Regulatory Agency Transparency for Drugs and Biologics: A Comparative Survey of the U.S. Food and Drug Administration, the European Medicines Agency, and Health Canada
BRENDA J. HUNEYCUTT, BRIAN J. MALKIN, VICTOR VAN DE WIELE, MARK P. WILLIAMS & RIKIN MEHTA*
ABSTRACT
This survey paper compares practices of the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Health Canada (HC) across key information and data disclosure requirements as well as practices across processes for obtaining marketing approval for drug products. As this survey illustrates, FDA, EMA, and HC share many procedural commonalities, but also differ in significant respects. That said, each regulatory agency has described its commitment to regulatory transparency in a similar way, focusing on benefits to public health, research and development, and patients. Further analysis can determine the pros and cons of specific enhancements in transparency, including whether greater transparency results in regulatory efficiencies.
INTRODUCTION
Recent developments in regulatory transparency, such as the European Medicines Agency’s (EMA’s) Policy 0070 and Health Canada’s (HC’s) clinical trial transparency initiative, reflect an increasing recognition that regulatory agencies want to make more data available to the public to further their mission of protecting and promoting public health and safety by reducing the redundant burden and risk of clinical trials in humans.1
* Brenda J. Huneycutt, PhD, JD, MPH, Merck & Co., Inc., Kenilworth, NJ, USA, Director, Global Regulatory Policy; Brian J. Malkin, JD, McDermott Will & Emery LLP, Partner; Katz School of Science and Health, Biotechnology Management and Entrepreneurship Program, Adjunct Professor; Victor Van de Wiele, LLM, Harvard Medical School; Mark P. Williams, M.Sc, FasterCures, a Center of the Milken Institute, Associate Director; Rikin Mehta PharmD, JD, LLM, Georgetown University Law Center, Adjunct Professor. The authors would like to acknowledge the following individuals for their review of this manuscript: Sara Faircliffe, Legal Director, Bird & Bird; Lincoln Tsang, PhD, FRSC, FRPharmS, FRSB, Partner, Arnold & Porter; Sara Zborovski, Partner, Stikeman Elliott LLP; and Ian Trimble, Partner, Stikeman Elliott LLP. 1 European Medicines Agency Policy on Publication of Clinical Data for Medicinal Products for Human Use, EUR. MEDS. AGENCY (2019), https://www.ema.europa.eu/en/documents/other/european- medicines-agency-policy-publication-clinical-data-medicinal-products-human-use_en.pdf [hereinafter EMA Policy on Publication of Clinical Data]; HEALTH CANADA, PUBLIC RELEASE OF CLINICAL INFORMATION: GUIDANCE DOCUMENT (2019). As a corollary, FDA believes for certain generic or follow- on products, in vivo waivers with in vitro data may be appropriate to reduce unnecessary clinical trials, which would be equally applicable to duplicating clinical trials for the same molecular or biological entity
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While this trend is promising for those calling for enhanced transparency, regulatory agency commitment to transparency is not new. Scott Gottlieb, MD, former U.S. Food and Drug Administration (FDA) Commissioner under the Trump Administration, made clear that FDA recognized the benefits of transparency in both regulatory decision-making and clinical data:
The exchange of information that informs decisions to undertake research, invest in new scientific endeavors, and prescribe and use certain treatments effectively are a critical part of enabling the development and dissemination of new medical technology. Transparency related to this information can play a critical role in maximizing the public health value of the resulting innovations.2
For example, in January 2018, FDA launched a new pilot program to evaluate whether disclosing certain information in an approved product’s clinical study reports (CSRs) would improve public access to drug approval information with “the potential to foster further research and discovery across the scientific community, and better inform patients and providers.”3 Gottlieb added: “We expect that making a CSR publicly available after a drug’s approval will provide stakeholders with more information on the clinical evidence supporting a drug application and more transparency into FDA’s decision-making process.”4 While this pilot ended in March 2020, the agency noted that harmonization efforts were needed, explaining that:
to realize the benefits and opportunities provided by a more transparent drug approval process, we must first identify, and address, some of the challenges facing the global drug development community. FDA is committed to improving collaboration efforts with drug-approving regulatory agencies in other countries, and to increasing transparency related to the scientific basis for drug approval decisions.5
While recent news focuses on clinical trial data, many argue that transparency across the regulatory approval process more broadly (i.e., beyond clinical trial data)
