficacy, this also may be a reason to prematurely stop the drug development program altogether in the adult indication(s) for an otherwise potential effective and safe drug in adults. It may be rare that a product would fail in adults but still be sufficiently covering the development costs from the pediatric market; making justifying the risk and expense of a pediatric program alone a challenge from the business perspective. In such a situation, the company may be concerned that early additional pediatric trials would be an investment without financial reward.

From a clinical design perspective, questions remain about the best approach to assess the risk and benefit of new pediatric clinical studies, especially with drugs still in the proof-of-concept stage. In a recent analysis conducted by the US FDA (Green, 2017), 6 of the 7 pediatric oncology studies conducted under FDAAA 2007 failed to demonstrate efficacy. FDA noted that,

…it is not clear whether these failures mean the drugs do not work in children or whether investigators did not select the right drug, identify the right patient population, choose the right dose, use the right trial design, or identify the right endpoints for their trials. Many sponsors also said they were unable to complete their studies because they couldn’t recruit subjects for the trials. (McCune, 2017)

The EMA and FDA have recently published a Strategic Collaborative Approach document on drug development in rare diseases using Gaucher disease as a guide and noted that this example may provide insights to other rare pediatric diseases, including cancers. It highlights some considerations when a step-wise age-cohort approach is used for pediatric clinical studies. For example, it questions whether specific pediatric expertise is needed related to assessing growth and puberty in the adolescent cohort when that cohort is part of the adult study and if there should be different long-term follow-up requirements for different cohorts (EMA, 2017b). A multi- stakeholder working group including patient advocates, industry, investigators, and regulators

recently issued an article to provide specific recommendations for children might be included in early-phase investigational cancer drug trials but

...discussing reasons for why a pharmaceutical sponsor may choose to include or exclude children in early-phase trials using the recommendations we propose is beyond the scope of this article. (Gore et al., 2017)

It is important to understand the industry’s perspective and experience regarding the challenges and potential opportunities of including pediatric patients earlier in the clinical drug development

(Figure 3 above). To date, most pediatric drug-development programs are tied to the adult development programs. Thus, it is also important to understand if the current incentives from the health authorities may attract companies to undertake a pediatric registration program, especially for childhood cancers that do not occur in adults (Figure 4).

Figure 4: Pediatric Focused Clinical Program Initiation

2.1.3.2 Current Clinical Study Landscape

Few pediatric cancer therapies have yet to be approved, so pediatric patients commonly gain access to treatment by either enrolling in clinical trials or receiving off-label therapy with

approved adult products. As discussed above, cancer studies unique for children are seldom carried out by industry, but rather are part of a program that also has ongoing or completed clinical studies in adults. In the US, most stand-alone pediatric trials are managed by specialized pediatric cancer centers belonging to national cooperative study groups (COGs) and funded by the National Cancer Institute (NCI). However, pharmaceutical companies may provide new drugs to NCI’s Cancer Therapy Evaluation Program (CTEP) for evaluation in children to facilitate early-phase pediatric cancer studies. COG clinical sites are estimated to treat about 90-

95% of children diagnosed in the US under the age of 15 (ACC, 2016). About 4,000 children enter NCI-sponsored clinical trials every year (NIH, 2013). Pediatric cancer trials, like other types of clinical trials, are typically listed on ClinicalTrials.gov, the US online registry of publicly and privately supported clinical studies. As of April 2013, 1,673 clinical trials relevant to pediatric cancer were listed as open for enrollment on this database. Of these, 46% were either being conducted at an NCI-designated cancer center or at a university with an NCI-designated cancer center (NIH, 2013).

A network for clinical research in pediatric oncology also exists in the EU. The European

Society for Paediatric Oncology (SIOP Europe) represents around 250 clinical centers in the EU that participate in major European phase 3 clinical trials for front-line therapies and late phase 2 trials for patients who have relapsed. The SIOP regards this collaborative approach as central to the development of new treatments:

Clinical research is necessary to combat the burden of cancer: over the past 40 years paediatric oncology in Europe made considerable progress in increasing patient survival rates of up to 80% from previously 10%. This was only achievable through close collaboration in multinational clinical trials (SIOP, 2017).

Pediatric cancer centers nationally and worldwide are a key resource for enrolling sufficient numbers of participants because of the rarity of the patients. In addition, only these specialty centers have the experts with direct experience and access to experimental therapies. These centers are also equipped with better expertise and technology to conduct genetic profiling, a key to identify the molecular characteristics of specific tumors.

2.1.3.3 Role of Precision Medicine

In the past, tumors were often defined by their site of origin in a specific part or tissue of the body. However, as discussed above in 2.2.1, the genomic characteristics of these patients may be at least as important in defining the nature and appropriate treatment for a tumor as its body location. This has begun to change the way that drug development is approached by scientists and regulators. Experience with adult cancers at the National Cancer Institute (NCI)-Molecular

Analysis for Therapy (MATCH) has shown that a “precision medicine” approach guided by molecular markers can be very powerful. Pediatric patients with advanced solid tumors including non-Hodgkin lymphomas, brain tumors, and histiocytoses that are not responding to treatment are assigned to an experimental treatment based on the genetic markers associated with their tumors rather than on their type of cancer or cancer site.

The primary study goal of pediatric MATCH is to determine the objective response rate of identified genomic mutations to specific pathway-targeted agents, selected and prioritized by the

Pediatric MATCH Target and Agent Prioritization (TAP) Committee. The identification of treatment arms relied on multi-stakeholder discussions with the US FDA and pharmaceutical companies to select agents of interest with good potential to treat a specific cancer. As of

August 2017, 7 treatment arms (paired with their respective molecular targets) have been opened

(NIH, 2017b). 37

It is encouraging that the lessons learned from the adult MATCH program are being used to improve pediatric cancer clinical research early in the drug development process. From that experience, a supportive research infrastructure and early consultations with regulators and industry appear critical to translate important opportunities into clinical trials. The TAP

Committee continues to evaluate whether target-agent pairs should be included/removed when additional evidence becomes available about the clinical activity of additional drugs and when knowledge of genomic makeup of cancers provides relevant further insights into appropriate choices (Allen et al., 2017).

2.1.3.4 Master Protocol Approach

Because pediatric cancer patients are often rare, traditional randomized studies requiring analysis with frequentist statistics can require unrealistically prolonged enrollment periods. One example of such a challenge is detailed below, in which a 7-year enrollment period was needed to test dinutuximab. The FDA has been encouraging pediatric master protocols with Bayesian models that allow data extrapolation from the results of previous studies, to facilitate pediatric trials as described in the MATCH study above (Cipriano, 2016). Having a Master Protocol is one overarching study design to evaluate one or more interventions in multiple diseases or a single disease. The goal of this innovative approach is to integrate predictive biomarkers to enable simultaneous study of multiple targeted agents across different tumor types in small populations of patients.

Because many new drugs are being evaluated in the early phase and because detection of a treatment effect can be diluted by heterogeneous groups, traditionally designed early phase studies that test treatments one at a time in heterogeneous groups of patients have not been optimal for evaluating treatment effect. Further, they may pose higher risks to patients who may 38

not receive the most promising therapy. Thus, the MATCH infrastructure can be used to add new agents into the same study as a different cohort, without having to initiate a separate study.

Some researchers also noted that such study designs bring multiple stakeholders (including different companies evaluating their respective drugs in the same study) together to improve efficiency and streamline regulatory review (Former, 2017) and study logistics. As noted in the published report by the American Cancer Society, “Translating Discovery Into Cures for Children

With Cancer”, the rarity of childhood cancer can make sufficient accrual into traditionally designed studies difficult. Competitions among research projects are fierce, with multiple studies targeting the same population. The small size of the population may offset an advantage promised by any financial incentives that might be in place. In particular, the incentive of a

6-month exclusivity extension may not be sufficient to justify investment for a pediatric development program. Adaptive multigroup trials such as those using a master protocol approach have the potential to answer several questions simultaneously and more efficiently than traditionally designed trials; i.e. which of several promising therapies appear best suited for larger, confirmatory trials? Which patients should be asked to participate in those trials? Is the chance of success in subsequent larger trials sufficient to justify the expense and time needed?

(Harrington & Parmigiani, 2016). How the data from Master Protocol design can be used for regulatory activities such as registration for pediatric indications, labeling for BPCA, or satisfying the PIP EU paediatric regulation (described below) is yet to be resolved.

Pediatric Cancer as a Regulatory Challenge

One of the most significant challenges facing the regulatory sector today is that of encouraging early pediatric cancer drug development, yet at the same time assuring that safety measures are in place for such a vulnerable population by designing the right study. It is also important that the 39

implementation of the pediatric plan does not jeopardize the development and approval of potentially lifesaving products for the general population. Thus, health authorities have made considerable efforts to understand and facilitate best practices for testing pediatric oncolytics.

The most influential approaches are those in the largest markets for medical products, the US and the EU. Over the last two decades, legislation implemented by the US Food and Drug

Administration (FDA) and the European Medicines Agency (EMA) has changed the landscape of pediatric drug development.

Pediatric Regulatory Framework in the United States (US)

2.2.1.1 Early Pediatric Regulations

Efforts to facilitate the development of pediatric products can be recognized as early as the 1970s when the FDA focused its attention on communicating information about the use of drugs for children on the labels of approved products. The 1979 Labeling Requirement mandated manufacturers to specify on the labels of pharmaceutical products whether safety and efficacy information for children had been established. However, this requirement did not assure sufficient prescribing information for pediatricians because sponsors were not required to perform specific pediatric research if information related to appropriate pediatric dosing did not exist.

Fifteen years later, the 1994 Pediatric Labeling Requirements (21 CFR 201.57) were enacted to ensure that drug sponsors included information from new clinical studies or publications relevant to pediatric use on the labeling when they submitted a supplement (sNDA) for FDA approval.

However, sponsors were still not required to conduct pediatric studies if such pediatric information was unavailable. Instead, the label could bear the statement, “Safety and effectiveness in pediatric patients have not been established”. An FDA analysis concluded that the 1994 Rule did not substantially increase the availability of safety and effectiveness

information for drug and biologic products in pediatric use (FDA, 1998). As stated by the FDA,

“Of the supplements submitted, approximately 75 percent did not significantly improve pediatric use information”. However, FDA did not have the authority to require that manufacturers carry out studies when existing information was insufficient to support the addition of pediatric-use information on the label.

2.2.1.2 Evolution through Legislative Actions

Figure 5: Timeline of US Laws and Regulations for Pediatric Drug Development

FDAMA=The Food and Drug Administration Modernization Act; BPCA=Best Pharmaceuticals for Children Act; PREA=Pediatric Research Equity Act; FDAAA=Food and Drug Administration Amendments Act; FDASIA=Food and Drug Administration Safety and Innovation Act; FDARA=Food and Drug Administration Reauthorization Act

Modified from (Turner, 2014)

The FDA could only go so far on its own to incentivize pediatric initiatives without stronger legislative authority. That authority soon was provided by a series of new laws as shown in

Figure 6. A first step took place in 1997 when the Food and Drug Administration Modernization

Act (FDAMA) of 1997 established marketing incentives for drug sponsors conducting studies of drugs in children. Specifically, section 505A of the FD&C Act provided six months of additional marketing exclusivity and patent protection for companies of on-patent drugs if they conducted trials in children in accordance with pertinent laws and regulations. A year later, the FDA published the Pediatric Rule, an important piece of legislation that required manufacturers to

conduct pediatric studies in certain drugs. The 1998 Pediatric Rule further required companies to include pediatric assessments in their supplemental NDA/supplemental BLA for new indications, dosage forms, dosing regimens, or routes of administration for indications in adults that were submitted on or after April 1, 1999. Companies could obtain a waiver or study deferral if the prevalence of the adult indication was low in the pediatric population. Without such a waiver or deferral, however, the product could be denied market authorization.

The Pediatric Rule has been controversial. The obvious goal of the Rule was to ensure that drugs commonly used in children were appropriately tested for safety and efficacy so that pediatricians would not have to estimate or extrapolate proper dosing. Not surprisingly, the FDA and

American Academy of Pediatrics (AAP) supported the rule (Arshagouni, 2002). However, the

Rule also had opponents in the medical community, such as the Association of American

Physicians and Surgeons (AAPS). The AAPS advanced the view that “the Pediatric Rule does harm” because it denies potentially life-saving drugs to adult patients by delaying drug approval until the drug has been tested in children. This was seen to be a particular problem in those cases in which the drug had little or no likely benefit in pediatrics (AAPS, 2002).

The Best Pharmaceuticals for Children Act (BPCA; Public Law 107-109) was then passed in

January 2002. It expanded on the approaches that regulators could take to encourage pediatric trials and to secure pediatric exclusivity. One goal of the BPCA remained the same as that of the

Pediatric Rule, to encourage industry-sponsored pediatric studies to improve the labeling of drug products used in children by granting an additional 6 months of patent exclusivity. Under BPCA,

FDA could issue a Written Request to the drug sponsor requesting it to conduct pediatric drug studies if the FDA determined that the drug could provide health benefits to children. FDA developed a program for pediatric oncology Written Requests (WRs) specifically to encourage

development of treatments for pediatric cancer. FDA was expected to issue WRs to sponsors of new drugs that could benefit the pediatric patients with cancers and provide them with guidance

(FDA, 2000). FDA would also be flexible in its regulatory approaches to refractory pediatric cancers with no available therapies. For example, approval could be based on meeting surrogate endpoint(s) likely to predict clinical benefits as described in Subpart H and Subpart E of 21 CFR

Part 314 and Part 601(Accelerated Approval). Unlike non-oncology programs, FDA could approve pediatric oncology drugs based on their Phase 2 study results (21 CFR 312.82(b)); in addition, Phase 3 studies usually would not be requested in a WR and would not be a prerequisite to a grant of Pediatric Exclusivity. Last, the FDA was directed to encourage applicants to discuss protocol designs and enrollment plans with a pediatric research cooperative group, such as

NCI-COG.

FDA now expects WRs for an overall pediatric development program of the drug whose plans will encompass a strategy from the early phase 1 studies for pharmacokinetics and dose-setting to

Phase 2 studies for evaluation of responsive tumors/cancer types. The general requirements for phase 1 and phase 2 study designs are outlined in Appendix A.

Exclusivities play an important role in defining a strategy for pediatric programs. FDA will add a

6-month period of pediatric extension to the existing exclusivity in the Orange Book based on the quality and ability of the submitted report to meet the terms outlined by the FDA issued Written

Request. However, the grant of PE does not imply that the results of the pediatric clinical program have demonstrated the medicine provides clinical benefits in the pediatric population.

Further, pediatric exclusivity does not apply to off-patent drugs, and without this incentive, companies might decline the request to conduct a pediatric trial. In such a case, the NIH has been authorized to conduct relevant studies instead. BPCA provides a mechanism for NIH to prioritize

therapeutic areas and sponsor clinical research on drug products that are seen to need further study in children (NIH, 2017a).

In 2002, the FDA created an Office of Pediatric Therapeutics (OPT) as mandated by Congress under BPCA. The OPT now is responsible to coordinate pediatric activities, including a mandated pediatric review on the safety of drug and biologic products, to take place 18 months after labeling changes driven by results from pediatric studies.

The FDA’s actions under the 1998 Pediatric Rule were soon to be challenged. In October 2002, the U.S. District Court for the District of Columbia held that FDA had overstepped its authority by demanding that testing be conducted for drug indications not claimed by the manufacturer/sponsor of the application. To address this problem, the Pediatric Research Equity

Act of 2003 (PREA) was signed into law on December 3, 2003. PREA amended the FD&C Act by adding section 505B, which explicitly authorized the FDA to require the conduct of pediatric studies for certain drugs and biologic products. In so doing, the Act codified the 1998 Pediatric

Rule. Like the Pediatric Rule, it required sponsors to conduct a pediatric assessment for all new

NDAs, BLAs, or supplements for new ingredients, indications, dosage forms, dosing regimens, or routes of administration filed on or after September 2007, unless they had a waiver or deferral for such assessment. Under PREA, the pediatric assessment had to contain data gathered using appropriate formulations for different age groups. Further supporting data had to show that the drug was sufficiently safe and effective for the claimed indications in all relevant pediatric subpopulations. The assessment also had to contain dosing and methods of administration appropriate for each pediatric subpopulation (FDA, 2005). However, PREA had exceptions for drugs/biologics granted with orphan drug designations. Congress felt that the need for an additional pediatric clinical trial might diminish the likelihood that a company would embark on

drug development for adult orphan diseases. This exception has recently changed for some products in the latest version of the FDA Reauthorization Act (FDARA) (H.R.2430) as of August

2017 (further described below).

In 2007, both BPCA and PREA were reauthorized under the Food and Drug Administration

Amendments Act (FDAAA). FDAAA broadened the definition of “pediatric studies” to include preclinical studies such as juvenile animal toxicity studies before initiating the pediatric clinical studies. It also narrowed the timeframe for sponsors to qualify for pediatric exclusivity; the sponsor must complete the studies in response to a Written Request, submit the data package to the Agency for review, and allow time for FDA’s determination of pediatric exclusivity, no later than 9 months prior to the expiration of existing patent/exclusivity. FDAAA also imposed new requirements directed at the FDA to increase transparency by tracking and making publicly available certain information from the pediatric clinical trials. Congress instructed FDA to establish a new committee, called the Pediatric Review Committee (PeRC), that would serve as a consultative body, and would review materials such as Pediatric Study Plans (under PREA) and

Proposed Pediatric Study Requests (under BPCA) submitted to the FDA by drug/biologics sponsors. By having a designated group of pediatric experts to review plans centrally, it was hoped that quality and consistency could be assured across the FDA review divisions (Woodcock,

2007).

Nonetheless, pediatric initiatives across therapeutic areas were still seen to be managed in a less controlled way than might be desired. In the decade to follow the 1998 Pediatric Rule, only one draft guidance, “Guidance for Industry: How to Comply with the Pediatric Research Equity Act”, has been issued to provide instruction on how to develop a pediatric plan. The lack of guidance appeared often to cause poorly developed or delayed submissions. For example, the FDA had

stated its expectation that “applicants are encouraged to submit and discuss the pediatric plan no later than the end-of-phase 2 meeting”. In 2008, however, the Pediatric Review Committee

(PeRC) commented that 57% of the PeRC Pediatric Plan submissions were last-minute rushes, with 74% and 57% submitted during the NDA/BLA review, just 4 weeks and 2 weeks before the completion of the NDA/BLA review, respectively. Thus, further measures to strengthen rather than weaken the incentives were seen to be important. In 2012, Congress took additional measures to address some deficiencies that were seen to cause problems and noncompliance, when it permanently authorized BPCA and PREA under the Food and Drug Administration

Safety and Innovation Act (FDASIA). Under FDASIA, PREA included a provision that required sponsors planning to submit an NDA application for a drug/biologics subject to PREA to provide their initial Pediatric Study Plan (iPSP) within 60 days of the End-of-Phase 2 FDA Meeting

(FDA, 2016b).

The BPCA and the PREA have often been characterized respectively as “a carrot”, that provides a financial incentive to sponsors, and “a stick”, that introduces mandatory testing requirements, enforced by threat of penalties (Table 2).

Table 2: PREA Versus BPCA (Under FDAAA)

List of Comparison PREA BPCA Scope ● Drugs and biologics ● Drugs and biologics ● Studies may only be required for ● Studies relate to entire moiety approved adult indication(s) and may expand indications beyond the approved adult indication(s) Required/Voluntary ● Required studies ● Voluntary studies Orphan Drug Context ● Products with orphan ● Studies may be requested for designation are exempted from products with orphan designation requirements ● Under 2017 FDARA, PREA applies to for certain molecularly targeted cancer drugs/biologics Outcome of Pediatric ● Pediatric studies, results positive ● Pediatric studies, results positive Studies or negative, must be included in or negative, must be included in the product label the product label Reward ● No reward as PREA ● 6-months extension to existing requirement. If not meeting pattern and exclusivity if studies requirement as Post-Marketing meet terms within FDA issued Required study, risk of non- Written Request compliance actions from the FDA (FDA, 2017b)

The complex system of requirements for pediatric studies seemed still to miss its goal of encouraging pediatric clinical trials, due in part to the waivers and exclusions for orphan drugs.

The carrot of BPCA was seen to need some form of sweetening, to encourage pediatric clinical evaluation earlier in the drug development process, particularly for rare pediatric diseases with no adult counterparts (FDA, 2016c). Thus, a new program of incentives, the Rare Pediatric

Disease Priority Review Voucher (RPDPRV) Program, under Section 529 of the FD&C Act, was developed as a collaborative effort that was championed by the non-profit patient advocacy group, Kids vs. Cancer.

The RPDPRV program was authorized under the Creating Hope Act in 2012 as part of FDASIA.

It was intended to encourage the development of new drugs and biologics for certain rare pediatric diseases by awarding a voucher for priority review from the FDA to the developer of that pediatric program upon approval of the pediatric indication. By applying the RPDPRV to a subsequent submission, the FDA committed to complete the review of the submission in

6 months (compared to the standard 10 months) even if the product did not meet any of the normal priority review requirements. Shortening the review clock was seen to give an important business advantage by allowing the approval of a submission ahead of that for a similar competing product. The value of the voucher was further increased by allowing the holder to apply the voucher not only to their own future product but alternatively to transfer or sell the voucher to another company. Further, the ownership of a voucher did not disqualify a sponsor from participating in other incentive programs, such as the 6-month pediatric exclusivity incentive under BPCA and/or the marketing exclusivity awarded under the Orphan Drug Act.

The rules to be eligible for a voucher have been clearly defined. The definition of a “rare pediatric disease” is consistent with that of the Orphan Drug Act, in that prevalence in the

U.S. had to lie below 200,000, but with the added requirement that more than 50% of patients with the disease would also have to be under through 18 years of age (FDA, 2014). Eligible applications had to satisfy the following criteria:

● Were for a human drug or biologic to prevent or treat rare pediatric disease containing no active ingredient that has been previously approved in any other application ● Were regulated under 505(b)(1) or 351(a) ● Were eligible for priority review ● Did not seek approval for an adult indication in the original rare pediatric disease product application ● Relied on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population 48

As stated in the fourth bullet, an applicant cannot receive a voucher if the applicant seeks approval for an adult indication as part of the original product application for a rare pediatric disease. However, if the applicant seeks approval for use by pediatric and adult populations with the SAME rare pediatric disease, the applicant would still be eligible for a voucher if the approved use includes both adult and pediatric use. An example is the award of a voucher to the first chimeric antigen receptor T cell (CAR-T) therapy, KYMRIAH, approved not only for the children below 18 years of age with B-cell precursor ALL that is refractory or in second or later relapse but also including young adults (up to 25 years old) in the same approved indication.

