OCTOBER 2017 12 Getting on Board with ICH GCP E6(R2) 26 New European Medical Device Regulation 32 Clinical Trial Operations: Who is Watching?
The Authority in Ethical, Responsible Clinical Research
Regulations and Compliance: The Climb is Worth It
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rhoworld.com/careers CONTENTS October 2017 • Volume 31, Issue 5 • ISSN 2334-1882
6 Feature PEER REVIEWED GUEST EDITOR’S MESSAGE Regulations and Compliance: The Climb is Worth It Glenda Guest, CCRA, RQAP-GCP, TIACR Clinical Researcher is your platform. Interested in writing Columns a peer-reviewed article 8 EXECUTIVE DIRECTOR’S or guest column? You’ll MESSAGE find our submissions 10 CHAIR’S MESSAGE 12 26 38 Getting on Board with The New European A Mixed Method guidelines at 18 CAREERS— PASSING IT ON ICH GCP E6(R2): Medical Device Approach to Assessing acrpnet.org/submit Impact on Study Regulation 2017/745: Good Clinical Practice 24 ICH IN FOCUS Quality and Main Changes and Computerized Online 30 OPERATING Operations Challenges Learning ASSUMPTIONS Jan S. Peterson, MS, CCRA, RAC, MICR, Norbert Clemens, MD, PhD, CPI Linda S. Behar-Horenstein, PhD; 50 RESEARCH ASQ CBA Wajeeh Bajwa, PhD; COMPLIANCE H. Robert Kolb, RN, CCRC; Alena Prikhidko
Home Study 56 INFORMATION
EARN 3.0 20 CREDITS Medical Devices IN THIS ISSUE Research in Latin 32 OF CLINICAL America Blind Spot in Clinical Trial Operations: Who 44 RESEARCHER Miguel A. Willis, PhD; OPINION: The Role Anne Blanchard, CCRA is Watching? of Certification in Clinical Researcher ISSN 2334-1882 Nadina Jose, MD; (Print) and ISSN 2334-1890 (Online) Roshan Padbidri, MS; Developing a Quality is published bimonthly. It is provided Suzette Cody, MA Clinical Workforce to ACRP members by the Association Kelly M. Cairns, MA, BASc, APRM, CCRA of Clinical Research Professionals Workforce (ACRP). The views, research methods, and conclusions expressed in material Innovation Also in This Issue published in Clinical Researcher are those of the individual author(s) and not necessarily those of ACRP.
© Copyright 2017 Association of 52 Clinical Research Professionals. All rights reserved. For permission to ACRP’s Career photocopy or use material published Development herein, contact www.copyright.com. For other information, write to editor@ Resources—Looking acrpnet.org. Beyond Competency Postmaster: Send address changes to Development Clinical Researcher Beth D. Harper, BSOT, MBA 99 Canal Center Plaza, Suite 200, Alexandria, VA 22314
+1.703.254.8102 (fax) 54 +1.703.254.8100 (phone) www.acrpnet.org On the CRbeat: The 4 17 48 Latest News from the IN MEMORIAM MEMBER PROFILE MEMBER PROFILE World of Workforce Margaret F. Fay, PhD, Christina L. Nance, Shirley Trainor- DESIGN Innovation RN, CCRC PhD, CPI, FAACI Thomas, MHSA TGD Communications tgdcom.com
October 2017 2 Clinical Researcher
IN MEMORIAM
EDITOR-IN-CHIEF James Michael Causey [email protected] (703) 253-6274
MANAGING EDITOR Gary W. Cramer (703) 258-3504
EDITORIAL ADVISORY BOARD CHAIR Jerry Stein, PhD Summer Creek Consulting LLC VICE CHAIR Paula Smailes, RN, MSN, CCRC, CCRP The Ohio State University Wexner Medical Center ACRP Mourns Passing of ASSOCIATION BOARD OF TRUSTEES LIAISON Margaret F. Fay, PhD, RN, CCRC, Ernest Prentice, PhD Board of Trustees Member University of Nebraska Medical Center TRAINING AND DEVELOPMENT COMMITTEE LIAISON Suheila Abdul-Karrim, CCRA, CCRT The Association of Clinical Research Professionals (ACRP) Freelancer was saddened by the passing in August of Margaret (“Peggy”) Victor Chen F. Fay, PhD, RN, CCRC, Board of Trustees Member. The C and K Clinical Group Dr. Fay was appointed to the Association Board of Trust- Fraser Gibson ees in June 2016. She was also the 2015 recipient of ACRP’s Advantage Clinical Innovation in Clinical Research Award. Gregory Hale, MD, CPI “Peggy was a pioneer in the world of clinical research All Children’s Hospital and was personally dedicated to ACRP’s mission,” said ACRP Stuart Horowitz, PhD, MBA WIRB-Copernicus Group Executive Director Jim Kremidas. “Her creativity and exper- Stefanie La Manna, PhD, ARNP, FNP-C tise were assets to our Board of Trustees. She will be missed Nova Southeastern University by the industry and the many who loved her.” Jamie Meseke, MSM, CCRA Dr. Fay has more than 38 years of progressive research PPD, Inc. and management experience in academic, hospital, corpo- Christina Nance rate, and independently owned research site organizations. Baylor College of Medicine She served as a clinical study coordinator, an auditor for Grannum Sant, MD, BCh, BAO (Hons.), MA, FRCS, FACS Tufts University School of Medicine human and animal research, a clinical research associate, Shirley Trainor-Thomas medical liaison, site director, and researcher. GuideStar Clinical Trials Management In her most recent role as Global Director, Clinical Heather Wright Research Monitor for Medtronic, Peggy was responsible for Tampa Bay Clinical Research Center 220 research professionals serving 10 individual businesses, and more than 400 clinical trials across the globe. She was a ADVERTISING consultant to the research industry and served as an advisor, Tammy B. Workman, CEM Director, Advertising & Exhibition Sales content expert, and medical writer for various pharmaceuti- (703) 254-8112 cal and medical device companies. She is the inventor of four [email protected] patents, two in the area of micro current technology and two For membership questions, contact ACRP at in the field of risk-based clinical trial conduct. [email protected] or (703) 254-8100
October 2017 4 Clinical Researcher ARE YOU READY FOR AN ADVERSE REACTION? STAT KITs include medications and devices to treat a variety of medical emergencies.
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[DOI: 10.14524/CR-17-4039]
Regulations and Compliance: The Climb is Worth It
I admit it. Over the span of more than 20 years as a clinical research professional, I have become what I affectionately refer to as a “Regulatory Geek.” While I learned the criticality of compliance with regulatory requirements early in my career as a research monitor, my appreciation and understanding of the concept evolved as I progressed through the ranks to my current role, which is focused on specialty auditing and advanced training. My volunteer efforts on behalf of the clinical research enterprise via my involvement with ACRP have also broadened my regulatory perspective.
I believe that there When I joined ACRP’s Regulatory Affairs Com- fields not necessary for our product—rather than mittee several years ago, I had no idea how much it requiring sites/monitors/data management teams are more similarities would impact my career and my desire to see global to accommodate slight study-specific differences than differences in the regulatory harmonization become a reality. Those with a completely different layout and form for each who know me via my volunteer efforts for ACRP rec- type of product and each sponsor? conduct of research, ognize my passion for standardization and harmo- Adoption of a standard form, with some fields whether it is a drug nization. I believe that there are more similarities “not applicable” for certain studies, would very likely than differences in the conduct of research, whether foster greater accuracy, less missing data, and fewer or a device product, it is a drug or a device product, or a U.S.-based study queries, which equates to saved time and costs asso- versus one conducted outside the U.S. Embracing ciated with query resolution. Even if the industry or a U.S.-based study this assumption enables one to focus on the critical were to accept just two such CRFs (Drug Concomi- versus one conducted differences, while maximizing the similarities via tant Medications and Device Concomitant Medica- efforts at standardization and harmonization. tions), it would be a step in the right direction. outside the U.S. Seeing these efforts through to completion in the As the world becomes a more global market- form of regulations and compliance expectations place, it seems logical to me that harmonization of that benefit the entirety of our global enterprise can global regulatory requirements would be a natural often seem like a long and uphill struggle, but the evolution, as well. Cross-country acceptance of climb is worth it. product approval data with fewer requirements for “country-specific” studies, other than those In Search of Harmony designed to address population-specific product interactions, could reduce burdens on both industry One arena in which to observe this could be the and regulatory authorities around the globe. As you standardization of select case report forms (CRFs). will appreciate from the contents of this issue, it is For example, nearly all studies require the collec- rewarding to see recent progress in this area. tion of concomitant medication data. Can we not use a standard form for all studies—omitting those
October 2017 6 Clinical Researcher As the world becomes Nadina Jose, Roshan Padbidri, and Suzette Cody address a topic of growing interest in the research a more global community as well, regarding how we detect, marketplace, it seems correct, and improve our risk-based decisions when unanticipated risks occur. Their “Tale of Two logical to me that Studies” informs us of issues and outcomes from harmonization of unanticipated and unmitigated risks, some of which appear to have been exasperated by a reduced global regulatory monitoring frequency approach (e.g., risk-based decision to reduce onsite visits). requirements would These authors also touch on one of the corner- be a natural evolution, stones to quality and risk reduction—workforce development. As we shift from 100% source data as well. verification and frequent face-to-face interaction with a site team to a more targeted and less frequent approach to monitoring visits, we need to modern- ize old training paradigms. Reduced “face time,” What’s Ahead… coupled with increased reliance on technology, will require changing attitudes, refocusing on stan- The International Council for Harmonization (ICH) dardized training, increasing reliance on utilizing E6 Good Clinical Practice (GCP) Guideline is a technology-savvy resources, and modernizing good example of a global harmonization effort. As old training paradigms to ensure a well-prepared a widely accepted global standard, the guideline workforce performs in a quality manner. has resulted in increased global harmonization Meanwhile, the absence of consistent, for decades, and the recent, much-needed E6(R2) competency-based training for all members of the Addendum addresses global trends of risk-based clinical research team is cited as a barrier in clinical oversight as well as technological evolution of data trial conduct by Linda S. Behar-Horenstein, Wajeeh recording methods around the world. Bajwa, H. Robert Kolb, and Alyona Pridhidko in While ICH E6(R2) has yet to be formally adopted their article on “A Mixed Method Approach to by the U.S. Food and Drug Administration as of this Assessing Good Clinical Practice Computerized writing, and though it will remain a “guidance” Online Learning.” rather than a “regulation” in the U.S., this standard This concept is further brought home by Kelly IS the regulatory expectation in many countries Cairns in her article regarding the role of obtaining around the world. Jan S. Peterson’s article in this and maintaining certification as a marker of work- issue about getting onboard with these revisions force quality. I would like to stress the fact that ACRP clearly demonstrates the hurdles to identifying a Certification is an ongoing process, and that achieving harmonized path, and yet the desirability of such it is not easy; that is why, as a hiring manager, ACRP a path as noted in the ever-expanding number of Certification is valuable beyond all others I have seen. countries endorsing the E6(R2) Guideline. However, one must maintain his or her certifica- Also in this issue, Miguel A. Willis shares an tion in order to claim the credential. I consider this update on medical device clinical research in Latin requirement a compliance issue. Whether you are America, and points out that although the leading a CPI®, CCRC®, or CCRA®, or you obtain the newest countries in the region still have divergent clinical “non-role based” ACRP Certified Professional trial procedures, ICH GCP is deeply incorporated in (ACRP-CP®) designation, if you claim ACRP Certifi- the requirements and other standards (such as ISO cation because you once achieved it, you are falsely 14155) are quickly adopted. representing your credentials if you continue to use Next, Norbert Clemens’ article describing the the designation without having maintained it. I have changes and challenges of the European Union cited this during audits and I have a reason for doing Medical Device Regulation, which is to transition so; maintenance involves continually learning and into full force by May 26, 2020, is exciting with updating your skills. regard to harmonization because of the possibility In this ever-changing global environment, we for submission of a single application for a clinical need to keep current. Certification is a symbol investigation involving multiple Member States of baseline quality to me, and maintenance is an established by 2027. Additionally, the requirement assurance of ongoing efforts to remain current with for Unique Device Identification (UDI) similar trends and best practices, as well as the changing to U.S. requirements should enable better global Glenda Guest, CCRA, RQAP- regulatory environment. oversight of device performance, monitoring of GCP, TIACR, (gmg@ncra. com) is vice president of NCRA adverse experiences, and identification of safety Conclusion (Norwich Clinical Research trends in devices of a similar type, which reaches Associates, Inc.) in New York, It has been an honor and pleasure to work with my a member of the Association beyond the borders of (and databases of) any one Board of Trustees for ACRP, country or region. colleagues in research in preparing this issue for and former chair of the ACRP you, and I hope you find the information helpful. Regulatory Affairs Committee.
Clinical Researcher 7 October 2017 EXECUTIVE DIRECTOR’S MESSAGE Jim Kremidas
[DOI: 10.14524/CR-17-4040]
Stop the Presses! We’ve Got Exciting News! You are holding the final printed issue of Clinical Researcher. As an ACRP Member, you will continue receiving the articles, columns, and peer-reviewed content you so highly value; but starting with the December issue, we are enhancing the journal to make it more relevant to your needs today.
Here’s Why… clinical research enterprise by evolving ourselves— by providing you with the content you value more We are building community in clinical research often and more quickly. by providing platforms to foster the exchange of Our goal is to continue building the competen- ideas and information among clinical research cies needed by the clinical research community and professionals. keep you informed through an enhanced Clinical Jim Kremidas (jkremidas@ The clinical research community has long relied Researcher that provides faster updates on changes acrpnet.org) is the Executive on Clinical Researcher, and The Monitor before it, Director of ACRP. affecting you, the ability to dive deeper into any as the go-to resource for community perspectives, given topic, and greater opportunities for inter- innovative ideas, best practices, and beyond. activity, engagement, and dialogue. We can only However, we can do more. We can do more to capitalize on this opportunity by embracing the help you keep pace with the rapid evolution in the digital tools available today and into the future. With this change, we are positioned to bring you more content at a faster pace; you will be connected with more voices from the field, more insights and perspectives, and more regulatory developments, news, and trends impacting clinical trials. We will also publish more frequently; you will receive 10 issues of Clinical Researcher each year, rather than six. Additionally, you will have access to more Home Study contact hours/education credits. Further, we are better positioned to build community by integrating the digital tools that will enable Clinical Researcher’s evolution toward a more “social” conduit of community engagement. This change is also in support of efforts to provide a more “green” method of providing the information you need. However, you will still have the opportunity to print Home Study articles in PDF How Will I Receive Clinical Researcher? 1. Log in to your account at acrpnet.org and click “My Profile” form if you like. under “My Account”. As an ACRP member, you can access Clinical Researcher at any time We have a lot more great news to share in the 2. Click “My Subscriptions’ under “My Account Links”. by visiting acrpnet.org/clinicalresearcher. Separate articles coming months as we prepare to make 2018 the best and columns have already been posted from print issues dating 3. Make sure the box next to “Membership” is selected to ensure back to February 2016, and full-issue PDFs of all issues dating back delivery of Clinical Researcher “issue alert” e-mails. yet, but we are excited to get a jump on the year by to April 2014 (when the journal was renamed) are available for 4. Select all other topics you want to hear about from ACRP. implementing this change in December. download. 5. Click the “Submit” button. Thank you for your continued support of ACRP You will continue receiving “issue alert” e-mails when issues are If your employer has strict e-mail filters in place that prevent you and our mission to promote excellence in clinical posted online. To ensure you receive these and other critical ACRP from receiving ACRP communications, please ask your information research. communications, please take a few minutes to update your e-mail technology department to “whitelist” [email protected] (they’ll subscriptions by following these steps: know what that means).
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[DOI: 10.14524/CR-17-4041]
Good Intentions May Still Go Astray on the Regulatory Pathway The more things change, the more they stay the same. Three years ago, I wrote a column for the Clinical Researcher titled “Global Regulatory Insights: Why Do We Have Regulatory Compliance Professionals?” Three years later, the U.S. Food and Drug Administration (FDA) has become more open and communicative, and regulatory bodies are acknowledging that change is needed. However, research continues to get harder as this pendulum continues to swing further toward constraint.
The regulatory framework is a patchwork of law. And then there’s guidance that comes out of All these laws, law, regulation, and guidance that has come from the FDA, but also out of the National Institutes of dozens or hundreds of federal, state, and local Health and the Office for Civil Rights, along with regulations, and government offices; each has the best of intentions, dozens or hundreds of other offices. guidances are built but combined, they form a thicket of unintended We can layer on top of all that the International consequences. Our regulatory compliance profes- Council for Harmonization’s tenets for Good with the best of sionals are as needed today to help us navigate this Clinical Practice, as well as state and local laws. intentions, and they all maze as they were the last time I broached this topic. Seeing the Forest for the Trees end with unintended Nothing’s as Simple as it Seems This situation has led to an industry of regulatory consequences. Then In the U.S., the Federal Food, Drug, and Cosmetic compliance and healthcare regulatory attorneys Act (FD&C Act) is a federal law enacted by Congress to navigate the tangled forest of expectations. I we create more laws giving the FDA its power. Congress delegated to FDA visualize a serene meadow in the midst of the wild to try and take care the ability to create regulations within the confines woods, where we can successfully conduct research, of the FD&C Act, and those regulations are treated as improve healthcare, and transact business. Finding of the unintended law. FDA guidance, however, describes the agency’s that tiny area of overlap where we’re in compliance consequences. current thinking on a regulatory issue. Guidance is with all these laws, regulations, and guidances can not law, but to be safe, everyone treats guidance as be tough—and sometimes, impossible. law anyway. All these laws, regulations, and guidances are Well, here’s an example of where things get built with the best of intentions, and they all end more convoluted. There are laws governing how with unintended consequences. Then we create businesses can interact and associate. These more laws to try and take care of the unintended govern, for example, the transactions that can consequences. take place between a pharmaceutical company, The OIG Safe Harbor Regulation would be an a hospital system, and a clinical investigator; and example. Within the U.S. Department of Health they govern what structures will have to be in place and Human Services (HHS) is the Office for Human in order for these transactions to occur. Research Protections (OHRP), and within OHRP Then there are laws—such as the Health Insur- is the Secretary’s Advisory Committee on Human ance Portability and Accountability Act Privacy Rule, Research Protections (SACHRP). Posted on the the Anti-Kickback Statute, and the Stark Law—that HHS website, the SACHRP readily acknowledges also have influence over what can and cannot the confusion that has been created by the overlap Jeff Kingsley, DO, MBA, CPI, happen, or more appropriately, under what circum- of unintended consequences. Within its meeting FACRP, (jkingsley@iacthealth. stances and structures the relationship can happen. minutes there are numerous references regarding com) is chief executive officer of IACT Health in Columbus, Then there are the FDA regulations, which guidances that have resulted in “much debate and Ga., and Chair of the 2017 are the same as law, and the Office of Inspector confusion throughout the research community.” Association Board of Trustees General (OIG) regulations, which are the same as But with the best of intentions. for ACRP.