or medical device. See, e.g., 21 C.F.R. § 320.25(a) (2020) (“The basic principle in an in vivo bioavailability study is that no unnecessary human research should be done.”); Abbreviated New Drug Application Regulations, 54 Fed. Reg. 28,872, 28,883 (proposed July 10, 1989) (stating in a discussion of 21 C.F.R. § 320.22 for waiver of in vivo bioavailability or bioequivalence, “the [A]gency does not believe that Congress intended that unnecessary human research be conducted . . . if the [A]gency concludes that bioequivalence can be demonstrated by in vitro tests, the agency proposes to require only such tests rather than in vivo studies”). 2 Press Release, U.S. Food & Drug Admin., FDA Commissioner Scott Gottlieb, M.D., on New Steps FDA is Taking to Enhance Transparency of Clinical Trial Information to Support Innovation and Scientific Inquiry Related to New Drugs (2018), https://www.fda.gov/newsevents/newsroom/pressannouncements/ ucm592566.htm [https://perma.cc/CNS5-HR8N]. 3 Id. 4 Id. 5 Press Release, U.S. Food & Drug Admin., FDA Continues to Support Transparency and Collaboration in Drug Approval Process as the Clinical Data Summary Pilot Concludes (2020), https://www.fda.gov/news-events/press-announcements/fda-continues-support-transparency-and- collaboration-drug-approval-process-clinical-data-summary [https://perma.cc/PQU2-H2G2]. 500 FOOD AND DRUG LAW JOURNAL VOL. 75 plays a critical role in accelerating research and development by minimizing costly duplication of effort, reducing regulatory uncertainty, and building trust in—and understanding of—regulatory agency decisions. The COVID-19 pandemic presents the latest situation in which calls for transparency to ensure public trust are again at the forefront of discussion. Taken with other environmental trends such as the rise of patient engagement and the integration of patient perspectives into research and development, the explosion of data and personalized medicine, and the rapidly-changing regulatory paradigm needed to keep up with new technologies (e.g., digital) and new ways of developing products (e.g., innovative trial designs), regulatory transparency may matter now more than ever. Many companies take a global approach to clinical research for similar products in multiple regulatory markets. There is increasing urgency, therefore, for the principal regulatory bodies to harmonize their regulatory disclosures, to prevent duplication of effort, and encourage the development of best practices in clinical approaches. As an example, adaptive clinical trials and real-time data analysis options provide greater opportunities for clinical study designs to be improved, and shared clinical data provides options for the development of additional indications without the need for physicians to dose off-label. Given these intersecting trends, we undertook a comprehensive survey of regulatory transparency across agencies focusing on drugs and biologics6 to ground the discussion regarding the need for enhanced transparency as well as international harmonization. Here, we do not take a normative position, but rather aim to clearly describe the current state of affairs, including in a table to allow the reader to quickly compare across agencies, to support future analyses and policy discussions on whether enhanced transparency is warranted and how it may be enabled. To that end, this paper compares practices of FDA, EMA, and HC across key information and data disclosure requirements as well as practices across processes for obtaining marketing approval for drug products. This paper aims to bring together comprehensively the practices of these three medical regulatory agencies thought to be largely harmonized in terms of regulatory requirements, in part from participation in efforts such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), to compare and contrast the legal underpinnings for their regulatory disclosure practices. With a clear understanding of these practices, follow-on research can help determine the pros and cons of specific enhancements in transparency, including whether greater transparency results in regulatory efficiencies, such as higher quality applications with fewer refusals to file or review cycles, as well as more indications being added to products rather than relying on off-label use. Future analyses can dissect what policy changes, whether statutory or regulatory, would be needed to enable a specific change in disclosure. The body of this paper explains each regulatory agency’s process and legal basis, while the table at the end pulls everything together in an easy-to-compare format.
6 We focus here solely on drugs and biologics given their similarity in development and review. A proper survey of regulatory transparency for devices would require significant additions to this work that we considered out of scope for a single manuscript. 2021 REGULATORY AGENCY TRANSPARENCY 501
I. LEGAL BASES UNDERLYING PUBLIC DISCLOSURES A. U.S. Food and Drug Administration (FDA) In the United States, the Federal Food, Drug and Cosmetic Act (FDCA) sets out the legal framework for FDA’s regulation of drugs.7 The statute outlines public disclosure of certain information about a drug’s safety and effectiveness data,8 but prohibits sharing of “any trade secret, confidential commercial or financial information,”9 defined in regulations as:
(a) A trade secret may consist of any commercially valuable plan, formula, process, or device that is used for the making, preparing, compounding, or processing of trade commodities and that can be said to be the end product of either innovation or substantial effort. There must be a direct relationship between the trade secret and the productive process.