The Act was enacted as a pilot program which was set to sunset one year after the issuance of three vouchers. The award of the third pediatric voucher for a neuroblastoma drug

(dinutuximab), triggered this sunset clause and drove the Creating Hope Act to expire on March

17, 2016. However, on September 30, 2016, the voucher incentive was re-authorized under the

Advancing Hope Act of 2016 (Public Law No: 114-229) which amended Section 529 of the

FD&C Act. The Act removed restrictions on the number of vouchers that could be issued and modified the definition of “rare pediatric disease” to include “any pediatric cancers” and “any form of sickle cell disease” regardless of numbers of patients. Pursuant to the 21st Century

Cures signed into law on December 13, 2016, the Creating Hope Act pediatric RPDPRV was reauthorized until September 20, 2020.

2.2.1.3 Effectiveness of PREA, BPCA, and RPDPRV in Pediatric Cancer Drug Development

The Stick: Pediatric Research Equity Act (PREA): The spate of legislative and regulatory activities to foster the study of pediatric oncology drugs is sufficiently mature that its effects can

be examined. The results are not encouraging. From January 2016 to September 2017, for example, 57 oncology and hematology drug and biologic products have received initial or supplemental drug/biologic approvals. Of these products, 35 were granted Orphan Drug designation (and so were PREA exempted) and 21 were given a pediatric waiver. Only 6 of the

57 approvals included pediatric indications as part of the approval.

Table 3: Approved Adult Oncology Products with PREA Exemption (January 2016 to September 2017)

Approval Date Sponsor Drug/Biologic Approved Indications 01 September Pfizer Inc. MYLOTARG Treatment of newly-diagnosed CD33-positive 2017 (gemtuzumab AML in adults and for treatment of relapsed or ozogamicin) refractory CD33-positive AML in adults and in pediatric patients 2 years and older 30 August 2017 Novartis KYMRIAH Treatment of patients up to age 25 years with Pharmaceuticals (tisagenlecleucel) B-cell precursor acute lymphoblastic leukemia Corp. (ALL) that is refractory or in second or later relapse 01 August 2017 Bristol-Myers OPDIVO Treatment of patients 12 years and older with Squibb (nivolumab) mismatch repair deficient (dMMR) and Company microsatellite instability high (MSI-H) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan 23 May 2017 KEYTRUDA Accelerated Approval: Treatment of adult and (pembrolizumab) pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan 23 March 2017 EMD Serono, BAVENCIO Accelerated Approval: treatment of patients 12 Inc. (avelumab) years and older with metastatic Merkel cell carcinoma (MCC) 15 March 2017 Merck and Co., KEYTRUDA Accelerated Approval: treatment of adult and Inc. (pembrolizumab) pediatric patients with refractory classical Hodgkin lymphoma (cHL), or those who have relapsed after three or more prior lines of therapy

This may not be surprising. PREA has been viewed as irrelevant in the pediatric cancer drug development setting as the requirement for pediatric studies is based on the adult indications and it is exempted for drugs with an orphan drug designation. Further, the FDA guidance, “Guidance for Industry: How to Comply with the Pediatric Research Equity Act”, provided a list of “adult- related conditions that may qualify the drug product for disease-specific waivers” (FDA, 2005); drugs for these indications could be waived from the pediatric-studies requirement. A review of recently approved oncology drugs shows that significant numbers of these products have approved adult indications eligible for pediatric waivers (FDA, 2018).

Table 4: FDA Approved Oncology Drugs Qualified for Disease-Specific Waivers (January 2016 to October 2017)

Adult-Related Conditions Approvals from January 2016 to October 2017 (Cancer) May Qualify for Disease-Specific Waivers under PREA (FDA, 2005) Basal cell and squamous cell cancer • Nivolumab (OPDIVO) approved on 10 November 2016 • Pembrolizumab (KEYTRUDA) approved on 5 August 2016 Breast cancer • Abemaciclib (VERZENIO approved on 28 September 2017 • Neratinib (NERLYNX) approved on 17 July 2017 • Palbociclib (IBRANCE) approved on 31 March 2017 and 19 February 2016 • Ribociclib (KISQALI) approved on 13 March 2017 Colorectal cancer • Mvasi (bevacizumab-awwb) approved on 14 September 2017 • Nivolumab (OPDIVO) approved on 01 August 2017 Lung cancer (small cell and non-small cell) • Pembrolizumab (KEYTRUDA) approved on 10 May 2017 for first line therapy • Pembrolizumab (KEYTRUDA)approved on 24 October 2016 • Atezolizumab (TECENTRIQ) approved on 18 October 2016 Ovarian cancer (non-germ cell) • Olaparib (LYNPARZA) approved on 17 August 2017 Pancreatic cancer Prostate cancer • Cabazitaxel (JEVTANA) modified dose approved on 14 September 2017 Renal cell cancer/ urothelial carcinoma • Pembrolizumab (KEYTRUDA) approved on 18 May 2017 Durvalumab (IMFINZI) approved on 01 May 2017 Nivolumab (OPDIVO) approved on 02 February 2017 • Atezolizumab injection (TECENTRIQ) approved on 18 May 2016 • Lenvatinib capsules (LENYIMA) approved on 13 May 2016 • Cabozantinib (CABOMETYX) approved on 25 April 2016 Uterine cancer Niraparib (ZEJULA) approved on 27 March 2017 Note: Endometrial cancer, hairy cell cancer, and oropharynx cancers (squamous cell) are included in the list but no products were approved for these indications during the timeframe of January 2016 to October 2017.

In order to supplement the information that was available in the literature, I conducted a search of the keyword, “orphan designation” under the FDA’s website on October 2017. A total of 374 products were listed under the search term of “cancer”, and over 800 products under other relevant search terms including carcinoma (187), melanoma (107), multiple myeloma (74),

glioma (80), lymphoma (172), tumor (90), sarcoma (1), and leukemia (271). Some of the adult cancers may have a prevalence of more than 200, 000 cases a year so technically would not be considered as orphan drugs according to the US FDA definition of orphan drugs. However, some have different subforms based on genomic phenotype and could be designated as potential orphans. These thousands of products that were designated as orphan drugs have been exempted from conducting pediatric clinical research. Table 5 below lists recent oncology approvals that have been granted with an Orphan Drug Designation and therefore are not subjected to PREA.

Table 5: Recent Adult Oncology Drugs Approvals Granted with Orphan Drug Designation (January 2016 to October 2017)

Products Approved between January 2016 to Overview of Approved Indications Granted October 2017 with an Orphan Drug Designation (Exempted from PREA) Acalabrutinib (CALQUENCE), approved on 31 Mantle cell lymphoma (MCL) October 2017 Avelumab (BAVENCIO) approved on 23 March 2017 Merkel cell carcinoma (MCC) Axicabtagene ciloleucel (YESCARTA), approved on Diffuse large B-cell lymphoma (DLBCL) 18 October 2017 RITUXAN HYCELA approved on 22 June 2017 Dabrafenib and trametinib approved on 22 June 2017 Non-small cell lung cancer (NSCLC) with RAF V600E mutation Certinib (ZYKADIA) approved on 26 May 2017 NSCLC with ROS-1 positive Brigatinib (ALUNBRIG) approved on 28 April 2017 NSCLC with anaplastic lymphoma kinase (ALK)-positive Osimertnib (TAGRISSO) approved on 30 March 2017 NSCLC with EGFR T790M mutation Lenalidomide (REVLIMID), approved on 22 February Multiple myeloma 2017 Daratumumab (DARZALEX) approved on 21 November 2016 Olaratumab (LARTRUVO), approved on 19 October Soft tissue sarcoma (STS) 2016 Inotuzumab ozogamicin approved on 17 August 2017 B-cell precursor acute lymphoblastic leukemia Blinatumomab (BLINCYTO) approved on 11 July (ALL) 2017

Ibrutinib (IMBRUVICA) approved on 02 August 2017 Chronic graft versus host disease (cGVHD) Gemtuzumab ozogamicin (MYLOTARG) approved on Acute myeloid leukemia (AML): CD33 positive 01 September 2017 VYXEOS approved on 03 August 2017 Acute myeloid leukemia (AML): with IDH2 Enasidenib (IDHIFA) approved on 01 August 2017 mutation Acute myeloid leukemia (AML): with FLT3+ Midostaurin (RYDAPT) approved on 28 April 2017 mutation

Products Approved between January 2016 to Overview of Approved Indications Granted October 2017 with an Orphan Drug Designation (Exempted from PREA) Pembrolizumab (KEYTRUDA) Gastroesophageal junction adenocarcinoma approved on 22 September 2017 Classical Hodgkin lymphoma (cHL) approved on 15 March 2017 Nivolumab (Opdivo) Hepatocellular carcinoma (approved on 22 September 2017) Classical Hodgkin lymphoma (cHL) on 17 May 2016 Copanlisib (ALIQOPA) approved on 14 September Follicular lymphoma (FL) 2017 Obinutuzumab (Gazyva Injection) approved on 26 Feb 2016 Everolimus (AFINITOR) approved on 26 February Neuroendocrine tumors (NET) 2016 Eribulin (HALAVEN) approved on 28 February 2016 Unresectable or metastatic liposarcoma Regorafenib (STIVARGA) approved on 27 April 2017 Hepatocellular carcinoma (HCC) Avelumab (BAVENCIO) approved on 09 May 2017 Urothelial carcinoma Niraparib (ZEJULA) approved on 27 March 2017 Ovarian cancer Rucaparib (RUBRACA) approved on 19 December Ovarian cancer with deleterious BRCA mutation 2016 Venetoclax (VENCLEXTA) approved on 11 April Chronic lymphocytic leukemia (CLL) with 17p 2016 deletion Ofatumumab (Arzerra Injection) approved on 19 Recurrent or progressive chronic lymphocytic January 2016 leukemia (CLL)

As discussed earlier, some adult cancers do not have a similar pediatric subtype(s); nonetheless, a recent review of cancer types by the FDA Pediatric Subcommittee noted that several tumor types in children were similar to those of adults based on appropriate genetic or biomarker evidence. In the July 2016 FDA Status Report to Congress, the FDA Commissioner at the time, Robert Califf, noted that,

…expanding the scope of PREA to require pediatric studies based on a pediatric tumor’s expression of a molecular target or the known molecular mechanism of a new drug could significantly increase the number of pediatric studies conducted under PREA...Because PREA does not apply to drugs for indications for which orphan designation has been granted even when the same cancer types occur in the pediatric population, there are substantial delays in the evaluation of highly effective cancer drugs in children. (FDA, 2016c)

However, the regulatory environment may be changing. The Research to Accelerate Cures and

Equity (RACE) for Children Act signed into law as part of the 2017 FDARA now requires companies to apply PREA to any treatment with a molecular target that is relevant to both an adult and a childhood disease. Despite having an orphan designation (21 USC 355a), original new drug applications (NDAs) and biologic licensing applications (BLAs) for a novel active ingredient submitted three years after the law was enacted would have to include reports on a

"molecularly targeted pediatric cancer investigation" if the drug or biologic were intended for treatment of an adult cancer whose molecular target was determined by FDA " to be substantially relevant to the growth or progression of a pediatric cancer". The expansion of PREA to certain types of pediatric cancers also removes the “inadvertent loophole” (Gottlieb, 2017) seen to exist because many adult cancers occur in organs different than those of genotypically similar childhood cancers.

The FDA acknowledged that the new requirement could be challenging for sponsors. Thus, they also provided more opportunities for sponsors to interact with FDA as they developed their pediatric strategy. Sponsors with drugs for serious or life-threatening diseases can now have a meeting to discuss preparations of an initial PSP not later than End-of-Phase 1 or within 30 days of the request. Additional meetings can be scheduled to discuss any deferrals or waivers from such trials. As part of FDARA, FDA was required to issue additional guidance to the sponsors.

Within the first year, after the law was enacted, the FDA was to post a list of molecular targets relevant to pediatric cancers and to develop a list of those targets that will get automatic waivers.

Such material is not yet available at time of writing.

The Carrot: Best Pharmaceuticals for Children Act (BPCA): Another way to gain insight into the effectiveness of the recent rules to foster pediatric trials is to analyze the 40 approved products for

adult cancers that were granted pediatric exclusivity (PE) as of 31 March 2017. These are posted on the FDA website (www.fda.gov) (Appendix B). Of the 211 pediatric exclusivities that were granted across all indications, 18 (8.53%) had a pediatric cancer indication (Appendix C). For these 18 drugs, the average time from first adult approval to pediatric exclusivity was 87 months

(range: 39 to 166 months). This verifies the perceived “lag” in pediatric development compared to the adult indications.

A few factors may explain the prolonged timeframe between the initial adult approval to the availability of information for pediatric treatment of the same drug. First are the challenges imposed by the number of pediatric subjects required for each study demanded in the Written

Request (WR). In addition, many sponsors still do not initiate pediatric studies until the adult indication has been approved. Finally, it might be the case that a lengthy period of consultation is needed to reach an agreement with the health authorities on study design. Only 5 of the 18 products (clofarabine, imatinib mesylate, premetrexed, ixabepilone, and temsirolimus) had been issued a WR prior to the initial adult approval (Appendix C). In most cases, that WR was not issued until years after the initial approval in adult indication(s). A recent Status Report to

Congress (FDA, 2016c) noted that, from 1998 to July 2012, FDA issued 54 WRs for pediatric studies of oncology products. Since the enactment of 2012 FDASIA to the date of the report,

FDA issued 12 WRs for oncology drug and biological products, plus 4 additional WRs under discussions at the time of the report. The significant increase in the rate of issued WRs was attributed to the proactive approach within the FDA, including their quarterly interactions with representatives of the pediatric oncology investigator community.

Creating Hope Act: Rare Pediatric Disease Priority Review Voucher (RPDPRV): One of the specific “carrots’ for some companies to conduct a pediatric program is the ability to gain a

priority review voucher that can be used in future or even sold to another company (Section

2.2.1.2). As of October 2017, a total of 11 RPDPRVs have been awarded (Table 6). Only two of these, UNITUXIN (dinutuximab) and KYMRIAH (tisagenlecleucel) were approved as a

“reward” for treating pediatric cancers.

Table 6: Listing of Rare Pediatric Disease Priority Review Vouchers Awarded (as of October 2017)

Drug Name Date Voucher Indication Received Endpoints of Comments Awarded and RPDPR Voucher Approval Drug Sponsor VIMIZIM 14 February Mycopolysaccharidosis Significantly Sold to Sanofi at (elosulfase alfa) 2014 Type IV (Morquio A improves $67.5 million, BioMarin Syndrome) patients’ ability excised in to walk November 2014 for a new cholesterol drug UNITUXIN 10 March 2015 High-risk Improves the Sold to AbbVie (dinutuximab) United neuroblastoma overall survival ($350 million) rates of affected children CHOLBAM 17 March 2015 Bile acid synthesis Improved liver Sold to Sanofi at (cholic acid) Asklepion disorders due to single functions, $245 million in enzyme defects, and increase body May 2015 peroxisomal disorder weight by 10% and survival > 3 years XURIDEN 4 September Hereditary orotic Stable pre- Sold to (uridine triacetate) 2015 aciduria specified AstraZeneca Wellstat hematologic parameters during the 6- week trial period STRENSIQ 23 October Hypophosphatasia Increase overall Unsold (asfotase alfa) 2015 Alexion (genetic, rare survival and metabolic disorder) alleviated symptoms KANUMA 8 December Lysosomal acid lipase Increase overall Unsold (sebelipase alfa) 2015 deficiency survival Alexion EXONDYS 51 19 September Duchenne muscular Accelerated Sold to Gilead (eteplirsen) 2016 dystrophy approval of for $125 million Sarepta Exondys 51 is in February 2017 based on the surrogate endpoint of dystrophin 57

Drug Name Date Voucher Indication Received Endpoints of Comments Awarded and RPDPR Voucher Approval Drug Sponsor increase in skeletal muscle observed in some Exondys 51-treated patients. SPINRAZA 23 December Spinal muscular Improvement in Unsold (Nusinersen) 2016 atrophy (SMA) motor Ionis milestones, such Pharmaceuticals as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking EMFLAZA 9 February 2017 Duchenne muscular Improvements in Unsold (deflazacort) Marathon dystrophy (DMD) a clinical Pharmaceuticals assessment of muscle strength across a number of muscles BRINEURA 27 April 2017 Batten disease (To Demonstrate Unsold (cerliponase alfa) BioMarin slow loss of walking fewer declines in ability (ambulation) in walking ability symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency) KYMRIAH 30 August 2017 B-cell precursor acute Overall Unsold (Tisagenlecleucel) lymphoblastic Remission Rate leukemia (ALL) that is (Complete refractory or in second remission + or later relapse complete remission with incomplete hematological recovery) (Gaffney, Mezher, & Brennan, 2018; http://priorityreviewvoucher.org/ accessed on 01 March 2018)

The effectiveness of the RPDPRV program has been controversial. As shown in the table above, the vouchers have gained notice in the pharmaceutical industry because of their value. Some vouchers have been sold to other drug sponsors for prices of up to $350 million; two companies,

BioMarin and Alexion, have already developed and received more than one RPDPRV. As identified by both the GAO and certain patient advocacy groups, sales of a voucher can fuel reinvestment in further research.

Four of five sponsors that were awarded or transferred and later sold vouchers told us that they plan to reinvest a portion of the proceeds they received into additional research and development of drugs to treat other rare pediatric diseases…

Patient advocacy groups also generally favor the program. For example, one group we spoke to said that the program has stimulated a transfer of cash from larger drug sponsors to smaller ones through the sales of the vouchers, and that these smaller drug sponsors may reinvest a portion of the proceeds to continue developing drugs for rare pediatric diseases. A few groups also indicated that the program could lead to the development of much-needed pediatric drugs without costing the government resources (GAO, 2016).

On the other hand, the FDA has had concerns with the program because it obligates the Agency to review an application under Priority Review that does not have priority status. It sees this requirement as running counter to its public health mandate of giving precedence for drugs with a high impact on disease (GAO, 2016). From the FDA’s perspective, some programs started pediatric development before FDASIA was enacted so the fact that they qualified for a voucher is insufficient evidence to argue the program has been effective (FDA, 2016c). The GAO report also expressed similar concerns about premature conclusions on the usefulness of the program.

Given that the typical drug development process often exceeds a decade, insufficient time has elapsed to gauge whether the 3-year-old pediatric voucher program has been effective at encouraging the development of drugs for rare pediatric diseases.

Nevertheless, industry and patient advocacy groups typically view this program as an important incentive for pediatric drug developments for rare pediatric diseases (GAO, 2016).

So far, only two vouchers have been awarded for a rare pediatric cancer. Nevertheless, those cases point to the potential importance of incentives to probe issues associated with the development process. For example, the approval of dinutuximab (UNITUXIN) has been showcased as a “lesson learned in expediting the development of rare pediatric cancer drugs”

(ASCO, 2016). Dinutuximab is the first FDA-approved treatment for patients with high-risk neuroblastoma. In the US, there are 250 to 300 such patients. The tumor develops predominantly in children; the median age at diagnosis is 19 months, and 90% of patients with neuroblastoma are diagnosed before the age of 5 (ASCO, 2016). The approval was based upon a clinical program designed specifically for this pediatric cancer and was conducted in a randomized study of 226 patients by the Children’s Oncology Group (COG) (Study ANBL0032) (FDA, 2015).

FDA explained the two major challenges, illustrated in Figure 7, that appeared to account for the lengthy period between the early evaluation of anti-GD2 antibodies in neuroblastoma (early

1990s) and FDA approval (2015) in a 2016 interview conducted by ASCO.

Figure 6: Timeline of Dinutuximab Development (Clinical to US BLA Approval)

First, they noted that it took 7 years to enroll the required participants. Second, an additional multi-year period was needed to scale up and supply commercial volumes of drug and to conduct comparability trials of the commercial product against drug used in the pivotal clinical trial.

However, some time was gained by leveraging regulatory incentives. The FDA’s Office of

Orphan Products Development designated neuroblastoma a “rare pediatric disease.” in 2013 and granted priority review to its BLA to shorten the review time from 10 months to 6 months. In addition, the manufacturer, United Therapeutics, received a RDPRPV as permitted under the

Creating Hope Act. This drug sets a precedent of a program specifically designed to secure a pediatric cancer indication. Its success and receipt of financial incentives show how public-private partnerships and regulatory acceleration can facilitate the drug development for pediatric cancers.

Paediatric (Pediatric) Regulatory Framework in the European Union (EU)

Europe has shared the concerns of the US regarding the need to increase pediatric research and product development. By the early 2000s, about 50 to 75% of approved medications still had not undergone adequate pediatric study (Vassal, 2009). In December 2000, the EU Parliament voted to address the need for better medicines for children, and six years later, approved the Paediatric

Regulation (EU 1901/2006) that entered into force on 26 January 2007. Its objective, like that of the FDA, was to improve the development and availability of medicines for children without subjecting the children to unnecessary clinical trials.

Pursuant to the Paediatric Regulation, companies were required to submit a Paediatric

Investigation Plan (PIP) for any medicinal product with a new or changed indication as soon as the adult pharmacokinetic studies of the drug program were completed. Under article 7, this PIP would have to be approved and included in the marketing authorization application unless an exemption has been granted. That exemption typically took the form of a waiver, granted by

EMA’s Paediatric Committee (PDCO). The PDCO was also given the role of reviewing and reaching an agreement with the sponsoring companies on the nature of studies to be carried out as part of their PIPs. To reward companies for carrying out the pediatric studies, a 6-month extension would be granted by awarding a Supplementary Protection Certificate (SPC) when the product was authorized in all Member States. Supplementary protection certificates (SPCs) are an intellectual property right that serves as an extension to a patent right. The extension was contingent only on carrying out the paediatric studies. It would be granted whether those trials showed efficacy in children or whether the drug was authorized for commercialization. Table 7 below summarizes the EU Paediatric Regulations in terms of obligations versus incentives.

Table 7: EU Paediatric Regulation: Obligations Versus Incentives

Type of Medicine Obligation Incentives (If Comments Product Compliance with the Agreed PIP) New PIP or Waiver 6 months extension of An agreed PIP is SPC required for validation of a MAA One Patent and Already PIP or Waiver 6 months extension of An agreed PIP is Approved/Authorized SPC required for validation of the variation application of new indication or new route or new pharmaceutical form Products Granted with PIP or Waiver 2 additional years of This is added to the Orphan Designation market exclusivity original 10 years = a (Orphan Medicine) total of 12 years of exclusivity Off Patent Medicine None (voluntary PIP 10 years of data no addition to possible for PUMA protection exclusivity or patent as both have expired for off-patent medicine MAA = marketing authorization application. PIP = Paediatric Investigational Plan. PUMA = paediatric-use marketing authorization. SPC = supplementary production certification. It is an intellectual property (IP) right that extends the duration of certain rights associated with a patent. (EMA, 2013b)

Key Differences Between the US and EU Pediatric Regulations

Most drugs are developed with the intent of marketing them at least in the EU and the US if not globally. However, efficient drug development can be hampered by dissonance in the legal and regulatory requirements in these two constituencies (Storm, 2018). Even differences in definitions or patient classifications can be present. For example, the US FDA considers pediatric patients to be those from birth up to the 16th birthday, and subdivides them into four age groups including neonates (0-1 month), infants (1 month to 2 years), children (2 years to 12 years) and adolescents (12 years to 16 years). The EU Pediatrics Regulation does not define the different age groups in the pediatric population that it identifies as ranging from birth and 18 years.