October 2017 10 Clinical Researcher
Getting on Board with ICH GCP E6(R2): Impact on Study Quality and Operations
PEER REVIEWED | Jan S. Peterson, MS, CCRA, RAC, MICR, ASQ CBA [DOI: 10.14524/CR-17-0032]
It took 20 years for the International Council for Harmonization’s separate, but coordinated, regulations for sponsors (ICH’s) 1996 ICH E6(R1) Guideline for Good Clinical Practice and monitors, institutional review boards (IRBs), 1–3 (GCP) to reach the maturity needed for significant amendment. An and clinical investigators. At the time, pharmaceutical industry repre- earlier attempt by the U.S. Food and Drug Administration (FDA) sentatives and many researchers voiced strong in 1977 to institute similar provisions by regulation was basically opposition to what FDA proposed. Citing the poten- unsuccessful, but lessons learned help develop the original ICH tial for enormous cost increases for compliance GCP document during the 1990s. and a slowing of research progress, they lobbied successfully to halt implementation of most of the proposed regulations. Of the original proposals, The ICH GCP E6(R2) update finalized in 2016 only the IRB regulations were successfully rewrit- was prepared as an integrated addendum with ten and issued in final form in 1981.4 insertions designed to keep the original structure FDA still regulated drug trials and the approval intact. These changes incorporated recent meth- process in the U.S., but even with incremental reg- odologies focused on risk-based approaches to ulatory improvements over time, what were to be quality, improved language to accommodate the considered broadly acceptable practices for clinical digital age, and additional clarifications for sponsor trials remained unsettled. Study sponsors and their and investigator responsibilities. consultants were on their own to create internal, With clinical research under increasing often proprietary, procedures. Worldwide, except pressure for safety, quality, and cost improvements, for the ethical considerations for informed consent ICH is proposing additional changes to GCP even published following World War II,5,6 there were no as implementation of the new E6(R2) version is just competent health authorities using an agreed-upon getting under way. set of guidelines for the conduct of clinical trials. Pharmaceutical companies were keenly inter- So Long Ago—A [Not-So] Brief History ested in using a commonly accepted framework Nearly 20 years before the ICH published its to gain marketing approvals in various national original E6(R1) GCP guideline in 1996, the FDA markets. This was because it was often a require- had published a series of proposed regulations ment to conduct essentially the same clinical about clinical research. In retrospect, these would trial in multiple countries to gain local product constitute much of what appeared later in ICH approvals. Thus, when ICH was created in 1990 (it GCP. FDA’s objective was to assure the quality and was known originally as the International Confer- integrity of the research activities subject to the ence on Harmonization of Technical Requirements agency’s jurisdiction, but the implications were for Registration of Pharmaceuticals for Human more widespread; the FDA proposals included Use), it was a joint effort by regulators and trade
October 2017 12 Clinical Researcher associations in Europe, Japan, and the U.S. to on quality and trial costs. By 2014, ICH created With clinical research create a commonly accepted set of guidelines—a an Expert Working Group (EWG) to update the “harmonized” voluntary consensus standard—for GCP guideline. The clinical research world was under increasing drug marketing approvals. By then, FDA had incor- evolving quickly, and revisions were needed due pressure for safety, porated some of the earlier proposed regulations to globalization, increasing study complexities, piecemeal into other rules and regulations, but the and technological capabilities.9 The EWG gath- quality, and cost original cohesive arrangement had been lost. ered representatives from European Union (EU) improvements, ICH is Senior FDA regulators were an integral part of regulatory authorities, the European Federation of the ICH E6 development, and were well aware of the Pharmaceutical Industries and Associations, FDA, proposing additional earlier proposed rules containing language about the Pharmaceutical Research and Manufacturers the responsibilities for sponsors, monitors, IRBs, of America, the Ministry of Health, Labor, and changes to GCP even as and clinical investigators. Rather than attempt Welfare (MHLW) in Japan, the Japan Pharmaceu- implementation of the another comprehensive regulatory approach such tical Manufacturers Association, Health Canada, as had been started 20 years earlier, FDA decided to and Swissmedic, and benefitted from additional new E6(R2) version is adopt the ICH GCP E6(R1) guideline, which agency resources from other organizations. just getting under way. representatives helped write, as an official “guid- The EWG made use of recent changes to clinical ance document” in 1997.7 The GCP guidance was research procedures and quality practices (e.g., not enforceable in the manner of other regulations published position papers and studies, other in the U.S., but it provided the industry and reg- consensus standards and guidance documents) to ulators with a clearer picture of what constituted help prepare the GCP update.10–17 Goals included acceptable practices. improved harmonization of practices with proactive quality management approaches and Jumping Forward risk-based monitoring (RBM), and integration across other ICH documents. These harmonized The E6(R1) GCP guideline from 1996 turned out to be practices were expected to relieve impediments to one of the most durable of international voluntary innovation while maintaining protection of trial consensus standards, absorbing 20 years of intensive participants and data quality.9 use before resigning to a second edition. An entire industry of clinical investigators, sponsors, moni- Consistency of approaches and clarification of tors, coordinators, nurses, IRB/institutional ethics earlier GCP misinterpretations were also expected committee members, trainers, consultants, auditors, to improve clinical drug development time and government regulators, and other research staff costs. The EWG used an “integrated addendum” members around the world interpreted and used approach to GCP document modifications, making the E6(R1) guideline, devised relevant procedures, changes to the original version as insertions while built training programs (including the professional retaining the original E6(R1) outline structure. certification programs sponsored by the Association The ICH EWG completed its first draft by June of Clinical Research Professionals, the Society of 2015, and the document was sent out for comments Clinical Research Associates, and others), received to ICH members and the public. The final text and documented their training, and managed (called Step 4 in the approval process) of the E6(R2) update was approved by ICH and published on thousands of clinical trials built largely around use 18 of the ICH GCP guideline. November 9, 2016. Regulatory authorities of many countries (ICH members in particular) adopted the original GCP Here We Are guidelines in a formal manner without modifica- The implementation stage (Step 5) for the E6(R2) tion, while some others (e.g., India) adapted them update is under way. Officially, the European Med- significantly to align with local laws and subse- icines Agency’s Committee for Medicinal Products quently published their own versions.8 for Human Use stepped up first and announced With the experience of widespread use under adoption of E6(R2) on December 15, 2016, with an evolving conditions, some misinterpretations effective date for the EU on June 14, 2017.19 Health of GCP were observed to have a negative impact Canada adopted the E6(R2) update next on May 25,
Clinical Researcher 13 October 2017 Rather than attempt 2017, announcing that full implementation would The following GCP changes in E6(R2) are likely occur in April 2018.20 Japan’s MHLW/Pharmaceuti- to have the greatest impact on existing operations another comprehensive cal and Medical Devices Agency, Swissmedic, and performed by sponsors, CROs, and clinical sites: regulatory approach the FDA have not yet announced official adoption • Certified copies [Section 1.63]: The medium is or effective dates. no longer the message. In the world of electronic such as had been The ICH membership’s expansion beyond the data, if you have a validated process to generate started 20 years earlier, original tripartite group (the EU, Japan, and the copies that make an accurate and complete U.S.) brought in regulatory members from Canada, copy, the copy you create can be considered FDA decided to adopt Switzerland, Brazil, China, and the Republic of certified. You have to take the non-trivial step to Korea. An expanding list of 23 official ICH observ- assure the process for making copies is vali- the ICH GCP E6(R1) ers now includes authorities from India, Cuba, dated, but when this is properly documented, a guideline, which Mexico, Singapore, South Africa, Kazakhstan, significant tool is at your disposal. agency representatives Russia, Chinese Taipei, and Australia, plus sev- • Monitoring plans and monitoring [Sections eral regional organizations (e.g., the Asia-Pacific 1.64 and 5.18.7]: Having a plan is not new, helped write, as an Economic Cooperation forum, the Association of nor is centralized monitoring, but E6(R2) now Southeast Asian Nations) and other international mentions “centralized” monitoring frequently, official “guidance organizations (e.g., the World Health Organization, so the emphasis is new. A focus on critical data document” in 1997. International Federation of Pharmaceutical Manu- and processes is specified, which relates to RBM facturers, Council for International Organizations methods. of Medical Sciences, United States Pharmacopeia, • Monitoring reports [Section 5.18.6(e)]: Since International Pharmaceutical Excipients Council). centralized monitoring is emphasized, docu- This means the E6(R2) update and related ICH ment that activity just as you would onsite visits. harmonization documents will have a growing Clarifies impact on an even larger part of the world’s health- • All trial information [Section 2.10]: that “all” applies to paper and electronic records. care industry as more stakeholders participate in developing and endorsing ICH guidelines. • Investigator responsibilities [Sections 4.2.5 and 4.2.6]: Delegation without supervision The E6(R2) Impact on Study Quality and is not acceptable. This extends to any service Operations—Focus on Changes provider, who must be qualified and have procedures to assure integrity of tasks and data. The E6(R2) GCP update is already creating a flurry • Investigator records [Section 4.9.0]: It is of new interpretations and additional training spelled out here, but you have the old ALCOA curricula by consultants, institutions, sponsors, principle (saying data should be Attributable, and contract research organizations (CROs). As Legible, Contemporaneous, Original, and the RBM adoption trend continues and sites and Accurate) from the FDA with the added “C” sponsors gain an increased understanding of the for complete: ALCOAC. The term audit trail 21 tenets of RBM, it should be noted that risk-based is added for non-paper records (but this was approaches to quality emphasized in the E6(R2) always a requirement in computerized clinical update are not new. These approaches have been data systems). established in other recognized quality standards, • including the International Organization for Stan- Sponsor responsibilities—Quality manage- A clear statement is given dardization’s ISO 9001:2015 (Quality management ment [Section 5.0]: here to let sponsors know they need to have a systems—Requirements) and ISO 31000:2009 (Risk quality system in place, and that a risk-based management—Principles and guidelines), as well approach is essential. One sentence should as regulatory positions in various countries.10,11,13 be memorized: “The methods used to assure ICH also has indicated that use and interpretation and control the quality of the trial should of the E6(R2) guideline should not be made in be proportionate to the risks inherent in the isolation from other ICH documents.9,18 trial and the importance of the information collected.” From this statement, the basic ideas of risk-based approaches and RBM will follow.
October 2017 14 Clinical Researcher The subsections outline the importance of trial types that can be accommodated under GCP, The recent ICH GCP risk-based thinking throughout the clinical trial including “real world” data from electronic health process—from inception and protocol devel- records, registries, and other sources not previously E6(R2) update is not opment, where risk identification may begin, recognized as suitable for analysis in the manner of the end of this story. through the evaluation, control, communica- traditionally controlled clinical trials. tion, review, and reporting of risks and how they The preliminary plans for this work are set to While implementation are addressed. begin late in 2017 or in 2018. The ICH effort may and training for the • Sponsor responsibilities—CRO oversight include developing a new ICH E6 “overarching [Section 5.2.2]: Sponsors remain responsible for principles” guideline, with a series of Annex docu- E6(R2) GCP update is oversight and documenting tasks they delegate ments focused on traditional interventional trials, under way now, more to others (parallel to investigator responsibili- nontraditional interventional trials, and other ties under Section 4.2.6). nontraditional trial designs. Like most consensus changes are in the • Sponsor responsibilities—Monitoring standards, significant revisions take time, but works down the road. [Section 5.18.3]: Risk-based approaches to RBM safety and quality standards remains paramount. are emphasized and can be flexible; centralized (or remote) monitoring methods for data quality Editorial issues can be effective.12,16,17 As the E6 renovation project gets under way, • Sponsor responsibilities—Monitoring and perhaps ICH will reconsider the guideline title as noncompliance [Section 5.20.1]: Consider that well. I have often observed that clinical investi- “noncompliance” has to “significantly affect” or gators primarily responsible for the execution of have “potential to significantly affect” human a research protocol misunderstand the term or subject protections or data reliability to require the responsibilities involved with “good clinical an active response; noncompliance means practice” as we use it. sponsors should take appropriate action when Perhaps the GCP term is confused with the needed. ordinary care investigators would deliver to their • Essential documents [Section 8.1]: Sponsors patients, since of course they trained for years to and investigators must manage essential provide “good”—if not superior—care, the service documents in a manner that permits search they provide is “clinical,” and they are in medical and retrieval regardless of storage format. It “practice.” This may not be so surprising knowing is possible that the essential documents list is that, on an annual basis, a high proportion of clinical incomplete for some trials, which may need investigators are research-naïve. Perhaps because supplemental materials included, or that some of their initial research experience and training—or documents maybe less relevant for a given trial. lack thereof—in leading a clinical research protocol, This is another risk-based decision to consider. many first-time investigators never return to utilize Documents generated by the investigator/insti- or improve upon their new skills. tution must remain under their control, and not Regulatory inspections seem to support this be subject to exclusive control by the sponsor. idea, since year after year, the most common citations issued to investigators are for not follow- ing the protocol. To help everyone recognize the Wrapping Up important difference between their clinical skills The recent ICH GCP E6(R2) update is not the end and the research activities they undertake, I’m of this story. While implementation and training hoping that the title “good clinical practice” (GCP) for the E6(R2) GCP update is under way now, more gets updated to “good clinical research practice” changes are in the works down the road. ICH has (GCRP), in recognition that this activity is clearly planned the modernization of the 1997 ICH E8 not at all like providing good patient care. guideline (General considerations for clinical trials) and simultaneously is proposing a subse- quent “renovation” of E6(R2).22 These changes are expected to add flexibility for the range of clinical
Clinical Researcher 15 October 2017 References 8. Central Drugs Standard 13. Ministry of Health, Labor, 18. International Council for 1. U.S. Food and Drug Control Organization, and Welfare. 2013. Basic Harmonization. 2016. Administration. 1977. Ministry of Health principles of risk-based Integrated Addendum to ICH Obligations of sponsors and Family Welfare, monitoring [provisional E6(R1): Guideline for Good and monitors of clinical Government of India. translation]. www.pmda. Clinical Practice E6(R2). investigations (proposed 2000. Good clinical practice go.jp/files/000215858.pdf www.ich.org/fileadmin/ rule). 42FR49612, guidelines. www.cdsco.nic. 14. International Council Public_Web_Site/ September 27. in/html/GCP1.html for Harmonization. ICH_Products/Guidelines/ Efficacy/E6/E6_R2__ 2. U.S. Food and Drug 9. International Council for 2005. ICH Harmonized Step_4.pdf Administration. 1978. Harmonization. 2014. Final Tripartite Guideline: Quality Standards for institutional concept paper: Addendum Risk Management, Q9. 19. European Medicines review boards for clinical for ICH E6: Guideline for November 9. www.ich. Agency/Committee investigations (proposed good clinical practice org/fileadmin/Public_ for Medicinal Products rule). 43FR35186, August 8. (dated June 2). www.ich. Web_Site/ICH_Products/ for Human Use. 2017. org/fileadmin/Public_ Guidelines/Quality/Q9/ Guideline for good clinical 3. U.S. Food and Drug Web_Site/ICH_Products/ Step4/Q9_Guideline.pdf practice E6(R2), Step 5. Jan S. Peterson, MS, CCRA, Administration. 1978. Guidelines/Efficacy/E6/ www.ema.europa.eu/ RAC, MICR, ASQ CBA, (jansp@ Obligations of clinical 15. Meeker-O’Connell A, E6_R2_Concept_Paper_ docs/en_GB/document_ erols.com) is senior regulatory investigators (proposed Glessner C, Behm M, July_2014.pdf library/Scientific_ affairs manager for the Emmes rule). 43FR35210, August 8. Mulinde J, Roach N, 10. U.S. Food and Drug Sweeney F, Tenaerts guideline/2009/09/ Corporation in Rockville, Md., 4. U.S. Food and Drug Administration. 2012. P, Landray MJ. 2016. WC500002874.pdf and the 2017 vice chair of Administration. 1981. Guidance for industry: Enhancing clinical 20. Health Canada. 2017. the ACRP Regulatory Affairs Protection of human Oversight of clinical evidence by proactively Guidance on Good clinical Committee. subjects; Standards for investigations — a building quality into practice: integrated institutional review boards risk-based approach to clinical trials. Clin Trials addendum to E6(R1) for clinical investigations monitoring. https://www. 13(4):439–44. ICH topic E6(R2). www. (final rule). 46FR8958, fda.gov/downloads/Drugs/ hc-sc.gc.ca/dhp-mps/ January 27. 16. Clinical Trials Guidances/UCM269919.pdf Transformation prodpharma/applic- 5. The Nuremberg Code. 11. European Medicines Initiative. 2011. CTTI demande/guide-ld/ich/ 1949. In Trials of War Agency. 2013. Reflection recommendations: efficac/e6r2-step4-eng. Criminals Before the paper on risk based effective and efficient php Nuremberg Military quality management monitoring as a 21. Peterson JS, King D. 2016. Tribunals Under Control in clinical trials. www. component of quality Before RBM was in vogue: Council Law, No. 10, ema.europa.eu/docs/ assurance in the conduct how NIH managed efficient Volume 2. Washington, en_GB/document_ of clinical trials. https:// monitoring. Presented D.C.: U.S. Government library/Scientific_ www.ctti-clinicaltrials. at Association of Clinical Printing Office, pp. 181–2. guideline/2013/11/ org/files/monitoring- Research Professionals 6. World Medical Association. WC500155491.pdf recommendations_1.pdf Meeting & Expo in Atlanta, 1964. Code of Ethics of the 12. Lindblad AS, Manukyan 17. TransCelerate BioPharma. Ga., on April 17. World Medical Association: Z, Purohit-Sheth T, 2013. Position paper: 22. International Council Declaration of Helsinki. Gensler G, Okwesili P, risk-based monitoring for Harmonization. Helsinki, Finland. Meeker-O’Connell A, Ball methodology. www.trans 2017. ICH reflection 7. U.S. Food and Drug L, Marler JR. 2014. Central celeratebiopharmainc. on “GCP renovation”: Administration. 1997. site monitoring: results com/wp-content/ modernization of ICH International conference from a test of accuracy in uploads/2013/10/ E8 and subsequent on harmonization; identifying trials and sites TransCelerate-RBM- renovation of ICH E6. www. good clinical practice: failing Food and Drug Position-Paper-FINAL- ich.org/fileadmin/Public_ consolidated guideline Administration inspection. 30MAY2013.pdf Web_Site/ICH_Products/ (availability notice). Clin Trials 11(2):205–17. GCP_Renovation/ICH_ 62FR25692, May 9. Reflection_paper_GCP_ Renovation_Jan_2017_ Final.pdf
October 2017 16 Clinical Researcher ACRP MEMBER PROFILE: CHRISTINA L. NANCE
Why did you enter the clinical People would be surprised research field? to know that: By training, I am a translational I singularly developed every scientist in the fields of immuno- component of my first Phase I logical/allergy/infectious disease clinical trial from scratch, inclusive (primary immunodeficiencies, of the complete Investigational food allergy, and HIV). My first New Drug application to the Food exposure in the clinical research and Drug Administration and field was my translational medi- multicenter trial sites. It should cine project on the development have been titled “trial by fire”! of a natural therapeutic agent for Professional heroes: HIV treatment. I then moved the therapeutic agent from “bench to The “virus hunters” at the Centers TITLE: bedside” as my first experience for Disease Control and Prevention. Christina L. Nance, PhD, ever in clinical trials. Hobbies: CPI, FAACI What is your favorite Traveling, singing (cantor and Assistant Professor, Pediatrics/ part of research? choir), and reading. Pathology/Immunology/ The jigsaw puzzle. The challenge School of Tropical Medicine Reason for joining ACRP: as the principal investigator of Baylor College of Medicine fitting/timing all the pieces of the Upon being immersed in the clin- Texas Children’s Hospital clinical trial together. ical trial field, I realized that this was a very key part of my life goals. Adjunct Assistant Professor, What is your least I joined ACRP to advance my skills Epidemiology, Human Genetics & favorite part? in the field, as this is where the Environmental Sciences When you are so close to interlock- experts would be to guide me. University of Texas Health ing ALL the pieces and that ONE Sciences-Houston piece of the clinical trial “falls out.”