(b) Commercial or financial information that is privileged or confidential means valuable data or information which is used in one’s business and is of a type customarily held in strict confidence or regarded as privileged and not disclosed to any member of the public by the person to whom it belongs.10
In addition, regulations and the agency’s internal manual of policies and procedures11 describe how the agency handles disclosing information,12 including information about and contained in an Investigational New Drug (IND) application13 and a New Drug Application (NDA)/Biologics License Application (BLA).14 Regulations include the agency’s general policy on sharing information with the public:
The Food and Drug Administration will make the fullest possible disclosure of records to the public, consistent with the rights of individuals to privacy, the property rights of persons in trade secrets and confidential commercial or financial information, and the need for the agency to
7 Federal Food, Drug, and Cosmetic Act, 21 U.S.C. §§ 301–399 (2018). 8 21 U.S.C. § 355(l). 9 21 U.S.C. § 355(l)(2)(E). In addition, the agency cannot disclose information listed in 5 U.S.C. § 552(b). Id. See also 21 U.S.C. § 331(j). Disclosure is allowed under certain prescribed circumstances, for example, to the courts or Congress. Id. Penalties for violation of § 331 are found in § 333. 21 U.S.C. § 333. 10 21 C.F.R. § 20.61 (2010). 11 U.S. FOOD & DRUG ADMIN., CTR. FOR DRUG EVALUATION AND RESEARCH, CDER MANUAL OF POLICIES & PROCEDURES (MAPP) (2020) [hereinafter MAPP], https://www.fda.gov/about-fda/center-drug- evaluation-and-research/cder-manual-policies-procedures-mapp [https://perma.cc/NK2S-ZFCB]. 12 See generally 21 C.F.R. Pt. 20 (2020). See also, e.g., MAPP, supra note 11, at 4520.1 Rev.2 (communicating drug approval information); MAPP, supra note 11, at 6020.8 Rev.1 (requiring disclosure review by Division of Information Disclosure Policy). 13 21 C.F.R. § 312.130 (2020); 21 C.F.R. § 601.50 (2020). 14 21 C.F.R. § 314.430 (2020); 21 C.F.R. § 601.51 (2020). 502 FOOD AND DRUG LAW JOURNAL VOL. 75
promote frank internal policy deliberations and to pursue its regulatory activities without disruption.15
In general, FDA does not proactively release any information (unless already publicly disclosed or acknowledged) about the existence or contents of either an IND or NDA/BLA unless and until the product is approved16 or the product is reviewed by a public Advisory Committee.17 In some instances, a court may direct FDA to disclose certain otherwise confidential information, but in litigation, confidential regulatory records typically are not disclosed according to joint protective orders between the parties. For some materials, however, the Freedom of Information Act (FOIA)18 allows any individual to request agency documents and requires FDA to share those documents (or parts of those documents) unless it determines that they fall within one of nine exemptions19 or the information has previously lawfully been disclosed to the public.20 According to the agency, the exemptions most often used to withhold documents (or parts of those documents) include: (1) protects certain records related solely to FDA’s internal rules and practices;21 (2) protects information that is prohibited from disclosure by other laws;22 (3) protects trade secrets and confidential commercial or financial information;23 (4) protects certain inter-agency and intra-agency communications;24 (5) protects information about individuals in personnel, medical, and similar files when disclosure would constitute a clearly unwarranted invasion of privacy;25 and (6) protecting records or information compiled for law enforcement
15 21 C.F.R. § 20.20(a) (2020). 16 21 C.F.R. § 314.430(e); 21 C.F.R. § 601.51(e). 17 21 C.F.R. § 314.430(d)(1); 21 C.F.R. § 601.51(d)(1). The Federal Advisory Committee Act (FACA) ensures that advisory committees are subject to transparency requirements such as advance notice of upcoming meetings, opportunities for public attendance and input, and the preparation of transcripts. 5 U.S.C. app. II §§ 10–11 (2018). See also U.S. FOOD & DRUG ADMIN., DEP’T OF HEALTH & HUMAN SERVS., GUIDANCE FOR INDUSTRY ADVISORY COMMITTEE MEETINGS—PREPARATION AND PUBLIC AVAILABILITY OF INFORMATION GIVEN TO ADVISORY COMMITTEE MEMBERS (2008), https://www.fda.gov/media/75436/ download [hereinafter FDA GUIDANCE FOR INDUSTRY ADVISORY COMMITTEE MEETINGS]. 18 The Freedom of Information Act, 5 U.S.C. § 552 (2018). 19 5 U.S.C. §§ 552(a)(3)(A), 552(b). See FOI Information, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/RegulatoryInformation/FOI/ucm390370.htm [https://perma.cc/MS9F-7S6R] (last updated Mar. 28, 2018). 20 21 C.F.R. § 20.81(a) (2019). 21 21 C.F.R. § 20.66 (2020) (describing internal personnel rules and practices). 22 21 C.F.R. § 20.67 (2008) (describing records exempted by other statutes). 23 21 C.F.R. § 20.61 defines trade secrets (in (a)) and commercial or financial information which is privileged or confidential (in (b)) and outlines the process for submitters of information (in (d)) to designate information as such and respond to a FOIA request that FDA determines disclosure may be required. 21 C.F.R. § 20.61. 24 Defined in 21 CFR § 20.62 (2005). 25 21 C.F.R. § 20.63 (2005) (describing personnel, medical, and similar files, disclosure of which constitutes a clearly unwarranted invasion of personal privacy). 