Instead, it follows the definitions in ICH Guidance E11 that groups pediatric patients into five

categories: preterm newborn infants; term newborn infants (0 to 27 days); infants and toddlers (28 days to 23 months); children (2 to 11 years); and adolescents (12 years to 16-18 years). Table 8 below outlines the key differences between the US and EU pediatric regulations.

Table 8: Differences in Pediatric Regulations: EU Versus US

US BPCA US PREA EU Paediatric Regulation Requirement or Not Voluntarily Mandatory Mandatory Documentation Written Request (issue by FDA) Pediatric Study Plan Pediatric (initiated by FDA or by request (submit by Sponsor, Investigation Plan from the Sponsor via agreement from (submit by Sponsor, submission of a Proposed FDA) agreement from Pediatric Study Request) EMA PDCO) Waiver Not applicable Allow Allow Timing of Initial Not specified (FDA suggested End of Phase 2 End of Phase 1 Plan Discussion early discussion, end of phase 2, or earlier for oncology products) Reward/Incentive 6 months addition to existing No reward 6 months addition to patent and exclusivity SPC/Patent Conditions Covered FDA may request a pediatric Same indications Same disease study to evaluate the same intended or approved condition intended or indications intended or for adults approved for adults approved for adults, but it may also request that a sponsor conduct a pediatric study for a different indication, including one not approved for adults Orphan Designation Applicable/Included Exempted from Required/Included Product requirement under 2012 FDASIA Transparency of Written Request not made PSP (issued to the Agreed Plan and Pediatric Plan to public by the FDA until Sponsor’s PDCO Public Pediatric Exclusivity is granted Investigational New Recommendations Drug Application) are made public by not made public by the EMA PDCO the FDA and not available via Freedom of Information Act

These differences impose different pediatric research obligations for the same drug product.

They also provide different incentives or similar-sounding incentives that nevertheless differ in

certain details. Thus, it is useful to examine the degree to which the rules in the two regions result in similar outcomes for the drug manufacturer. One area, for example, is that of pediatric waivers.

Pediatric studies may be waived under both PREA and the EU Pediatrics Regulation as a partial waiver (study is not feasible or appropriate or safe for a specific age group; hence, waving a specific age group from pediatric study requirement) or as a full waiver for all age groups. Under

PREA, the FDA assesses a waiver for the same indication that is planned in adults based on established criteria, for some or all pediatric age groups. FDA grants a full or partial waiver specific to the drug product based on the adult indications. In contrast, the EU PDCO assesses waivers for a condition, but the full waiver can apply for any indication of a specific product.

Waivers can also apply to a class of products. The EMA (but not the FDA) publishes a class waiver list that identifies classes of drugs/biologics that are waived from the pediatric study requirement.

The need for a paediatric development may be waived for classes of medicines that are likely unsafe or ineffective in children, that lack benefit for paediatric patients or are for diseases and conditions that only affect the adult population. (EMA, 2017b)

Nevertheless, the reasons for waiver requests are similar between the EU Pediatric Regulation and US PREA (Table 9).

Table 9: Grounds for Waiver Request for Pediatric Studies

PREA Pediatric Regulation

Partial waivers for specific age groups or full waiver Class waivers – for specific medicinal products or for the indication: classes of medicine products that:

PREA Pediatric Regulation

● Necessary studies are impossible or highly ● Are likely to be ineffective or unsafe in part or impracticable (due to small number of patients) all of the pediatric population ● There is evidence strongly suggesting that the ● Are intended for conditions that occur only in drug or biologic product would be ineffective adult populations; or unsafe in that age group ● Do not represent a significant therapeutic ● The product does not present a meaningful benefit over existing treatments for pediatric therapeutic benefit over existing therapies (and patients. not likely to be used by a substantial number of pediatric patients in that age group) ● The applicant can demonstrate that reasonable attempts to produce a pediatric formulation for that age group have failed.

A recent retrospective comparison of product-specific pediatric full waivers granted by FDA and

EMA across all therapeutic areas between 2007 and 2013 (Egger et al., 2016) shows that their waiver decisions were consistent in most cases (66 of 80, 83%). The authors attributed the converging approaches to the monthly meetings held between two agencies. The cases of divergent requirements appeared to be associated with two issues. First was the occasional difference in the definition of indication vs. condition. In the US, PSPs are for the exact indications for which the company intends to develop the product in adults, whereas PIPs take into account the whole of the corresponding condition. The condition may include one or more indications falling below/within the condition (EMA, 2012). For example, the PSP was waived for pembrolizumab in the NSCLC indication but a PIP was issued to cover pediatric solid tumors including CNS tumors. Second was a difference in the weight given to potential therapeutic benefits for children or considerations for study feasibility, resulting in a difference of assessment between PDCO and PeRC regarding potential benefit versus risk. Understanding the factors leading to the misaligned outcomes would help the applicant to assess the timing and the need for joint-discussion with FDA and EU on the pediatric development program, based on the

perception of therapeutic needs in the respective region and the potential of broader condition consideration per examples above.

2.2.3.1 Difference in US and EU Pediatric Oncology Study Requirement: Recent Example

Differences in the US and EU approaches to pediatric oncology programs can also be discerned from an examination of certain types of drugs currently in development. A case in point are the immune checkpoint inhibitors that have shown efficacy in some chemotherapy-resistant adult cancers Four agents acting through the programmed cell death-1 (PD-1) pathway (nivolumab, pembrolizumab, atezolizumab, and durvalumab) have recently been approved for adults and may have promise for certain refractory pediatric malignancies such as sarcoma, neuroblastoma, and high-grade glioma. Table 10 summarizes the US and EU pediatric regulatory status based on publicly available information as of October 2017. This reflects the following differences in pediatric regulatory status in the US and EU of all 4 products:

1) There were no PSPs in the US either because they had PREA orphan drug exemption or

had a pediatric waiver

2) There were PIPs requirement and the studies outlined within the agreed PIPs of the same

class of medicine product are consistent,

3) There were important differences between the decisions of the two agencies, particularly

with regard to regulatory decision-making outcomes based on the pediatric data (further

explained in the paragraph after Table 10).

Table 10: US and EU Pediatric Status of Approved Anti-PD1/L1 Agents (as of October 2017)

Anti-PD1/L1 US Regulatory (Pediatric Status) EU Paediatric Status (PIP) Agents including PIP Condition/Indication(s) Nivolumab Written Request Issued, but not made ● Malignant neoplasms excl. nervous public system, hematopoietic and lymphoid Approved indication (MSI-H) included tissue / Melanoma & solid tumors pediatric ● Malignant neoplasms of lymphoid tissue & CNS / rrHL; rrNHL; glioma ● No inclusion of pediatric in the SmPC Pembrolizumab Pediatric study conducted (PK and ● Malignant neoplasms excl. nervous Safety) in ped. ST pts system, hematopoietic and lymphoid Approved indications (cHL and MSI- tissues / Melanoma & PD-L1(+) H) included pediatric solid tumors. Written Request not issued ● HL / 2L cHL & rrHL ● No inclusion of pediatric in the SmPC Atezolizumab Written Request issued, but not made Malignant neoplasms excl. nervous public system, hematopoietic and lymphoid Held Ped. ODAC in 2016 with FDA tissue / 1L PD-L1(+) solid tumors Durvalumab Written Request not yet issued ● Malignant neoplasms excl. nervous system, hematopoietic and lymphoid tissue; awaiting PIP decision ● Malignant neoplasms of haematopoietic and lymphoid tissue: awaiting PIP decision Source: list of WR issued as of 31 Oct 2017 (https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/ucm050002.htm) SmPC = Summary of Product Characteristics. CNS=central nervous system;MSI-H=microsatellite instability-high;rr=relapsed/refractory;HL=hodgkin's lymphoma;cHL=classic hodgkin's lymphoma;SmPC=Summary of Product Characteristic;ODAC=Oncologic Drugs Advisory Committee; PK=pharmacokinetics; ST=solid tumors.

The toxicities of these compounds are nearly similar, with autoimmune adverse events being most common and concerning (Wagner & Adams, 2017). The similar agreed-upon PIPs across all four agents in the same class of therapy (see a summary in Appendix D) may have raised concerns about requiring companies to complete for the rare pediatric cancer patients to meet regulatory obligations, rather than assigning patients to more promising studies based on scientifically and medically available data. It points to a need for effective collaboration between stakeholders,

including sponsors, in the broader plan to target the development of related drugs, especially if they all targeting the same disease pathway or disease.

The US FDA and EMA have had differing perspectives on data supporting their regulatory decisions. Recent (2017) FDA approvals of nivolumab and pembrolizumab in microsatellite instability-high cancer (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that included pediatric patients (12 years and older) were based on a tissue- agnostic approach that used a biomarker, rather than an organ to define the disease across.

Inclusion of the adolescent population in the approved indication was based on data extrapolation.

As of October 2017, these indications were not reflected in the marketing authorization for the same drugs in the EU Summary of Product Characteristics; instead, their approved indications have only been based on organ types.

Framing the Study of Pediatric Oncology Drug Development

The goal of pediatric regulations in the US and the EU is to encourage and accelerate the development of new therapies for pediatric diseases. In the pediatric oncology arena, the health authorities (FDA and EMA), academia, and patient advocacy groups encourage early clinical evaluation of targeted drugs developed for adult cancers in children with relapsed/refractory cancers. Both the FDA and EMA now require pediatric investigations of drugs directed at molecular targets considered substantially relevant to pediatric cancer even when the adult cancer indication does not occur or is biologically different in the pediatric population. Both agencies express the hope that targeted amendments to PSP/PIP and issuance of WRs in the US under

BPCA earlier in product development would improve the timeliness of pediatric evaluations and ultimately market introductions. Thus, at this point, the views and motivations of the regulatory agencies appear quite clear. 69

Workshops on pediatric oncology drug development usually included representatives from the industry; however, the few industry representatives selected to provide the industry’s perspective on specific regulatory initiatives were mainly from major pharmaceutical companies and their discussions at the workshops usually focused on a specific regulatory regulation or new initiative.

What is not clear is the views of industry across company sizes, the sector most affected by these efforts, and most able to translate these incentive-based intentions into actionable activities, outputs, and outcomes with regard to the broader regulatory landscape. In this current research, I explored the perspectives and experience of industry stakeholders, through the eyes of regulatory experts from small to large companies, who I consider to be the subset of personnel best placed to describe the experience, outcomes, and views related to pediatric incentive programs advanced by regulatory agencies. Their experience in adapting, planning and implementing drug development programs may provide insights into the issues that they have encountered with the staging of trials and the impact that incentives and regulatory requirements have had on their strategies.

This study used a systematic approach based on the conceptual framework outlined in the

National Implementation Research Network’s (NIRN) publication, “Improving Programs and

Outcomes: Implementation Frameworks” (Bertram, Blase & Fixsen, 2014). This framework provided refinements to the initial iteration of the implementation constructs and frameworks by

Fixsen and coworkers in 2005 (Fixsen, Naoom, Blasé, Friedman & Wallace, et al., 2005). The

NIRN implementation framework was utilized for this research because it has been applied over the last three decades to study gaps and challenges in the implementation of diverse programs, from education to human service initiatives. It has also been applied in other studies of implementation in the regulatory sector (Church, 2017; Pire-Smerkanich, 2016).

The four stages basing the Implementation Framework described by Bertram et al served as the platform of this research (Figure 7).

Figure 7: Four Stages of Implementation Framework

(Copied from Bertram et al., 2014)

The evolving pediatric regulations and scientific knowledge impact the way that industry makes its decisions about staging and implementing a pediatric trial. As they force change on the clinical trial strategy, the experiences gained from the practice level have educational value by giving feedback to inform the policymakers about the effectiveness of their policies (NIRN,

2018). The Practice-Policy Communication Cycle, outlined in Figure 8, illustrates one goal of implementation research, to provide information bidirectionally to both the industry and health authorities regarding implementation barriers and opportunities to encourage better alignment of goals and capabilities to support effective pediatric drug development.

Figure 8: Feedback Loop: Practice-Policy Communication Cycle

Copied from (NIRN, 2018), aiHUB: http://implementation.fpg.unc.edu

By considering the Practice to Policy Feedback Loops into each stage of the implementation, the framework was used as a practical guide to constructing appropriate survey questions that explored all stages of the implementation process (Table 11). It provided a systematically staged method to explore where challenges were faced with respect to the adoption and implementation of programs that attempt to respond to drug development regulations focused on pediatric cancers.

Table 11: Outline of Implementation Stages: Industry’s Feedback of the Practice-Policy Loop

Exploration Internal: • Are the regulations clear for the company? “Get Ready” • Does everyone involved embrace the new regulatory directions regardless of whether opportunity or challenge may result? External: • Does the company take part in policy shaping discussion related to pediatric rules and staging?

Installation Internal: • Do companies have an organizational structure to address pediatric “Get Set” drug development per current policy? • How does the company decide at what point a pediatric development plan will be introduced? • Who leads the pediatric trial initiatives and how do they interact with the teams pursuing adult trials? • Are pediatric waivers explored as an option and at what point are they pursued? • Have the company applied or proposed innovative study design? External: • How satisfactory are the channels to get feedback from health authorities about pediatric plans? What have been areas of challenge or disagreement with the pediatric development plan? • Have the health authorities been receptive to innovative study design to meet PIP/PSP requirement? Initial Implementation Internal: • Did the company have the relevant expertise? any anticipated “Go” constraining factors? • Are sufficient resources made available to implement the plan effectively? • Any resistance to organizational or process adjustments? • How did the development of a pediatric plan affect the timelines of other ongoing programs and why? External: • Were there any issues that require external alignment/collaborations, i.e. nonclinical advancement? • Were modifications needed and did those require extensive regulatory interactions? If yes, what was the experience with those interactions? Full Implementation Internal: • Is there a metric in place to measure the effectiveness of pediatric “Keep Going” program? • Is the process in a sustainable manner for all applicable programs? • Did the program follow intended milestones/ If no why not? External • Did regulators move the goalposts during the implementation of the program? • Were reporting structures for program progress and completions handles smoothly?

CHAPTER 3. METHODOLOGY

Introduction

The research was conducted in 5 steps: 1) Literature review and analysis of current product landscape, presented in Chapter 2; 2) Development of a survey instrument to solicit industry inputs; 3) Critical review of the survey instrument by a focus group of experts; 4) Revision and dissemination of the final survey; and 5) Analysis of the results.

Survey Development and Focus Group Feedback

A draft survey was developed based on the foundational framework outlined in Chapter 2. Some questions had multiple-choice, Likert or scaled choice formats; others had open text fields that allowed respondents to enter written comments. Questions were designed to solicit industry’s inputs on the challenges that they face as they develop and implement programs that attempt to respond to regulations relevant to the development of drugs to treat pediatric cancers.

The draft survey was provided to a focus group who were tasked with giving critical feedback on the survey questions and identifying any gaps in the content of the survey. The focus group included 9 participants from industry and academia. Certain members of the focus group were selected because they had extensive knowledge and/or previous experience in the field of pediatric cancer drug development from a clinical and/or regulatory perspective. Others were chosen to contribute their extensive expertise with survey preparation and development. The focus group members are described in Table 12. An additional participant provided comments on the questions related to European pediatric regulation and experience via electronic correspondence.

Table 12: List of Focus Group Participants

Participant Name Affiliation

Frances Richmond, PhD USC Regulatory Science (Chair of Focus Group) Nancy Smerkanich, DRSc USC Regulatory Science

Florence Houn, MD, MPH Former FDA Review Division Director. Executive Regulatory Affairs Professional in Pharmaceutical Industry Jennifer Wiley, MS Senior Regulatory Affairs Professional in Pharmaceutical Industry Neal Storm, DRSc Senior Regulatory Affairs Professional in Pharmaceutical Industry Michael Jamieson, DRSc USC Regulatory Science

Patricia Duchene Senior Regulatory Affairs Professional in Pharmaceutical Industry Gilbert Burckart, Pharm.D. Pediatric Expert at the US FDA Office of Clinical Pharmacology Julien Rongere Senior Regulatory Affairs Professional in Pharmaceutical Industry in Europe (Provided feedback via e-mail)

Prior to the focus group meeting, all participants were provided with an electronic copy of the survey. The meeting was held on 11 June 2018, in person for the attendees close to the Health

Sciences campus of the University of Southern California and via an online web conference link for those who could not attend in person. The meeting was approximately 90 minutes long. It started with a short presentation of the intended research, the framework used to structure the survey, and the purpose of the study. Following the presentation, the group reviewed each survey question in order and discussed possible improvements in the wording and/or structure, for example, by combining certain questions into groups or removing questions that might yield duplicate responses, to improve clarity and to assure that data would be collected in a way that facilitated effective statistical description and data display. 75

Based on feedback from the focus group, the survey was revised and sent for final review to three individuals to ensure that all comments and action items from the discussion had been addressed appropriately. The final survey consisted of 37 questions (see Appendix D).

A validation test run was conducted by sending a preliminary copy of the survey via the Qualtrics system to two individuals in the focus group. They ensured that the survey was delivered as intended, could be filled out appropriately, and would provide data in a form suitable for the intended analyses.

Survey Dissemination and Analysis

The survey was disseminated via the Qualtrics system between 12 September 2018 to 10 January

2019 to 113 participants working in the industry who had experience in cancer drug development and held positions in clinical or regulatory affairs. Potential participants were solicited through industry working groups focusing on pediatric initiatives (i.e. BIO Pediatric Working Task

Group), industry lists of companies with oncology programs, or individuals whose contact information could be obtained via LinkedIn Premium and contacted by in-mail. Potential respondents were also asked to refer/recommend other individuals or contacts who might be qualified to address this research topic. No financial compensation or incentive was offered to participants of this research. Email reminders were sent to individuals who had not completed the survey 3 weeks after receipt. Because limited numbers of individuals have experience in pediatric oncology drug/biologic development, a link to the survey was also posted on LinkedIn under the

Regulatory Affairs Professional Society page to solicit potential qualified respondents from additional sources.

Survey results were collected electronically and analyzed graphically when possible. Because the numbers of respondents in this exploratory survey were predictably small, statistical analyses were mainly descriptive. Open-ended questions and written inputs from participants were reviewed and examined for content and grouped according to identified categories of information.

A preference index was established for those questions that solicited degrees of agreement, importance or preference regarding certain statements. To identify overall levels of preference or importance, individuals who identified that they could not answer were removed, and then the number of respondents with a particular level of preference was multiplied by the score assigned to that level of preference. The most positive level of preference was assigned a score of 1 and progressively lower preferences were assigned progressively higher scores. For example, a question asking to rate a statement on a 3-point scale of “very important”, “somewhat important” and “not important” would be scored 1, 2 and 3 respectively. The multiplied scores were then summed and divided by the number of individuals who expressed a view. The preference index could then be used as an additional metric of positivity or agreement - a low resulting number meant that respondents as a group felt a statement to be more important or were more than a higher number would indicate.

CHAPTER 4. RESULTS

The survey was disseminated from mid-September 2018 through early January 2019 to

113 individuals via email. Twenty additional individuals were also identified by a search on clinicaltrials.gov that lists companies with recent pediatric oncology studies. Two clinical and regulatory professionals from the respective companies were identified and contacted via

LinkedIn in-mails. The survey period closed on 10 January 2017, after 46 of the contacted individuals had completed the survey, reflecting a participation rate of 41%.

Profiles and Background of Participants

As shown in Figure 9, most respondents were at the Director level (56%, 26/46). The remaining respondents self-identified as Vice Presidents (15%, 7/46), Managers (15%, 7/46), and

Specialists/Associates (4%, 2/46). Four respondents (8%) self-identified as “Other” and provided titles of “Associate Director” (1), “Consultant” (1), “Senior Vice President” (1), and “Owner” (1).

Figure 9: Current Job Title of Respondents

What title best describes your current responsibilities in your company/organization?

As shown in Figure 10, most of the survey participants worked in Regulatory Affairs (63%,

29/46), but 20% (9/46) worked in Clinical Development, 9% (4/46) in Project Leadership/Project

Management and 9% (4/46) in other types of positions. The four identified as “Others” identified roles in Business Development (1), Pharmacovigilance (1), Product Late Stage Development (1), and Quality Assurance (1).

Figure 10: Functional Areas of Respondents Within the Company

Which statement best describes your department's activities? (If you are a consultant, please select the primary service that you provide):

As shown in Figure 11, almost half of the respondents (41%, 19/46) worked for large companies with 10,001+ employees and about a quarter (26%, 12/46) were in small companies

(1-500 employees). Smaller proportions of respondents were employed by mid-size companies, with 13% (6/46) from companies with 501-2,500 employees and 20% (9/46) from companies with 2,501-10,000 employees.

Figure 11: Size of Company by Number of Employees

Which statement best describes the size of your overall company/organization? (If you are a consultant, please select one organization for which you provide service and estimate its size):

Experience in Pediatric Oncology Development for Drugs/Biologics

Because this survey aimed to understand the industry’s experience in pediatric oncology drug development, a discriminatory question was included to identify the respondent’s familiarity with either the US or the EU pediatric regulations. Two respondents identified that they had “no” familiarity with either set of regulations. These respondents were directed to the end of the survey and therefore did not answer any of the subsequent questions. Thus, results were based on the answers of 44 of the 46 respondents who replied “Yes” to indicate experience in pediatric oncology drug development.

Most respondents were familiar with the pediatric oncology development plan across the US and

EU. However, 5% (2/44) respondents identified no experience with development plans for the

US and 11% (5/44) respondents were not familiar with those for the EU. The personal experiences ranged across the categories of very knowledgeable and somewhat knowledgeable as shown in Table 13. Under the category of “knowledgeable”, more respondents were familiar with or had personal experiences with development plans for the US (39%) than the EU (27%)

(Table 13).

Table 13: Personal Experience in Pediatric Oncology Drug/Biologic Development in the US and in the EU

Which of the following best describe your personal experience in pediatric oncology development for drugs and/or biologics?