HOMETOWN: St. Louis, Mo.
LIVE NOW: Houston, Texas
Clinical Researcher 17 October 2017 CAREERS—PASSING IT ON Christine Senn, PhD, CCRC, CPI
[DOI: 10.14524/CR-17-4042]
A Q&A with Samuel Whitaker, Chief Technology Officer for Bracket
Editor’s Note: Bracket Q: There are many initiatives to make in the Department of Obstetrics and Gynecology, clinical research more efficient through primarily managing the transcription of paper is a company focusing technology. What initiatives are you most diaries to their electronic forms and administering on clinical research excited about? patient payments. I didn’t end up going to medical school like I data services and had originally set out to do, but I still worked on the A: My move to Bracket has allowed me to strate- technology based in gically shift gears as an innovator. I am most excited periphery when I was an investment banking ana- about disrupting established clinical technologies lyst. From there, I went on to work in acquisitions Wayne, Pa. and paradigms in traditional product sets (such as and product management. My journey eventually electronic patient-reported outcomes, electronic led me to the field of clinical research when I clinical outcome assessment, randomization and decided that I wanted to make use of my unique trial supply management, electronic data capture, skillset to serve patient communities. etc.) with the work I do at Bracket. Steve Jobs didn’t invent the MP3 player; he perfected the design in the iPod and went on to com- Q: You founded Greenphire, a vendor for pletely change the way music was consumed with sites to pay subject stipends. How did you the creation of iTunes. I believe that there are similar identify this need in clinical research, and opportunities in the field of clinical research. I aim how did you go about solving this industry to replicate this model of disruption in clinical pain? technologies, and to dedicate time and energy to correcting pain points and improving what those in A: Before I founded Greenphire, I was working the industry work with on a daily basis. as a product manager for a payment technology My hope is that introducing disruptive tech- company. My ambition at the time was to start my nology will drive the entire industry to evolve and own company, and my goal was to find a situation place a higher focus on improving outcomes for in which I could apply my knowledge of payment sponsors and patients. technology in a unique way—to an industry that had not yet experienced innovative payment solutions. Exploring the field of clinical research Q: I have always been intrigued by how was the first idea that came to mind as a result of people got into clinical research, but every- my experience in college and my proximity to my body’s path is different. What was your wife’s work and experiences. journey? Over the years, our iterative approach to software development yielded a market-leading A: When I started college at the University of solution set that was uniquely designed to solve Pennsylvania, my ambition was to go to medical the pain points of our clients and those at the site and patient level. In my role at Bracket, I’m tasked Christine Senn, PhD, CCRC, school. Throughout my undergraduate career, I CPI, ([email protected]) worked at the Hospital of the University of Penn- with addressing larger and more global pain points is the chief implementation sylvania, essentially as a junior site coordinator. throughout the clinical trial environment, which officer and a member of we do by optimizing clients’ experiences with our the Quality Assurance and The experience I had working at the hospital set Compliance Committee with the foundation for my interests and pursuits later unique solutions. IACT Health in Columbus, Ga. in life. I helped to support several clinical studies
October 2017 18 Clinical Researcher Clinical Researcher 19 October 2017 Medical Devices Research in Latin America
PEER REVIEWED | Miguel A. Willis, PhD | Anne Blanchard, CCRA [DOI: 10.14524/CR-17-0031]
Latin America comprises the region stretching from the southern Regulatory Landscape border of the United States all the way south to Antarctica (see In general, Latin America has more than 13,000 Figure 1). Anyone who travels the territory will encounter a great ongoing pharmaceutical and medical device clin- range of idiosyncratic diversity, but also cultural and linguistic ical trials, according to ClinicalTrials.gov, but as of July 11, 2017, the majority were being conducted in similarities. Brazil, México, Argentina, Chile, and Colombia (see Table 2). Although pharmaceutical trials dominate the scene, medical device studies are increasingly Spanish (spoken in most of the region’s coun- common as more researchers and institutions see tries) and Portuguese (especially prevalent in such studies as career and economic opportu- Brazil) are the most widespread languages among nities to work on cutting-edge technologies and the population, although there are some countries treatments. where the official language is French, English, or Meanwhile, although the region has experi- Dutch. Although this trend represents an advan- enced or rapidly maturing competent authorities tage for researchers in the region, as study docu- (see Table 2) and efforts have been made at harmo- ments in the same language can be used in several nizing the regulatory environment across various countries, there are some idioms specific to each borders, the leading countries in the region for country that should be considered. Although the 20 sovereign states and several territories of Latin America come in all shapes and sizes, one of the most outstanding characteristics México of the region is that its people clutter in and around a few major cities (see Table 1), resulting in densely populated areas. For example, Argentina nucleates FIGURE 1: Map of Latin more than half its population around the metro- America Showing the politan areas of its principal cities of Buenos Aires, Countries Where Most Colombia Córdoba, and Rosario, whereas Brazil concentrates Clinical Studies are Argentina’s entire population and triples the Conducted Chilean population in only four of its main cities— Sao Paulo, Rio de Janeiro, Velho Horizonte, and Fortaleza. The same trends apply to México, with its Brazil principal city being México City, but the country’s several other densely populated cities include Guadalajara and Monterrey.
Chile Argentina
October 2017 20 Clinical Researcher TABLE 1: Population Concentration in Latin America’s Principal Cities (in millions)
Argentina Population: 43.4M Buenos Aires Metropolitan Region ≈20M Córdoba ≈1.5M Rosario ≈1.4M Brazil Population: 191M Sao Paulo Metropolitan Area ≈21.9M Rio de Janeiro ≈12.1M Belho Horizonte ≈5.7M clinical studies still have many divergent proce- Fortaleza ≈2.5M dures. On the positive side, the tenets of the Inter- national Council for Harmonization’s Guideline for Chile Population: 16.6M Santiago Metropolitan Area ≈6.3M Good Clinical Practice (GCP) have been incorpo- Colombia Population: 48.7M Bogota ≈8M rated deeply in the region, and other standards like ISO 14155 from the International Organization for Medellin ≈2.5M Standardization are quickly being adopted. Barranquilla ≈1.2M The divergent procedures and requirements of México Population: 123.2M México City Metropolitan Area ≈20.1M different countries impact directly on the regulatory timeline expectations for setting up clinical studies Guadalajara ≈4.4M (see Figure 2). All countries require local adaptation Monterrey ≈4.1M of trial-related documents, and this means certified translation to local languages of all critical docu- ments. Although this by itself does not present a TABLE 2: Competent Authorities by Country and Number of Studies Being Conducted challenge, sponsors should have all critical docu- per Country (as of July 11, 2017) ments ready for translations as soon as possible, or Country Competent Authority Clinical Trials unnecessary delays may arise. Also, although the official language of most Latin American countries Brazil ANVISA www.anvisa.gov.br/eng/index.htm 5,773 is Spanish (excluding Brazil for the purposes of this México COFEPRIS www.cofepris.gob.mx 2,832 paper), companies managing translations should Argentina ANMAT www.anmat.gov.ar 2,225 be deeply aware of local idioms and/or use local translators to avoid misuse of terms. Chile Instituto de Salud Publica de Chile 1,272 www.ispch.cl/dispositivos-medicos In most Latin American countries, study proto- cols and other critical documents must go through Colombia INVIMA www.invima.gov.co 1,038 both institutional review board (IRB) and compe- Costa Rica Ministerio de Salud (MoH) www.ministeriodesalud.go.cr 149 tent authority review and approval. (In Chile, the competent authority is only notified about studies, Uruguay Ministerio de Salud Pública www.msp.gub.uy 59 and in cases of postmarketing studies in Argentina, the same holds true.) The expectation of two levels of review impacts timelines and additional submission In Argentina, core regulations and IRB/ethics The expectation of efforts, so a smart and clear regulatory strategy must committee (EC) procedures are mostly oriented be laid out when approaching IRBs and competent toward pharmacological studies, though device two levels of review authorities. Brazil has, by far, the longest regulatory studies can also be performed—even if the impacts timelines and timelines; in addition to IRB and competent author- regulations for them could stand clarification and ity evaluations, submission of study details must be refinement. Argentina remains an ideal setting additional submission made to CONEP (the National Ethics Committee), for postmarketing research studies in relation to efforts, so a smart although the competent authority and CONEP timelines, since these can be implemented with reviews can be done in parallel. EC approval and with no need to notify ANMAT if and clear regulatory importation is required. Brazil, as stated above, has the longest regu- strategy must be laid latory timelines, but since 2015 ANVISA has been out when approaching issuing new regulations specific to medical device studies, aiming to accelerate approvals. ANVISA IRBs and competent demands the language of trial documents to be authorities. Brazilian Portuguese, and there are few exemptions when submitting for approval. Chile currently has one of the simplest regula- tory setups for medical devices, as once an IRB/EC
Clinical Researcher 21 October 2017 FIGURE 2: Regulatory Timelines in Latin America
Docs Local Adaptation Pre-Market Ethics Committee Post-Market Competent Authority ARGENTINA CONEP
Pre-Market Post-Market CHILE
Pre-Market
BRAZIL Post-Market
Pre-Market Post-Market COLOMBIA
Pre-Market Post-Market MÉXICO 2 Weeks Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8
Research sponsors approves the study, the competent authority is only Research Resources, Facilities, to be informed and importation is authorized with and Capabilities may find in the region no subsequent need of approvals. a convergence of the In Colombia, there are no specific regulations The operations of healthcare systems in Latin for devices, and the Ministry of Health (INVIMA) American countries vary greatly (see Table 3), different variables that acknowledges the same type of requirements and even show extremes ranging from costly healthcare treatment in Chile to free public allow for designing that would apply to pharmacological research according to the research phase. Trying to obviate health coverage in Argentina that is also taken a study strategy the regulations on the grounds there is no specific advantage of by citizens of neighboring countries device-oriented regulation without adequate by crossing the border for treatment. The region’s that meets the justification can lead to setbacks and delays. densely populated cities offer access to treatments goals of timeliness, Investigational sites implementing medical device whose complexity ranges from simple to high-end interventional studies must be certified for GCP by levels in facilities with technical capabilities and cost effectiveness, INVIMA. numbers of hospital beds similar or even higher recruitment potential, México has specific regulations for medical than those seen in developed countries. devices, but the requirements are very similar to Latin American physicians are highly and other critical those for pharmacological studies. As medical respected members of their communities, and factors. device research is not very widespread in México, finding the right site to launch a study might repre- sent a challenge, although the latest trends indicate increasing levels of activity in this arena.
October 2017 22 Clinical Researcher TABLE 3: Health Indicators in Latin America Compared to North American and European Countries
Hospital Bed Density Physician Density Health Expenditures Country (Beds/1,000 Population)* (Physicians/1,000 Population)* Life Expectancy (Years)* (% of GDP*+ $/capita**) Argentina 4.7 3.86 Total: 77.1 Male: 74 Female: 80.4 4.8 %* $1,137** Brazil 2.3 1.89 Total: 73.8 Male: 70.2 Female: 77.5 8.3 %* $1,318** Chile 2.1 1.02 Total: 78.8 Male: 75.7 Female: 81.9 7.8 %* $1,749** Colombia 1.5 1.47 Total: 75.7 Male: 72.6 Female: 79 7.2 %* $962** México 1.5 2.1 Total: 75.9 Male: 73.1 Female: 78.8 6.3 %* $1,122** Canada 2.7 2.07 Total: 81.9 Male: 79.2 Female: 84,6 10.4 %* $4,641** United States 2.9 2.45 Total: 79.8 Male: 77.5 Female: 82.1 17,1 % *$9,403** United Kingdom 2.9 2.81 Total: 80.7 Male: 78.5 Female: 83 9,1 % *$3,377** Denmark 3.5 3.49 Total: 79.4 Male: 77 Female: 82 10.8 % $4,782** *CIA World Facts **World Health Organization often have trustful relationship with their patients, access to medical attention ranging from low- to Resources especially in Argentina, Chile, and Brazil. Most of high-complexity treatment and procedures, and Central Intelligence Agency: https://www.cia.gov/library/ them have educational backgrounds and clinical highly trained physicians in high-end facilities publications/the-world- expertise comparable to physicians in the U.S. and with research backgrounds and experience. factbook/ Europe, as it is common for them to have trained Further, research sponsors may find in the ClinicalTrials.gov: www. abroad in an effort to stand out. On the other hand, region a convergence of the different variables that clinicaltrials.gov World Health Organization: medical school training in Argentina is free, which allow for designing a study strategy that meets the www.who.int generates conditions of high physician density in goals of timeliness, cost effectiveness, recruitment a very competitive environment. On the opposite potential, and other critical factors. So, for example, end of the spectrum, becoming a physician in if you are looking for short regulatory timelines, Chile is very expensive, and only students earning Chile will fit best. On the other hand, if you need the highest grades have the opportunity to be high recruitment levels and are willing to endure trained, so this creates a similar environment in long regulatory timelines, Brazil is the place to which they need to be outstanding just to survive land. If you need both acceptable timelines and in their careers. recruitment in premarketing studies, Argentina Regarding costs for conducting a clinical study, can offer both, and may be your best choice for sponsors should estimate that in Latin America in postmarketing studies overall. Multinational strat- general, total costs for professional services will egies could also be a wise approach in the region, be around 25% less than in the U.S. Regulatory depending on the study needs. setup costs will be outweighed by the recruitment The key element to success in the region is Miguel A. Willis, PhD, potential of sites, if they are chosen with care. choosing the right partner with which to team up to (miguel@blanchardy guide the project through the legal and regulatory asociados.com) is a clinical research associate with Conclusions hurdles, while maintaining a close and transparent Blanchard y Asociados, a rapport with the study sponsor team. regional contract research Latin America is a promising region for clinical organization based in Buenos studies, given that it presents the key characteris- Aires, Argentina. tics for a successful study. We mean this in terms Acknowledgment of densely populated cities and subjects with The authors wish to acknowledge our colleagues and strategic partners—Miguel Botero Montaño from JSS Research in Colombia, Elizabeth Alpizar from ICRI in México, and Joyce Marinho from Blanchard y Asociados in Brazil—for their contri- butions to this article.
Anne Blanchard, CCRA, (anne@blanchardyasociados. com) is CEO and director of clinical operations for Blanchard y Asociados, and a member of the Association Board of Trustees for ACRP.