2021 REGULATORY AGENCY TRANSPARENCY 503 purposes.26 In addition, regulations require that, in general, any record FDA discloses must be made available to all members of the public.27 A Web-based resource, ClinicalTrials.gov,28 provides patients, their family members, health care professionals, researchers, and the public with access to publicly and privately supported clinical studies.29 ClinicalTrials.gov was created under the Food and Drug Modernization Act of 1997 (FDAMA), which required the U.S. Department of Health and Human Services (HHS), through the National Institutes of Health (NIH), to establish a registry of clinical trial information derived from INDs granted for testing the effectiveness of experimental drugs for serious or life- threatening diseases.30 NIH and FDA worked together to develop the site, made public in February 2000.31 Registration requirements for the site were expanded in the FDA Amendments Act of 2007 (FDAAA) to include all efficacy clinical studies, as well as requiring expanded clinical trial registration information and the submission of summary results, including adverse events, for certain trials.32 The law also included penalties for noncompliance, such as withholding NIH grant funding and civil money penalties up to $10,000 a day.33 But as alleged in the two cases referenced below, FDA and NIH have done little to enforce the law, leading to incomplete or nonexistent reporting of required clinical data information, especially concerning clinical study results. In July 2018, the Media Freedom and Information Access Clinic (MFIA) filed a complaint on behalf of the Yale Collaboration for Research Integrity and Transparency (CRIT), urging a federal district court in Connecticut to compel HHS, NIH, and FDA to comply with legal obligations to report clinical trial results on ClinicalTrials.gov and avoid loopholes that permit certain clinical trials to avoid reporting results.34 The lawsuit was filed under the Administrative Procedure Act.35 Perhaps in response, FDA published a draft guidance in September 2018 about FDA’s current thinking regarding the assessment of civil money penalties for violating reporting requirements related to
26 21 C.F.R. § 20.66 (describing records or information compiled for law enforcement purposes); FOI Information, supra note 19. See also HHS Fiscal Year 2017 Freedom of Information Annual Report, U.S. DEP’T OF HEALTH & HUMAN SERVS., https://www.hhs.gov/foia/reports/annual-reports/2017/index.html [https://perma.cc/32QM-TP8L]. 27 21 C.F.R. § 20.21 (2003). Exceptions include that information subject to trade secret and confidential commercial or financial information and personal privacy can only be shared with individuals whom these exemptions protect. 21 C.F.R. § 20.21(a). 28 ClinicalTrials.Gov, NAT’L INSTS. OF HEALTH, NAT’L LIBRARY OF MED., https://www.clinicaltrials.gov/ [https://perma.cc/H32L-TWWR] (last visited Jan. 5, 2021). 29 ClinicalTrials.gov Background, NAT’L INSTS. OF HEALTH, NAT’L LIBRARY OF MED., https://clinicaltrials.gov/ct2/about-site/background [https://perma.cc/H467-9TPT] (last visited Jan. 5, 2021). 30 Id. 31 Id. 32 ClinicalTrials.gov Background, supra note 29; Food and Drug Administration Amendments Act (FDAAA), Pub. L. No. 110–85, sec. 801, 121 Stat. 823, 904 (2007). 33 See ClinicalTrials.gov Background, supra note 29; FDAAA sec. 801. 34 Corrected Complaint, Collaboration for Research Integrity and Transparency v. HHS, No. 3:18-cv- 1181 (D. Conn. July 19, 2018), https://law.yale.edu/sites/default/files/area/clinic/document/mfia_cr it_complaint.pdf [https://perma.cc/B7PR-3UUA]. 35 Id. at 1. 504 FOOD AND DRUG LAW JOURNAL VOL. 75
ClinicalTrials.gov.36 The lawsuits alleged that HHS, NIH, and FDA had failed to post any notices of non-compliance with clinical data reporting, let alone levied any civil money penalties, further depriving researchers and the public with knowledge of what clinical data is missing based on the reporting requirements.37 The lawsuit was voluntarily dismissed on October 23, 2018, presumably to pursue a slightly different approach as next described. In December 2018, the MFIA and New York University Technology Law and Policy Clinic (TLP), with the support of the CRIT and the Universities Allied for Essential Medicines, then brought another lawsuit on a related issue.38 This time the lawsuit was brought on behalf of two leading researchers on clinical trials whose research had been affected by the lack of clinical trial data information on ClinicalTrials.gov: Charles Seife and Dr. Peter Lurie.39 Seife is an investigative journalist at NYU whose work focuses on science and technology.40 Lurie is a family physician, president of the Center for Science in the Public Interest, and a former associate commissioner of FDA.41 The lawsuit sought to close a loophole created by a rule promulgated by the NIH and HHS that exempted sponsors of clinical trials of FDA-approved products completed between 2007 and 2017 from an obligation to report their results to ClinicalTrials.gov.42 At the heart of the issue is that sponsors of clinical trials could then “cherry-pick” their reported data, leaving out unfavorable results that could be useful for patients, clinicians, and medical researchers to analyze to discern adverse events from use of such products.43 On February 24, 2020, Judge Naomi Reice Buchwald of the Southern District of New York held that FDA, NIH, and HHS misinterpreted FDAAA and ordered the government to collect and post about a decade’s worth of trial results that should be public under FDAAA, which would make this data from potentially hundreds of clinical trials available for the first time.44 At the same time, the court also held that it