Very Knowledgeable Somewhat None Total Knowledgeable Knowledgeable Pediatric Oncology 14 (32%) 17 (39%) 11 (25%) 2 (4%) 44 Drug/Biologic Development Plan in the US Pediatric Oncology 13 (30%) 12 (27%) 14 (32%) 5 (11%) 44 Drug/Biologic Development Plan in the EU

Respondents were asked to indicate the functional area that best described their role related to pediatric oncology drug/biologic development. Table 14 demonstrates that the respondents had overlapping responsibilities/involvement across multiple functional activities. Thus, the number of selections made across all of the offered areas of responsibility were much higher than the number of respondents. Almost half of the respondents participated as the lead responsible party in regulatory strategy. Many also participated in clinical development but there they more commonly played a role as team members than lead. A smaller number had ancillary roles in

specialized areas including statistics, nonclinical development, formulation or translational development. The 9 responses listed under “others” included functional areas not captured in the choices- Project Leadership, Project Management, and Regulatory Affairs Vice President with supervisory roles.

Table 14: Roles in Pediatric Oncology Drug/Biologic Development Within the Organization

Which of the following best describe your role related to pediatric oncology drug/biologic development in your organization?

Lead Party Team Member Ad Hoc No Involvement Total Member for Input Regulatory Strategy (including 15 (47%) 8 (25%) 7(22%) 2 (6%) 32 coordination with Health Authorities) Clinical Development 4 (15%) 13 (48%) 7 (26%) 3 (11%) 27 Clinical Pharmacology 0 8 (33%) 10 (42%) 6 (25%) 24 Statistics 0 4 (17%) 14 (58%) 6 (25%) 24 Nonclinical/Translational Development 0 4 (17%) 11 (48%) 8 (35%) 23 Formulation and CMC 0 5 (21%) 11 (46%) 8 (33%) 24 Other (please specify) 5 (56%) 0 0 4 (44%) 9

The FDA has issued detailed guidance and provided different mechanisms to communicate pediatric regulations/guidance to applicants/sponsors. Respondents were asked to identify the degree to which they had used certain of these FDA guidance documents as they prepared a pediatric study plan (PSP) or proposed pediatric study request (PPSR) (Figure 12). Using a preference index calculated from a 4-point scale that included “Always”, “Most of the time”,

“Sometimes”, and “Never”, the most utilized document appeared to be the “Guidance for

Industry – Pediatric Study Plan”, with an average score of 1.6. Both the “Guidance for Industry –

How to Comply with the Pediatric Research Equity Act” (average score of 2.1) and the

“Guidance for Industry - Qualifying for Pediatric Exclusivity” (average score of 2.1) were the next most commonly used. Both the “Guidance for Industry – Rare Pediatric Disease Priority

Review Vouchers” (2.5) and the guidance governing “Pediatric Information Incorporated into

Human Prescription Drug and Biologic Products Labeling” (2.3) were typically identified to be consulted less commonly. Two text responses provided “other” resources, that included the FDA

Reauthorization Act of 2017 (FDARA) and “Consideration for the Inclusion of Adolescent

Patients in Adult Oncology Clinical Trials”.

Figure 12: Utilization of FDA Guidance Documents

In the US, which of the following FDA guidance documents have you used when preparing a pediatric study plan (PSP) or proposed pediatric study request (PPSR) for oncology drug/biologic development?

The use of other forms of assistance was also explored. These resources included the templates posted by FDA explaining the specific information and format needed for the proposed pediatric plan; the link to Written Requests (WR) and any amendments associated with approved drugs for which a pediatric exclusivity determination was made; workshops; Q&A documents; and the established Pediatric Mailbox. Using a 4-point scale, respondents most commonly selected the

PSP and Written Request (WR) templates as the tools always utilized (average score of 1.7), followed by the publicly available information of WR/PSPs from other sponsors (2.2), “General

Clinical Pharmacology Consideration for Pediatric Studies” (2.4), and FDA Workshop/public meetings (2.4). Only a few respondents identified that they utilized the Pediatric Mailbox on the

FDA website (3.6).

Figure 13: Utilization of Other FDA Information and Mechanisms

In the US, which of the following information/mechanisms have you used when preparing a pediatric study plan (PSP) or proposed pediatric study request (PPSR) for oncology drug/biologic development?

When asked about the clarity of the FDA’s guidance documents, respondents noted that most of the types of information provided as options were very clear. Using a 3-point scale, respondents seemed to rate the timing of the requirement (average score of 1.5) and the incentive/reward system (1.5) as especially clear. In comparison, more respondents regarded as “somewhat clear” the information and details needed for the pediatric plan (1.8) and whether such a plan was required (1.7).

Figure 14: Clarity of FDA Guidance Documents and Information on Pediatric Study Plan Development

Are the US FDA guidance and statutory requirements related to pediatric oncology drug/biologic development clear to your organization?

A similar question was also included to characterize the respondents’ experience with regard to the use of EMA guidelines related to pediatric oncology drug/biologic development. As shown in

Figure 15, most respondents utilized the guideline on the format and content of application

(average score of 1.8), followed by publicly available agreed PIPs (1.9), and templates related to the format and content of the applications (2.0) as the resources that they consulted most.

However, the majority of respondents who answered the question used all of the identified documents at least “most of the time”. Very few (1-2) respondents identified that they never used these documents.

Figure 15: Utilization of EMA Guideline and Information on Pediatric Investigational Plan Development

In the EU, which of the following EMA guidelines and mechanisms have you used to prepare the paediatric investigational plan (PIP) for an oncology drug/biologic development program?

Respondents were asked to express their views about clarity of guidance related to EU pediatric oncology drug development using a 3-point scale. Most respondents found that the guidance related to the timing of the requirement was very clear (average score of 1.4). Somewhat less clear for most respondents were the guidances related to waiver/deferral qualification (1.7), incentives/reward (1.7), and levels of details required in PIP (1.8) (Figure 16). Very few (1-3) respondents characterized the EU documents as unclear.

Figure 16: Clarity of EU Guidance Documents and Information

Are the EMA guidelines and regulation/legislation related to pediatric oncology drug/biologic development clear to your organization?

Respondents were asked to identify the usefulness of other sources of publicly available information from 7 listed choices (Figure 17). Most respondents considered these resources to be helpful. However, two sources, “the agreed PIPs that were publicly posted” and “the pediatric study notes on FDA approval letters” were characterized as “very helpful” (average scores of 2.0 and 2.1, respectively, on a 3- point scale) more often than the other choices. Written Requests posted by the FDA were also found to be helpful (2.2). Notably, 6 respondents were unaware of the EPARs on pediatric variations, but only 1-3 respondents were unaware of the listed sources on FDA’s public information on pediatric studies.

Figure 17: Helpfulness of Publicly Available Information

Do you find the following sources of publicly available information helpful when preparing a pediatric oncology drug/biologic development plan?

In the US, pediatric study designs submitted under an Investigational Drug Application are considered to be proprietary so it cannot be made publicly available by the FDA until pediatric exclusivity is granted or until the product is approved (when the pediatric required study becomes part of the approval letter). Respondents were asked whether they believe that this information should be publicly available earlier in the US. Two-thirds of the respondents (66%, 21/32) expressed the view that it should be made available earlier, nearly a quarter (22%, 7/32) that it should not, and 15% (4/32) could not answer. Certain respondents who felt that the information should NOT be released earlier provided the reasons for that view:

Reveals too much confidential information that should not be released early in development (especially since PIPs are expected to be completed earlier in development).

Written Requests are voluntary and therefore are not binding. Given this they should never be made public. The EC has received considerable pushback that their disclosure of certain data related to PIPs in early stage jeopardize CCI as PIPs are agreed in early stage development. Trial disclosure requirements bind all study sponsors (including academia) to post trial designs in reality/

Strategic advantages

High likelihood of revealing trade secrets before marketing authorization.

Companies that take the initiative should get the reward. Not companies that notice a competitor is doing it, then finish sooner.

Competitive reasons

Organizational Structure for Pediatric Oncology Development

The timing of pediatric studies appeared to vary with respect to studies in adults. A minority of respondents identified that they have always positioned their trials in a certain order. In some cases, this was after Phase 1/2 studies in adults had efficacy results (8/28), or less frequently, once data was available from nonclinical pediatric models (3/27), at the time that phase 3 trials in adults had been initiated (6/23) or completed (4/26). However, more respondents appeared to introduce those discussions at different times, by answering “sometimes” to most of the choices.

Thus, the number of chosen answers exceeded the number of respondents. One respondent noted in the associated text box that the timing depended on the program, for example, due to the mechanism of action of the product, and another respondent gave the added choice of the availability of proof-of-concept in adults. Nine respondents identified that they never introduced those discussions “after phase 3 adult studies were completed”, and 7 never discussed them “once data is available from a nonclinical pediatric model”, but a few identified “never” for the remaining choices (Table 15). 91

Table 15: Timing of Pediatric Planning Initiation

In your company/organization, when is pediatric planning initially discussed for an oncology drug/biologic program?

Always Sometimes Never Do Not Total Know After Ph1/2 Studies in 8 (29%) 17 (61%) 1 (3%) 2 (7%) 28 Adults with Efficacy Results Once Data is Available 3 (11%) 14 (52%) 7 (26%) 3 (11%) 27 from a Nonclinical Pediatric Model At the time that Ph3 in 6 (23%) 16 (62%) 3 (11%) 1 (4%) 26 Adults is Initiated

After Ph3 in Adults has 4 (15%) 12 (46%) 9 (35%) 1 (9%) 26 been completed

Other (Please Specify) 2 (33%) 1 (17%) 0 3 (50%) 6

Reasons provided under Other: • This is entirely dependent on the mechanism of action • Once Proof-of-Concept data is generated in adults

Historically, pediatric development has been tied to an adult clinical program, but some stakeholders have encouraged the industry to develop therapies that are not linked to an adult study. Respondents were asked if the organizations for which they worked had ever considered or implemented stand-alone pediatric oncology programs without a tie to an adult program. The majority of respondents (63%, 17/27), stated “No”, but approximately 30% (8/27) stated “Yes”, and 7% (2/27) stated, “Cannot answer”.

Respondents were also asked to indicate if they or their company/organization had taken part in discussions related to policy-setting opportunities or in industry discussions related to pediatric

oncology drug development. About half participated in FDA/CHMP meetings or health authorities/industry workshops, respectively (50%,14/28; 54%,15/28). Others have provided comments to those discussions; a few only followed webcasts of announcements from those meetings or not participate at all. Relative breakdowns are shown in Table 16. Two did not know the answer to the question.

Table 16: Participation in Meetings and Workshops

Do you or does your company/organization take part in influencing policy or industry working group(s) discussions related to pediatric oncology drug/biologic development regulation?

We We Provide We do not We have never Do not Participate Review Participate but participated Know in Comments Attend Workshops Webcasts/ / Follow Meetings Announcements FDA or CHMP 14 (50%) 4 (14%) 6 (21%) 2 (7%) 2 (7%) Organized Meetings (e.g. Pediatric ODAC, ACCELERATE) Health Authorities/ 15 (54%) 5 (18%) 4 (14%) 2 (7%) 2 (7%) Industry Workshops Provision of 7 (25%) 9 (32%) 5 (18%) 4 (14%) 3 (11%) Review Comments

When asked how their pediatric teams are organized to support oncology drug development, relatively few identified that internal resources were dedicated to pediatric programs only (40%,

11/28) and this appeared to be more typical in clinical development than other divisions of the company, i.e. regulatory affairs (23%, 6/26). Instead, most identified that their internal resources, such as nonclinical development, translational medicine, safety, clinical pharmacology, and formulation development worked both on pediatric and non-pediatric programs. The use of

external consultations appeared to be rare, reported by only 1-3 individuals regardless of job function (Figure 18).

Figure 18: Resources Within Organizations for Pediatric Oncology Development

In your company/organization, how is the pediatric team organized to support oncology drug/biologic development?

Text provided under Other: • Cross-functional Project leadership • Pharmacometrics

Respondents were asked if the development of a pediatric oncology plan or pediatric requirement has affected the timelines and planning of other ongoing programs in the organization. A few of the individuals who chose to answer this question (11%, 3/27) identified that they could not answer. Most (63%, 17/27) responded “No”, whereas 26% (7/27) responded “Yes” with the following reasons:

Allocation of limited resources Peds is now considered much earlier in development and across more indications than ever before All portfolio Obtaining regulatory agreement In Europe, the PIP activities remain a high risk, rate limiting procedure for expedited filing plans due to a ‘late’ start to the procedure. This is partly because our development plans were expedited, and we inherited a Phase 3 program from an academic institution.

Respondents were asked to identify if they faced one or more of five offered challenges when planning for pediatric oncology drug/biologic development (Figure 19). Most participants strongly agreed or agreed (44%, 12/27 and 25%, 7/27, respectively) that competing for resources with other programs was a challenge; only 4% (1/27) somewhat disagreed. Respondents also somewhat agreed that limited understanding of requirements within the organization (41%,

11/27) and limited internal expertise in the pediatric field (33%, 9/27) also posed challenges.

Limited support from management on pediatric programs had mixed responses, including 29%

(8/28) who “somewhat disagreed”. Using the 5-point scale to describe the listed elements, most challenging appeared to be “competition for resources” with a score of 2.0 compared to limited internal expertise (2.8), limited understanding of requirement (2.9), and limited support from management (3.2).

Figure 19: Challenges in Pediatric Oncology Development Plan

What would best describe the challenges your team has encountered within the company/organization when planning for pediatric oncology drug/biologic development?

Other included: • Applicability of adult drug targets to pediatric populations (science). • Limited appropriate pediatric targets for our agents. As a follow-up question, respondents were also asked to rank the challenges offered in Figure 27.

Consistent with the results described above, “competition of resources with other programs” was rated as most challenging (average score of 1.9, with 1 representing the most challenging)

(Table 17), followed by “limited internal expertise in pediatric clinical science” (2.4). “Support from management” (3.4) and “understanding of regulatory requirements” (3.5) had immediate scores and “logistics related to submissions” had lowest scores (4.3).

Table 17: Ranking of Challenges Within the Company/Organization in Pediatric Oncology Development Planning (n =26)

Please rank the challenges that your team has encountered within the company/organization when planning for pediatric oncology drug/biologic development, where 1 represents most challenging and 5 least challenging.

1 2 3 4 5 Average Most Least Score Challenging Challenging Competition for 14 7 2 1 2 1.9 Resources With Other Programs Limited Internal 7 8 6 3 2 2.4 Expertise in Pediatric Clinical Science Limited Support from 2 5 6 8 5 3.3 Management for Pediatric Program Limited 0 6 8 7 4 3.5 Understanding of Regulatory Requirements Limited 1 0 4 7 13 4.3 Understanding of Logistics Related to Submissions

Respondents were asked about the degree of challenge or disagreement related to certain key elements of their pediatric development plans (Figure 20). “Timing of the study” stood out as a challenge that was rated most often as “always” (18%, 5/28) or “most of the time” (39%, 11/28);

However, 7 respondents identified this challenge “sometimes” (25%, 7/28) and two identified it as “never” happening (7%, 2/28). Other challenges/disagreements that were most commonly identified “most of the time” was “dosing” (33%, 9/27) and “pediatric study endpoints” (32%,

9/28). The remaining elements were most commonly selected “sometimes”: age group inclusion

(32%, 9/28), formulation development (29%, 8/28), animal study planning (35%, 10/28), and

safety follow-up (50%, 14/28). When applying a 4-point scale, “timing of study” had the highest average score (2.2) as a disagreement compared to other listed elements: pediatric study endpoints (2.7), dosing (2.8), age group inclusion (2.8), and formulation development (2.9). Both safety follow-up and animal study planning had an average score of 3. About 20-30% of the respondents could not give an answer to each of the choices.

Figure 20: Challenges/Disagreements in Key Elements of Pediatric Oncology Development Plan

When working within the company/organization, what have been the areas of challenges or disagreement in the key elements of a pediatric oncology drug/biologic development plan? Select all that apply.

Note: Total of 28 responses for each listed element, except for “dosing” with a total of 27 responses, and “Others” with 6 responses.

Text reported under “Others”: • Patient criteria • Decision-making criteria (Go/No-Go) • Patient Population • Overall trial design

Respondents were also asked to identify the extent to which they had experienced challenges related to five listed external factors that had previously been mentioned in the literature

(Figure 21). The two factors considered extremely challenging by most respondents were both related to recruitment, including “enrollment delays related to small participant pool” (extremely challenging: 50%, 14/28; very challenging: 32%, 9/28) (average score of 2.0 in a 4-point scale); and “competing enrollment with trials for drugs in the same class” (extremely challenging: 44%,

12/27; very challenging: 18%, 5/27) (average score of 2.3). “Study conduct challenges” were identified most frequently as a “slightly challenging” (43%, 12/28) (average of 2.9) but several participants found study conduct to be extremely (11%, 3/28) or very challenging (25%, 7/28).

“Ethics board negotiations” and “lack of interest from investigators” appeared to be the less significant challenges, ranked by most as “slightly challenging” (46%, 13/28) (average of 3.2) but several participants found ethics board review as extremely challenging and very challenging

(14%, 4/28 and 7%, 2/28, respectively). “Lack of interest from investigators” was mostly viewed as “slightly challenging” (36%, 10/28) and rated most commonly as “not challenging at all” compared to the other provided choices. About 15-25% of the respondents could not answer these questions.

Figure 21: External Factors Contributing to Challenges in the Implementation of the Pediatric Oncology Development Plan

How serious are the following types of challenges when implementing the pediatric oncology drug/biologic development plan?

Note: Total of 28 responses for each listed element, except for “competing enrollment with trials for drugs in the same class” with a total of 27 responses, and “Others” with 4 responses

Respondents were asked to rank by frequency the approaches to pediatric oncology drug development that their organization has taken from 5 options, with 1 being most frequent to 5 being least. As shown in Table 18, respondents identified “full waiver request” approaches or

“orphan drug exemption” approaches as most frequent (10/25 and 8/25 respectively) (average score of 2 and 2.7 on a scale of 1 to 5). “Full deferral post adult approval” also had a relatively similar score (2.9) to that of orphan drug exemptions, but the distribution of answers related to full deferrals was weighted toward intermediate rankings whereas the choices related to orphan

100

product designations were more bimodal. Least frequent approaches included “written request in the US” (3.5) and “early pediatric study in parallel with Phase 2 in adults” (3.8).

Table 18: Ranking of Frequency of Approaches Taken by Organizations for Development Programs

Please rank by frequency the approaches that your current company/organization has taken with regard to the approach in your oncology drug/biologic development programs (with 1 as the most frequent approach, 5 as the least).

1 2 3 4 5 Preference Most Least Rating Frequent Frequent Full Waiver Request (n = 25) 10 8 3 4 0 2.0

Early Pediatric Study in Parallel 2 3 4 4 12 3.8 with Phase 2 in Adults (n = 25) Full Deferral Post Adult 4 5 9 4 3 2.9 Approval (n = 25) Orphan Drug Exemption in the 8 5 2 6 4 2.7 US (n = 25) Written Request in the US 1 4 7 7 6 3.5 (n = 25)

Experience with FDA and EMA Interactions

Respondents were asked whether their organizations have proposed any of the four study design elements encouraged by the health authorities in their pediatric development plan (Table 19).

Approximately one-third of respondents have proposed the inclusion of adolescents as part of the adult program in either the US (36%, 16/44) or the EU (33%; 14/42) proposals. Relatively common as well as the use of extrapolation, modeling, and simulation in both US and EU proposals (30%, 13/44; 29%, 12/42 respectively). A smaller number of respondents used real-world evidence as a comparator (US, 14%, 6/44; EU, 17%, 7/42) or the use of a master protocol design (US, 18%, 8/44; EU, 21%, 9/42).

101

Table 19: Experience in Inclusion of New Study Design Elements in Proposals to Health Authorities

Has your company/organization proposed any of the following design elements in the pediatric oncology drug/biologic development plan? If yes, please select all that are appropriate.

Proposal Included in US Proposal Included in EU (PSP/PPSR) (PIP) n=44 n=42 Inclusion of adolescents as 16 (36%) 14 (33%) part of adult program Master Protocol Design 8 (18%) 9 (21%) Real World Evidence as 6 (14%) 7 (17%) Comparator Use of Extrapolation, 13 (30%) 12 (29%) Modeling and Simulation Other 1 (2%) 0 Text provided under “Other” • Every early development program is different

As a follow-up question, respondents were asked to rate the degree to which health authorities were receptive to the novel study design elements listed above (Figure 22 and Figure 23). The US

FDA appeared most receptive when respondents proposed the inclusion of adolescents as part of the adult program (48%, 12/25 as very receptive and 36% and 9/25 as somewhat receptive) or proposed the use of a master protocol approach (32%, 7/22 as very receptive and 32%, 7/22 as somewhat receptive). On a scale of 1-3 from very receptive to not very receptive, “inclusion of adolescents as part of adult program” and “master protocol design) had very similar average scores, 1.4 and 1.5, respectively. No respondents selected “not very receptive”. The use of

“Extrapolation, Modeling and Simulation” was also somewhat acceptable to the US FDA (1.9) with most respondents selecting “somewhat receptive” (43%, 12/28). “Using real world evidence as comparator” elicited more mixed responses (average of 2.4) with only 5% of respondents

102

(1/22) selecting “very respective”, 32% (7/22) as somewhat receptive and 27% (6/22) as not very receptive. About 25-30% of the respondents selected “do not know”.

Figure 22: Receptivity of the US FDA to Novel Study Design Elements

From your experience, how receptive are the health authorities to the following design elements for pediatric oncology PSP/PPSR/PIP?

Note: Total of 28 responses for “Inclusion of Adolescent as part of the adult program” and “Use of Extrapolation, Modeling & Simulation”. Total of 22 respondents for “Master Protocol Design” and “Real World Evidence as Comparator”. Three respondents selected “Other”. One text statement provided under “Other”: • “we have an orphan exemption in the US so do not have PSP obligations, however, at a recent conference I spoke with an FDA official who endorsed our plans to include children of any age in our pivotal study, which has no upper or lower age range. In Europe, we are still in the midst of PIP negotiations, but they were fine with the approach though of course they want to see a minimum number of pediatric subjects”

Overall, respondents considered the EMA to be less receptive than the FDA to most of the listed selections (Figure 23), except for “use of extrapolation, modeling and simulation” (very receptive: 22% (5/23); somewhat receptive: 45% (10/23). None selected “not very receptive”

(average score of 1.7). The EMA was identified to be very or somewhat receptive to “inclusion of adolescents” [very receptive: 22% (5/23); somewhat receptive: 48% (11/23); average score of

103

1.8]. When ranking “Master protocol design”, most respondents selected “somewhat receptive”

(45%, 9/20) but a few selected “very receptive” and “not very receptive” (2/20 each, 10%). More respondents answered “do not know” (36%, 32/89) of all the answers when asked about the experience with the EU than the US on these study design elements.