Clinical Researcher 23 October 2017 ICH IN FOCUS Madeleine Kennedy, PhD, DBioethics It is also essential that the third parties receive and document any study-specific training that is [DOI: 10.14524/CR-17-4043] pertinent to their roles. Furthermore, it is not ade- quate for investigators/institutions to assume that the services performed by the third parties and the data generated will meet integrity expectations. The investigator/institution should put in place a ICH E6(R2): What process for assuring themselves of this throughout the study, and should retain evidence that the Does Third-Party process has been followed. In some cases, the investigator will contract Oversight Mean with the third party, while in other cases the institution will assume the obligation. Even if the institution holds the contract, the investigator for Investigators, is ultimately accountable for the quality of the services being provided by any third parties on Sponsors, and CROs? their studies. Sponsor Oversight of CROs Over the past 20 years, the outsourcing of research and Now let’s turn to sponsor oversight of CROs. Just development (R&D) has become increasingly prevalent. The as in the prior version of ICH E6, Section 5.2 of ICH E6(R2) addresses the fact that sponsors may regulatory impact of this trend is reflected in the ICH Guideline transfer responsibilities to CROs, that this transfer E6(R2) from the International Council for Harmonization, in should be in writing, and that any responsibilities that several addenda have been made under the “Investigator” not specifically transferred are retained by the sponsor. In addition, this section states that where and “Sponsor” sections of the guideline. In this column, we will responsibilities are delegated to CROs, the CROs examine these updates and suggest ways that investigators, are responsible for complying with all ICH require- sponsors, and contract research organizations (CROs) can ments related to those sponsor responsibilities. implement these changes. What is different in ICH E6(R2) is the additional requirement under section 5.2.2 that, “The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, includ- Investigator Oversight of Third Parties ing trial-related duties and functions that are ICH E6(R2) addresses investigator oversight subcontracted to another party by the sponsor’s responsibilities of third parties in Addendum 4.2.6: contracted CRO(s).” Let’s examine the first part of this sentence. “If the investigator/institution retains the Similar to Addendum 4.2.6 in the “Investigator” services of any individual or party to per- section of the guideline, it is not sufficient for form trial-related duties and functions, the sponsors to assume that because they have investigator/institution should ensure this subcontracted services, the services performed by individual or party is qualified to perform their third parties are being performed according those trial-related duties and functions and to the guideline. Sponsors need to ensure that should implement procedures to ensure the there is appropriate oversight, and the evidence of integrity of the trial-related duties and func- the oversight needs to be retained. tions performed and any data generated.” When inspecting sponsors, regulators are To comply with this new requirement, inves- increasingly assessing the sponsor’s oversight of tigators/institutions should retain in their files the CROs it utilizes. The types of evidence that evidence that the third parties are qualified to regulators look for include the following: assume responsibilities for the specific study 1. Selection and qualification of the CRO to and the contractual agreements with the third ensure that the CRO that has been selected parties. Where the third parties are individuals, meets the requirements of the sponsor these should be listed in the site’s delegation of 2. A contractual agreement that makes clear authority log. Where the third parties are entities exactly which tasks have been delegated to (e.g., a pharmacy), a responsible party of that entity the CRO should be listed in the site’s delegation of authority 3. Ongoing oversight of the CRO to confirm log, and the entity should maintain its own internal throughout the study that the CRO continues delegation of authority log. to meet the sponsor’s requirements
October 2017 24 Clinical Researcher Ongoing oversight has been handled differ- different CROs, those CROs will need to become What is different in ICH ently across sponsors, ranging from a hands-off more comfortable sharing data from their quality approach to one that can feel like micromanage- risk management activities with other CROs con- E6(R2) is the additional ment to the CRO. The challenge is finding a middle tracted to perform different functions on the study. requirement under ground where the sponsor has sufficient data to This might include data that a CRO previously be confident that it has a finger on the pulse of the considered proprietary (whether shared directly section 5.2.2 that, services being provided by the CRO. or indirectly through the sponsor), which will “The sponsor should Many sponsors have traditionally relied on a likely impact the current outsourcing model that quality plan or agreement to document quality minimizes interactions among the CROs support- ensure oversight of any expectations to be met by the CRO. Such plans or ing a given study. agreements may include, but are not limited to, trial-related duties and reports required of the CRO, criteria for and/or Oversight of CRO Subcontractors functions carried out frequency of communications with the sponsor, Now let’s turn to the second part of Addendum and details on the handling of escalations (e.g., on its behalf, including 5.2.2: “The sponsor should ensure oversight of any regarding quality issues). However, these types of trial-related duties and functions carried out on its trial-related duties quality plans/agreements have typically been more behalf, including trial-related duties and functions reactive than proactive, in that their focus has been and functions that that are subcontracted to another party by the more on issue management, audits, and inspec- sponsor’s contracted CRO(s).” are subcontracted to tions than on proactive risk management. In the past, it was thought to be acceptable for another party by the a sponsor not to intervene to a great extent in CRO Enhanced Oversight by Collaborative subcontractor arrangements, since the contract sponsor’s contracted Quality Risk Management was between the CRO and its subcontractor. Most CRO(s).” ICH E6(R2) provides the perfect platform for sponsors limited their oversight to assuring them- enhancing sponsor oversight. The guideline invites selves through audits that their CROs had a process sponsors to partner with their CROs early on to in place for qualifying their subcontractors, while proactively identify the critical data and processes some went further by requiring their CROs to associated with their protocol, to assess the asso- seek sponsor pre-approval of their third parties. ciated risks that will inform the cross-functional This level of oversight is no longer adequate, as monitoring strategy, and to perform ongoing risk responsibility has been put squarely on sponsors management throughout the study. If these steps to ensure oversight of functions that their CROs are performed in a collaborative and transparent subcontract. manner, sponsors will benefit by having the data What does this mean? Sponsors will most likely they need to feel confident they have adequate require that all subcontractors be pre-approved oversight of their CROs. It will also reassure them by them, and they will expect to be provided with that the CRO is not just informing them of issues more details on the results of the qualifications once they have occurred, but is also actively performed by their CROs. They will also want engaged in preventing the issues from occurring in evidence that the CROs are actively managing the first place. their subcontractors throughout their studies. In Technology can also significantly assist in addition, more sponsors will likely be inserting enabling sponsor oversight. By using “Key Risk third-party beneficiary language into agreements Indicator” dashboards and sharing the data with with their CROs, to allow the sponsors to have their sponsors, CROs can provide real-time data and more direct oversight of these subcontractors. evidence of proactive risk management on the study. Conclusion Impact on CRO Interactions Given the increasing prevalence of outsourcing For quality risk management to be effective, in R&D, it is not surprising that ICH E6(R2) has it needs to include all functions involved in a addressed in more detail third-party oversight study—beginning with investigator site selection expectations of both investigators and sponsors. The and covering all interactions among the func- addenda will result in a number of changes in con- tions, all the way to the generation of the clinical tractual agreements as well as investigator, sponsor, study report. For example, data reviews by data and CRO processes that will enable effective quality management units will inform the monitoring risk management critical to the protection of human performed at the investigator site and vice versa. subjects and reliability of trial results. This cross-functional approach allows the sponsor Madeleine Kennedy, PhD, to have a holistic picture of the state of quality for DBioethics, (madeleine. the duration of the study. [email protected]) As a result, if study functions are outsourced to is senior vice president for corporate quality with INC Research/inVentiv Health.
Clinical Researcher 25 October 2017 The New European Medical Device Regulation 2017/745: Main Changes and Challenges
The new European Medical Device Regulation 2017/745 (MDR)1 and the European Union (EU) In Vitro Diagnostic Medical Devices Regulation 2017/746 (IVDR)2 passed in the European Parliament on April 5, 2017. The MDR was published in the Official Journal of the European Union on May 5, 2017, and entered into force on May 25, 2017.
PEER REVIEWED Norbert Clemens, MD, PhD, CPI
GUIDE TO ABBREVIATIONS USED IN THIS ARTICLE
AIMDD Active Implantable Medical Devices Directive CER Clinical Evaluation Reports EEC European Economic Community EU European Union EUDAMED European Database on Medical Devices GCP Good Clinical Practice HRI Human Readable Interpretation IVD In Vitro Diagnostic IVDR In Vitro Diagnostic Medical Devices Regulation ISO International Organization for Standardization MDD Medical Device Directive MDR Medical Device Regulation NB Notified Body PMCF Post-Market Clinical Follow-Up PIP Poly Implant Prothèse UDI Unique Device Identification UDI-DI Unique Device Identification Device Identifiers
October 2017 26 Clinical Researcher [DOI: 10.14524/CR-17-0028]
TABLE 1: What’s Found in the New Medical Device Regulation
Location Content Articles
Chapter I Scope and definitions 1 to 4 This article focuses solely on the impact of the MDR on clinical evaluations and clinical investiga- Chapter II Making available on the market and putting into service of devices, obliga- 5 to 24 tions. The new MDR will repeal two directives that tions of economic operators, reprocessing, CE marking, free movement are currently in place: Chapter III Identification and traceability of devices, registration of devices and of 25 to 34 • Medical Device Directive (MDD 93/42/EEC) economic operators, summary of safety and clinical performance, European • Active Implantable Medical Devices Directive database on medical devices (AIMDD 90/385/EEC) Chapter IV Notified bodies 35 to 50 PEER REVIEWED These directives have been labeled as “New Norbert Clemens, MD, PhD, CPI Approach Legislation,” with the aim to protect Chapter V Classification and conformity assessment 51 to 60 public health mainly based on self-regulation by the industry. Legislation valid in all 28 Member Chapter VI Clinical evaluation and clinical investigations 61 to 82 States of the EU is either imposed through direc- Chapter VII Post-market surveillance, vigilance, and market surveillance 83 to 100 tives addressed to national authorities, who must take action to make them part of national law, or Chapter VIII Cooperation between Member States, Medical Device Coordination Group, 101 to 108 through regulations; as soon as they are passed, expert laboratories, expert panels, and device registers they have binding legal force throughout every 109 to 113 Member State, on par with national laws. Chapter IX Confidentiality, data protection, funding, and penalties Chapter X Final provisions 114 to 123 Background The medical device industry and market has Annex I General safety and performance requirements steadily grown over the past decades, with a vast Annex II Technical documentation variety of sophisticated and advanced products in the pipeline. Due to this fact, the European Annex III Technical documentation on post-market surveillance Commission and EU Parliament decided to adapt the existing legislation (initially installed in 1990 Annex IV EU declaration of conformity and 1993, with amendments in 2003 and 2007) to Annex V CE marking of conformity the significant technological and scientific progress occurring in this sector in the past 20 years. Annex VI Information to be submitted upon the registration of devices and economic operators in Furthermore, the European Commission accordance with articles 29(4) and 31, core data elements to be provided to the UDI database argues: “Problems with diverging interpretation together with the UDI-DI in accordance with articles 28 and 29, and the UDI system of the current Directives as well as the incident Annex VII Requirements to be met by notified bodies concerning fraudulent production of the Poly Implant Prothèse (PIP) silicone breast implants in Annex VIII Classification rules 2012 highlighted weaknesses in the legal system in place at the time and damaged the confidence of Annex IX Conformity assessment based on quality management system and on assessment of patients, consumers and healthcare professionals technical documentation 3 in the safety of medical devices.” Annex X Conformity assessment based on type-examination One of the key objectives of the new MDR is to ensure a consistently high level of health and safety Annex XI Conformity assessment based on product conformity verification protection for EU citizens using these products. Making clinical investigation and evaluation Annex XII Certificates issued by a notified body requirements more stringent is aimed at improv- Annex XIII Procedure for custom-made devices ing health and safety through transparency and traceability. Annex XIV Clinical evaluation and post-market clinical follow-up The MDR consists of 10 chapters with 123 articles and 17 annexes (see Table 1), and covers Annex XV Clinical investigations clinical evaluations and clinical investigations with Annex XVI List of groups of products without an intended medical purpose referred to in article 1(2) medical devices in the EU, depending on any type of sponsor (industry, noncommercial, academia). Annex XVII Correlation table It will fully apply from May 26, 2020, and manufac- turers have the duration of the three-year transition period to update their technical documentation and processes to meet the new requirements.
Clinical Researcher 27 October 2017 Article 120 of the MDR states a or therapeutic options addressed in the CER and number of transitional provi- diagnostic/therapeutic alternatives. sions, and should be referred to The following text is an extract of section 1, Part for more detail. Certificates issued A of Annex XIV (Clinical evaluation): to the MDD and AIMDD during the To plan, continuously conduct and document a transition period will remain valid for the clinical evaluation, manufacturers shall: entire period indicated on the certificate. (a) establish and update a clinical evaluation plan, which shall include at least: The medical device What’s New in the MDR? `` an identification of the general safety and per- industry and market Main changes introduced by the MDR are (some formance requirements that require support are described in more detail below): from relevant clinical data; has steadily grown • Clinical investigations and evaluations are `` a specification of the intended purpose of the over the past decades, regulated in more than 20 articles of the MDR device; `` Clinical evidence: Sufficient high-quality data `` a clear specification of intended target groups with a vast variety to allow a qualified assessment of whether with clear indications and contraindications; of sophisticated and the device achieves the intended clinical `` a detailed description of intended clinical benefit(s) and safety, when used as intended. benefits to patients with relevant and speci- advanced products in `` Clinical evaluation: Systematic and planned fied clinical outcome parameters; the pipeline. process to continuously generate, collect, `` a specification of methods to be used for analyze, and assess the clinical data pertain- examination of qualitative and quantitative ing to a device. aspects of clinical safety with clear reference • The technical documentation (Annex II) must to the determination of residual risks and be updated continuously side-effects; • Labeling requirements have been massively `` an indicative list and specification of param- increased eters to be used to determine, based on the • Notified bodies (NBs), manufacturers, and state of the art in medicine, the acceptability importers will have to be registered (MDR of the benefit-risk ratio for the various certificate) indications and for the intended purpose or purposes of the device; • Installation of a scrutiny procedure for NBs (class IIb and III devices) `` an indication how benefit-risk issues relat- ing to specific components such as use of • A Unique Device Identification (UDI) will be pharmaceutical, non-viable animal or human required tissues are to be addressed; and • Extension of the EUDAMED Database `` a clinical development plan indicating pro- `` Access to competent authorities, manufactur- gression from exploratory investigations (such ers, NBs, and the public. as first-in-human studies), feasibility studies, `` Display of certificates, vigilance reports, and pilot studies to confirmatory investiga- clinical investigations, PMCFs. tions (such as pivotal clinical investigations), • Harmonized evaluation of high-risk devices and a PMCF as referred to in Part B of this Annex with an indication of milestones and a Clinical Evaluations description of potential acceptance criteria Class III and implantable devices must have Demonstration of clinical evidence is not a new clinical data derived from clinical investigations requirement. Under the aforementioned MDDs, that were conducted under the supervision of a lower risk devices were required to have clinical sponsor. Those clinical studies need to follow Good evaluation reports (CERs) and higher risk devices Clinical Practices (GCPs), such as those outlined in had to present clinical data. CERs are still required ISO 14155:2011 from the International Organization (Annex XIV, Part A) but the content is changing. for Standardization and in the Medical Association In addition to CERs, a public summary of safety Declaration of Helsinki on Ethical Principles for and clinical performance (Article 32) is now Medical Research Involving Human Subjects. Com- required for certain types and classes of devices. pliance with the Charter of Fundamental Rights of This summary is expected to consider diagnostic
October 2017 28 Clinical Researcher As a result of the new MDR, many adjustments will be required in the roles and responsibilities of all involved in manufacturing and distribution of medical device products into Europe.
the European Union, which governs personal data Core data elements must be submitted to the References protection, is required as well. UDI database prior to placement of a device on the 1. Regulation (EU) 2017/745 of the European Currently marketed devices will not be market, and the devices and the device packages Parliament and of the automatically grandfathered into the new MDR must have UDIs visible via an approved UDI carrier Council of 5 April 2017 without need for further clinical investigation or [e.g., a bar code accompanied by Human Readable on medical devices, amending Directive documentation. In the case of implantable devices Interpretation (HRI)]. 2001/83/EC, Regulation and class III devices, clinical investigations shall be (EC) No 178/2002 and Regulation (EC) No performed, except if (under Article 61): EUDAMED 1223/2009 and repealing • the device has been designed by modifications Council Directives 90/385/ Several articles in the regulation address require- of a device already marketed by the same EEC and 93/42/EEC ments to register information electronically under manufacturer; 2. Regulation (EU) 2017/746 EUDAMED, as part of the MDR, for the economic of the European Parliament • the modified device has been demonstrated to operators. The European database on medical and of the Council of be equivalent (to be endorsed by the NB); and 5 April 2017 on in vitro devices will be transformed into a public tool. diagnostic medical devices • the clinical evaluation is sufficient to demon- Previously, EUDAMED has been an information and repealing Directive strate conformity with the relevant safety and 98/79/EC and Commission repository exclusively accessible to national compe- Decision 2010/227/EU performance requirements. tent authorities and the European Commission. 3. http://ec.europa.eu/ From 2027 onward, the submission of a single The new MDR is now mandating use of this web- growth/sectors/medical- based portal for economic operators and notified devices/regulatory- application for a clinical investigation involving framework/revision_de multiple Member States will be established (compa- bodies to provide data related to various articles 4. Freunscht R, Clemens N. rable to the rules for pharmaceuticals coming into of the MDR, including clinical investigations and 2014. The new European 4 summaries of safety and performance for class III clinical trial regulation: force much earlier). administrative and and implantable devices. The database is expected to operational changes. Unique Device Identification (UDI) be operational in May 2020, but delays may occur. Clin Res 28(6):48–51. doi:10.14524/CR-14-0030 Requirements Conclusion There are many requirements associated with verifying a medical device product through the UDI The new MDR imposes significant changes, System, including an obligation to place relevant including verification of the Declaration of Confor- information on the label of the device and all higher mity and technical documentation, the addition levels of packaging. In addition, UDI device identi- of a designated person responsible for regulatory fiers (UDI-DIs) must appear on the EU Declaration compliance, verification that UDIs are properly of Conformity. used, new labeling requirements, demonstration of The European UDI System has been designed device conformity to regulations, and involvement to improve the traceability of medical devices in post-market surveillance. and IVDs, and to improve incident reporting and As a result of the new MDR, many adjustments oversight by the competent authorities. UDI will will be required in the roles and responsibilities be used to report serious incidents and field safety of all involved in manufacturing and distribution corrective actions. MEDDEV templates have been of medical device products into Europe, which are developed that will include numeric descriptions covered in articles 10–15 of the MDR. and UDI, with the task of keeping the list of UDIs Economic operators commercializing medical up to date being the responsibility of the manu- devices in the EU must be prepared to adopt facturer. Further, manufacturers of implantable these new rules, as “grandfathering in” will not be devices must provide UDIs on the devices’ accom- allowed. Each device must be certified under the panying implant cards. new rules in the transitional time frames that have been defined: with medical device manufacturers Norbert Clemens, MD, PhD, Annex V indicates a new UDI-DI is required CPI, ([email protected]) whenever there is a change that could lead to mis- having 36 months from May 26, 2017 to meet the is vice president for clinical identification of the device and/or ambiguity in its new requirements. operations with Impulse Time is flying, therefore it is important to start Dynamics Germany GmbH, a traceability, such as alterations of the brand name, past chair of the Association of the device version or model, in requirements for planning as soon as possible to be ready for the Board of Trustees for ACRP, numerous requirement changes. and a current member of sterile packaging or for sterilization before use, in the Board of Trustees for the the quantity of devices provided in a package, in Academy of Clinical Research critical warnings, or in contraindications. Professionals, an affiliate of ACRP for its certification programs.