36 Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank and Draft Guidance, 83 Fed. Reg. 47,926 (Sept. 21, 2018). This guidance has recently been updated. Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank and Draft Guidance, 85 Fed. Reg. 50,028 (Aug. 17, 2020); U.S. FOOD & DRUG ADMIN., U.S. DEP’T OF HEALTH & HUMAN SERVS., CIVIL MONEY PENALTIES RELATING TO THE CLINICALTRIALS.GOV DATA BANK—GUIDANCE FOR RESPONSIBLE PARTIES, SUBMITTERS OF CERTAIN APPLICATIONS AND SUBMISSIONS TO FDA, AND FDA STAFF (2020), https://www.fda.gov/media/113361/ download [https://perma.cc/36VC-7BDA]. 37 See MFIA, CRIT Sue Government Over Clinical Trial Data, YLS TODAY (Jul. 18, 2018), https://law.yale.edu/yls-today/news/mfia-crit-sue-government-over-clinical-trial-data [https://perma.cc/JU A6-UFBU]. 38 See Complaint, Seife v. HHS, 440 F. Supp. 3d 254 (S.D.N.Y. 2020) (No. 1:18-cv-11462); Seife v. HHS, 440 F. Supp. 3d 254 (S.D.N.Y. 2020); Seife v. HHS, MEDIA FREEDOM & INFO. ACCESS CLINIC, YALE LAW SCH., https://law.yale.edu/mfia/projects/open-data/seife-v-hhs [https://perma.cc/5JQJ-8F9H] (last visited Jan. 5, 2021) [hereinafter MFIA Case Summary]. 39 Complaint, supra note 38, at 11–12; MFIA Case Summary, supra note 38. 40 Complaint, supra note 38, at 11; MFIA Case Summary, supra note 38. 41 Complaint, supra note 38, at 12. 42 Id. at 7, 36; MFIA Case Summary, supra note 38. 43 MFIA Case Summary, supra note 38. 44 Seife v. HHS, 440 F. Supp. 3d 254, 283–84 (S.D.N.Y. 2020). 2021 REGULATORY AGENCY TRANSPARENCY 505 could not grant relief on a separate claim, which asked for an order to require the NIH to post public notices of noncompliance whenever sponsors fail to submit results.45 In addition, authority exists for FDA’s Commissioner, at his or her discretion, to disclose part or all of any FDA record that is exempt from disclosure, unless it is a record that is (disclosure exempted) trade secrets and commercial or financial information that is privileged or confidential; personnel, medical, and similar files, disclosure of which constitutes a clearly unwarranted invasion of personal privacy; or prohibited from public disclosure under statute.46 As the regulation explains:
The Commissioner shall exercise his discretion to disclose such records whenever he determines that such disclosure is in the public interest, will promote the objectives of the act and the agency, and is consistent with the rights of individuals to privacy, the property rights of persons in trade secrets, and the need for the agency to promote frank internal policy deliberations and to pursue its regulatory activities without disruption.47
B. European Medicines Agency (EMA) In the EU, the European Medicines Agency (EMA) conducts a centralized process for the review of marketing authorization applications for medicines.48 EMA makes a recommendation on the application to the European Commission (EC), which then makes a final marketing decision.49 EU law sets forth certain transparency requirements,50 and EC regulation requires EMA to “adopt rules to ensure the availability to the public of regulatory, scientific, or technical information concerning the authorization or supervision of medicinal products which is not of a confidential nature.”51 In addition to the centralized process, all EU Member States also have their own national regulators, which operate according to national laws and procedures, while broadly governed by EU-level legislation.52 EMA has gone above and beyond the minimal transparency requirements to publish additional information on medicines under review (following the transparency policy), EMA’s decision-making, and clinical trial information. For example, law requires EMA to publish information on its assessment of applications, including both approved and rejected applications, as well as withdrawn applications,53 and EMA is
45 Id. 46 21 C.F.R. § 20.82 (2007). 47 21 C.F.R. § 20.82. The regulation explains that disclosure “shall not set a precedent for discretionary disclosure of any similar or related record and shall not obligate the Commissioner to exercise his discretion to disclose any other record that is exempt from disclosure.” Id. 48 Council Regulation 726/2004, 2004 O.J. (L 136) (EC) [hereinafter EC Regulation 726/2004]. 49 Id. 50 About us: Transparency, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/about-us/how-we- work/transparency [https://perma.cc/QB2L-5MKU] (last visited Jan. 6, 2020). 51 EC Regulation 726/2004, supra note 48, at arts. 80, 64. 52 See The European Regulatory System for Medicines: A Consistent Approach to Medicines Regulation Across the European Union, EUR. MEDS. AGENCY, (2016), https://www.ema.europa.eu/en/ documents/leaflet/european-regulatory-system-medicines-european-medicines-agency-consistent- approach-medicines_en.pdf [https://perma.cc/YQV3-GMAL]. 53 EC Regulation 726/2004, supra note 48, at art. 13(3), 18. 506 FOOD AND DRUG LAW JOURNAL VOL. 75 required to publish proceedings of the Agency’s scientific committees.54 EMA currently has a number of policies that require the disclosure and sharing of various clinical trial information.55 In fact, EMA publishes a guide to what documents the Agency releases (and when).56 For requesting documents EMA does not proactively share, Article 10 of Regulation (EC) No 1049/2001, similar to FOIA in the U.S., describes how to obtain public access to European Parliament, Council, and Commission documents, while Article 2 sets out the scope of access, describing the legislative purpose to favor access but subject to balancing access against the listed exceptions.57 As EMA’s policy on access to documents (Policy 0043) explains:
Openness and transparency are paramount values enshrined in the [Treaty of European Union] TEU1 and in the [Treaty on the functioning of the European Union] TFEU2 as they contribute to strengthen the principles of democracy and good administration. According to Article 15 of the TFEU, a right of access to documents of the EU Institutions, Bodies, Offices and Agencies is granted according to the principles and further conditions as defined by Regulations, namely Regulation (EC) No 1049/2001. In principle, all documents of the EU Institutions and of the European decentralised Bodies, such as the European Agencies, are accessible to the public. However, certain public and private interests, such as the privacy and integrity of the individual, in particular in accordance with EU legislation regarding the protection of personal data, or the commercial interests of a natural or legal person, shall be protected by way of exceptions in line with the provisions of Regulation (EC) No 1049/2001. In addition, EU Institutions and Agencies are entitled to protect their internal consultations and deliberations where necessary to carry out their tasks.58