Figure 23: Receptivity of the EU CHMP to Novel Study Design Elements

From your experience, how receptive are the health authorities to the following design elements for pediatric oncology PSP/PPSR/PIP?

Note: Total of 23 responses for “Inclusion of Adolescent as part of the adult program” and “Use of Extrapolation, Modeling & Simulation”. There were 20 respondents for “Master Protocol Design”, 21 respondents for “Real World Evidence as Comparator”. Two respondents selected “Other” but no details were provided.

The respondents were asked to share their levels of satisfaction with the current mechanisms to obtain feedback about their development plans from the US FDA and/or EU PDCO (Table 20).

More than half of those who offered an assessment were satisfied with each of the 4 listed mechanisms from the US FDA. With respect to the “Initial Pediatric Study Plan”, 63% (17/27) were satisfied, 15% (4/27) had a neutral view and 11 % (3/27) were dissatisfied. The rest could not answer. With respect to “US Pediatric Study Plan Amendments”, 56% (14/25) were satisfied, 104

12% (3/25) were neither satisfied nor dissatisfied and 16% (4/25) were dissatisfied. With respect to “US Written Request Amendments”, 52% (14/27) selected “satisfied”, 30% (8/27) selected

“neither satisfied nor dissatisfied” and only 1 respondent (4%) selected “dissatisfied”. With respect to “US Proposed Pediatric Study Plan”, 50% (13/26) selected “satisfied”, 23% (6/26) selected “neither satisfied nor dissatisfied”, and 11% (3/26) selected “dissatisfied”. A somewhat different experience was typical for the EU PDCO process. Only approximately 30% (8/27) of respondents were satisfied with the PIP and PIP modification processes, compared to 41%

(11/27) who were neither satisfied or dissatisfied and 19% (5/27) who were dissatisfied.

105

Table 20: Satisfaction with Current Mechanisms for Development Plan Feedback from the US FDA and/or EU PDCO Satisfied Neither Dissatisfied Cannot Total Preference Satisfied Comment Rating* nor Dissatisfied US FDA on 17 (63%) 4 (15%) 3 (11%) 3 (11%) 27 1.4 initial Pediatric Study Plan (iPSP) US FDA on PSP 14 (56%) 3 (12%) 4 (16%) 4 (16%) 25 1.5 Amendment

US FDA on 13 (50%) 6 (23%) 3 (11%) 4 (15%) 26 1.6 Proposed Pediatric Study Plan (PPSR) US FDA on 14 (52%) 8 (30%) 1 (4%) 4 (15%) 27 1.4 Written Request (WR) Amendment EU PDCO on 8 (30%) 11 (41%) 5 (19%) 4 (15%) 27 1.9 Paediatric Investigational Plan (PIP) EU PDCO on PIP 7 (26%) 11 (41%) 5 (19%) 4 (15%) 27 1.9 Modification

Other 0 0 0 5 (100%) 5 3

From your experience, how satisfied are you with the mechanism in obtaining feedback from the US FDA and/or EU PDCO about pediatric oncology drug/biologic development plan?

Notes from respondents: • The CHMP SCA Working Party was not on the listed mechanism – their input on paediatric programs is more important than PDCO • All have been orphan, so no FDA interaction * “Cannot Comment” removed in the preference scale

106

Respondents were also asked to share the approaches that they have taken regarding the timing of

PSP and PIP coordination (Figure 24). The most common approach taken by the companies was to obtain the PIP first and the PSP/PPSR second as reflected by the fact that more respondents selected this sequence was the approach that was always (18%, 5/27) or sometimes taken (59%,

16/27). Somewhat less frequently taken was the approach in which the PIP and PSP were pursued in parallel but not under the Parallel Scientific Advice pathway (always taken: 7%, 2/27; sometimes taken: 52%, 14/27; never: 26%, 7/27). Companies pursued PIP and PSP submission under parallel advice much less frequently. Three (11%) respondents selected “always” and 5

(8%) selected “sometimes”, but most selected “never” (52%, 14/27). This pattern of frequency was consistent with that assessed by examining the preference rating using a 3-point scale. The selection, “obtained PIP agreement followed by PSP/PPSR” had an average score of 1.9, compared to “pursued PIP/PSP in parallel but not under Parallel Scientific Advice” (2.2), and

“Parallel Scientific Advice” (2.5). About 20% of respondents selected “do not know” to the offered choices.

107

Figure 24: Respondents’ Experience on Timing of PSP and PIP Coordination

Regarding timing of PSP and PIP coordination for pediatric oncology drug/biologic planning, how often have you taken the following approaches?

Note: Total of 27 responses for each field except for 3 responses under “Other”. Text input under “Other”: • All have been orphan, so no FDA interaction

Respondents were asked to share the issues of challenge/disagreement that they had experienced during their discussions with the FDA on the proposed pediatric development plan from a list of 7 options (Table 21). This was measured by assessing if more than one round of discussion is required on any specific elements in the study design. Based on the feedback, the elements that required more than one discussion were age group inclusion and dosing (48%, 12/25 and 46%,

12/26 respectively). More mixed experiences were evident for the timing of the study (46%,

12/26, agreement in initial discussion vs. 38%, 10/26, requiring more than one discussion); safety follow-up (50%, 13/26 vs. 38%, 10/26); formulation development (35%, 9/26 vs. 38%, 10/26); and pediatric study endpoints (same percentage: 42%, 11/26). “Animal study planning 108

agreement” was least likely to require more than one discussion (50%, 13/26 agreement in initial discussion vs. 27%, 7/26 requiring more than one discussion). About12% to 27% of respondents could not comment on various elements presented in this question.

Table 21: Experience Regarding FDA Discussions on Selected Topics Related to Pediatric Development Plans

What have been the areas of challenging or disagreement during the review of the proposed pediatric oncology development plan (PSP/PPSR or PIP) with health authorities? Select all that apply.

Reach Require More Cannot Total Agreement in Than One Comment Initial Discussion Discussion Timing of Study 12 (46%) 10 (38%) 4 (15%) 26

Dosing 9 (35%) 12 (46%) 5 (19%) 26

Age Group Inclusion 7 (28%) 12 (48%) 6 (24%) 25

Formulation 9 (35%) 10 (38%) 7 (27%) 26 Development

Animal Study Planning 13 (50%) 7 (27%) 6 (23%) 26

Pediatric Study 11 (42%) 11 (42%) 4 (15%) 26 Endpoints

Safety Follow-up 13 (50%) 10 (38%) 3 (12%) 26

Others 0 1 (20%) 4 (80%) 5

109

A similar question was asked regarding respondents’ experience with discussions with the EMA

(Table 22). Based on the feedback, most of the study plan elements required more than one discussion than reaching agreement in first round, i.e. “dosing” (32%, 7/22 vs. 41%, 9/22), “age group inclusion” (29%, 7/24 vs. 41%, 10/24), and “animal study planning” (29%, 7/24 vs. 28%,

9/24). There were more respondents (25-38%) selected cannot comment than the previous question on the US FDA experience. A relatively even split was seen for most topics between the need for one discussion versus multiple discussions, including “timing of study” (33%, 8/24 vs.

27%, 9/24), “formulation development” (29%, 7/24 vs. 33%, 8/24), “pediatric study endpoints”

(25%, 8/23 vs. 39%, 9/23), but the topic “safety follow-up” more frequently required only one discussion (46%, 11/24) .

110

Table 22: Experience Regarding EMA Discussions on Selected Topics Related to Pediatric Development Plans

What have been the areas of challenge or disagreement during the review of the proposed pediatric oncology development plan (PSP/PPSR or PIP) with health authorities? Select all that apply.

Reach Require More Cannot Total Agreement in Than One Comment Initial Discussion Discussion Timing of Study 8 (33%) 9 (37%) 7 (29%) 24

Dosing 7 (32%) 9 (41%) 6 (27%) 22

Age Group Inclusion 7 (29%) 10 (41%) 7 (29%) 24

Formulation 7 (29%) 8 (33%) 9 (38%) 24 Development

Animal Study Planning 7 (29%) 9 (38%) 9 (33%) 24

Pediatric Study 8 (35%) 9 (39%) 6 (26%) 23 Endpoints

Safety Follow-up 11 (46%) 7 (29%) 6 (25%) 24

Others* 1 (14%) 2 (28%) 4 (57%) 7

*Note from respondents: • Scope of PIP condition/indication • minimum number of pediatric subjects for study • Patient Population, Go/No-Go criteria

Respondents were asked if they were able to reach an agreement with the FDA on a proposed pediatric study plan (PPSR) for their pediatric oncology drug/biologic program within the estimated timeframe (Figure 25). About two-thirds (66%, 18/27) of respondents identified that 111

they were able to reach agreement within the estimated timeframe, only four respondents reported that they could not, and five could not answer.

Figure 25: Experience in Reaching Agreement on PPSR with the FDA within the Estimated Timeframe (N=27)

Based on your experience, have you been able to reach agreement with the FDA on the Proposed Pediatric Study Plan (PPSR) in your pediatric oncology drug/biologic program within the estimated timeframe?

Respondents were also asked whether delays have occurred in the initiation of a pediatric oncology study that could be attributed to challenges in reaching an agreement on pediatric study design with the US FDA or the EU PDCO (Figure 26). About one-third of respondents (33%,

9/27) reported no such delay. Amongst the respondents who had experienced delays, 4% (1/27) were delayed by less than 3 months, 15% (4/27) between 3 to 6 months, and 22% (6/27) between

6 to 12 months of delay. Seven respondents were not able to answer this question.

112

Figure 26: Experience on Timing and Delay in Reaching Agreement with the US FDA or the EU PDCO

Based on your experience, has there been delay in the initiation of a pediatric oncology study due to reaching agreement with the US FDA or the EU PDCO on pediatric study design elements? If yes, please estimate the delay.

Respondents were asked if their organizations had received any pediatric reward/incentives associated with their oncology drug/biologic development program (Figure 27). Only a few respondents (11%; 3/26) had received a rare pediatric disease priority review voucher. About a quarter of the respondents had received either a 6-month pediatric exclusivity/extension from the

FDA or from the EMA (26%, 7/27 for each). Most respondents received no pediatric rewards/incentives, especially the rare pediatric disease priority review voucher (81%, 21/26).

113

Figure 27: Experience in Receiving Pediatric Rewards/Incentives

Has the company/organization received the following for an oncology drug/biologic program?

In follow-up questions, respondents were asked why they did not receive a 6-month pediatric exclusivity from the US FDA (Table 23) or a 6-month extension to SPC from the EU CHMP

(Table 24). The majority of the reasons (35%, 8/23 and a few reasons under “others” 30%, 7/23) was because the company did not or has not submitted a PPSR, followed by Written Request terms were not met (22%, 5/23). In the EU, as it is a requirement for PIP unlike the PPSR as voluntarily, the most selected reason for not receiving the 6 months pediatric extension was the timing of PIP completion (47%, 9/19), followed by “others” (42%, 8/19).

114

Table 23: Reasons for Not Receiving 6-Months Pediatric Exclusivity from the US FDA

In your most recent experiences, if the organization has not received 6-months of pediatric exclusivity from the US FDA on a pediatric oncology program, please select one of the following:

Reasons Total (N=23) Did not submit a PPSR 8 (35%) Submitted a PPSR, not received a Written Request 3 (13%) Received a Written Request, not meeting terms in the 5 (22%) Written Request Others 7 (30%) • Did not apply for one • We have not yet submitted • In process of receiving WR • Not completed yet and not meaningful for biologic anyway • Study ongoing Table 24: Reasons for Not Receiving 6-Months Pediatric Extension from EU CHMP

In your most recent experience, if the organization has not received the 6-months extension to SPC with the completion of an agreed PIP on a pediatric oncology program, please select one of the following reasons for not receiving the extension:

Reasons Total (N=19) Timing of PIP completion 9 (47%) Not meeting study elements in agreed PIP, other than the timing 1 (5%) Non-compliant PIP as determined by PDCO 1 (5%) Others 8 (42%) • Study ongoing • Did not apply for one • The SPC was already expired at the time of PIP completion • We have not yet submitted • In progress

115

Respondents were asked about their organization’s view of the adequacy of the current incentives

(Table 25). When applying a weighted average using a 5-point scale (extremely adequate to extremely inadequate), all listed US incentives had scores of about 2.0. Pediatric rare disease priority voucher was viewed as marginally more adequate (average of 1.9; 30%, 8/27 extremely adequate; 41%, 11/27 somewhat adequate, 22%, 6/27 neither adequate nor inadequate, and none for somewhat or extremely inadequate) than the EU’s 2-year pediatric extension of orphan market exclusivity (2.1), the 6-month exclusivity in the US (2.3 and 2.1 for orphan drug with small market potential) and SPC extension in the EU (2.2). Only a small percentage (7-11%) of respondents selected “do not know”.

116

Table 25: Industry’s Perspective on Adequacy of Current Incentives for Pediatric Oncology Drug Development

Does your organization view the current regulation as adequate in providing incentives to stimulate pediatric oncology drug/biologic development?

Extremely Somewhat Neither Somewhat Extremely Do Total Adequate Adequate Adequate nor Inadequate Inadequate not Inadequate know BPCA: 6- 3 (11%) 17 (63%) 1 (4%) 3 (11%) 1 (4%) 2 (7%) 27 months Pediatric Exclusivity BPCA for 5 (19%) 14 (52%) 3 (11%) 1 (4%) 1 (4%) 3 (11%) 27 Orphan Drug with small market potential Pediatric 8 (30%) 11 (41%) 6 (22%) 0 0 2 (7%) 27 Rare Disease Priority Voucher EU: 6- 3 (11%) 17 (63%) 0 3 (11%) 1 (4%) 3 (11%) 27 months SPC Extension EU: 2- 5 (19%) 16 (60%) 0 2 (7%) 1 (4%) 3 (11%) 27 years Pediatric Extension of Orphan Market Exclusivity

Respondents were also asked for their opinions on the key drivers to advance early pediatric oncology drug development from a list of previously suggested drivers (Table 26). Using weighted average for a 5-point scale from “extremely important” to “not at all important”,

117

“harmonization of pediatric development plan across the FDA and PDCO” appeared to be the most important factor overall (average of 1.7, with 63% (17/27) extremely important, 26% (6/27) very important, and only 11% (3/27) as not at all important). It was followed by “a longer exclusivity extension” (average of 2.0, with 37% (10/27) extremely important and very important each, and none for not at all important) and “better knowledge to decrease high rate of failure”

(average of 2.0 with 40% (10/25) extremely important and very important each, 8% (2/25) as moderately or slightly important each). “Cooperative efforts related to disease-specific working groups” and “additional funding structure and partnerships” were also rated as very important factors (average of 2.4 and 2.7, respectively), with more respondents selecting very important

(31-41%) versus slightly important. The least selected as important was “additional and specific guidance” (average of 3.6, with only 1 respondent (10%) viewed this as extremely/very important and most (40%, 4/10) noted this was not important at all.

118

Table 26: Respondents’ Opinion on Key Drivers to Advance Early Pediatric Oncology Drug Development

In your opinion, what would be the key drivers to advance early pediatric oncology drug/biologic development? Extremely Very Moderately Slightly Not at all Total Average Important Important Important Important Important Score Longer Exclusivity Extension 10 (37%) 10 (37%) 5 (18%) 2(7%) 0 27 2.0

Harmonization of Pediatric Study Plan 17 (63%) 6 (26%) 1 (4%) 0 3 (11%) 27 1.7 between US FDA and EU PDCO Additional and Specific Guidance 1 (10%) 1 (10%) 3 (30%) 1 (1%) 4 (40%) 10 3.6

Disease Specific Working Groups with HAs, 5 (19%) 11 (42%) 6 (23%) 3 (12%) 1 (4%) 26 2.4 Academies, and Industry Additional Funding Structure and Partnership 5 (19%) 8 (31%) 5 (19%) 6 (23%) 3 (12%) 26 2.7

Better Knowledge to Decrease High Rate of 10 (40%) 10 (40%) 2 (8%) 2 (8%) 1 (4%) 25 2.0 Failure Other Incentives 1 (25%) 1 (25%) 1 (25%) 0 2 (40%) 5 3.2

Other 1 (25%) 1 (25%) 0 0 3 (60%) 5 3.6

Notes from respondents under “Other” • Linked to driving innovative development • Efficient trial design (platform trials/master protocols)

119

At the end of the survey, respondents were given the opportunity to expand on what they believed to be the key drivers to increase stand-alone programs specific for pediatric patients (Table 27).

Their multiple answers have a few themes: incentives for industry to compensate risks and financial investment; appropriate clinical trial structure globally across partnerships; and increased understanding of pediatric disease biology and science-driven study designs.

Table 27: Respondents’ Opinion on Key Drivers to Increase Pediatric Stand-Alone Programs Specific for Pediatric Cancers

In your opinion, what would be the key drivers to increase pediatric stand-alone programs specific for pediatric cancers?

They are not very relevant in the new area of targeted medicines and immune-oncology For my company, we do this as it is essential to our mission. For other companies, it seems that regulatory requirements are the only solution. No comments – not aware No application fee. Longer exclusivity. Use of novel study designs and surrogate endpoints. More incentive to encourage companies to invest in pediatric research A platform that evaluates scientific merit and relevancy of conducting the trial in a pediatric population. If relevancy exists, then pediatrics should be introduced into the adult studies in a stepwise manner (soon after relative safety is established in adults). More focus on understanding pediatric disease biology and biomarkers (translational science) rather than attempting to translate adult targets/data to pediatric disease. Developing an appropriate clinical trial infrastructure (cooperative groups, industry, investigators) to support the efficient design and conduct of trials with novel agents and combinations (platform trials, umbrella and basket studies). Connecting the regulators to the real-life challenges of conducting pediatric development and setting pragmatic regulatory expectations that take into account data that has been generated across a class of agents (meta-analyses), real work evidence and various sources of data generation/exploration (investigator sponsored trials). More incentives for the organization Management/market drivers for the pediatric indication; absent market driver, more regulation to mandate with incentives While additional incentives would likely work, the bigger question is around understanding the safety profile sufficiently in the absence of adult data and ethical issues

120

In Europe, studies with children need to be reviewed by pediatric ECs, which adds a lot of complexity to the inclusion of adolescents in adult trials. A market driver – commercially there is limited to no real potential for ROI

Respondents were also asked if certain experiences with pediatric oncology programs were not captured fully in this survey (Table 28). This question elicited only two responses:

Table 28: Other Experience with Pediatric Oncology Development Programs

Do you have certain experience with pediatric programs that we have not explored fully in the survey above? If yes, we would value your additional comments.

Collaborating with NCI CTEP is helpful While these studies are difficult, we just need to initiate, help patients, learn and re-adjust. We have a shared responsibility with regulators and academia to address grievous diseases.

Exploratory: Cross Tabulations by Size of Organizations

To understand if the experience of respondents differs in relation to the size of the organization with which they were associated, the size of the company (1-500 employees;501-2,500 employees; 2,501-10,000 employees; and 10,001+ employees) was cross-tabulated with responses with other questions. Typically, no major differences appeared to be associated with the size of the company with which respondents were associated. However, a few instances where such relationships may exist are described below. Because the number of respondents in each size category was small, results should be reviewed with caution.

Implementation Within the Organization: In your company/organization, how is the pediatric team organized to support oncology drug/biologic development?

121

As might be expected, larger companies more typically had dedicated resources and experts for

pediatric programs, particularly in clinical development and clinical pharmacology development

(Table E.1 in Appendix E). The largest companies (10,001+ employees) also appeared to have

dedicated resources in other areas, including regulatory affairs and translational medicine.

Experience in Pediatric Programs: What would best describe the challenges your team has encountered within the organization?

The types and ratings of challenges were generally similar in companies of different sizes.

However, the largest companies typically appeared to have more support from management, better internal expertise, and a better understanding of pediatric programs (Table E.2 in

Appendix E)

Long-term Implementation: Does your organization view the current regulation as adequate in providing incentives to stimulate pediatric oncology drug/biologic development?

Most respondents from companies of large size (10,000+ employees) noted the existing US

pediatric incentives (6-months pediatric exclusivity and Pediatric Rare Disease Priority Voucher)

as extremely or somewhat adequate. Half of the respondents of small companies

(1-500 employees) rated the existing 6-month pediatric exclusivity as somewhat inadequate or

extremely inadequate (Table E.3 in Appendix E).

122

CHAPTER 5. DISCUSSION

The regulatory requirements for pediatric oncolytic drugs have evolved and continue to evolve, even as this research project has progressed. As might be expected in a time of change, considerable variation appears to be present in the ways that companies interpret and implement regulatory recommendations into their pediatric programs. Their activities are particularly important to understand because the current status quo is not seen to be adequate by many stakeholders, such as academic and patient-advocacy groups. Those groups question why pediatric studies are often delayed until one or more adult clinical trials have been carried out or even until the drug has been marketed for adults. They argue that such delays deny children of potentially effective new therapies and contribute to their unsafe use in the absence of pediatric dosing and safety information. This study provides a more systematic analysis of industry’s views with regard to incentives and challenges, including insights into their experiences when interacting with health authorities and attempting to implement pediatric trials operationally. It also provides information on the industry perspective related to the effectiveness of incentives to stimulate pediatric oncology drug/biologic development.

Methodological Considerations

Delimitations

This research was delimited to regulatory and clinical professionals with experiences in pediatric oncology drug and biologic development. Pediatric oncology has the special challenge that pediatric cancers are most often dissimilar to cancers found in adults. Thus, it was important to choose a homogeneous pool of respondents with experience in pediatric oncology development,

123

so that the research could focus more specifically on experiences with FDA and EMA pediatric processes.

The scope of this research was delimited to regulatory professionals in industry. The views of other stakeholders, such as health authorities, investigators, or patient advocacy groups, are likely to differ for the reasons outlined in Chapter 2. The research was also delimited to the examination of experiences in two regulatory systems, those of the US and EU. The specialized group of respondents surveyed here may also have had experience in other countries that were not studied in this research. However, it is likely that those experiences will differ in some respects because the foreign health authorities often interact with companies according to different conventions

(Thomsen, 2019). This could complicate the analysis. Further, it is likely that fewer of the respondents would have sufficient information about these other regulatory regimes to provide a sufficient picture of issues and implementation there. Regulatory interactions in other countries are often conducted by local regulatory experts who have the linguistic and cultural capabilities to operate more effectively in that specialized system. Even when comparing only two economies in this study, it seemed that the level of expertise for each system was not identical. More individuals in the respondent pool appeared to consider themselves to be knowledgeable or very knowledgeable with regard to FDA regulations and submission practices than with EU practices, despite the fact that these two markets often receive submissions for market approval for a single product at or close to the same time (Downing et al., 2012).