Clinical Researcher 29 October 2017 [DOI: 10.14524/CR-17-4037]
OPERATING ASSUMPTIONS Ronald S. Waife
The End Beginning is the
egin with the end in mind” is one of those classic business “B medicine executive says we’re going to have a flood phrases which is no less valuable for the number of times it of pharmacogenomics data coming in, so let’s get is ignored. Clinical research sponsors are guilty of often fatal one of those “data warehouses.” forgetfulness of this key concept when planning the development, What’s missing from these situations is sufficient implementation, and use of new software applications or major consideration by the company of what the strategic benefits and daily operational impacts will be, what organizational change. the software’s users will have to change to use it properly, and overall what will the benefit be two years from now? What is the tie-in between the Clinical research sponsors generally start an initial impetus—the needle in the backside or the organizational change or a software acquisition not business trigger—and the actual output the change with the end results firmly planted in their minds, will provide? but with some “stimulus” having been applied to This disconnect is particularly critical in enter- their backsides: a department is complaining that prise software projects or major business acquisitions, everybody else gets new tools except them; the because we all know that the cost in money, time, competition changed its outsourcing model so headcount, and disruption will be high. The benefit the firm’s executives think it should too; someone therefore must be high as well, or the cost reduced, to met a smooth-talking salesperson on an airplane; be in line with the diminished (and realistic) results. a vendor just announced an upgrade and it won’t The good news is that analyzing a potential project’s support the old version anymore; the firm just hired end-user benefit compared to the initial impetus need a new vice president and she prefers vendor “X” not be fatally time-consuming, which is the usual over vendor “Y.” While some or all of these situa- reaction to the suggestion; however, it can save large tions may justify change, they do not in themselves amounts of wasted time and money. sufficiently define the “why” and “what.” We should recognize that it is very easy to fall into the disconnect trap. For instance, let’s consider Starting Isn’t the Hard Part the situation where clinical operations becomes Sponsors may also start from some business frustrated about the multiple investigator databases trigger which gives them the illusion that the end being used. The complaint is forwarded to the is in mind: we need to save headcount, so let’s use information technology department (or worse, a electronic data capture (EDC); or we’re frustrated naïf goes to a booth at a trade show), and the answer with having multiple overlapping and out-of-date comes back: there is no “investigator database investigator databases, so let’s buy a clinical trial fixer” product out there, but there are these CTMS management system (CTMS); we just acquired packages and boy, they do everything. Before you Teeny Biotech and we don’t have anyone in-house know it, you are installing a multimillion-dollar in its therapeutic area, or our new translational application over multiple years, you’ve doubled the
October 2017 30 Clinical Researcher amount of training everyone has to go through, engineers, they see and build it linearly (they begin How useful are e-tools and you have all this rich functionality, and no one at the beginning and end with the end). As a conse- can or wants to use it because it’s not relevant— quence, they inevitably run out of time and money if the “back end” of the neither to the original trigger or to the actual user before they reach the output function (reporting). workflow stays “paper- circumstances. How many times do we hear vendors do their I would suggest that even a good understanding demos this way: they start with the very first point minded” in its policies of how the end-user works, and what he or she of data entry, move through to the point everyone and procedures, needs, is not sufficient in today’s business envi- is waiting for (getting something back for all that ronment. We have fewer and fewer in-house staff, entry), and then they say, “well, there was no point reflected in unchanged we are narrowing our “distinctive competencies,” in re-inventing a report writer, so you should use we have uncertain economic and reimbursement something standard and off-the-shelf.” The “data workflows, double- conditions, and we have unrelenting competitive out” are what matter in the actual business context, checks, and review pressures. All of this mitigates against expensive but to a software engineer it looks like a data pro- multiyear infrastructure projects unless we cessing problem, not a business use problem. If this practices? do more to predict and understand the future were true, and off-the-shelf reporting was adequate, end-user business need. What should the future so too would be off-the-shelf entry—so actually, identity, purpose, and constitution of our business let’s forget the whole thing; and yet there really look like, and therefore, what changes and tools do is a utility for clinical research–specific software we need to get there? products, if built with the end in mind. Even for projects where the pain and the Today’s software vendors need a knowledgebase solution appear more clear and pragmatic, we are and a discipline not commonly found. The need for usually missing a robust and detailed visualization vendor domain knowledge is greater than ever, plus of how a tool will be used, and without this, we will an understanding and vision of where their custom- misconfigure and misspend our time and money. ers are going. Certainly, sponsors have the bulk of For instance, how does a shift to outsourcing the responsibility in teaching this, but for the ven- change who the users are for a CTMS, document dors, the discipline is in rejecting enhancements for management system, EDC, and similar programs? enhancements’ sake and leading their customers How useful are e-tools if the “back end” of the toward being enabled to handle the future. workflow stays “paper-minded” in its policies and procedures, reflected in unchanged workflows, Is There an End? double-checks, and review practices? Another way that clinical research sponsors get ahead of themselves is to assume that once the first And Vendors, Too wave of interest and urgency is sated, the project The developers of software used in clinical is done. This is hardly the case. Yes, processes may research are equally guilty of forgetting the context have been rewritten, software configured, and of how customers use their tools. Vendors have newly reorganized staff trained in their altered great opportunities to add significant value to their jobs, but the work does not, and cannot, stop there. customers by helping sponsors see the possibili- The second and third waves of change wash over ties that their tools open up, and by knowing the the organization as the “lower priority” staff need clinical research business as deeply and broadly to be oriented, and as the new processes need to as possible. This knowledge should translate into be iterated to reflect actual experiences versus the more focused and anticipatory designs, creating original assumptions. more powerful and efficient tools. Too often, how- It sounds like “continuous quality improve- ever, vendors and contract research organizations ment” for those sponsors who have process see educating their clients as a danger to future improvement staff. Except, for sponsors with such sales, and try to over-simplify change. staff, they themselves are moving from project Typical software development—even the to project—working continuously, perhaps, but industry-specific kind we in clinical research not necessarily improving. They too get bored (or usually encounter—tends to chase after customer- run out of resources) with the first wave of the driven enhancement requests that are often short- project, and are not there to reconsider the impact sighted for all the reasons cited above (responding and effectiveness of new work models or software to the “needle in the backside”). The result is applications. So, in some senses there is no end, but needlessly complex software with features even the rather steady re-examination of purpose, needs, requesting sponsors may forget they wanted! More and solutions. damaging than needless complexity is that the “Begin with the end in mind” is certainly the effort to chase enhancements takes money away start of a solution. “Begin with an understanding from the literal “end”—the output, reporting, and of the end” is probably more profound. Identifying visualization of information (which is all a tool is possible “ends” is one thing; understanding their really good for). meaning to the user and the enterprise requires This irony plagues each aspect of the research more thought, breadth, and management than most Ronald S. Waife (ronwaife@ waife.com) is president of software universe. Vendors may see the whole sponsors or vendors are used to providing. Waife & Associates, Inc. (www. gamut of functionality possible, but as professional waife.com).
Clinical Researcher 31 October 2017 [DOI: 10.14524/CR-17-0015]
Blind Spot in Clinical Trial Operations: Who is Watching?
PEER REVIEWED Nadina Jose, MD | Roshan Padbidri, MS | Suzette Cody, MA
Who is watching when clinical trial stakeholders—the sponsors, contract research organizations (CROs), and sites involved—are spread out doing simultaneous business on multiple trials across the globe? Who is watching to make sure that every individual clinical trial project is proceeding through its milestones with every possible issue and risk properly identified and responded to?
The assumed answer is usually everyone—as in in two studies. We reviewed the available data every stakeholder—and therein lies the problem. and results of interviews with the project team Everyone thinks everyone else is watching; how- during the January–May period in 2012. Several ever, the truth is, with everyone being overloaded unattended and unmitigated risks contributed to with information, it is not humanly possible to track delays in completion and increased budgets for every issue in real time. Study A (Oncology) and Study B (Diabetes) (see Mostly, issues are reported much later than is Figure 1). The issues listed below interrelate and ideal, and with little or inadequate action taken.1 impact each other, and many of them are broken Consequently, for example, one unattended query out for examination in the sections to come: could become the basis for escalated data manage- 1. Many unresolved queries2 (Study A alone ment discrepancies. Project delays and increases in had nearly 10,000 total queries) projected study budget are more the norm than the 2. Insufficient monitoring caused by inade- exception. More important than the consequent quate processes increase in cost is the painful loss of timely access 3. Lack of staff training to treatment by waiting patients. 4. Lack of documented communications A Tale of Two Studies among the stakeholders 5. Lack of structured handover Without disclosing either study’s profile, we 6. Insufficient vendor oversight illustrate the philosophy behind “Who is Watch- ing?” by describing the issues underlying delays 7. Insufficient contract oversight and tracking
October 2017 32 Clinical Researcher FIGURE 1: Time and Cost Analysis
DELAYS WITH SIGNIFICANT INCREASE IN COST, WHICH COULD HAVE BEEN AVOIDED…
2.5 2.5
2 2 31% 1.5 1.5 34%
1 1
0.5 0.5
0 0 Start January Ongoing Planned end Readjusted end Start September Ongoing December Ongoing December Planned end 2006 2009 February 2011 March 2013 2009 2010 2011 March – Delayed to September 2012 STUDY A – ONCOLOGY STUDY B – DIABETES
Additional Budget TIMELINES BUDGET Used Budget A: Delayed A: 31% increase from the planned study cost Available Budget B: Delayed B: 34% increase from the planned study cost
Unresolved Queries visits, it is essential to have processes to continue Although it is to monitor the quality of the data that the studies About 40% of the queries for Study A were repetitive are generating. Since these were missing, several acceptable for long- in nature, and about 30% were more than nine quality issues were overlooked, including monitor- months old with no apparent documentation of term studies to have ing of critical data points. reasons for the delay in being addressed. Multiple Monitoring data deficiencies were mainly due a reduced number of changes of project managers and local country to limited onsite visits. Case report forms (CRFs) operations teams were the immediate reasons for visits, it is essential that were sent to data management did not undergo unresolved queries. Lack of query details in project source data verification (SDV), resulting in repeated to have processes to management and communications documents queries. with the data management vendor also helped to Other issues were related to delayed completion continue to monitor worsen the condition of outstanding queries. of CRF (e.g., data entry was delayed for almost For Studies A and B, contracts failed to ade- the quality of the data one year in some cases, thus query resolution was quately establish thresholds or specify how to man- also delayed). Changes in principal investigators that the studies are age the numbers and kinds of queries. Unresolved in some institutes occurred without proper queries alone resulted in an increase in change generating. handover and documentation. In addition, on the orders that then increased the budget. Further, specific datapoint of efficacy, the follow-up data there were no interim face-to-face meetings or to treatment outcomes were missing; names of communication between the key clinical trial sites concomitant medication were missing and not and the sponsor or monitoring staff. Reviewing the reconciled; and safety database reconciliation was communication logs, particularly where minutes never performed. were kept, revealed that regular communications The resulting delayed interim analysis was were nonexistent. costly because the needed data for planned conference publications were not available. This Insufficient Monitoring postponed product launches and key opinion Both studies lacked sufficient monitoring visits and leader engagement activities. well-defined processes. Although it is acceptable for long-term studies to have a reduced number of
Clinical Researcher 33 October 2017 Using innovative Lack of Training information generated should therefore be sufficient to support good decision making.”5 Since both were long-running studies in multiple technology that is While the intents of the FDA’s guidance and countries in Asia, the Middle East, and Eastern EMA’s reflection paper are similar, two major issues the personification Europe, several regulatory and pharmacovigilance are noted with the adoption of the tenets of both changes occurred. Training related to new regu- of a well-trained, documents: interpretation and implementation. lations, policies, and standard operating proce- Depending on the functional structure of a cost-oriented, and dures (SOPs) was not implemented in real time at sponsor’s or CRO’s project team, there is a shift from several clinical sites in different countries, which independent (human) 100% SDV with frequent face-to-face interaction resulted in protocol deviations such as missed with a site team to a more targeted and less frequent visit windows, noncompliance to study product quality checker in a approach to monitoring visits. The decision-making intake, and inadequate safety reporting. Correcting process on how to adopt the guidance hinges upon complicated assembly these deficiencies required time-consuming and first tweaking conventional, proven, and tested resource-intensive efforts. Lack of a proper training line, but a hundred processes (re-prioritizing the budgets that come matrix and poor delivery of the existing training with them), and then to assume that the expected times better than any were at the root of this issue.3 outcome of the tweaked actions will yield the same human, is no easy task. result. Unfortunately, this is not the case. Lack of Stakeholder Communication Updating processes is not the only key that Our analysis of the issues also revealed a lack defines compliance with both the guidance doc- of proper communication channels to not only ument and the reflection paper. For the paradigm address the issues, but to determine their severity. to shift, the mindset must change. Along with Had there been proper risk monitoring through this change must come acceptance of the initial quality tracking or oversight, the issues could have increase in cost to leverage new or already available been identified and resolved in a timely manner. technology. A robust quality oversight system would The cost of change will not be readily visible have prevented the delays and increased costs until a few years down the line. In performing the experienced during both studies. By applying the root cause analysis and identifying the factors spirit and concept behind the U.S. Food and Drug that contributed to the increase in cost and delay Administration’s (FDA’s) guidance on risk-based in completion of the studies mentioned earlier, monitoring and the related European Medicines it became more evident that it was only after the Agency’s (EMA’s) reflection paper, the study company decided to retrospectively review its owner—a major pharmaceutical company—could processes and identify the gaps that things became have alleviated the situation by combining the right more obvious. technology with trained personnel. The old adage of “learning from one’s mistake” In 2012, the FDA encouraged “sponsors to not only resounded clearly, but also highlighted the develop monitoring plans that manage important fact that in today’s current clinical trial manage- risks to human subjects and data quality and ment environment, staying ahead and being first to address the challenges of oversight in part by taking market must take into account changing attitudes, advantage of the innovations in modern clinical tri- refocusing on standardized training, increasing als. The FDA asserts that [RBM] could improve spon- reliance on utilizing technology-savvy resources,6 sor oversight of clinical investigations.”4 Further, in and reconfiguring budgets to include (during the 2013, the EMA came out with its own views on RBM start-up phase) technology that can do half the for quality purposes in clinical trials, in a paper that work for people who will be spending more of their states the purpose is “to encourage and facilitate the time in-house or homebound versus continuing to development of a more systematic, prioritized, risk- work as “road warriors.” based approach to quality management of clinical trials, to support the principles of Good Clinical Quality Oversight Technology Practice and to complement existing quality prac- Finding the technology these days that best suits tices, requirements and standards. Quality in this what project teams need is like differentiating context is commonly defined as fitness for purpose. between wheat and rice noodles in a bowl of soup. Clinical research is about generating information to Technology platforms from different vendors have support decision making while protecting the safety major similarities in vision, and all promise to track and rights of participating subjects. The quality of and trend in as close to real time as possible.
October 2017 34 Clinical Researcher Using innovative technology that is the remain mostly unidentified. Who can quantify the The industry’s tradition personification of a well-trained, cost-oriented, loss of life or diminishment in quality of life due to and independent (human) quality checker in a delays in terms of improved treatments reaching of using mostly batch complicated assembly line, but a hundred times market? data transfers is not better than any human, is no easy task. The sponsor The prevailing cost of a clinical trial program for is the best stakeholder to utilize such technology, the development of a single new drug could range effective in helping since other than the patient, the sponsor is the most from millions to billions of dollars.10 Only the big improve data-driven impacted by delayed clinical trials and consequent pharmaceutical companies will long be able to increase in budget allocation. manage this because they have the resource, but decision-making The ability of the sponsor’s clinical research even these firms are complaining; their investment team to use, at any time of the day and night, their must translate to bigger returns, thus costlier abilities. With QROT, smart phones or tablets to check the status of their drugs.11 The ones who are excluded from the big however, tracking studies in real time is to this day still in question. trials are the small, innovative pharmaceuticals The goal of being able to rely on technology to see and biotechnology companies, and it is difficult for quality and risk the number of queries, or patients enrolled, or risks them to compete due to cost; however, they could indicators (including identified and graded, as well as the cost for each be the source of life-improving drugs and devices. activity and the site’s actual performance remains financial data from on the project team’s wish list. To date, project Quality and Risk Oversight Tracking enterprise solutions) teams are still dependent on reports being spit out (QROT) by data management or study management systems in real time is very QROT12 is the use of Big Data analytics and purchased by their companies, or must rely on valuable in assessing Excel spreadsheets as their backup.7 patient-centric solutions that are transparent, and that promote integrity with the ultimate goal of The questions remain: How can innovative cost and performance bringing medicines swiftly to patients at affordable treatments be made available faster and improve prices (see Figure 2). The industry’s tradition of of projects any time of the trends toward disease management? How do using mostly batch data transfers is not effective in we ensure that both data quality and the means of day or night in smart helping improve data-driven decision-making abil- collection are reliable? ities. With QROT, however, tracking quality and risk With a new political administration in the U.S. devices. indicators (including financial data from enterprise and with forecasts of deregulation in the FDA8 solutions) in real time is very valuable in assessing leading to faster cheaper drug development, a cost and performance of projects any time of day or system that functions as an independent quality and night in smart devices. risk tracker may be needed more than ever to ensure the “no blind spots” mentality. Any risks or quality issues detected compromise clinical trial safety and efficiency without timely responses. Hence, such a system should be configured to be able to track and FIGURE 2: Quality and Risk Oversight Tracking trend issues in as close to real time as possible. Com- pany and site processes will need to be reviewed and QUALITY OVERSIGHT—WHO IS WATCHING? enhanced to adapt to the changing landscape. There is an opportunity for the FDA to once End-to-end, real-time, risk-based oversight of again focus on its mission of ensuring that patients the industry process using a fresh approach have access to better drugs faster and at lower cost.9 For years, the agency appeared risk averse, because it is answerable to Congress and the public when risks of adverse side effects from approved drugs PLANNING STUDY CONDUCT PRODUCT LAUNCH become apparent. FDA’s risk aversion converts to complicated • Forecasting • Site management • Submission regulations that contribute to delays due to lack of • Budgeting • Data management • Publications resources at sites to comply with the regulations, • Risk management • Safety management • Life cycle management or due to failures to fully understand the intents of planning the regulations on the parts of clinical trials teams. Meanwhile, as the clear victims of side effects are Technology + Trained Staff accounted for, those patients who have yet to access Pharma/Biotech, CROs, Sites or even know of better drugs to improve their lives
Clinical Researcher 35 October 2017 This QROT concept is further exemplified by the References 8. Wechsler J. 2016. 1. Getz KA. 2011. Low Biomedical R&D faces Quality Management Institute, which ascribes to new regulatory policies 13 hanging fruit in the fight having a “Zero Defect Attitude.” As applied to the against inefficiency. App and priorities. App Clin process of QROT, this attitude means that having Clin Trials 20(3). www. Trials 25(12). www. appliedclinicaltrialsonline. “pride of workmanship” leads to people doing appliedclinicaltrialsonline. com/low-hanging-fruit- com/biomedical-rd-faces- things right for the client, and delivering as close to fight-against-inefficiency new-regulatory-policies- and-priorities what was promised as accurately as humanly pos- 2. Medidata Solutions. EDC sible. Adopting a “Zero Defect Attitude” empowers autoquery rate – a marker 9. Brennan Z. 2015. Amended for site quality. 2012. App ICH GCP guideline project teams to focus on using solutions that can Clin Trials 21(10). www. addresses evolution of diminish possible deficiencies. appliedclinicaltrialsonline. trials landscape. Regulatory com/edc-autoquery-rate- Focus. www.raps.org/ marker-site-quality Regulatory-Focus/ News/2015/09/29/23282/ Conclusion 3. Robinson M. 2012. The Nadina Jose, MD, (nadina. Amended-ICH-GCP- GXP training guidelines: [email protected]) is Relating back to the case studies presented, the Guideline-Addresses- raising standards president and founder of Evolution-of-Trials- lack of quality oversight resonated from all the through competence- Anidan Group Pte Ltd. in Landscape/#sthash. based training. App Singapore. deficiencies identified. The underlying thought that M4A7cZxU.dpuf Clin Trials 21(12). www. followed was the need to avoid having the same appliedclinicaltrialsonline. 10. Sertkaya A, Wong HH, problematic issues arise again and again. com/gxp-training- Jessup A, Beleche T. The owner of the studies eventually embarked guidelines-raising- 2016. Key cost drivers of standards-through- pharmaceutical clinical on trying something different; using the outcomes competence-based- trials in the United States. from the root cause analysis as a tool to defend training Clin Trials 13(2):117–26. doi: 10.1177/174077451 4. U.S. Food and Drug the study budgets and to secure the use of a new 5625964 Administration. 2013. technology for quality risk oversight that tracked Guidance for Industry: 11. Adams CP, Brantner VV. and trended data as they came in. Oversight of Clinical 2006. Estimating the cost Two new, smaller scale studies were launched. Investigations—A of new drug development: Risk-Based Approach to is it really $802 million? This time, the project team used the information Monitoring. https://www. Health Aff 25:420–8. from the systems dashboard to closely monitor the fda.gov/downloads/Drugs/ 12. Mitchel JT, et al. progress of the studies. In the process of having a Guidances/UCM269919.pdf 2014. Three-pronged 5. European Medicines approach to optimizing more robust and updated tracking of how the stud- Agency. 2013. Reflection trial monitoring. App Roshan Padbidri, MS, ies were doing, they were also able to enhance their Paper on Risk Based Clin Trials 23(6):37–44. (roshan.padbidri@ Quality Management http://alfresco.ubm-us. SOPs, propose the continued use of the technology anidangroup.com) is CEO and in Clinical Trials. www. net/alfresco_images/ managing director of Anidan for quality risk oversight, and justify more training ema.europa.eu/docs/ pharma/2015/12/18/ Group Pte Ltd. for their project team. en_GB/document_ b2bc0683-9872-4e76- 82bc-e5a5838028b2/2014- After 12 months, these two new studies had library/Scientific_ guideline/2013/11/ 06ACT.pdf clear outcomes in terms of finishing on time and WC500155491.pdf 13. Quality Management within budget, and more importantly, being avail- 6. DiMasi J, Hansen R, Institute. Executive Bulletin able for publication per the targeted date. No more Grabowski H. 2003. The Archive. Q&A from QM price of innovation: Nation on Zero Defects blind spots were noted after adequate tracking had new estimates of drug Attitude©. http:// been initiated. development costs. J qualitymanagement Health Econ 22:151–85. institute.com/ebarchive/ EB111.aspx 7. Henderson L. 2017. The clinical trial of tomorrow. App Clin Trials 26(2). www. appliedclinicaltrialsonline. com/clinical-trial- tomorrow
Suzette Cody, MA, (suzette. [email protected]) is vice president and global head for business development and client relations management with Anidan Group Pte Ltd.