These exceptions (some of which are absolute and some to be balanced against the public interest to disclose) laid out in the regulation (when disclosure requests would be denied) include when disclosure would undermine the protection of the public
54 EC Regulation 726/2004, supra note 48, at art. 26, 29; Council Directive 2001/83, art. 126b, 2001 O.J. (L 311) 118 (EC). 55 See, e.g., EMA Policy on Publication of Clinical Data, supra note 1. 56 What EMA publishes and when: Guide to information on human medicines evaluated by EMA, EUR. MEDS. AGENCY (2019), https://www.ema.europa.eu/en/documents/other/guide-information-human- medicines-evaluated-european-medicines-agency-what-agency-publishes-when_en.pdf [https://perma.cc/4X87-7GA7]. 57 Council Regulation 1049/2001, 2001 O.J. (L 145) 43–48 (EC). 58 European Medicines Agency Policy on Access to Documents, EUR. MEDS. AGENCY (2018), https://www.ema.europa.eu/en/documents/other/policy/0043-european-medicines-agency-policy-access- documents_en.pdf [https://perma.cc/HJD3-NVX9] [hereinafter EMA Policy on Access to Documents]; see About us: Access to Documents, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/about-us/how-we- work/access-documents [https://perma.cc/7KYB-HNXJ]; see also About us: Transparency, supra note 50; see Rules for the Implementation of Regulation (EC) No 1049/2001 on Access to EMEA Documents, EUR. MEDS. AGENCY (Dec. 19, 2006), https://www.ema.europa.eu/en/documents/other/rules-implementation- regulation-ec-no-1049/2001-access-emea-documents_en.pdf [https://perma.cc/D2NB-97VF]. 2021 REGULATORY AGENCY TRANSPARENCY 507 interest (e.g., public security), privacy of the individual,59 commercial interests, or seriously undermine the institution’s decision-making process, unless there is an overriding public interest in disclosure.60 As for commercial confidential information, as the Agency’s policy explains:
EMA will ensure protection of commercial interest in accordance with the notion of commercial confidential information. In view of the lack of a legal definition and for the purpose of this policy ‘commercial confidential information’ shall mean any information which is not in the public domain or publicly available and where disclosure may undermine the economic interest or competitive position of the owner of the information.61
Further, case law requires the data holder to justify how the disclosure could actually and specifically undermine the commercial interest.62 As for protecting the institution’s decision-making process, EMA only releases documents regarding the decision or procedure once it has been decided or completed.63 However, EMA will (either on its own initiative or by request for access) consider the need to disclose these documents prior to a decision/completion of procedure in care of an overriding public interest in sharing the documents.64 EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) is the European database counterpart to the U.S.’s ClinicalTrials.gov for all interventional clinical trials on medicinal products authorized in the European Union (EEA) and outside the EU/EEA, if they are part of a Paediatric Investigation Plan (PIP) from May 1, 2004 onwards. EudraCT was established in accordance with Directive 2001/20/EC. Clinical protocol and results information on interventional clinical trials are made publicly available through the European Union Clinical Trials Register since September 2011. In a joint letter dated July 2019 posted by the European Commission, EMA, and Heads of Medicines Agencies (HMA), clinical researchers were reminded that clinical trial summary results are required under European Commission Guideline 2012/302 03/EC. According to this letter, as of April 2019, 27,093 clinical trials had been completed out of 57,687 clinical trials in the EudraCT database, of which 18,432 should have results posted, which means that 68.2% are in compliance and 31.8% are missing.65 In contrast, the U.S. site, ClinicalTrials.gov, currently lists 368,184 clinical trials in its database from 50 states and 219 countries.66
59 Council Regulation 45/2001, art. 9, 2001 O.J. (L 008) 1–22 (EC); Council Directive 95/46, art. 30, 1995 O.J. (L 281) 31–50 (EC). 60 Council Regulation 1049/2001, art. 9, 2001 O.J. (L 145) 46 (EC). 61 See EMA Policy on Access to Documents, supra note 58. 62 Case T-729/15, MSD Animal Health Innovation GmbH v. Eur. Meds. Agency, 2018 E.C.R. 67. 63 Id. 64 Id. 65 Joint Letter by the European Commission, EMA and HMA: Letter to Stakeholders Regarding the Requirement to Provide Results for Authorised Clinical Trials in EudraCt, EUR. MEDS. AGENCY (2019), https://eudract.ema.europa.eu/docs/guidance/1R%20-%20Joint%20letter%20signed%20by%20EC,%20E MA,%20HMA_en.pdf [https://perma.cc/RH2F-S7UV]. 66 See CLINICALTRIALS.GOV, https://www.clinicaltrials.gov/ct2/home [https://perma.cc/Y6SD- 508 FOOD AND DRUG LAW JOURNAL VOL. 75
C. Health Canada In Canada, HC’s authority is derived from the Food and Drugs Act of 1985 and the Food and Drug Regulations (FDR).67 Under the Access to Information Act, HC cannot disclose any third party information (e.g., trade secrets or “financial, commercial, scientific or technical information that is confidential information supplied to a government institution by a third party”), including product information deemed confidential business information (CBI), except in circumstances described below.68 The Food and Drugs Act defines “confidential business information” as “in respect of a person to whose business or affairs the information relates, means—subject to the regulations—