This survey also focused on the regulatory environment in place as of Jan 2019 and thus will reflect industry’s experience and thinking at that time. Since that time, additional guidance documents (i.e. “Considerations for the Inclusion of Adolescent Patients in Adult Oncology

Clinical Trials Guidance for Industry – March 2019”; “Cancer Clinical Trial Eligibility Criteria:

124

Minimum Age for Pediatric Patients; Draft Guidance for Industry – March 2019”) have been issued. For this reason, the results presented here must be interpreted in light of the practices prior to 2019; practices and opinions may change with the changing regulatory climate.

Limitations

This research was conducted using an online survey, an approach known to have certain potential limitations. For this research, the most important of these potential limitations were seen to be the availability of representative participants and the validity/reliability of the survey method.

5.1.2.1 Availability of Representative Participants

Survey validity is driven by the number and representativeness of its respondents (Fincham,

2008). Perhaps the largest potential limitation, then, was to assure the participation of a sufficient number of engaged respondents who have had pediatric oncology drug/biologic experience. The number of experienced clinical and regulatory professionals with such experience is relatively small. Identifying appropriate regulatory and clinical professionals was particularly challenging because they are not listed in a centralized database or registry from which their contacts could be obtained. I, therefore, had to use a number of different methods to find experienced participants.

As a starting point to identify individuals with such specific experience, names were collected by first collating the names of companies with pediatric oncology studies posted on clinicaltrials.gov

(a total of 54 as of 30 Apr 2019) or were correspondents on oncology drugs approved with a pediatric indication (see Chapter 2). This approach was relatively unsuccessful because only a small number of names could be identified using this process, and because the contact information for those individuals was not listed. To locate contact information, the next step was to invite, via the professional networking platform, LinkedIn, the regulatory and clinical representatives from companies identified in those first searches. Additional sources, such as 125

industry working groups or individuals known to me or my colleagues, were also added to the roster of those approached to participate. To assure that only experienced participants were included, a question at the beginning of the survey was used to filter out participants unfamiliar with US or EU pediatric requirements. Thus, even though only 113 potential participants from about 65 companies were approached, this group of individuals probably represented a significant fraction of those working in the pediatric oncology field. Of those individuals, 46 (41%) completed the survey. This response rate falls within a range of response rates typically considered as reasonable for academic studies. For example, Baruch reported that studies involving top management/organizational representatives had an average response rate of 36.1%, with a standard deviation of 13.3 (Baruch, 1999). By identifying the companies to be approached, it was possible to ensure that the search was relatively wide-ranging and inclusive across companies, thus improving the representativeness and external validity of the results (Devroe,

2016).

Of those who responded, a majority were at the level of Director or above in regulatory or clinical positions, suggesting that the responses were obtained from appropriate individuals at a level sufficiently senior to have a good overall picture of the regulatory environment and its impact on pediatric development plans. Although the sample size was too small to support sophisticated statistical comparisons, the spread of responses from participants in companies of different sizes suggested that a reasonable cross-section of the industry was engaged. Even though the variety of companies might have been considered to introduce some degree of heterogeneity, cross- tabulation of results for companies of different sizes yielded no apparent trends in views or experiences, suggesting that the size of the company had little impact on the experience of the practitioners (Section 4.5).

126

5.1.2.2 Survey Methodology

There are advantages and drawbacks to the use of an online survey. Electronic dissemination is convenient for the researcher because it ensured that all participants received the survey at a specified point in time. In a field where regulations may be changing, such an approach would reduce the variation that might be encountered if some respondents completed the survey before an important regulation had changed whereas others completed it after. Electronic surveys are also convenient for participants who can complete the survey at their own pace without having to pick up documents at a particular street address and then mail the documents back. Convenience was considered to be a particularly important consideration for busy professionals who are often traveling because electronic surveys can be accessed at any location (Fincham, 2008).

In the past, electronic approaches have been criticized because they may deny access to individuals who are uncomfortable with computerized documents. However, the types of regulatory personnel in this study are likely to be well experienced with computerized approaches to documentation and are required to submit drug applications in electronic format (FDA, 2019).

Thus, the electronic systems were seen to be better suited to this study than paper-based methods to improve participation and thus external validity.

The designs of survey tools, as opposed, for example, to interview methods, can impose limitations related to the numbers and format of questions that can reasonably be presented to the respondents (Galesic & Bosnjak, 2009). A busy professional may fail to participate in a survey if it is too lengthy (Galesic & Bosnjak, 2009). The draft survey for this research had 46 questions, but some of these questions were combined or streamlined based on the advice of the focus group. The fact that most respondents completed the survey suggests that the questions were not too numerous. It is possible that it also reflects a high level of interest and engagement in this 127

topic because it links directly to the professional experiences and concerns of the respondents.

However, by limiting the number of questions, certain topics could not be explored in any depth.

To reduce the likelihood that questions were focused too narrowly or were biased, a question was included at the end of the survey to offer respondents the opportunity to address issues or topics that might not have been covered sufficiently. Only two participants provided text responses, but both noted that “collaborations” could be another topic to assess further if additional research were to follow.

Consideration of Results

The present research attempted to answer the question, “Are the current regulatory and incentive structures and support systems sufficient to stimulate and accelerate pediatric oncology drug development?”. To systematize the research, a conceptual framework articulated by Bertram

(Bertram et al., 2014) was used to assess industry experiences at different stages of development from conceptualizing the development strategy to planning and executing it. This framework recognizes that implementing a program of any kind will typically involve stages. In this discussion, the use of the framework helped to separate the experiences and challenges associated with three specific stages- exploration, installation, and implementation.

From Exploration to Installation

5.2.1.1 Obtaining Information about Regulatory Requirements

The first stage of developing a pediatric strategy for any company would typically be to educate the involved team members about the current regulatory and clinical considerations inherent to pediatric oncology. Typically, it begins by consulting several types of educational materials, including regulatory documents, materials documenting the experiences of precedent products,

128

and other sources of input such as presentations at meetings or writings in trade journals. Of some interest then were the opinions of the surveyed participants regarding not only the sources of information that they consulted but also the perceived usefulness of those materials. It was clear from their responses that companies were educating themselves broadly from not only the regulations themselves but also guidance documents and associated FDA-published materials. It was perhaps not surprising that almost all companies operating in the US used the draft guidance on pediatric study plans all or most of the time, given that this guidance so directly addresses the planning phase, compared, for example, to the guidance on labeling, which might be more relevant at later stages of the program. In addition, US templates for PSPs and WRs were consulted with the highest frequency. The key document consulted for PIPs in the EU was comparable guidance on formatting and content of a pediatric plan. Thus, the most frequently consulted guidance documents seem to be administrative in nature, focusing on formatting a submission and completing the templates to support the adult marketing applications. Guidance documents focusing on pediatric strategy, i.e. expansion of inclusion criteria to younger age group, qualifying for pediatric exclusivity (BPCA), or obtaining a rare pediatric disease priority review voucher, appeared to be resources seldom or never assessed by many survey respondents at the exploration phase. However, some of the programs described in these less-consulted guidance documents identify important incentives that could affect a go-no-go decision about the timing and structure of a pediatric program. The fact that they were less commonly consulted may support the often-advanced view that pediatric oncology planning is regarded by many companies as a pro forma activity ancillary to their adult programs rather than a program with potential strategic significance (Angelini, 2013).

A particularly interesting observation was the less frequent use of the “Rare Pediatric Disease

Priority Review Voucher” guidance in the US than might be expected. Given that cancer is rare in 129

pediatric patients, one would expect that all companies would want to consider the business aspects of seeking this kind of incentive and assessing the feasibility of embedding this goal early into their strategies, even before commencing the clinical trials. Perhaps part of the reason relates to the relatively limited experience with these voucher programs to date. In 2016, a GAO report assessing the effectiveness of FDA’s pediatric voucher program (GAO, 2016) concluded that too little time had passed (the program was only 3 years old at the time) to evaluate its effectiveness.

Most pediatric development programs will take more than 10 years to reach regulatory approval.

Our findings are consistent also with the evidence of others that voucher programs have not provided sufficiently strong incentives for the development of pediatric drugs, at least for those already advanced in the pipeline. For example, Hwang (Hwang et al., 2019) concluded, in a study of clinical protocols listed in two commercial pharmaceutical research databases between

2008 to 2015, that the introduction of the voucher program had not caused rarer pediatric disease treatments to move into the clinical development phase. These results are surprising because the voucher program can be valuable. Vouchers are transferrable and can be sold at high prices to other companies; four of the six pediatric vouchers awarded to date have been sold for prices ranging from $67.5 million to $350 million (GAO, 2016). However, the decision to adopt this strategy into an overall pediatric program must be taken early because specific upfront nonclinical and clinical activities are required to support an original pediatric product application that does not seek approval for an adult indication. It would be of interest to explore in the future why these incentive programs are not considered by some companies and whether additional guidance is required to encourage the use of this mechanism further.

Were the consulted documents sufficiently clear for the experts in this study? Most clear appeared to be materials dealing with the timing of different requirements and incentive structures. These elements are discussed using direct language several times throughout the 130

regulations and guidance documents in both the EU and the US. Less clear appeared to be the specific requirements and details needed to formulate a product-specific plan. One reason why the requirements and expectations are less clear for product-specific submissions, however, is probably because these rules are not generic, but rather can change according to differences in preliminary safety concerns related to the product under consideration and the needs and severity of the disease being studied. The need for more information on specific elements of a product specific-plan may in part explain why health authorities have had to hold multiple public workshops with specific industry groups. The FDA also conducted product-specific advisory committee meetings to clarify expectations related to the use of modeling and simulation, extrapolation, and master protocol study design. One example is the public discussion of the atezolizumab pediatric development strategy held at the Advisory Committee in 2016 (FDA,

2016a). In that meeting, FDA advocated the use of a master protocol design based on mechanism of action in the pediatric population across a range of age groups and cancer types.

What other method might educate regulatory teams as they explore the development of a pediatric program? One way that has been identified anecdotally is enhancing public access to informative information such as the study designs of similar drugs that have been shared with the health authorities and/or the experiences of relevant precedents (FDA, 2017a). From the results here, most regulatory departments seem already to be using the publicly available information accessible to them when preparing a pediatric study plan. However, the FDA publishes many potentially useful documents only after pediatric exclusivity is granted. Most respondents would prefer the FDA to provide those documents for public access earlier in the regulatory approval cycle. Their reports on experience with comparable EU documents suggest that the precedent protocols published in the EU before product approval helped them to clarify the scope of requirements acceptable by the PDCO. Nevertheless, a significant minority of companies did not 131

support such release. When asked to explain their reluctance, main concerns centered on the release of competitive and proprietary information, particularly for companies developing first-in- class therapies. For those companies, details contained in a pediatric plan are usually tied to a highly confidential overall development program. Their views are consistent with comments previously raised in a public forum (FOCR, 2018), in which concerns were voiced about releasing such information for first and second-in-class therapeutics because that release would put them at a competitive disadvantage. The first-in-class company might be required to do pediatric studies as a requirement of approval, but once the results of those studies are published, follow-on products in the same class might be able to use their results to gain exemption from performing similar studies. The concern is underlined by the frequently discussed experience with approvals of immune checkpoint inhibitors PD-L1 products. In that case, the fact that three PD-1/PD-L1 products have now been approved may open the door for the seven or more follow-on products in clinical development to apply for waivers. Those follow-on companies can argue that compounds with the same mechanism of action have already been studied extensively in pediatric patients and thus meet the waiver condition, “the medicinal product is not expected to represent a significant therapeutic benefit over existing treatments for pediatric patients” (ACCELERATE,

2018).

From Installation to Implementation

The installation phase has a few key activities, including the formation of a pediatric development team, the allocation of resources and the provision of management support. Results suggest here that companies typically develop teams that draw on several different functional groups, a finding that is consistent with approaches for other kinds of submissions (McNeely, 2019). What does seem to differ, however, is the extent to which these teams have other responsibilities, usually in

132

the adult programs for the same types of products. It was predictable, perhaps, that the members of the team would have different levels of commitment to the pediatric program. Results suggest that staff members from clinical development departments are more likely to be dedicated to the pediatric program. This might be explained by the fact that the design and execution of such clinical trials are time-intensive and likely to require specific expertise in trial conduct for both the therapeutic area and the pediatric population. In contrast, other functional areas with more modest contributions to the overall program more typically support both the adult and pediatric programs.

It was interesting to compare the nature of team organization in small and large companies by substratifying the responses of companies according to size. More large than medium/ small companies identified that they had clinical and regulatory affairs personnel dedicated to pediatric drug development activities. One likely interpretation is that the larger companies have more such products in their portfolios and more resources to expend on their pediatric programs. However, companies without a dedicated group could be more vulnerable to delays in pediatric development, considering that respondents on average regarded competition for resources and limited internal expertise in pediatric clinical science as the top challenges for their pediatric programs. The fact that teams in many companies are drawn from personnel who are participants in other adult programs would seem to create a situation in which team members are pulled in different competing directions. The use of such a matrixed organization is well-known to introduce challenges of competition for the time and energy of the team members (Davis, 1978).

This could threaten the efficient completion of the pediatric development program. About one- quarter of the participants identified that the pediatric requirements affected the timelines and planning of other programs. Nevertheless, most companies across company sizes, with or without dedicated pediatric clinical resources, had no such delays. Perhaps the challenges associated with 133

having competing responsibilities are offset by the learnings that come from having a broader view of the overall strategy for the development of both adult and pediatric populations.

Alternatively, it may be that the installation stage involves only a few activities that can be slotted easily into the overall responsibilities of the various team members. This would be particularly the case if the company is considering to apply for a waiver or exemption for the pediatric clinical trials. Results suggest that a full waiver request or orphan drug exemption continues to be the most frequent approach to satisfy regulatory requirements in the US currently. In such a case, the pediatric program might not have to progress to the installation phase, at least until the adult product is approved and marketed, as commonly acknowledged in other literature (Bourgeois,

2019). However, reliance on such exemptions may be less common in future, because by August

2020, the RACE for Children Act ends an exemption from PREA requirements for cancer drugs that have orphan status. That change will force many companies to make early plans for a robust pediatric trial. Although the requirement is not yet in force, individual sponsors that expect to file new drug/biologic applications in 2020 have already started to approach the FDA to clarify their path forward (Sutter, 2019). In future, it will be useful to explore how companies approach these early implementations and whether failure to plan early will result in delay for the adult registration program.

Two positive findings were notable during this early implementation phase. First, gaining support from management for the pediatric program was not seen to be problematic for most companies, compared for example, to the challenges that they face when competing for resources with other programs or finding internal expertise for such pediatric trials. Second, most companies, regardless of size, appear to be incorporating pediatric strategy and assigning resources within the company itself, instead of relying on ad hoc consultants. The reliance on

134

internal expertise may be challenging for some companies if companies have limited internal expertise related to pediatric trials. One way to improve the level of expertise in a company is by using consultants. Others who have studied various types of regulatory activities have reported that external consultants are commonly utilized in the installation stage and identified to be useful for short-term programs or programs that occur infrequently (Griffin, 2017); (Pire-Smerkanich,

2016). Further, the characteristics of pediatric cancers are often quite specialized, so outside experts in translational medicine and nonclinical development could be quite helpful at the installation stage to educate the team about scientific or regulatory aspects important, for example, to the clinical design or selection of biomarkers and outcome measures (Saletta et al.,

2014). One reason why the team may prefer to depend on internal staffing may be that pediatric planning requires longer-term involvement of key personnel and a thorough understanding of the overall development program with which it must integrate across functional areas. These are not activities easily done by short-term consultants.

When do companies begin to install and implement their pediatric programs? Results demonstrated that the timing of pediatric planning varies based on certain attributes of the programs such as the mechanism of action of the compound; only a minority of companies position the trials in a particular epoch of development. The timing appears more often to be determined by the availability of adult clinical data than the availability of nonclinical pediatric data. However, the absence of appropriate preclinical models and deficiencies in the data to confirm the relevance of molecular targets in pediatric patients have been identified as potential barriers to early planning (Langenau et al., 2015). Further advances in preclinical testing and model development may provide additional confidence for industry to move such planning to a point before the adult program is advanced.

135

As new legislation (i.e. the FDARA RACE Act), and guidance (i.e. expansion of clinical trial eligibility criteria) continue to emerge, it is helpful to understand if companies are playing an active role in the development of those rules and policies. Results here underline differences in the degree to which companies of different sizes participate in those activities. Not surprisingly, medium-sized and large companies appeared to take a greater role in workshops/meetings organized by health authorities and in providing comments on draft guidance. Most small companies have not or have never participated in such activities. This supports the assumption made even before the survey that the few selected industry representatives at workshops/meetings were mainly from major pharmaceutical companies. These results raise a red flag that such discussions may lack the perspective from smaller/start-ups companies where innovations often take place (HBM Partners, 2019).

Full Implementation

The implementation phase of any program can be the most difficult as companies face the logistical challenges of conducting the activities needed to satisfy the goals laid out during the installation phase. This exploratory study was not designed to examine specifically the types and level of complexity of pediatric study designs being implemented across companies but instead was directed at understanding the experiences that those companies had with regulatory and logistical implementation. The data suggested that most companies had similar challenges; a few of the areas of particular concern were those of clinical trial development, interactions with global health authorities, current incentive structures, and collaboration with other stakeholders.

5.2.3.1 Challenges in Clinical Programs

One of the major challenges identified by respondents was enrollment delay. Their experiences are consistent with the analyses of Hwang and colleagues (Hwang, 2018) who also identified that 136

many pediatric studies required under the EU Paediatric Regulation and US PREA have been delayed. Further, they found that pediatric studies that were conducted after marketing authorization were less likely to be completed in a timely manner. Multiple factors undoubtedly contribute to these delays (Rose & Senn, 2014). Children are a vulnerable population whose trial participation often depends on a complicated set of permissions and assents from both the parent and the child. Further, pediatric development is commonly based on a precedent or concurrent adult development program for a superficially similar cancer, but in fact, may be targeting cancer with a rare and different pathology for which the adult data may not be predictive. In addition, because regulatory obligations mandate pediatric studies, multiple programs developed across different companies compete for the same, limited patient pool.

The current system of mandatory requirements and financial rewards are not the solution for the logistical challenges identified here. To address these more pragmatic concerns, US and EU health authorities have encouraged industry to improve trial efficiency by harnessing regulatory science and novel trial design. Some of the suggested steps are described in guidance documents that discuss, for example, increasing the inclusion of pediatric patients as part of earlier adult oncology trials, or using extrapolation, modeling, and simulation to reduce the numbers of children who must be tested. The applications of master protocol design and real-world evidence to replace experimental comparator groups have also been discussed in public fora between the health authorities and industry (Former, 2017).

Are these ideas adopted by industry? Research here shows that about 1/3 of the respondents have included adolescents as part of the adult program. A similar number has proposed the use of extrapolation, modeling, and simulation to the US FDA and EU PDCO; they identify that the regulatory agencies, and especially the US FDA, have been receptive to such proposals. These

137

findings suggest some level of welcome by regulators that hopefully will help to reduce regulatory uncertainty and encourage more sponsors to consider the use of novel study designs.

Amongst the newest of the proposed options to modify study design are the use of master protocols and real-world evidence. These have not yet been featured in programs that have matured to the point of approval. Further, experience amongst regulatory and clinical professionals with these approaches appears to be limited; fewer than 20% of respondents in this survey had applied these approaches. They were also identified to be received with less enthusiasm by both health authorities. Consequently, it remains unclear whether and when these types of approaches will be acceptable to meet pediatric regulatory requirements or to satisfy regulatory reviewers during NDA submission.

5.2.3.2 Interactions with Health Authorities

Often it is only during implementation that companies encounter concerns related to their pediatric plans. At these points, they may find it necessary to seek the advice of regulatory agencies. Most respondents in this study appeared to be relatively satisfied with the existing mechanisms for obtaining feedback from the US FDA on their iPSPs, PSP amendments, PPSRs, and WR amendments. However, only 1/3 of respondents rated the EU PIP and PIP modification procedure as satisfactory. It is possible this reflects the differences in granularity required in the

PIP versus the PSP; PIPs require a complete investigational plan, from phase 1 to phase 3, when only limited adult clinical data are available to inform such a plan or even the indication being developed (Adamson et al., 2014). However, it is also important to note that majority of the respondents who completed the survey were more familiar with the US procedures- 11% of the respondents had no experience with EU procedure at all. Cross-tabulation analyses of respondents knowledgeable with both the US and EU regulations also show more “dissatisfaction” with 138

mechanisms for PIPs and PIP amendments. Failure to reach a timely agreement with a health authority can delay the start of the pediatric oncology study (Adamson et al., 2014). Such issues may contribute at least in part to the finding in this survey that 30% of respondents have experienced delays of 6 to 12 months because of challenges in reaching agreement on the pediatric plan with the US FDA or the EU PDCO. Under the new rules in FDARA, a company may find that it has to discuss its pediatric study plans with the FDA earlier than might have been necessary in the past. This may help to align the timing of PSP in the US with the EU PIP.

Further, the US FDA included an explicit statement that the “sponsor may be able to meet the requirements in sections 505A and 505B of the FD&C Act by including pediatric patients in adult clinical trials” (FDA, 2019). This may reduce the amount of information needed for FDA compared to the EMA even as it accelerates the timeline for the initiation of appropriate pediatric studies (FOCR, 2018). As the FDA and the industry gain more experience with the new requirements of FDARA, which impose deadlines in the summer of 2020, changes in the approaches to pediatric planning should become clearer. It is likely, for example, that additional types and timings of early interactions, such as face-to-face discussions different from those typically scheduled at 210 days for PSP review, will be needed to facilitate timely agreements.

5.2.3.3 Current Incentive Structures

Previous research has described the clear benefits of incentives associated with pediatric trials in the US (McKinsey, 2013). In particular, market exclusivity is often seen as a strong reward.

Accordingly, most participants seem to agree the current incentives offered by the US FDA or

EMA are adequate in advancing pediatric oncology drug development. A third of respondents suggested that even longer exclusivity periods would be important to encourage early pediatric development. However, the usefulness of such exclusivities may not be equally motivating across

139

different product lines. A review by McKinsey that analyzed 69 approved NDAs in 2001 showed that 11 of the 69 were granted pediatric exclusivity between 2001 and 2006 and 10 of the 69 between 2007 and 2011. However, the remaining majority (48/69) had not received pediatric exclusivity. The findings also showed that number of exclusivity extensions did not correlate closely to the total number of ongoing pediatric clinical trials, with an emerging trend of decreased exclusivity extensions after 2009. When comparing to sales from analyst estimates, the finding also suggested that the benefits were more important to encourage the conduct of dedicated pediatric trials for medications with blockbuster revenue (> $1 million) than for drugs with annual sales below $100 million (McKinsey, 2013). The value of this incentive has also been questioned by a study by Angelini and colleagues (Angelini, 2013), who showed that the introduction of financial rewards by the FDA and EMA have not translated into an increase in the number of pediatric clinical trials, or of drugs with pediatric indications.