October 2017 36 Clinical Researcher Learning
Clinical Researcher 37 October 2017
Full Page Ad October Clinical Researcher ACRP outlines.indd 1 9/7/17 11:34 AM [DOI: 10.14524/CR-17-0013]
A Mixed Method Approach to Assessing Good Clinical Practice Computerized Online Learning
Clinical research translation requires a trained, well-prepared PEER REVIEWED workforce of clinical research professionals who can effectively Linda S. Behar-Horenstein, PhD conduct critical testing in clinical trials.1 However, trials funded Wajeeh Bajwa, PhD by industry and governmental sources have been criticized for H. Robert Kolb, RN, CCRC inconsistencies in the design, execution, analysis, and reporting of Alena Prikhidko clinical trial activity,2 even as development of new drugs, devices, and behavioral interventions is one of the most highly regulated endeavors in the United States.3
October 2017 38 Clinical Researcher Recently, the National Institutes of Health (NIH) mandated “all NIH-funded investigators and staff engaged in clinical trials research be trained in Good Clinical Practice (GCP).”
Management of clinical research at the site level The nonprofit Association of Clinical Research is largely delegated to study coordinators who may Professionals (ACRP), meanwhile, which offers a manage multiple studies for principal investigators variety of training, networking, and self-directed (PIs) with a high degree of autonomy. This takes resources to its members and other stakeholders place in an evolving interdisciplinary arena, where in the research community, has an on-demand complexity is the rule rather than the exception. eLearning platform designed to equip learners Importantly however, consistent requirements with the core concepts of GCP, among other topics.8 for providing and ensuring an appropriate level of Approximately 30% of CTSA institutions also qualifications do not exist. utilize ACRP training. A critical barrier to clinical trials is inconsistent— CITI and ACRP platforms introduce users to or even absent—competency-based training for all the clinical research environment and regulations. study personnel involved in clinical trials,4 even Whether or not the process of obtaining compe- as the Declaration of Helsinki opines, “medical tences is better achieved through online learning research must be conducted by individuals with or structured work experience and mentoring appropriate training and qualifications in clinical has not been shown.8 The purpose of the research research.”5 While training and education of research described here was to assess the quality of online staff is integral to the success of the team and the training in the ACRP and CITI learning platforms. studies they work on, standardization of training is A randomized, mixed-method, quantitative- limited.6 qualitative, sequential, explanatory design framed Training for research staff often takes place this study. Analysis of focus group data was used within isolated academic departments, where to corroborate, refute, or explain the results of the there is variable quality in the content delivery. survey. A competency tracking system to validate that staff have the knowledge and skills to meet data Participants and Their Preferences and safety standards may not be present. Further, Participants (interviewees) included volunteers inadequate training can lead to delayed startup, involved in human subject research at any level at unmet enrollment goals, poor data integrity, and a large, public university in the southeastern U.S. compromised research participant safety (e.g., that is part of the aforementioned CTSA program, during the consenting process), although clinical without differentiation for gender and race. After research professionals are held accountable for institutional review board (IRB) approval, partici- meeting these measures. pants were recruited by placing posters on campus and sending e-mails to various mailing lists used Background by the research community. A total of 128 partic- Recently, the National Institutes of Health (NIH) ipants were needed to provide sufficient power mandated “all NIH-funded investigators and staff analysis for this study. engaged in clinical trials research be trained in Consenting participants accessed a CITI- Good Clinical Practice (GCP),”7 the tenets of which developed online presentation on “GCP for Clinical are promulgated by the International Council for Trials with Investigational Drugs and Biologics Harmonization (ICH) and followed by researchers in (ICH Focus)” and an ACRP-developed online such locations as the U.S., Canada, European Union, presentation on “Good Clinical Practice: An Intro- Japan, and Switzerland. Many programs, such as duction to ICH GCP.” Each participant was paid the Collaborative Institutional Training Initiative $100 for completing the training modules and the A critical barrier (CITI), which provides peer-reviewed, web-based pre- and post-training surveys for both modules. to clinical trials is educational courses in research, ethics, regulatory After first completing the randomly selected oversight, responsible conduct of research, research training module and survey, participants then inconsistent—or even administration, and other topics pertinent to the completed the alternate training platform and absent—competency- interests of member organizations and individual survey a minimum of one week later. The Wilcoxon learners, rely on standardized training systems; 60 signed-ranks test was used to test for differences based training for of the 62 institutions supported by the NIH Clinical between the paired observations. Participants’ and Translational Science Award (CTSA) program responses determined their preference for one all study personnel currently use CITI training. of the learning platforms on student learning involved in clinical trials.
Clinical Researcher 39 October 2017 CITI and ACRP platforms introduce users to the clinical research environment and regulations. Whether or not the process of obtaining competences is better achieved through online learning or structured work experience and mentoring has not been shown.
variables including: (a) engaging, (b) ease of navi- This single focus group was conducted to better gation, (c) satisfaction with scenarios, (d) content understand participant experiences with the relevance, organization, and feedback, (e) hours to online learning platforms. Participants were all complete the online learning courses, (f) number female; two African American and seven White. of attempts to pass the module, (g) number of years This methodology relies heavily on the skills of the engaged in research, and (h) type of responsibility. moderator (interviewer) who: (1) introduces the Level of significance in testing was set at p ≤ .05. topic in the same way, (2) ensures the conversation Participants’ preference for the ARCP training remains on track, (3) collects data related to the was statistically significant on the variables of shared experiences among a group of partici- engaging (p ≤ 0.0003), ease of navigation (p ≤ pants, (4) develops an understanding regarding a 0.0205), and hours to complete the course (p ≤ phenomenon, and (5) encourages all participants 0.0006) (see Table 1). Compared to the mean of 2.3 to respond to questions (see Table 2).9–12 hours for the ACRP training, it took participants Three of the authors independently read the a mean of 3.26 hours to complete the CITI course. focus group transcript and formulated impressions Participants reported a preference for content of emergent themes. During a meeting, they organization and the opportunity for feedback in reached consensus on the emergent themes and ACRP. Those with a preference for CITI were slightly related conceptual definitions. Next, two authors more satisfied with the relevance of the content and selected two of the four themes and, while reading expended less time in passing this course. line by line, extracted selected text representative of the conceptual definition related to the theme. Focus Group Analysis These authors then audited each other’s analysis to indicate agreement or disagreement Further, 10 individuals were randomly invited from with selected text. Use of the constant comparative a pool of 132 participants for a focus group discus- method assisted in moving data to better fitting sion, with nine individuals eventually participating codes and codes to other categories or themes. and being compensated an additional $100. Partic- This process resulted in some themes coalescing ipants’ demographic information and responses to and others expanding; it involved coding, refining 22 survey questions were recorded in, and housed codes, identifying examples to support themes, at, secure servers. Participants were asked to: making a master outline to illustrate relationships, (a) indicate time taken to complete the training and locating quotations to support the outline. The modules, (b) preferred presentation style/method, third author resolved any differences in opinion. (c) satisfaction with the material presented, and (d) Four themes emerged, including: Self-Evaluation, satisfaction with the learning objectives. Missing Components, Deviations, and Preferences (see Table 3). Self-evaluation refers to assessing personal skill level. Missing components refers to TABLE 1: ACRP vs. CITI Learning Platforms on Student Learning Variables identifying content and topics not presented in the learning platforms. Deviations refers to pointing out Wilcoxon ACRP Mean CITI Mean Two-Sample Test protocol violations. Preferences refers to expressing Variable (Standard Deviation) (Standard Deviation) p-value (Two-Sided) predispositions for one of the two particular learning platforms. Engaging 2.23 (0.84) 1.69 (0.97) 0.0003 Due to space limitations in the print edition of Easy to Navigate 3.38 (0.92) 3.2 (0.65) 0.0205 this journal, the research team’s summary of the Satisfaction with Scenarios 2.33 (0.54) 2.25 (0.54) 0.4265 qualitative results from this portion of the overall research is shared as a supplemental document in Satisfaction with Relevance 2.41 (0.62) 2.43 (0.55) 0.9937 the “Good Clinical Practice & Ethics” Interest Group Satisfaction with Content 2.38 (0.58) 2.23 (0.57) 0.1338 hosted in the ACRP members-only Online Commu- Satisfaction with Feedback 2.21 (0.64) 2 (0.64) 0.0581 nity (see https://www.acrpnet.org/networking/ interest-groups/), and can be requested by Hours to Complete 2.3 (1.25) 3.26 (1.71) 0.0006 non-members by contacting [email protected]. Attempts to Pass Module 1.44 (0.62) 1.26 (0.44) 0.0961 Responsibility 1.98 (0.63) 2.1 (0.65) 0.3650
October 2017 40 Clinical Researcher Discussion Overall, the survey findings showed participants found the ACRP course more engaging, easier to navigate, and requiring less time to complete than the CITI course. Findings from the focus group confirmed those results. Notably, online training accentuated the integral role of the coordinator in ensuring the quality and veracity of research, and enhanced participants’ confidence levels. Also reported was how vastly different the training platforms TABLE 2: Focus Group Questions were in terms of content relevance, organization, applicability, and assessments. Inability to have 1. Which platform, CITI or ACRP, best addressed your training needs? face-to-face interaction was an impediment to 2. Which section or module was the most important to you? Why? observation, and prevented opportunities for spontaneous peer-to-peer and peer-to-instructor 3. Was there any element that was missing from either of these training modules that you feel would help you in carrying out your responsibilities as a coordinator? interaction. Other criticisms of the online learning plat- 4. How well did the CITI and ACRP platforms measure GCP competencies? forms were that the questions and scenarios 5. Can you recommend a platform for GCP training at the University of Florida: (a) CITI, (b) ACRP, (c) presented did not reflect the realities of day-to-day classroom, or (d) a combination? Explain why. work. The findings supported the notion that the 6. What essential skills or competencies for coordinator training and professionalization were not online learning platforms offered (a) no mecha- addressed in the GCP training program? nism to validate staff attainment of knowledge or 7. Has your confidence in your level of professionalization increased or decreased as a result of this GCP skills, (b) no evidence participants could consis- training program? Explain why. tently meet data and safety standards, and (c) no mechanism to ensure competency. 8. How has GCP training program influenced your role as a research coordinator? Overall, the findings highlight how obtaining 9. What aspects of the GCP training program influenced your own sense of being/becoming an ideal competencies cannot be solely achieved through research coordinator? online learning. Further research is warranted, 10. As a result of the GCP training how confident are you in: (a) Identifying ethical and professional including replicating this design to see if the conflicts in conjunction with clinical trials and (b) Bringing observed ethical/professional conflicts results are unique to our locale or if they will be within clinical trials to the attention of the PI or other designated authorities? similar at other CTSA institutions. 11. How often have you observed deviations in the last 12 months? Coordinators felt vulnerable in a culture (a) Did you bring this deviation to the PI’s attention? designed to protect institutions. Future research (b) If so, did you discuss it verbally, via e-mail, or through both methods? How did the PI respond? might be directed toward examining the inequal- (c) In other words, did the PI take your observation seriously and make the appropriate changes? ities and systems of power as they interlock (d) Did the PI simply acknowledge your concern, but not act on it? with GCP regulations in a “relational, dynamic, (e) Did the PI reject your observation of the deviation? processual, and mutually transforming character (f) How would you handle a situation where you observe a serious deviation, but the PI does not take [as found] in any system of power differentials.”13 any action?
Limitations The researcher-constructed survey was not a TABLE 3: Main Themes from Participants validated scale. Without established psycho- metrics, the utility of the study findings must be Themes Conceptual Definitions considered in the context of these observations. Self-Evaluation Assessing personal skill level Perhaps participants simply provided responses in Missing Components Identifying content and topics not presented in the learning platforms terms of what they believed was essential, selected responses they thought researcher sought, or Deviations Pointing out protocol violations over-rated their skills. The study was carried out at Preferences Expressing predispositions for particular learning platforms single health science center, representative of only one of the 62 CTSA hubs.
Clinical Researcher 41 October 2017 Consenting participants All nine individuals participated actively advantages and disadvantages. Participants during the focus group; however, it is possible showed a clear preference for the ACRP platform, accessed a CITI- some may not have felt comfortable voicing their and the ACRP course took less time to complete developed online opinion or may have felt pressure to conform to compared to the CITI course. the group’s consensus opinion. Overall, the focus The findings suggest that no single online presentation on group findings are not generalizable. Also, the training product adequately meets the guidelines “GCP for Clinical Trials number of questions asked was restricted; the set forth by ICH GCP or the intentions of NIH, in available response time for any participant to terms of developing a fully competent translational with Investigational answer each question was necessarily limited in workforce. Future research should determine how order to hear from everyone. Despite efforts made competencies can be effectively and efficiently -cer Drugs and Biologics to systematize data collection through use of a tified. Developing rubrics and criterion indicators (ICH Focus)” and an standardized protocol, the potential for moderator and calibrating raters will likely be the next steps. ACRP-developed online influence cannot be determined. Acknowledgments The authors want readers to know that we have Research reported in this publication was sup- presentation on “Good no potential conflict of interest with the products ported by the University of Florida Clinical and assessed in this study. Clinical Practice: An Translational Science Institute, which is supported in part by the NIH National Center for Advancing Introduction to ICH GCP.” Conclusions Translational Sciences under award number Although the CITI and ACRP platforms provide a UL1TR001427. The content is solely the responsibil- solid introduction to the clinical research envi- ity of the authors, and does not necessarily represent ronment and regulations, they are not without the official views of the National Institutes of Health.
References 5. World Medical Association. 8. Association of Clinical 12. Tracy SJ, Lutgen-Sandvik 1. Zerhouni EA. 2005. 2013. World Medical Research Professionals. P, Alberts JK. 2006. Translational and clinical Association Declaration of https://www.acrpnet.org/ Nightmares, demons science—time for a new Helsinki: ethical principles types/elearning/ and slaves: exploring the vision. NEJM 353(15):1621–3. for medical research 9. Greenbaum T. 2000. painful metaphors of involving human subjects. workplace bullying. Mgmt 2. Rosenberg RN. 2003. Moderating focus groups. JAMA 310(20):2191. Comm Qtrly 20:148–85. Translating biomedical Thousand Oaks, Calif.: Sage research to the bedside: a 6. Duane CG, Granda SE, Publications, Inc. 13. Azocar MJ, Ferree MM. national crisis and a call to Munz DC, Cannon JC. 10. Creswell JW. 2013. 2016. Engendering the action. JAMA 289(10):1305– 2007. Study coordinators’ Qualitative inquiry and sociology of expertise. Soc 6. perceptions of their work research design: choosing Compass 10(12):1079–89. experiences. The Monitor 3. Sparrow MK. 2011. The among five approaches. 21(5):39–42. regulatory craft: controlling Thousand Oaks, Calif.: Sage risks, solving problems, and 7. National Institutes of Publications, Inc. managing compliance. Health. 2016. Policy on 11. Creswell JW. 2014. Brookings Institution Press Good Clinical Practice Educational research: (Kindle edition). Training for NIH Awardees planning, conducting and Involved in NIH-funded 4. Sung NS, Crowley Jr WF, evaluating quantitative and Clinical Trials. NIH Genel M, Salber P, Sandy L, qualitative research (5th NOT-OD-16-148. https:// Sherwood LM, Rimoin D. edition). Pearson. grants.nih.gov/grants/ 2003. Central challenges guide/notice-files/ facing the national clinical NOT-OD-16-148.html research enterprise. JAMA 289(10):1278–87.