Business information (a) That is not publicly available, (b) In respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available, and (c) That has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors.”69
Under the Access to Information Act, HC can disclose requested information if:
(a) The disclosure would be in the public interest as it relates to public health, public safety or protection of the environment; and (b) The public interest in disclosure clearly outweighs in importance any financial loss or gain to a third party, any prejudice to the security of its structures, networks or systems, any prejudice to its competitive position or any interference with its contractual or other negotiations.70
In addition, the Food and Drugs Act includes provisions that allow HC to disclose product information deemed CBI when “the product may present a serious risk of injury to human health”71 or “if the purpose of the disclosure is related to the protection or promotion of human health or the safety of the public,” information can be shared
DSYC] (“Explore 368,184 research studies in all 50 states and in 219 countries.”). 67 Food and Drugs Act, R.S.C. 1985, c F-27 (Can.); Food and Drug Regulations, C.R.C., c 870 (Can.). 68 Access to Information Act, R.S.C. 1985, c A-1 (Can.) (Article 20(1) Third Party Information). 69 Food and Drugs Act, R.S.C., 1985, c F-27 (Can.). 70 Access to Information Act, R.S.C. 1985, c A-1 (Can.) (Article 20(6) Disclosure authorized if in public interest). 71 Food and Drugs Act, R.S.C., 1985, c F-27 (Can.) (Article 21.1(2)). 2021 REGULATORY AGENCY TRANSPARENCY 509 with a government, a person72 from whom the Minister is seeking advice, or a person whose job is to protect human health or public safety.73 As explained in a Guidance document on disclosures for the protection or promotion of human health and safety:
Information disclosed under this authority should contribute to improving the health of Canadians. Requests for disclosure under this authority are to clearly define how the purpose relates to this objective and should include a formal plan to use the information to advance knowledge, including making results publicly available.74
Importantly, such disclosures are not public, the disclosed information must remain confidential (and only used for non-commercial purposes75), but results of analyses of the disclosed information may be published.76 As such, researchers and non-profit organizations can request CBI (after exhausting trying to get the information from other sources) for purposes relevant to public health and safety issues related to products on the market.77 All personal information will be protected, including redacting or de-identifying patient-level data.78 HC makes public “information regarding the request, including the requester, a description of the project, date filed, date the review was complete, and the review outcome.”79 Recently, HC revised its regulations to allow public release of certain clinical trial information (i.e., excluding this information from CBI) after a drug receives a final decision on its marketing application.80
72 A “person” means an individual or an organization. See Food and Drugs Act 1985, supra note 67, at 2 (Definitions). 73 Food and Drugs Act, R.S.C., 1985, c F-27 (Can.) (Article 21.1(3)); see also Health Canada, Guidance Document: Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and Drugs Act (2017), https://www.canada.ca/content/dam/hc-sc/documents/services/drug-health- product-review-approval/cbi-gd-ld-ccc-eng.pdf [https://perma.cc/6F4D-FWUS] [hereinafter HEALTH CANADA GUIDANCE DOCUMENT: DISCLOSURE OF CBI]. 74 HEALTH CANADA GUIDANCE DOCUMENT: DISCLOSURE OF CBI, supra note 73. 75 Id. at 6 (“PROTECTION AGAINST COMMERCIAL USE”). For purpose of this authority, commercial purpose means the use of the information to support a marketing authorization anywhere in the world or selling or trading the data to another person. The use of clinical information for comparative effectiveness research is not considered a commercial use. 76 Id. at 6–7 (“MAINTAINING CONFIDENTIALITY OF DISCLOSED INFORMATION”). 77 Id. at 8–9 (“REQUIREMENTS FOR PERSONS REQUESTING DISCLOSURE OF CONFIDENTIAL BUSINESS INFORMATION UNDER PARAGRAPH 21.1(C)(3)”). 78 Id. at 6 (“PROTECTION OF PERSONAL INFORMATION AND RESPECTING PARTICIPANTS’ INFORMED CONSENT”), in accordance with the Privacy Act. 79 Completed requests for disclosure of confidential business information under s.21.1(3)(c) of the Food and Drugs Act, HEALTH CANADA, https://www.canada.ca/en/health-canada/services/drug-health- product-review-approval/request-disclosure-confidential-business-information/completed-requests.html [https://perma.cc/YMZ5-YYK7] (last visited Sept. 11, 2019); see also HEALTH CANADA GUIDANCE DOCUMENT: DISCLOSURE OF CBI, supra note 73, at 7 (“PROCESS TO REVIEW REQUESTS FOR DISCLOSURE”). 80 Food and Drug Regulations, C.R.C., C.08.009 (Can.); see also Public Release of Clinical Information: guidance document, HEALTH CANADA, https://www.canada.ca/en/health- canada/services/drug-health-product-review-approval/profile-public-release-clinical-information-guidance /document.html [https://perma.cc/CT3H-TYHX] (last visited Mar. 4, 2021). 510 FOOD AND DRUG LAW JOURNAL VOL. 75