What was the experience with pediatric incentives from the respondents in this research? Only a few respondents in this survey had received a 6-month pediatric exclusivity extension and 3 received the rare pediatric disease priority review voucher. Most either did not submit a PPSR, had not been issued with a Written Request in the US or did not complete the PIP on time in the

EU. In fact, as of the date of this research, only two oncology products have been rewarded with the Rare Pediatric Priority Review Voucher (https://priorityreviewvoucher.org/). Other recent research also finds a small increase of early (Phase 1 to Phase 2) rare pediatric-disease trials but no significant difference in the number of rare pediatric-disease treatments starting post Phase 2 clinical development, when numbers before or after the Rare Pediatric Priority Voucher incentive are compared (Gingery, 2019). Why the rare pediatric priority review voucher has not been more effective in motivating companies could be an important future study.

140

5.2.3.4 Global Collaboration and Knowledge Sharing

What else might encourage industry to launch earlier pediatric plans? The top two key drivers identified by respondents here were not additional incentives but rather 1) advocating a change in the degree of regulatory harmonization between the US FDA and EU PDCO, and 2) fostering a platform for better knowledge to decrease the currently high rate of study failures.

The improvement in the convergence between regulators is particularly important to industry in order to ensure efficient investigations. Although both the FDA and EU have frequent interactions, adoption of a singular pediatric plan has often been difficult. The result can be requirements to conduct duplicative or meaningless trials (Thomsen, 2019). The pathway of

Parallel Scientific Advice is considered by many to be convoluted and burdensome (Thomsen,

2019). Most respondents in this study have never taken the approach but rather had stepwise and separate PSP/PIP interactions. FDA noted that both agencies have been attempting to engage in regular communication to facilitate the implementation of international master protocols (Former,

2017). However, industry is asking for more clarification and transparency from the results of these agencies' communications/meetings because understanding the rationale of any divergent views may be important in reaching the best compromise for all stakeholders (FOCR, 2018).

Although many may believe that the development of standardized regulations and pediatric plan is unlikely to be possible across the two regions, new initiatives might be able to reduce bureaucratic and administrative burden on the industry. Global consistency would also be important to reduce regulatory uncertainty for sponsors.

The second potential driver, noted from the respondents in the survey, would be to gain a better understanding of pediatric cancers, and thereby reduce the high failure rate of pediatric studies.

As more is known about molecular targets, we might expect that already small pediatric cancer 141

populations will be subdivided further. These small subpopulations will be even harder to find so streamlining clinical study designs based on a better understanding of disease biology (i.e. identifying clinically meaningful pharmacodynamic (PD) endpoints) is essential to minimize study failure in this vulnerable population. The success in translating this approach from preclinical discoveries to clinical applications (i.e. utilizing specific clinical endpoints not necessary mimicking the adult population study design) can only be achieved by public-private partnerships of all appropriate stakeholders. In the preclinical space, discussions are underway to establish a noncompetitive infrastructure that could be used to develop preclinical data needed to prioritize decisions about new anti-cancer agents that could be relevant to the growth or progression of one or more childhood cancers and to disseminate these data to all appropriate stakeholders (FOCR, 2018). Knowledge sharing can be one of the key factors in decreasing the high rate of failure of pediatric oncology studies. Some fear that more clinical studies under

FDARA requirements may not translate into successful studies (Terry, 2019) if there continues to be a knowledge gap related to the underlying science. Thus, it is essential for companies to collaborate with research facilities and cooperative groups to understand disease biology and identify actionable targets in hard to treat childhood and adolescent cancers. Since health authorities review PSP/PIP/PPSR from multiple sponsors potentially developing the same class of therapy (i.e. with the same molecular target), it is also important for health authorities be engaged in open-forum discussions, providing non-confidential/non-product specific information such as statistics/experience of programs reviewed on a specific molecular target (i.e. via the

Transparency Initiatives at the FDA). Such knowledge sharing would help companies to select the strongest candidates based on preclinical and early clinical data and to prioritize clinical studies based on mechanisms of action underlying childhood cancers. One area of future research may be to examine how stakeholders can work together most effectively in sustainable public-

142

private partnerships from precompetitive, preclinical science to effective and efficient protocol design with agreements on disease-specific pediatric endpoints.

Conclusions and Future Directions

The results presented here paint a picture of a drug development process that is still in evolution.

Most companies that participated in this research are familiar with the requirements and have allocated resources. They have also implemented a structure to initiate pediatric development and, in some cases, are pursuing clinical trials. However, their responses suggest several challenges with implementation. These are in some degree responsible for the persistent lag of pediatric drug approvals and the high failure rate in pediatric oncology studies. Additional pediatric requirements will not necessarily produce greater efficiencies in pediatric drug development. As shown in the statistics (Chapter 2) and survey results (Chapter 4) presented here, few companies have been successful in developing safe and effective cancer therapies in children, and many are struggling to complete the studies that have been required by the regulations. The results observed here are consistent with a recent survey conducted by the Tufts Center for the

Study of Drug Development (Yen, 2019) on industry’s perspective of progress in the area of pediatric drug development in general. They align also with the industry comments collected by

Yen et al that evolution in the area of pediatric rare disease more generally was “slow but moving in the right direction”. Moving forward, an ecosystem to increase the clarity and consistency between global health authorities could assist in reducing regulatory uncertainty for sponsors.

Also, important may be better sharing of certain types of evidence- from preclinical and translational discoveries to pediatric disease-specific clinical protocol/endpoints-, between industry, governmental agencies, and academia. A concerted public-private effort will be essential to improve timely access to innovative and effective therapies for children with cancer.

143

REFERENCES

ACC. (2016). Childhood cancer research landscape report. Retrieved from Alliance for Childhood Cancer and the American Cancer Society website: https://www.cancer.org/research/currently-funded-cancer-research/childhood- cancer-research-highlights/childhood-cancer-research-landscape-report.html

ACCELERATE. (2018). 3rd paediatric strategy forum: Checkpoint inhibitors in combination. Accelerate Platform, London, UK.

Adamson, P.C., Houghton, P.J., Perilongo, G., & Pritchard-Jones, K. (2014). Drug discovery in paediatric oncology: Roadblocks to progress. Nat Rev Clin Oncol, 11(12), 732-739. doi:10.1038/nrclinonc.2014.149

Allen, C.E., Laetsch, T., Mody, R., Irwin, M.S., Lim, M.S., Adamson, P.C., Janeway, K. (2017). Target and agent prioritization for the children's oncology group. National Cancer Institute Pediatric MATCH Trial. J Natl Cancer Inst, 109(5). doi:10.1093/jnci/djw274

Angelini, P., Pritchard-Jones, K., Hargrave, D.R. (2013). Challenges in incentivizing the pharmaceutical industry to supporting pediatric oncology clinical trials. Clin. Invest., 3(2), 101-103.

Arshagouni, P. (2002). Federal court invalidates FDA pediatric rule, health law & policy institute. Retrieved from Health, Law & Policy Institute website: https://www.law.uh.edu/healthlaw/perspectives/Children/021223Federal.html

ASCO. (2016, December 10). Approval of dinutuximab for high-risk neuroblastoma: Lessons learned in expediting the development of pediatric cancer drugs. Retrieved from The ASCO Post website: http://www.ascopost.com/issues/december-10-2016/approval-of-dinutuximab-for- high-risk-neuroblastoma-lessons-learned-in-expediting-the-development-of- pediatric-cancer-drugs/

Association of American Physicians and Surgeons (2002). Pediatric rule (Letter to Senator Gregg). Retrieved from AAPS website: from http://www.aapsonline.org/legis/pedrule.htm

Baruch, Y. (1999). Response rate in academic studies-A comparative analysis. Sage 52(4). https://doi.org/10.1177/001872679905200401.

Beaver, J.A., Ison, G., & Pazdur, R. (2017). Reevaluating eligibility criteria — Balancing patient protection and participation in oncology trials. http://dx.doi.org/10.1056/NEJMp1615879 144

Bertram, F.M., Blasé K.A., & Fixsen D.L. (2014). Improving Programs and Outcomes: Implementation Frameworks and Organization Change. Research on Social Work Practice 25(4) 477-487. doi: 10.1177/1049731514537687

Bourgeois, F.T., & Kesselheim, A.S. (2019, August 29). Promoting Pediatric Drug Research and Labeling — Outcomes of Legislation. Retrieved from The New England Journal of Medicine website: https://www.nejm.org/doi/full/10.1056/NEJMhle1901265

Certara. (2016, March 17). Pediatric Drug Development. Retrieved from Certara website: https://www.certara.com/solutions/pediatrics/

Church, T. (2017). Continuity management in biobank operations: a survey of biobank professionals: University of Southern California Dissertations and Theses (16). (Doctor of Regulatory Science). University of Southern California, United States of America. Retrieved from http://digitallibrary.usc.edu/cdm/ref/collection/p15799coll40/id/444409

Cipriano, M. (2016). FDA encourages pediatric master protocols with Bayesian approach. Retrieved from The Pink Sheet website: https://pink.pharmaintelligence.informa.com/PS119209/FDA-Encourages- Pediatric-Master-Protocols-With-Bayesian-Approach

Davis, S.M., & Lawrence, P.R. (1978). Problems of matrix organizations. Retrieved from Harvard Business Review website: https://hbr.org/1978/05/problems-of-matrix- organizations

Devroe, R. (2016). How to enhance the external validity of survey experiments? A discussion on the basis of a research design on political gender stereotypes in Flanders. Paper presented at the ECPR General Conference – Prague Panel 391: Survey Experiments II: From Design to Implementation. https://biblio.ugent.be/publication/8507141/file/8507144.pdf

Downing, N.S., Aminawung, J.A., Shah, N.D., Braunstein, J.B., Krumholz, H.M., & Ross, J.S. (2012). Regulatory review of novel therapeutics — Comparison of three regulatory agencies. http://dx.doi.org/10.1056/NEJMsa1200223, 366, 2284-2293.

Egger, G.F., Wharton, G.T., Malli, S., Temeck, J., Murphy, M.D., & Tomasi, P. (2016). A comparative review of waivers granted in pediatric drug development by FDA and EMA from 2007-2013. Ther Innov Regul Sci, 50(5), 639-647. doi:10.1177/2168479016646809

145

EMA. (2012). EMA/272931/2011 policy on the determination of the condition(s) for a paediatric investigation plan/waiver (scope of the PIP/waiver). Retrieved from European Medicines Agency website: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/09/WC500 133065.pdf

EMA. (2013a). Standard acute myeloid leukaemia paediatric investigational plan. Retrieved from Euopean Medicines Agency website: http://www.myendnoteweb.com/EndNoteWeb.html?func=downloadInstallers&ca t=download&

EMA. (2013b). Key concepts of the paediatric regulation and latest developments. European Medicines Agency. Presented by Paolo Tomasi, Head of Paediatric Medicine, EMA. Retrieved from EMA website: https://www.ema.europa.eu/en/documents/presentation/presentation-key- concepts-paediatric-regulation-latest-developments-paolo-tomasi_en.pdf

EMA. (2017a). Class waivers. European Medicines Agency - Paediatric Investigation Plans. Retrieved from European Medicines Agency website: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_ content_000036.jsp&mid=WC0b01ac0580925cca

EMA. (2017b). Paediatric Gaucher disease A strategic collaborative approach from EMA and FDA. Retrieved from European Medicines Agency website: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/20 17/06/WC500230342.pdf

FDA. (1998). 21 CFR Parts 201, 312, 314 and 601 regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients; Final rule. Retrieved from US Food and Drug Administration- Federal Register website: https://www.fda.gov/ohrms/dockets/ac/03/briefing/3927B1_05_1998%20Pediatri c%20Rule.pdf

FDA. (2000). Guidance for industry: Pediatric oncology studies in response to a written request. Retrieved from US Food and Drug Administration - Federal Register website: https://www.federalregister.gov/documents/2000/06/21/00-15629/draft- guidance-for-industry-pediatric-oncology-studies-in-response-to-a-written- request-availability

FDA. (2005). Guidance for industry: How to comply with the Pediatric Research Equity Act. Retrieved from US Food and Drug Administration website: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Developme ntResources/UCM077855.pdf

146

FDA. (2010). Guidance for industry:M3(R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. U.S. Retrieved from US Food and Drug Administration website: https://www.fda.gov/downloads/drugs/guidances/ucm073246.pdf

FDA. (2014). Rare pediatric disease priority review vouchers, guidance for industry draft guidance. Retrieved from US Food and Drug Administration website: https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM423325. pdf

FDA. (2015). Dinutuximab summary review (Application 125516Orig1s000). Center for Drug Evaluation and Research. Retrieved from US Food and Drug Administration website: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125516Orig1s000Sum R.pdf

FDA. (2016a). Pediatric oncology subcommittee: Atezolizumab 2016 pediatric: Briefing package. Submitted by GENENTECH, INC. Retrieved from US Food and Drug Administration website: https://www.fda.gov/media/99199/download

FDA. (2016b). Pediatric study plans: Content of and process for submitting initial pediatric study plans and amended initial pediatric study plans: Guidance for industry (draft guidance). Retrieved from US Food and Drug Administration website: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio n/Guidances/UCM360507.pdf

FDA. (2016c). Best pharmaceuticals for Children Act and Pediatric Research Equity Act: July 2016 status report to Congress. Retrieved from US Food and Drug Administration website: https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherape uticsResearch/UCM509815.pdf

FDA. (2017a). Office of New Drugs Unit List: Pediatric Regulations. Retrieved from US Food and Drug Administration website: https://www.accessdata.fda.gov/scripts/cderworld/index.cfm?action=newdrugs:m ain&unit=4&lesson=1&topic=5

FDA. (2017b). FDA Reauthorization Act of 2017 (FDARA) | FDA. Retrieved from US Food and Drug Administration website: https://www.fda.gov/regulatoryinformation/selected-amendments-fdc-act/fda-reauthorization-act-2017-fdara

147

FDA. (2018, April 17). Approved drugs - hematology/oncology (cancer) approvals & safety notifications. Retrieved from US Food and Drug Administration website: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.ht m

FDA. (2019). Electronic common technical document (eCTD). FDA. Retrieved from US Food and Drug Administration website: https://www.fda.gov/drugs/electronic- regulatory-submission-and-review/electronic-common-technical-document-ectd

Fincham, J.E. (2008). Response rates and responsiveness for surveys, standards, and the journal. Am J Pharm Educ, 72(2), 43.

Fixsen, D.L., Naoom, S.F., Blasé, K.A., Friedman, R.M., Wallace, F. (2005). Implementation research: A synthesis of the literature. Retrieved from the University of South Florida website: https://nirn.fpg.unc.edu/sites/nirn.fpg.unc.edu/files/resources/NIRN- MonographFull-01-2005.pdf

Former, M. (2017). Accelerating pediatric drug development: Master protocols may be a way to go. Retrieved from The ASCO Post website: http://www.ascopost.com/issues/april-25-2017/accelerating-pediatric-drug- development-master-protocols-may-be-a-way-to-go/

Friends of Cancer Research (2018, Feb 20). Molecularly targeted therapies in pediatric cancer. Retrieved from Friends of Cancer Research website: https://www.focr.org/events/molecularly-targeted-therapies-pediatric-cancer

Gaffney, A., Mezher, M. & Brennan, Z.B. (2018). Regulatory explainer: Everything you need to know about FDA’S priority review vouchers. Retrieved 01Mar2018 from RAPS Focus website: https://www.raps.org/regulatory-focus/news- articles/2017/12/regulatory-explainer-everything-you-need-to-know-about-fdas- priority-review-vouchers

Galesic, M., & Bosnjak, M. (2009). Effects of questionnaire length on participation and indicators of response quality in a web survey. Public Opinion Quarterly, 73(2), 349-360. doi:10.1093/poq/nfp031

GAO. (2016). Rare diseases: Too early to gauge effectiveness of FDA's pediatric voucher program. U.S. Government Accountability Office (GAO-16-319).

Gingery, D. (2019). Rare pediatric disease priority review voucher not generating new drug trials. Retrieved from The Pink Sheet website: https://pink.pharmaintelligence.informa.com/PS124744/Rare-Pediatric-Disease- Priority-Review-Voucher-Not-Generating-New-Drug-Trials

148

Gore, L., Ivy, S.P., Balis, F. M., Rubin, E., Thornton, K., Donoghue, M., & Reaman, G. (2017). Modernizing clinical trial eligibility: Recommendations of the american society of clinical oncology. Friends of Cancer Research Minimum Age Working Group. J Clin Oncol, 35(33), 3781-3787. doi:10.1200/jco.2017.74.4144

Gottlieb, S. (2017). FDA is advancing the goals of the Orphan Drug Act. Retrieved from FDA Voice website: https://blogs.fda.gov/fdavoice/index.php/2017/09/fda-is- advancing-the-goals-of-the-orphan-drug-act/

Green, D. (2017). Pediatric trial design & endpoint considerations. Paper presented at the Pediatric Trial Design and Modeling: Moving into the Next Decade, US FDA White Oak.

Griffin, G. (2017). Sharing the results of clinical trials: industry views on disclosure of data from industry-sponsored clinical research: University of Southern California dissertations and theses (16). (Doctor of Regulatory Science). University of Southern California, United States of America. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll40/id/387 811/rec/1

Harrington, D., & Parmigiani, G. (2016). I-SPY 2 — A glimpse of the future of phase 2 drug development? | NEJM. New England Journal of Medicine, 375, 7-9.

HBM Partners. (2019). HBM new drug approval reports: Analysis of FDA new drug approvals in 2018 (and multi-year trends). Retrieved from HBM Partners website http://www.hbmpartners.com/media/docs/industry-reports/Analysis-of-FDA- Approvals-2018-and-Previous-Years.pdf

Hwang, T.J., Bourgeois, F.T., Franklin, J.M., & Kesselheim, A.S. (2019). Impact of the priority review voucher program on drug development for rare pediatric diseases. Retrieved from PubMed website: https://www.ncbi.nlm.nih.gov/pubmed/30715972

Hwang, T.J., Tomasi, P.A., & Bourgeois, F.T. (2018). Delays in completion and results reporting of clinical trials under the paediatric regulation in the European Union: A cohort study. PLoS Med (Vol. 15). doi: 10.1371/journal.pmed.1002520.

Jenks, S. (2017). Improving children’s access to cancer clinical trials. Journal of the National Cancer Institute, 109(2). doi:10.1093/jnci/djx021

Kids Vs. Cancer (2017). Kids' eligibility for trials. Retrieved from Kids Vs Cancer website: https://www.kidsvcancer.org/including-kids-in-trials/

Langenau, D.M., Sweet-Cordero, A., Wechsler-Reya, R.J., & Dyer, M.A. (2015). Preclinical models provide scientific justification and translational relevance for 149

moving novel therapeutics into clinical trials for pediatric cancer. Cancer Res.15(75(24): 5176-5186. doi:10.1158/0008-5472. CAN-15-1308

McKinsey Center for Government (2013). Do incentives drive pediatric research? Retrieved from McKinsey Center for Government website: https://www.mckinsey.com/~/media/McKinsey/dotcom/client_service/Public%20 Sector/Regulatory%20excellence/Do_incentives_drive_pediatric_research.ashx

McCune, S. (2017). FDA Awards funding to support pediatric clinical trials research. |Retrieved from FDA Voice website: https://blogs.fda.gov/fdavoice/index.php/2017/11/fda-awards-funding-to-support- pediatric-clinical-trials-research/

McNeely, R. (2019). eCTD submission management. Retrieved from Regulatory Focus website: https://www.raps.org/news-and-articles/news-articles/2019/8/ectd- submission-management

Milne, C. P. (2017). More efficient compliance with European Medicines Agency and Food and Drug Administration regulations for pediatric oncology drug development: Problems and solutions. Clin Ther, 39(2), 238-245. doi:10.1016/j.clinthera.2017.01.002

NIH. (2013, September). An analysis of the National Cancer Institute’s investment in pediatric cancer research. Retrieved from National Institute of Health website: https://www.cancer.gov/types/childhood-cancers/research/pediatric-analysis.pdf

NIH. (2015). NCI initiative to speed development of childhood cancer therapies. Retrieved from National Institute of Health website: https://www.cancer.gov/news-events/cancer-currents-blog/2015/PPTC-awards

NIH. (2017a). Best Pharmaceuticals for Children Act (BPCA). Retrieved from National Institute of Health website: https://www.ncbi.nlm.nih.gov/pubmed/

NIH. (2017b). NCI-COG Pediatric MATCH - National Cancer Institute. Retrieved from National Institute of Health website: https://www.cancer.gov/about- cancer/treatment/clinical-trials/nci-supported/pediatric-match

The National Implementation Research Network's Active Implementation Hub (NIRN) (2018). Topic 3: Practice - Policy Feedback Loops | AI HUB. Retrieved from Frank Porter Graham Child Development Institute website: http://implementation.fpg.unc.edu/module-5/topic-3-practice-policy-feedback- loops

150

Norris, R.E., & Adamson, P.C. (2012). Challenges and opportunities in childhood cancer drug development. Nat Rev Cancer, 12(11), 776-782. England. doi:10.1038/nrc3370

Pearson, A.D., Herold, R., Rousseau, R., Copland, C., Bradley-Garelik, B., Binner, D., & Vassal, G. (2016). Implementation of mechanism of action biology-driven early drug development for children with cancer. Eur J Cancer, 62, 124-131. doi:10.1016/j.ejca.2016.04.001

Pire-Smerkanich, N. (2016). Benefits-risk frameworks: implementation by industry. University of Southern California Dissertations and Theses (16). (Doctor of Regulatory Science). Retrieved from University of Southern California digital library: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll40/id/207 725/rec/1

Premier Research. (2012). New survey reveals companies’ concerns about too few pediatric patients for clinical trials premier research’s survey also reveals confusion about PREA and its EU counterpart. Retrieved from Premier Research website: https://premier-research.com/new-survey-reveals-companies-concerns- about-too-few-pediatric-patients-for-clinical-trials-premier-researchs-survey-also- reveals-confusion-about-prea-and-its-eu-counterpart/

Raeman, G. (2015). Challenges to pediatric cancer drug development. Paper presented at the Stakeholder Input - BPCA & PREA Meeting, Silver Spring, Maryland.

Ratain, M. (2016). The seamless approach to drug development in oncology. Clinical Advances in Hematology & Oncology, 14(12), 958-959.