Linda S. Behar-Horenstein, Wajeeh Bajwa, PhD, H. Robert Kolb, RN, CCRC, Alena Prikhidko PhD, ([email protected]) is ([email protected]) is ([email protected]) is Assistant ([email protected]) a Distinguished Teaching Director of the CTSI Regulatory Director of Clinical Research is a doctoral candidate in Scholar and Professor with Knowledge and Support with the Translational Counselor Education in the the Colleges of Dentistry, Program at the University of Workforce Directorate and a College of Education at the Education, Pharmacy, and Florida. Research Participant Advocate/ University of Florida. Veterinary Medicine and Consultant for the Regulatory Director of CTSI Educational Knowledge, Research Support, Development and Evaluation and Service Center at the at the University of Florida. University of Florida.
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Clinical Researcher 43 October 2017 PEER REVIEWED | Kelly M. Cairns, MA, BASc, APRM, CCRA [DOI: 10.14524/CR-17-0030] PINION: The Role of Certification in Developing a Quality Clinical Workforce
“Quality” is a term that is thrown around at will when speaking about clinical research— we speak of quality by design, quality systems, quality endpoints, quality management plans, quality data, quality outcomes, etc. We have been talking about quality for as long as I have been involved in clinical research, and that has been for more than 20 years.
The goal of One thing I’ve noticed in the clinical research Why Certification? enterprise is that we spend a lot of time focusing There are some obvious benefits to an individual certification is not on quality goals, quality outcomes, and quality from becoming certified (see Figure 1). Achieving processes, yet we spend very little time focusing on to educate, but to certification demonstrates that you have met or “quality resources” and—in particular—“quality exceeded the quality standards required in the provide a means by human resources.” I would like to focus our atten- industry and have validated your competence. It tion in this article on the importance of the “quality which proficiency furthermore demonstrates a level of profession- clinical workforce.” alism and indicates a commitment to quality and knowledge can As used in various situations, the word quality standards. may convey the standard of something as measured In essence, certification defines you as a be measured, hence against other things of a similar kind; the general “quality resource” in your industry. As specifically degree of excellence of something; or a distinctive measuring “quality.” considered within the clinical research enterprise, attribute or characteristic possessed by someone there are many pros to certification, including how or something. As nebulous as these uses may be, it improves the conduct and public perception of how do we measure quality when we are speaking research by establishing and continually raising about the “workforce” or human resources? That the levels of quality to which we are held. More is where certification comes in, as certification is pointedly, sponsor companies and study sites are a formal recognition of professionals who have able to use certification as a yardstick by which demonstrated the knowledge, skills, and abilities to they can have their quality resources assessed and perform their duties by passing a certification exam measured. based on international standards. Further, certification is a voluntary process to recognize individuals for meeting standards Sources of Certification in terms of their professional experience, and for Currently, there are several organizations that offer achieving educational requirements before taking clinical research certification. To date, the Associ- the exam. Certification assures the public that ation of Clinical Research Professionals (ACRP) is an individual demonstrates specific knowledge the only organization that offers role-specific cer- required of a practitioner at a certain level. The tification programs (through its affiliated Academy goal of certification is not to educate, but to provide of Clinical Research Professionals) for the clinical a means by which proficiency and knowledge can research coordinator (CCRC®), clinical research be measured, hence measuring “quality.” associate (CCRA®), and principal investigator (CPI®)
October 2017 44 Clinical Researcher FIGURE 1: REASONS BEHIND CERTIFICATION
22.9% In time, perhaps roles, as well as a general certified professional (ACRP-CP®) program since 2017 for anyone who regulatory does not neatly fall into the other roles. Validates stakeholders around Other organizations, such as the Society of Clinical Research Associates, offer more generic certi- Job-Specific the world will also fications covering multiple roles and functions. Many Competencies other organizations offer various types of role-specific embrace certification certifications such as the Society for Clinical Data as a quality Management, the Society of Quality Assurance, the Clinical Research Society, and the Regulatory Affairs measurement, and will Professionals Society, to name a few. deem that certification Any respectable organization that offers certification will take the steps necessary to ensure of anyone performing that certain levels of quality have been achieved 19.4% clinical research through their programs. Although ACRP may have led the way in the certification of clinical research Promotes Professional activities be required. professionals, there have been other organizations that have followed—not because any higher Standards authority mandated it, but because their members asked them to. In time, perhaps regulatory stakeholders around the world will also embrace certification as a quality measurement, and will deem that cer- tification of anyone performing clinical research activities be required. This may be “pie in the sky” 18.4% FIGURE 2: thinking, but it would go a long way toward making our study volunteers feel confident that they are MAINTENANCE OF being protected and are in “good hands.” Indicates Profession CERTIFICATION Maintenance of Certification Growth Maintenance For those of us who have achieved certification, equally as important is the subsequent mainte- • Ongoing validation nance of the designation. Throughout our careers, of knowledge and skills we want to continue to demonstrate that we are meeting or exceeding the quality standards set • Keeps current with changes in by the industry. Maintenance can be achieved 14.6% industry through continuing education in both research- and healthcare-related subjects, as well as through Job Mobility continuing involvement in clinical research activities. Certification Since most individuals would prefer not to have to take a certification exam over again following • Baseline assessment of key a lapse in their certification status, the option for competencies continuing education and continuing involvement 14.1% • Reflects current is the more popular one, and the benefit to the practice industry is the assurance that certificants are Personal staying abreast of the latest and greatest trends and topics in clinical research. In short, maintenance Accomplishment of certification validates that certificants continue to demonstrate their knowledge and skills as their Knowledge careers progress (see Figure 2). and Skills Employer Requirement6.8% Source: Survey of ACRP Certificants (January 2013 - April 2014)
Clinical Researcher 45 October 2017 FIGURE 3: INDICATORS OF CERTIFICATION’S CONTRIBUTIONS TO SITE PERFORMANCE
Average Amount of Average Reported Average Number of Total Study Grants Operating Profit Clinical Trials Initiated Invoiced in 2013 in 2013 in 2013
18.2% 20.9 $1,613,281 13.9% $466,690 6.9
Fewer Certified Staff More Certified Staff Source: CenterWatch/ACRP Site Benchmarking Survey (2014)
Linked to Fewer Protocol Other Considerations for Certification himself or herself. In fact, misrepresentation of Deviations one’s certification status through ACRP is grounds As the clinical research industry has become more CCRC® and CPI® certification for disciplinary action through the aforementioned competitive, the need for its professionals to differ- have the potential to Academy of Clinical Research Professionals, entiate themselves from one another has become increase protocol adherence according to its “Code of Ethics and Professional and improve clinical trial a more cogent reality. The use of credentials to Conduct” policy. quality through links to demonstrate certification has become increasingly fewer protocol deviations This, once again, points to the fact that certifi- important when trying to promote one’s curricu- (Clinical Research and cation is formal recognition of professionals in the lum vitae to the top of the pile. Regulatory Affairs, 2009). industry who perform at or above a certain quality Unfortunately, there has been some rather neg- standard. Prospective employers and regulatory ative press regarding resume fraud, and one recent, Linked to More Favorable inspectors can search a registry to ensure that any- controversial article cited that, out of more than Outcomes from one using the ACRP credential is actually currently 40,000 CRAs being captured by one recruitment Regulatory Audits certified. Falsifying credentials is a serious blemish firm, approximately 17% had falsified all or part of A positive correlation exists when it comes to tarnishing one’s quality reputa- between the CPI® designation their resumes. As a hiring manager in the industry, tion, and no one wants that. and favorable outcomes (No I too have witnessed my share of “creative writing” Action Indicated) for FDA Getting back to the issue of “quality,” it has been when it comes to prospective applicants. This is audits according to the article demonstrated that certification through ACRP has where certification can play a role in ensuring that “CPI® Certification as Predic- a positive impact on clinical trial quality surro- tor of Clinical Investigators’ those applicants presenting with the credential gates, such as stated at left. From the sponsor’s Regulatory Compliance” (Drug of “certified” can be held accountable to a higher perspective when looking at potential sites, quality Information Journal, 2012). level, and employers can be assured of a standard- plays a role. Studies have shown that having certi- ized level of quality. fied staff at a site leads to fewer protocol deviations ACRP takes the use of its credentials very and potentially increases trial adherence, and that seriously, and has strict policies pertaining to the a positive relationship can be seen between a certi- continued use of the “certification credential.” Any- fied PI and more favorable audit outcomes with the one who fails to maintain their certification must U.S. Food and Drug Administration (FDA). immediately stop using the credential to promote
October 2017 46 Clinical Researcher From a site’s perspective, we can see a positive join a clinical trial, the study coordinator doesn’t As the clinical research relationship between the number of certified need a license or to even be credentialed.” He has staff and the number of study grants received, a very good point; does it seem right that we place industry has become the operating profit achieved, and the number of so little value on quality when it comes to clinical more competitive, the clinical trials initiated (see Figure 3). These site research? performance metrics are all very important when To be sure, there are certain jurisdictions need for its professionals trying to attract studies to your site; certification around the globe where qualifications for clinical to differentiate can therefore be seen as an investment in the research are taken more seriously. In some coun- professional development of a site’s research per- tries, for example, study coordinators must hold at themselves from one sonnel and the site’s commitment to quality in the least a bachelor’s degree, but this is not universal. conduct of clinical trials. The return on investment Unfortunately, we have a long way to go to stan- another has become a for a site from having certified staff can be easily dardize these requirements on a global scale. more cogent reality. demonstrated. Ultimately, if we want to improve the quality of Furthermore, certification can be used as a research, then industry needs to come together to proxy for improved outcomes, which can be demon- make sure we have competent “quality resources” strated through adherence to the protocol, com- and a “quality workforce” conducting our clin- pliance with the regulations, ethical practice, trial ical trials. There is an ever-increasing wealth of subject safety, and ultimately end-consumer safety. evidence as to why we need these quality human With respect to our quality clinical workforce, resources—among it, the fact that the equivalent of certification can be used as an acceptable method a bad haircut in clinical research can be deadly. to validate that study coordinators, monitors, inves- tigators, and other clinical research professionals have the knowledge, skills, and abilities fundamen- tal to accomplishing their job roles. As the arena of certification products offered through various organizations expands, there is a recognized need for more formal study of the Resources ACRP (2017)—Blog entry on “Guest Blogger Addresses impact on quality from the perspective of the site, ACRP (2005)—Article on Clinical Trial ‘Fraud’ the sponsor, and ultimately the patient. For now, “ACRP Certification of Clinical Controversy.” https://www. Research Professionals.” The the ship is moving in the right direction. acrpnet.org/2017/06/29/guest- Monitor 19(4):45–9. blogger-addresses-clinical- ACRP (2013)—Article by trials-fraud-controversy/ Conclusion Morgean Hirt on “Why CenterWatch (2017)—Three Certification Should be Now that we know what a quality resource is, we Questions: Jim Kremidas, ACRP. Important to Employers.” The CWWeekly 21(27). https://www. can measure that quality through certification. Monitor 27(2):67–9. acrpnet.org/2017/07/11/three- We also can demonstrate continued commitment ACRP (2013)—Article by Dennis questions-jim-kremidas-acrp/ R. DeRosia on “We Are Not to quality through maintenance of certification, Sage Journals (2012)— Alone.” The Monitor 27(6):77–9. and we are now moving to a more data-driven Article by David M. Vulcano place whereby we can demonstrate improvements ACRP (2014)—Data collected on “CPI™ Certification from surveys of ACRP as Predictor of Clinical in quality through the use of “quality human certificants (January 2013–April Investigators’ Regulatory resources.” 2014); n=1,516. Compliance.” Therapeutic Certification can be a valuable resource for a Innovation & Regulatory ACRP (2014)—CenterWatch/ Science 46(1):84–7. http:// variety of stakeholders to validate that the clinical ACRP Site Benchmarking journals.sagepub.com/doi/ research professionals with whom they are Survey. https://www.acrpnet. abs/10.1177/0092861511427862 org/resources/financial- engaging—in whatever relationship that may be operating-benchmarks- Taylor & Francis Online (i.e., site-sponsor, sponsor-employee, site-employee, investigative-sites/ (2009)—Article by Jean-Marc C. Haeusler on “Certification etc.)—have the knowledge, skills, and abilities ACRP (2017)—Code of Ethics Kelly M. Cairns, MA, BASc, in good clinical practice APMR, CCRA, (kelly.cairns@ fundamental to their role, and that they truly are and Professional Conduct. and clinical trial quality: A https://www.acrpnet.org/ boehringer-ingelheim.com) a quality human resource and part of the “quality retrospective analysis of is Leader of Clinical Trial about/code-of-ethics/ protocol adherence in four clinical workforce.” Operations for Boehringer ACRP (2017)—Blog entry on multicenter trials in the Ingelheim Canada Ltd. and In a recent CenterWatch publication, ACRP “Is CRA Fraud Undermining USA.” Clinical Research and the 2017 Chair of the Board of Executive Director Jim Kremidas stated, “If you get Clinical Trial Integrity?” https:// Regulatory Affairs 26(1-2):20–3. Trustees for the Academy of www.acrpnet.org/2017/06/05/ www.tandfonline.com/toc/ Clinical Research Professionals, your hair cut, the barber cutting your hair must cra-fraud-undermining- icrr20/26/1-2?nav=tocList ACRP’s affiliate body for its have a license. In many parts of the world, if you clinical-trial-integrity/ certification programs.
Clinical Researcher 47 October 2017 ACRP MEMBER PROFILE: SHIRLEY TRAINOR-THOMAS
Why did you enter the clinical Personal or professional research field? heroes: Like many, I fell into the clinical Amelia Earhart, because of her adven- research space. Most of my career has turist spirit. been in healthcare management, and I Margaret Thatcher, because of her paid little to no attention to clinical trial ability to command and her absolute activity. So, it’s ironic that my focus determination. now is on educating healthcare leaders about the benefits of having a clinical My grandmother, because she taught trials program and guiding them on me to be strong and always find a how to operate one as a business. reason to laugh. TITLE: I am not a clinician, but function on Favorite quote: the business and marketing side of Do right. Do your best. Treat others as Shirley Trainor-Thomas, MHSA clinical research, and believe that you want to be treated. – Lou Holtz Chief Strategy Officer, GuideStar clinical trials should be available to patients at their local healthcare Hobbies: HOMETOWN: facilities. I also believe if the proper structure exists to support physicians, Boating, fishing, and golf (because, Charleston, S.C. more would become involved. you know, I live in Charleston!). I have become passionate about LIVE NOW: People would be surprised enlightening healthcare leaders about to know that: Charleston, S.C. the strategic, financial, and quality benefits trials bring to a healthcare My undergraduate degree is in Jour- organization; but more importantly, nalism. I certainly didn’t take a normal about the impact offering trials at path to clinical research! a local level makes on the future of healthcare. Reason for joining ACRP: I joined ACRP because I saw a wave of What is your favorite positive change, with a strengthened part of research? commitment to a broadened popu- I always take delight in seeing the lation—not just the clinicians, but to eyes of a hospital or health system those who have been in the clinical CEO light up the moment the benefits trial industry in supportive roles. of clinical trials “click” with them. My life philosophy: They become excited and supportive— especially in these days of tightening Humor, honesty, and undying hope are belts—and it’s nice to see some essential tools of life. administrators ramping up research efforts because they believe in it from both the altruistic and business perspectives. They also get excited about the possibility of participating in trials that can change the current standard of care.