Rose K. & Senn S. (2014). Drug development: EU paediatric legislation, the European Medicines Agency and its Paediatric Committee--adolescents' melanoma as a paradigm. (Abstract) Europe PMC. Pharmaceutical Statistics, 13(4), 211-213. doi:https://doi.org/10.1002/pst.1623

Saletta, F., Wadham, C., Ziegler, D., Marshall, G.M., Haber, M., McCowage, G., Norris, M.D., & Byrne, J.A. (2014). Molecular profiling of childhood cancer: Biomarkers and novel therapies. |Elsevier Enhanced Reader. BBA Clinical, 1, 59-77. doi:10.1016/j.bbacli.2014.06.003

SIOPE Europe. (2017). Clinical trials in paediatric oncology. Retrieved from SIOPE - the European Society for Paediatric Oncology website: https://www.siope.eu/european-research-and-standards/clinical-trials-in- paediatric-oncology/

151

Sharma, V. (2018). EFPIA picks holes in EMA's pediatric extrapolation proposals. Retrieved from The Pink Sheet website: https://pink.pharmaintelligence.informa.com/PS122549/EFPIA-Picks-Holes-In- EMAs-Pediatric-Extrapolation-Proposals

Storm, N. (2018). Regulatory dissonance in the global development of drug therapies: a case study of drug development in postmenopausal osteoporosis. University of Southern California Dissertations and Theses. (Doctor of Regulatory Science). Retrieved from University of Southern California digital library: http://digitallibrary.usc.edu/cdm/ref/collection/p15799coll3/id/345661

Sutter, S. (2019). Oncology sponsors getting a jump on pediatric study requirements, US FDA says. Retrieved from The Pink Sheet website: https://pink.pharmaintelligence.informa.com/PS124960/Oncology-Sponsors- Getting-A-Jump-On-Pediatric-Study-Requirements-US-FDA-Says

Terry, M. (2019, January 17). “RACE for Children Act” may result in more drugs appropriate for children. Retrieved from Biospace website: https://www.biospace.com/article/-race-for-children-act-may-result-in-more- drugs-appropriate-for-children/

Thomsen, M.D.T. (2019). Global pediatric drug development.| Elsevier Enhanced Reader. Current Therapeutic Research, 90, 135-142. doi:10.1016/j.curtheres.2019.02.001

Toretsky, J. (2009). Pediatric Oncology: Illustrations of biology translations to therapy. Paper presented at the Cancer: Pathophysiology, Current Therapies, Clinical Trials and Drug Development. Washington, DC: Pharmaceutical Education & Research Institute.

Turner, M.A., Catapano, M., Hirschfeld, C., Giauinto, C. & GRiP (Global Research in Paediatrics) (2014). Paediatric drug development: The evolving regulations. Advanced Drug Delivery Reviews, 73(30 June 2014), 2-13. doi:https://doi.org/10.1016/j.addr.2014.02.003

Vassal, G. (2009). Will children with cancer benefit from the new European Paediatric Medicines Regulation? Eur J Cancer, 45(9), 1535-1546. doi:10.1016/j.ejca.2009.04.008

Vassal, G., Rousseau, R., Blanc, P., Moreno, L., Bode, G., Schwoch, S., & Zwierzina, H. (2015). Creating a unique, multi-stakeholder Paediatric Oncology Platform to improve drug development for children and adolescents with cancer. Eur J Cancer, 51(2), 218-224. doi:10.1016/j.ejca.2014.10.029

152

Wagner, L.M., & Adams, V.R. (2017). Targeting the PD-1 pathway in pediatric solid tumors and brain tumors. Onco Targets Ther, 10, 2097-2106. doi:10.2147/ott.s124008

Woodcock, J. (2007). Establishment of the Pediatric Review Committee (PeRC). Memorandum to Andrew C. von Eschenbach, October 23, 2007. Retrieved from http://www.fda.gov/downloads/drugs/developmentapprovalprocess/developmentr esources/ucm049871.pdf.

Yen, E., Davis, J.M. & Milne, C.P. (2019). Impact of regulatory incentive programs on the future of pediatric drug development. Therapeutic Innovation & Regulatory Science, 53(5), 609-614. doi:DOI: 10.1177/2168479019837522

153

APPENDIX A.

PHASE 1 AND PHASE 2 STUDY PROTOCOL REQUIREMENT OUTLINE

(from FDA Guidance for Industry: Pediatric Oncology Studies in Response to a Written Request)

Phase 1 Study Protocol Study Outcome Next Step Requirement

Includes:

• Rationale for the starting If found unacceptable If FDA considers WR dose (from adult or toxicity and FDA met and no further nonclinical) agrees with findings pediatric studies are • Plan to gather after review of the required. pharmacokinetic data study report in the Include information in • Definition of maximal application. labeling. tolerated dose (MTD) FDA may grant PE. • Stopping rules for toxicity • Statistical plan based on escalation scheme, cohort size and stopping rules If found acceptable level of safety Proceed to Phase 2 Study(-ies) Patient population: 18 to 25

Phase 2 Study Protocol Next Step FDA Decision Requirement Consider for a range of potential indications If studies met WR

• Rational for the proposed dose Submit reports to application for review • Design based on patients benefit (i.e. add-on design Grant PE by adding the new drug to a standard regimen and Labeling changes upon compare to the standard approval of application regimen alone) • Statistical plan based on cohort size, cohort phase and stopping rules

154

APPENDIX B.

LIST OF FDA PEDIATRIC WRITTEN REQUEST ISSUED (ADULT CANCER TREATMENT)

As of 07 April 2017, FDA has issued a total of 429 approved active moieties with Written Request for Pediatric Studies under Section 505A of the Federal Food, Drug, and Cosmetic Act.

The following list included the WR issued for active moiety approved for cancer treatment in the adult populations:

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor

Atezolizuab Programmed death-ligand Locally advanced or metastatic urothelial carcinoma (2016) Genentech, Inc. 1 (PD-L1) blocking antibody

Bendamustine Alkylating drug Chronic lymphocytic leukemia (CLL) and Indolent B-cell non-Hodgkin Cephalon, Inc. lymphoma (NHL) (2008)

Bortezomib Proteasome inhibitor Multiple myeloma. Mantle cell lymphoma. (2003) Millenium Pharm

Bosutinib Kinase inhibitor Ph+ chronic myelogenous leukemia (CML) (2012) Wyeth Pharmaceuticals, Inc.

Cabazitaxel Microtubule inhibitor Hormone-refractory metastatic prostate cancer (2010) Sanofi-Aventis

155

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor

Capecitabine Nucleoside metabolic Adjuvant colon cancer. Metastatic colorectal cancer. Metastatic breast HLR inhibitor with cancer. (1998) antineoplastic activity

Carboplatin Platinum-based Ovarian carcinoma. (1989) Bristol-Myers Squibb

chemotherapy

Carfilzomib Proteasome inhibitor Multiple myeloma (2012) Onyx Therapeutics, Inc.

Clofarabine Purine nucleoside First approved indication: in pediatric acute lymphoblastic leukemia ILEX Products, Inc. metabolic inhibitor (2004)

Crizotinib Kinase inhibitor Non-small cell lung cancer that is anaplastic lymphoma kinase (ALK)- Pfizer, Inc. positive (2011)

Cytarabine Cell cycle phase-specific Leukemias. Lymphomatous meningitis (1998) SkyePharma Inc. antineoplastic agent, affecting cells only during the S-phase of cell division

156

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor

Dabrafenib Kinase inhibitor Melaoma with BRAF V600E mutation. (2013) Novartis Pharmaceuticals Corporation

Darbepoetin Erythropoiesis-stimulating Anemia due to chemotherapy (2001) Amgen, Inc. agent (ESA)

Dasatinib Kinase inhibitor Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia BMS (CML). Ph+ acute lymphoblastic leukemia (2006)

Decitabine Nucleoside metabolic Myelodysplastic syndromes (MDS) (2006) Eisai medical Research, Inc. inhibitor agent

Denosumab RANK ligand (RANKL) Increase bone mass of patients at high risk for fracture from cancer Amgen, Inc. inhibitor treatment (2010).

Docetaxel Microtubule inhibitor Breast cancer. Non-small cell lung cancer. Hormone refractory prostate. Sanofi-Aventis, U.S., Inc. Gastric adenocarcinoma. Squamous cell carcinoma of the head and neck cancer. (1996)

Eribulin Microtubule inhibitor Breast cancer (2010) Eisai, Inc.

157

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor

Erlotinib Kinase inhibitor Non-small cell lung cancer (NSCLC) whose tumors have epidermal OSI Pharm growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. Pancreatic cancer. (2004)

Everolimus Kinase inhibitor Hormone receptor-positive, HER2-negative breast cancer (advanced HR+ Novartis BC). Progressive neuroendocrine tumors of pancreatic origin (PNET). Renal cell carcinoma (RCC). Renal angiomyolipoma and tuberous sclerosis complex (TSC). Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TSC). (2009)

Fludarabine Antimetabolite, B-cell chronic lymphocytic leukemia (CLL). (1991) Berlex chemotherapy

Gefitinib Tyrosine kinase inhibitor Non-small cell lung cancer whose tumors have epidermal growth factor AstraZeneca receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations(2015)

Gemcitabine Nucleoside metabolic Advanced ovarian cancer. Breast cancer. Non-small cell lung cancer. Lilly inhibitor Pancreatic cancer. (1996)

158

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor

Imatinib Kinase inhibitor Ph+ CML. Ph+ ALL. myelodysplastic/myeloproliferative diseases Novartis (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements. Aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation. Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1- PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion). Unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). (2001)

Ipilimumab Human cytotoxic T- Melanoma. (2011) Bristol-Myers Squibb lymphocyte antigen 4 Company (CTLA-4)-blocking antibody

Irinotecan Topoisomerase inhibitor Metastatic carcinoma of the colon or rectum. (1996) Pharmacia & Upjohn

Ixabepilone Microtubule inhibitor Breast cancer. (2007) Bristol-Myers Squibb Company

159

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor

Lenalidomide Thalidomide analogue Multiple myeloma (MM). Transfusion-dependent anemia due to low- or Celgene Corporation intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality. Mantle cell lymphoma (MCL). (2005)

NAB-paclitaxel Microtubule inhibitor Breast cancer. Non-small cell lung cancer. Pancreas cancer. (2005) Celgene Corporation

Nivolumab Programmed death BRAF V600 wild-type melanoma. BRAV V600 mutation-positive Bristol-Myers-Squibb receptor-1 (PD-1) melanoma. Non-small cell lung cancer. Advanced renal cell carcinoma. Company blocking antibody Hodgkin lymphoma. Squamous cell carcinoma of head and neck. Urothelial carcinoma. (2014)

Oxaliplatin Platinum-based drug Advanced colorectal cancer (2002) Sanofi-Synthelabo, Inc.

Pemetrexed Folate analog metabolic Nonsquamous non-small cell lung cancer (2004) Eli Lilly & Co. inhibitor

Pomalidomide Thalidomide analogue Multiple myeloma (2013) Celgene Corporation

Sunitinib Kinase inhibitor Gastrointestinal stromal tumor (GIST). Advanced renal cell carcinoma C.P. Pharm c/o Pfizer, Inc. (RCC). pancreatic neuroendocrine tumors (pNET). (2006)

Temozolomide Alkylating drug Glioblastoma multiforme (GBM). (1999) Schering

Temsirolimus Kinase inhibitor Renal cell carcinoma. (2007) Wyeth-Ayerst

160

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor

Topotecan Topoisomerase inhibitor Small cell lung cancer (1996) SmithKline Beecham

Trametinib Kinase inhibitor Melanoma with BRAF V600E or V600K mutations. (2013) Novartis Pharmaceuticals Corporation

Vinorelbine Vinca alkaloid Non-small cell lung cancer (NSCLC). (1994) Glaxo Wellcome

List: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/ucm077570.htm, assessed on 17 April 2017

161

APPENDIX C.

TIMING OF ADULT INITIAL APPROVAL TO PEDIATRIC EXCLUSIVITY GRANTED (ONCOLOGY INDICATIONS)

Of the total 211-pediatric exclusivity granted across therapeutic areas (as of 31 March 2017), 18, 8.53% had a pediatric cancer indication.

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE Vinorelbine PPSR 8/15/02 Leukemia/lymphoma 12/23/1994 First line treatment of 7 years 8 mths = 92 submitted ambulatory patients with mths on unresectable, advanced 11/15/2000 nonsmall cell lung cancer WR issued on 1/9/2001 Temozolomide No PPSR 11/20/02 Refractory/relapse 08/11/1999 Treatment of adult patients with 3 years 3 mths = 39 noted. malignancies 142 refractory anaplastic mths WR issued astrocytoma, i.e., patients at first on1/9/2001 relapse who have experienced disease 143 progression on a drug regimen containing a nitrosourea and procarbazine

162

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE Topotecan PPSR note 11/20/02 Refractory/relapsed 05/28/1996 Treatment of metastatic 6 years 6 mths = 78 noted. WR malignancies carcinoma of the ovary after mths issued disease progression on or after on5/16/2000 initial or subsequent chemotherapy mall cell lung cancer platinum- sensitive disease in patients who progressed after first-line chemotherapy combination therapy with cisplatin for Stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment Fludarabine PPSR 4/3/03 Refractory/relapse 04/18/1991 Treatment of patients with B- 12 years = 144 mths submitted acute leukemia cell chronic lymphocytic on leukemia (CLL) who have not 07/09/2001 responded to or whose disease has progressed during treatment

163

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE WR issued with at least one standard on alkylating-agent containing 11/09/2001 regimen Irinotecan PPSR 3/10/04 Refractory tumors 06/14/1996 First-line therapy in 7 years 9 mths = 93 submitted combination with 5-fluorouracil mths on and leucovorin for patients with 10/30/2000. metastatic carcinoma of the WR issued colon or rectum. (1) • Patients on1/22/2001 with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil- based therapy. Carboplatin WR issued 4/30/04 Refractory tumors 03/03/1989 Initial treatment of advanced 15 years and 1 mths = on ovarian carcinoma in 181 mths 4/11/2001 established combination with other approved chemotherapeutic agents.

164

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE Clofarabine No PPSR 7/14/04 Refractory 12/28/2004 Treatment of pediatric patients 1 Best example! First recorded. Leukemias First approval in to 21 years old with relapsed or approval was in WR issued pediatric, not adult! refractory acute lymphoblastic pediatric! on 3/7/2003 leukemia after at least two prior regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted Gemcitabine PPSR 1/27/05 Refractory or 05/15/1996 In ombination with cisplatin for 8 years and 8 mths = submitted relapsed leukemia the first-line treatment of 104 mths on and non-Hodgkin’s patients with inoperable, locally 09/20/2000 lymphoma advanced (Stage IIIA or IIIB) or WR issued metastatic (Stage IV) non-small on1/9/2001 cell lung cancer. s first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV)

165

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE adenocarcinoma of the pancreas. Gemzar is indicated for patients previously treated with 5-FU.

Imatinib Mesylate PPSR: 6/9/06 Philadelphia positive 05/10/2001 Treatment of patients with 5 years 1 mth = 61 01/21/2000 (Ph+) leukemia chronic myeloid leukemia mths WR issued (CML) in blast 145 crisis, on accelerated phase, or in chronic 9/20/2000 phase after failure of interferon- alpha therapy Oxaliplatin PPSR 9/27/06 Refractory tumors 08/09/2002 In combination with infusional 4 years 1 mth = 49 submitted: 5-FU/LV, is indicated for the mths 07/29/2004; treatment of 178 patients with WR issued metastatic carcinoma of the on colon or rectum whose disease 12/9/2004 has recurred or 179 progressed during or within 6 months of completion of first line therapy

166

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE with the combination of 180 bolus 5-FU/LV and irinotecan Docetaxel PPSR 3/17/10 Solid Tumors 05/14/1996 Treatment of patients with 13 years 10 months submitted locally advanced or metastatic = 166 mths on breast cancer after failure of 01/31/2007 prior chemotherapy WR issued treatment of patients with on locally advanced or metastatic 06/11/2007 non-small cell lung cancer after failure of prior platinum-based chemotherapy Pemetrexed PPRS 12/3/10 Refractory and 02/04/2004 In combination with cisplatin is 6 years 10 mths submitted recurrent solid indicated for the treatment of = 82 mths on 05/24/01. tumors, including patients with malignant pleural WR issued osteosarcoma, Ewing mesothelioma whose disease is on 10/5/01 sarcoma/peripheral either unresectable or who are PNET, otherwise not candidates for rhabdomyosarcoma, curative surgery and neuroblastoma

167

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE Ixabepilone PPSR 4/5/11 Solid Tumors 10/16/2007 In combination with 3 years 6 mths = 42 submitted capecitabine is indicated for the mths on treatment of metastatic or 11/20/2006 locally advanced breast cancer WR issued in patients after failure of an on anthracycline and a taxane. 6/22/2007 monotherapy is indicated for the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline, a taxane, and capecitabine Temsirolimus No PPSR 2/28/12 Treatment of 05/30/2007 Treatment of advanced renal 4 years 9 mths = 57 noted relapsed/refractory cell carcinoma mths WR issued solid tumors on 1/12/2001 Bendamustine PPSR 5/24/12 Relapsed or 03/20/2008 Treatment of patients with 4 yrs and 2 months = submitted refractory acute chronic lymphocytic leukemia 50 mths leukemia (CLL)

168

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE on 07/27/2009 WR issued on 01/19/2010 Capecitabine PPSR 8/28/13 Non-disseminated 04/30/1998 Treatment of patients with 5 years 4 mths = 64 submitted intrinsic diffuse metastatic breast cancer mths on brain stem gliomas resistant to both paclitaxel and 11/01/2004 an anthracycline-containing WR issued chemotherapy regimen or on resistant to paclitaxel and for 3/16/2005 whom further anthracycline therapy is not indicated Erlotinib PPSR 3/18/15 Cancer (recurrent 11/18/2004 Treatment of patients with 10 years 4mths = 124 submitted ependymoma) locally advanced or metastatic mths on non-small cell lung cancer after 05/01/2009 failure of at least one prior chemotherapy regimen

169

Drug Written Date of PE Indications Granted First Adult Approval Indication in Adult From First Adult Request Granted with PE Approval to PE WR issued on 05/07/2010 Bortezomib PPSR 8/14/15 Acute lymphocytic 05/13/2003 Treatment of multiple 11 years 3 mths = 135 submitted leukemia (ALL) myeloma patients who have mths on received at least two prior 10/21/2009 therapies and have WR issued demonstrated on disease progression on the last 04/27/2010 therapy PPSR = Proposed Pediatric Study Request. WR = Written Request. mths = months. Source: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM514985.pdf, accessed on 05 April 2017

170

171

APPENDIX D.

FINAL VERSION OF PEDAITRIC ONCOLOGY DRUG DEVELOPMENT INDUSTRY

SURVEY

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

APPENDIX E.

CROSS-TABULATIONS

Table E.1: Cross Tabulation of Company Size and Dedicated Resources on Pediatric Programs

In your company/organization, how What statement best describes the size of is the pediatric team organized to your overall company/organization support oncology drug/biologic 1-500 501-2,500 2,501- 10,000+ employees employees 10,000 employees employees Clinical Internal research dedicated 0 1 4 6 Development for pediatric programs only Internal resource but also 6 2 2 4 working on non-pediatric programs External consultations 1 0 0 0

Do not know 1 1 0 0 Regulatory Internal research dedicated 0 0 0 6 Affairs for pediatric programs only Internal resource but also 5 3 5 3 working on non-pediatric programs External consultations 2 0 1 0 Do not know 0 1 0 0 Clinical Internal research dedicated 0 0 1 2 Pharmacology for pediatric programs only Internal resource but also 5 3 3 6 working on non-pediatric programs External consultations 1 0 2 0 Do not know 2 1 0 1

187

In your company/organization, how What statement best describes the size of is the pediatric team organized to your overall company/organization support oncology drug/biologic 1-500 501-2,500 2,501- 10,000+ employees employees 10,000 employees employees Translational Internal research dedicated 0 0 0 2 Medicine for pediatric programs only Internal resource but also 6 3 6 7 working on non-pediatric programs External consultations 1 0 0 0 Do not know 0 1 0 0

Table E.2: Cross Tabulation of Company Size and Internal Challenges on Pediatric Programs What would best describe the What statement best describes the size of challenges your team has your overall company/organization encountered with the company/organization 1-500 501-2,500 2,501- 10,000+ employees employees 10,000 employees employees Competing Strong agree 4 3 2 3 for resources with other Somewhat agree 1 0 3 3 programs Neither agree nor disagree 1 1 1 3

Somewhat disagree 0 0 0 1 Strongly disagree 0 0 0 0 Cannot answer 1 0 0 0 Limited Strong agree 1 2 2 0 internal expertise in Somewhat agree 1 2 1 5 pediatric field Neither agree nor disagree 3 0 2 2

Somewhat disagree 0 0 1 0 Strongly disagree 0 0 0 3 Cannot answer 2 0 0 0 Limited Strong agree 2 0 2 0 support from Somewhat agree 1 2 2 0 188

What would best describe the What statement best describes the size of challenges your team has your overall company/organization encountered with the company/organization 1-500 501-2,500 2,501- 10,000+ employees employees 10,000 employees employees management Neither agree nor disagree 1 0 1 3 on pediatric programs Somewhat disagree 2 1 1 4 Strongly disagree 0 0 0 3 Cannot answer 2 0 0 0 Limited Strong agree 2 1 1 0 understanding of Somewhat agree 2 3 3 3 requirements Neither agree nor disagree 1 0 1 1 within the organization Somewhat disagree 1 0 0 2 Strongly disagree 0 0 1 4 Cannot answer 1 0 0 0

189

Table E.3: Cross Tabulation of Company Size and Views on Current Pediatric Incentives in the US Does your organization view the What statement best describes the size of current regulation as adequate in your overall company/organization providing incentives to stimulate pediatric oncology drug 1-500 501-2,500 2,501- 10,000+ employees employees 10,000 employees development? employees BPCA: 6 Extremely adequate 0 0 1 2 months Pediatric Somewhat adequate 4 3 5 5 Exclusivity Neither adequate nor 0 0 0 1 inadequate Somewhat inadequate 1 0 0 2 Extremely inadequate 1 0 0 0 BPCA: 6 Extremely adequate 0 1 2 2 months Pediatric Somewhat adequate 4 2 4 4 Exclusivity Neither adequate nor 1 0 0 2 for Orphan inadequate Drug with Small Market Somewhat inadequate 1 0 0 0 Potential Extremely inadequate 0 0 0 1 Rare Extremely adequate 2 1 3 2 Pediatric Disease Somewhat adequate 1 2 2 6 Priority Neither adequate nor 3 0 1 2 Review inadequate Voucher Somewhat inadequate 0 0 0 0 Extremely inadequate 0 0 0 0

190