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Regulations, Competent Authorities, and Compliance in the News
FDA’S GOTTLIEB PROMISES EUROPEAN MEDICINES AGENCY FDA OFFERS TIPS ON WHAT AGENCY WILL HELP SPEED RELEASES FIRST-IN-HUMAN TRIGGERS INSPECTIONS CLINICAL TRIALS TRIAL GUIDELINES Clinical trial sponsors, clinical It’s not going to be The European investigators, and business as usual at Medicines Agency institutional review the U.S. Food and (EMA) recently boards often struggle Drug Administra- unveiled a guidance to understand what tion (FDA) going for first-in-human most often triggers a forward, new clinical trials U.S. Food and Drug Commissioner Scott designed to help Administration (FDA) inspection—espe- Gottlieb told stakeholders cially one that is unannounced. attendees of the RAPS (Regulatory Affairs identify and address risks for trial The prospect of an unannounced FDA Professionals Society) 2017 Regulatory participants. inspection can loom over a clinical trial Convergence conference on September 11. “Participants in these trials, often site. While the vast majority of inspections There are many areas where the healthy volunteers, face an element of are prescheduled, FDA is more likely to agency wants to increase its activity, risk as the ability of researchers to predict arrive without warning if the inspection Gottlieb said. For example, the agency the effects of a new medicine on people was assigned as a result of information needs to more proactively work with all is limited before it is actually studied in that raises concern about the site, such stakeholders in clinical trials to get them humans,” EMA said in a press release as about the adequacy of its subject to cooperate with one another and better accompanying the new guidance. protection measures, or issues with data share information. The FDA is pushing The revision, years in the making, is integrity, and/or a history of problems with many new initiatives Gottlieb believes also designed to recognize the increasing the inspected party, FDA officials say. will speed trials and improve efficiency complexity of clinical trial protocols FDA inspections of entities involved and efficacy. Members of clinical over the past decade. Studies now often in clinical trials are considered biore- research teams can look for a number include different subsections within search monitoring (BIMO) inspections, to of agency guidances and open meetings a single clinical trial protocol that are differentiate them from the manufacturing on a variety of topics over the next 12 aimed as assessing such factors as inspections more commonly conducted months, Gottlieb advised. single- and multiple-ascending doses, by FDA inspectors. FDA BIMO inspections FDA is also committed to modern- food-drug interactions, or a drug’s effect are usually preannounced. izing how it collects trial information, on members of different age groups, EMA In most cases, the FDA investigator supporting intelligent use of adaptive noted. contacts the site and suggests a date for approaches that can help to identify (Source: ACRP Blog, https://www.acrpnet. org/2017/08/09/european-medicines-agency- the inspection, rather than offering to patients less likely to suffer adverse releases-first-human-trial-guidelines/) schedule it. This usually occurs about five events during or after a trial, and that days prior to the date the FDA investigator promote “seamless” trials. In the latter, has chosen to start the inspection. In other Phase I, II, and III trials are hewn into words, they won’t call until they’re about a single trial with connective breaks ready to move. in-between the project’s transitional (Source: ACRP Blog, https://www.acrpnet.org/ movement through the trial process. 2017/08/30/fda-offers-tips-triggers-inspections/) (Source: ACRP Blog, https://www.acrpnet. org/2017/09/11/fdas-gottlieb-promises- agency-will-help-speed-clinical-trials/)
October 2017 50 Clinical Researcher SHOULD PHYSICIANS BE SOLELY staff to communicate information to PROPOSED NEW JERSEY RULE RESPONSIBLE FOR INFORMED patients as part of the informed consent COULD HAVE CHILLING EFFECT CONSENT? ONE STATE THINKS SO process, in addition to their personal ON CLINICAL TRIALS obligation to discuss the procedures and A recent Pennsylva- consent with the subject. A proposed new rule nia Supreme Court (Source: ACRP Blog, https://www.acrpnet. could have a decision has ruled org/2017/08/11/physicians-solely-responsible- chilling impact on that physicians, not informed-consent-one-state-thinks/) clinical trial their delegates, research in the state should obtain FDA WARNS AGAINST WELL- of New Jersey. It’s no consent for “… INTENTIONED BACKDATING stretch to imagine administering an You may have the similar bills experimental medication or device” (40 best motive and cropping up in other states. The rule P.S. § 1303.504). It is unclear how this will intent in the world would set a $10,000 cap on the amount a impact obtaining consent in a research when you backdate prescriber can accept from manufacturers setting. ACRP reached out to Glenda a clinical trial in a calendar year for bona fide services. Guest, vice president of Norwich Clinical document. You may Fair market payments for speaking Research Associates (NCRA) and member also still have a engagements at continuing education of the ACRP Association Board of problem with the events are excluded from this cap. Trustees, who offered some initial U.S. Food and Drug Administration “As written, this rule could have the thoughts. (FDA). unintended consequence of doing more According to Guest, this ruling will Example: A subject signs the wrong harm than good,” says Jim Kremidas, have a major impact on how physicians informed consent form (ICF) during a Executive Director of the Association of across Pennsylvania obtain informed screening visit. The study coordinator Clinical Research Professionals (ACRP). consent from their patients. In Shinal v. later realizes that a signed copy of the “New Jersey lawmakers may be trying Toms M.D., 2017 WL 2655387 (Pa. June 20, correct form is not among the subject’s to ensure prescribers are not influenced 2017), the court ruled 4-3 that only phy- source materials, and asks the subject to inappropriately by payments from sicians, not members of their staff, may fax him a signed copy of the correct ICF pharmaceutical companies, but this law obtain informed consent from patients signature page. A fax of the ICF signature could have unintended consequences on before performing medical procedures. page dated November 15 is filed in the the advancement of medicine.” Empha- Similar to the California Research subject’s source; however, the fax header sizing that research must be “pristine,” Subject Bill of Rights requirement, the shows that the fax actually arrived Kremidas worries that the current rule, situation in Pennsylvania is another several days later and yet the study as written, would hamper important example of state-specific laws of which coordinator’s signature is also dated clinical trials across the state. researchers must be aware because the November 15. Visit the full posting at the link below, laws are more restrictive than federal When a visiting clinical research where guest blogger and former Chair regulations regarding clinical trial associate asks about the discrepancy, the of the ACRP Board of Trustees David M. informed consent. The decision could study coordinator explains that he did Vulcano, LCSW, MBA, CIP, RAC, offers be overturned in future court decisions not really sign the ICF on November 15, his perspective on the topic, based on regarding the case, but right now, if one but thought he should backdate the fax his experience as a healthcare executive is conducting research in the Common- copy to the same date that the subject for clinical research with the Clinical wealth of Pennsylvania, it appears that signed. Eventually, the study coordinator Services Group of HCA (Hospital Corpo- you must comply with this requirement. is able to get both his and the patient’s ration of America) in Nashville, Tenn. (Source: ACRP Blog, https://www.acrpnet. The Pennsylvania Supreme Court signature on an original copy of the decision is not specific to only clinical org/2017/09/08/proposed-new-jersey-rule- correct ICF with the same date. chilling-effect-clinical-trials/) research informed consent—it covers Should the study coordinator have not treatments specified in the Medical signed off on the fax copy and, instead, Care Availability and Reduction of Error documented the situation in the source (MCARE) Act—but it does include studies and reported the discrepancy to the of experimental medications and devices. institutional review board? The FDA’s The MCARE Act is being interpreted short answer? Yes. differently between the litigating parties (Source: ACRP Blog, https://www.acrpnet.org/ in this case. The major issue appears to be 2017/08/23/fda-warns-well-intentioned- whether a physician may rely on qualified backdating/)
Clinical Researcher 51 October 2017 [DOI: 10.14524/CR-17-4038]
WORKFORCE INNOVATION
ACRP’s Career Development Resources— Looking Beyond Competency Development Beth D. Harper, BSOT, MBA
As a former volunteer and now the newly appointed Workforce Innovation Officer, I am pleased to continue to support ACRP’s ongoing efforts to further enhance the quality and competency of the clinical research workforce. From informal activities to formal, industry-wide programs, ACRP is involved in a wide variety of initiatives about which I will be providing updates in the coming months. In the meantime, I wanted to take this opportunity to re-cap many of the existing resources of which you can take advantage for enhancing your career.
From informal activities What’s on Tap Beyond curiosity about developing competen- cies, many of the questions we receive are more If you’ve been a member long enough, you are to formal, industry- related to the practical aspects of career develop- no doubt familiar with our general educational ment, such as job searching, resume enhancement, wide programs, ACRP programs and webinars, our award-winning salary negotiations, formal academic degrees, Clinical Researcher journal, the annual Meeting & is involved in a wide career mapping, mentorship opportunities, and Expo (formerly known as the Global Conference more. Let’s take a brief walk through ACRP’s variety of initiatives & Exhibition), and chapter events which provide website to orient you to where you can find all of the ample opportunities for ongoing continuing about which I will be available resources surrounding these topics. education on a wide range of topics. Many of these providing updates in programs and resources have been mapped to the Career Development Webinars Joint Task Force (JTF) for Clinical Trial Compe- the coming months. tency Framework domains to facilitate your ability Archived and upcoming webinars will continue to to strengthen your knowledge, skills, and abilities focus on the logistics of career development. Recent across the eight competency categories: topics cover a broad range of topics, including but • Scientific Concepts and Research Design not limited to: • Ethical and Participant Safety Considerations • Evolving Roles of Clinical Research Associates (CRAs)—How to Successfully Elevate Perfor- • Medicines Development and Regulation mance in a Transitioning Environment • Clinical Trials Operations (Good Clinical • Career Compass: Steer Your Clinical Research Practices) Career by Leveraging Real-World Trends • Study and Site Management • Beat the Heat—Stay Cool in Your Next Interview • Data Management and Informatics • Negotiation: The Why and The How • Leadership and Professionalism • Reinvent Your Job: Extend Your Worth and Job • Communication and Teamwork Satisfaction The competency framework provides an excellent • The 5 “Cs” of a Successful Mentoring Program guidepost for prioritizing the content areas that As a member, you are entitled to a substantial you need to focus on as your career evolves. The discount for the webinars (fee of $25 for members framework has recently been updated, as more vs. $75 for nonmembers per webinar). If you have academic programs and other stakeholder groups an idea for a future webinar and/or would like to gain experience with the framework and identify contribute as a subject matter expert, please contact areas for refinement. To keep up with the progress Jill Chapman, our Senior Manager of Training and of these refinements, be sure to periodically check Development, at [email protected]. out the JTF website: https://www.clinicaltrial competency.org/news-updates/.
October 2017 52 Clinical Researcher You can access the current and recorded webinars Even if you aren’t currently looking for a new Beyond curiosity in the “Training Programs” area under the “Pro- job, you can get a sense of the ever-expanding fessional Development” tab at www.acrpnet.org. range of career opportunities by exploring the job about developing You can also search for specific topics as well as postings, which may inspire you to advance your competencies, many download a directory of all training programs at career path in ways never previously imagined. this portion of the website. of the questions we Clinical Researcher—December 2017 receive are more related Online Conference Library Careers Issue to the practical aspects Career development sessions are always the Back by popular demand next issue in ACRP’s Clin- highlight of the ACRP Meeting & Expo. In case you ical Researcher journal will be our periodic focus on of career development, missed one of the recent annual events, or a par- career challenges and opportunities. This issue will ticular session at an event, the Online Conference cover a broad range of hot topics facing professionals such as job searching, Library of recorded conference sessions currently in roles across the clinical research enterprise. Until resume enhancement, includes most, but not all, of the sessions delivered then, be sure to check out the December 2016 issue at the 2015 (Salt Lake City), 2016 (Atlanta), and on trends in workforce development by visiting salary negotiations, 2017 (Seattle) gatherings. Topics from recent years https://www.acrpnet.org/resources/clinical- formal academic included sessions such as: researcher/; it spotlights why workforce develop- • So You Want to Be an Independent Consultant ment is important and why it should be an ongoing degrees, career • Fast Track to Success for New Clinical Research priority for all clinical research professionals. mapping, mentorship Most online articles and columns from past issues Coordinators opportunities, and • CRAs in 2010 and 2020: CRA Career Ladder of Clinical Researcher can be seen as separate postings Survey II and/or through full-issue, downloadable PDFs by more. ACRP members only; however, the December 2017 • A Creative Solution to Staffing in a Competitive issue will be open online to the general public. Hiring Environment • Manage Your Career or Someone Else Will Career and Salary Benchmark Survey Pricing for the recorded presentations varies based Last, but not least, be on the lookout in October for on the volume of presentations purchased. You can our next biennial salary survey, which we imple- peruse the Online Conference Library at http:// ment in partnership with CenterWatch to provide acrp.digitellinc.com/acrp/. you the opportunity to contribute anonymous data Mentorship Programs that support the industry’s leading benchmark report on clinical research professional salaries. Mentor Match is a new program that provides The 2017 report should be available early in 2018, ACRP Members the opportunity to serve in both and members will receive information on the the capacity of mentor and mentee. The program is discounted price to purchase the report. You can about growing professionally and networking with still purchase the previous benchmark report for fellow ACRP members; it is not about finding a job. a discount at the CenterWatch store by visiting Mentor Match is available free to ACRP members. https://store.centerwatch.com/p-456-2015-career- To learn more, visit https://www.acrpnet.org/ and-salary-benchmark-reports.aspx. membership/mentor-match/. In Closing Career Center Make the most of your ACRP membership by taking The ACRP Career Center is all about bringing full advantage of all these career development together employers and talent. For your chance to resources. Please feel free to reach out to us with Beth D. Harper, BSOT, MBA, get discovered, post your resume and/or search for other ideas and ways that we can help support your ([email protected]) open jobs (in the U.S.) at https://www.acrpnet.org/ ongoing professional development. was appointed ACRP’s new Workforce Innovation Officer professional-development/career-center/. in July 2017.
Clinical Researcher 53 October 2017 ON THE CRbeat
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The Latest News from the World of Workforce Innovation
LEVERAGE BUDGETING AS DOCTORS REMAIN KEY TO FOCUS ON PATIENT-CENTRIC OPPORTUNITY TO BOOST BOOSTING CLINICAL TRIAL INFORMED CONSENT YIELDS COMPETITIVE EDGE PARTICIPATION DIVIDENDS Believe it or not, a More than 80% of Long-time pediatric sponsor who pushes people are likely to trial professional back on a site’s participate in a Halle Showalter budget requests clinical trial if it is Salas is “firmly might be doing the recommended by convinced” that site’s leaders a favor. their doctor. The bad patient-centric “In some cases, it news? Less than 20% informed consent can show that the say their doctor has improves compli- site has hidden inefficiencies that make it ever broached the subject, according to a ance and retention throughout a clinical charge [above the going rate] for a trial or new survey conducted by Zogby Analyt- trial. She spent more than seven years as specific piece of a trial,” says Jennifer ics. While the latter figure is discouraging, a research and family liaison and vice Goldfarb, MSN, RN, CCRP, senior director it’s worth nothing that it’s up from 9% in chair of the institutional review board of the Clinical Research Support Office at 2013. (IRB) at Seattle Children’s Hospital. Children’s Hospital of Philadelphia. The study, funded in part by the Currently, she’s senior internal consultant Example: A site in good conscience Association of Clinical Research Orga- for employer market strategy with might seek $300 per blood draw as part of nizations (ACRO), surveyed 1,000 adults Premera Blue Cross. its budget request. Most sponsors would nationwide in July 2017 and further found In the end, a better informed consent balk at that dollar figure. However, neither that an overwhelming majority (86%) of process comes down to establishing rela- side is engaging in gamesmanship. respondents believe that doctors should tionships with patients and their broader Instead, the site has just learned through discuss clinical trials with patients as part support group, Salas says, adding that its budgeting that its costs are probably of standard care. in her days at the IRB, they labeled the out of whack. “It might take them $300 The survey suggests patients are open approach “participant-centric,” because per blood draw, but it probably shouldn’t,” to participating in trials. Three-quarters of in some cases the focus may be on a Goldfarb says. Thus, “Budgeting presents survey respondents feel that participating subject’s family or other helpers during an opportunity [for sites] to look at their is as important to public health as giving the informed consent process. “We try to own operational efficiencies.” blood. Additionally, more than half believe make sure the patient’s whole journey is In addition, working up a study budget that the federal government should provide taken into account,” she says. That means effectively should help the site identify tax incentives—as many other countries assessing who will help them to make questions its leaders need to ask the do—for trials run in the U.S. their participation a success. sponsor. “It’s not up to the sponsor to tell (Source: ACRP Blog, https://www.acrpnet.org/ The strongest patient relationships you what you need to do to get something 2017/09/06/doctors-remain-key-boosting- begin with honesty. For example, “We’re done,” Goldfarb says. clinical-trial-participation/) very careful to make sure a patient under- (Source: ACRP Blog, https://www.acrpnet.org/ stands it when [the fact is] a trial may not 2017/08/28/leverage-budgeting-opportunity- directly help them,” Salas says. They’ll boost-competitive-edge/) point out that the trial is an option or a choice to potentially help someone else, without pressing the point too hard. (Source: ACRP Blog, https://www.acrpnet.org/ 2017/09/08/focus-patient-centric-informed- consent-yields-dividends/)
October 2017 54 Clinical Researcher
Regulations and Compliance HOME STUDY TEST Earn 3.0 Continuing Education Credits
ACRP EDITORIAL Three articles from this issue of Clinical Researcher will be selected as the basis for a Home ADVISORY BOARD Study test that contains 30 questions. For your convenience, the selected articles and test Jerry Stein, PhD (Chair) questions will be combined and posted online in the form of a printable PDF at https://www. Ernest Prentice, PhD (ABoT Liaison) Suheila Abdul-Karrim, CCRA, CCRT acrpnet.org/professional-development/training/home-study/ in October 2017, and the test Victor Chen will be active until October 31, 2018. This activity is anticipated to take three hours. Fraser Gibson, CCRA, CCRP Gregory Hale, MD, CPI Answers must be submitted using the electronic answer form online (members Stuart Horowitz, PhD, MBA only, $60). Those who answer 80% of the questions correctly will receive an electronic Stefanie La Manna, PhD, ARNP, FNP-C Jamie Meseke, MSM, CCRA statement of credit by e-mail within 24 hours. Those who do not pass can retake the test Christina Nance, PhD, CPI for no additional fee. Grannum Sant, MD, BCh, BAO (Hons.), MA, FRCS, FACS Paula Smailes, RN, MSN, CCRC, CCRP ACRP DISCLOSURE STATEMENT CONTINUING EDUCATION (Vice Chair) As an organization accredited by the Accreditation INFORMATION Shirley Trainor-Thomas, MHSA Heather Wright, BS, BA: Council for Continuing Medical Education (ACCME®), The Association of Clinical Research Professionals Nothing to Disclose the Association of Clinical Research Professionals (ACRP) is an approved provider of medical, nursing, (ACRP) requires everyone who is in a position to and clinical research continuing education credits. control the planning of content of an education ACRP STAFF/ activity to disclose all relevant financial relationships Contact Hours VOLUNTEERS with any commercial interest. Financial relationships The Association of Clinical Research Karen Bachman in any amount, occurring within the past 12 months Professionals (ACRP) provides 3.0 James Michael Causey contact hours for the completion of this of the activity, including financial relationships of a educational activity. These contact hours Gary W. Cramer spouse or life partner, that could create a conflict of Jan Kiszko, MD can be used to meet the certifications maintenance requirement. Jo Northcutt interest are requested for disclosure. (ACRP-2017-HMS-010) Deepti Patki, MS, CCRC The intent of this policy is not to prevent indi- Barbara van der Schalie viduals with relevant financial relationships from Continuing Nursing Education Christine Streaker: participating; it is intended that such relationships The California Board of Registered Nurs- Nothing to Disclose be identified openly so that the audience may form Glenda Guest, CCRA, RQAP-GCP, TIACR: ing (Provider Number 11147) approves their own judgments about the presentation and the the Association of Clinical Research Major shareholder and employee of Norwich Clinical Research Associates presence of commercial bias with full disclosure of Professionals (ACRP) as a provider of con- (NCRA) the facts. It remains for the audience to determine tinuing nursing education. This activity whether an individual’s outside interests may provides 3.0 nursing education credits. (Program Number 11147-2017-HMS-010) reflect a possible bias in either the exposition or the conclusions presented. Continuing Medical Education The Association of Clinical Research Professionals (ACRP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing The pass rate for the medical education for physicians. The 80% Home Study Test is now Association of Clinical Research Profes- sionals designates this enduring material 80% to be in alignment with ACRP for a maximum of 3.0 AMA PRA Category professional development standards. 1 Credits™. Each physician should claim only the credit commensurate with the extent of their participation in the activity.
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