Similar to action in the U.S., prior to a law change regarding the confidentiality of clinical trial data, a researcher brought a lawsuit in Canada requesting access to clinical trial data for academic research unfettered by an agreement of confidentiality that would prevent publication of his research. Dr. Peter Doshi, an Assistant Professor at the University of Maryland, sought judicial review of an order of mandamus requiring the Minister of Health to release certain clinical trial data that Health Canada had received from product manufacturers.81 Dr. Doshi had applied to Health Canada for access to “complete copies of all sections of all clinical study reports,” as well as “all electronic datasets from these same trials, including participant level datasets.” He claimed that he needed the information for his systematic review. Health Canada claimed that the data was confidential business information that required him to sign a confidentiality agreement. Dr. Doshi opposed the confidentiality terms and argued that Health Canada’s refusal had no basis in law and the confidentiality agreement would be a hindrance to his ability to conduct the research project and publish results.82 The Court held that it was unreasonable for Health Canada to impose a confidentiality requirement as a condition to disclose the requested data in view of various administrative law principles concerning the exercise of discretionary powers, in particular “Vanessa’s Law,” which amended the Food and Drugs Act to add subsection 21.1(3), permitting the Minister of Health to disclose confidential business information about a therapeutic product in circumstances such as those presented by the applicant—that is, for use in academic research—specifically to improve clinical trial transparency.83 Moreover, those regulations implied that “there is no legitimate interest in keeping the results of clinical trials private” for Dr. Doshi, “a person who carries out functions relating to the protection or promotion of human health or the safety of the public,” and that disclosure would be “related to the protection or promotion of human health or the safety of the public,” as required under section 21.1(3).84 In addition, the confidentiality agreement would have prevented Dr. Doshi from publishing his research based on the clinical trial reports, which would restrict his freedom of expression under section 2(b) of the Canadian Charter of Rights and Freedoms.85 The Court, however, noted the privacy and anonymity of clinical trial participants remains critical and “[t]here will be situations where Health Canada may validly impose a confidentiality requirement with respect to specific categories of information, but that decision must be made on a case-by-case basis.”86 Following the decision, in March 2019, HC further revised its policies to post clinical study reports within 120 days of a decision to approve or reject an application, starting with drugs that contain novel active ingredients, supplementary new drug submissions, and submissions to switch prescription drugs over-the-counter and adding medical devices and other drugs such as generic drugs over a four-year phase-
81 See Doshi v. Canada (Att’y Gen.), [2018] 2018 F.C. 710, paras. 22, 91 (Can. Ont.), https://decisions.fct-cf.gc.ca/fc-cf/decisions/en/item/315985/index.do [https://perma.cc/ES22-YSDQ]. 82 Id. at para. 22. 83 Id. at para. 75. 84 Id. at paras. 81–82. 85 Id. at paras. 8–84. 86 Id. at para. 74. 2021 REGULATORY AGENCY TRANSPARENCY 511 in-period. As stated in HC’s guidance: “HC’s objective is to make anonymized clinical information in drug submissions and medical device applications publicly available for non-commercial purposes following the completion of HC’s regulatory review process, while adhering to Canada’s Privacy Act.”87 Unlike ClinicalTrials.gov and EudraCT, HC’s Clinical Trials Database is managed by HC and is not a registry with comprehensive information about each clinical trial. HC recommends that sponsors register in registries like ClinicalTrials.gov and, as applicable, a Canadian-based registry for clinical trials, Canadian Cancer Trials, or a clinical trial database maintained by the World Health Organization (WHO) of clinical trials in several international registries. HC includes in its database clinical trials authorized by HC starting April 1, 2013, after HC issues a No-Objection Letter, and expects the database will start small but grow as more clinical trials are initiated.88 As seen in Table 1, many similarities exist among FDA, EMA, and HC, but some differences in practice exist as well.
II. PRE-MARKETING APPLICATION DISCLOSURES A. Filing of an Investigational New Drug Application (IND) (U.S.), Request for Authorization to Conduct a Clinical Trial (EU), or Clinical Trial Applications (Canada) An IND is an exemption that permits a sponsor to ship an unapproved drug across state lines for the purpose of clinical research and contains information relating to the clinical study, including the drug manufacturer and proposed use.89 Current federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from FDA. FDA regulations prohibit the agency from disclosing the existence of an IND, unless it has been publicly disclosed.90 However, the agency discloses the number of IND applications received throughout the year (by quarter).91
87 Public Release of Clinical Information: guidance document, HEALTH CANADA (Mar. 12, 2019), https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/profile-public- release-clinical-information-guidance/document.html [https://perma.cc/5A3Q-PXFA]. 88 See Health Canada’s Clinical Trials Database, GOVERNMENT OF CANADA, https://www.canada.ca /en/health-canada/services/drugs-health-products/drug-products/health-canada-clinical-trials-database.ht ml [https://perma.cc/PG22-UWGM] (last visited Aug. 12, 2020).
89 See Investigational New Drug (IND) Application, U.S. FOOD & DRUG ADMIN. https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application [https://perma.cc/ 8LB5-JT5Q] (last visited Feb. 23, 2021). 90 21 C.F.R. § 312.130(a); 21 C.F.R. § 601.50. 91 Number of Original Investigational New Drug (IND) applications received in the quarter, U.S. FOOD & DRUG ADMIN., https://www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cber& status=public&id=CBER-All-IND-and-IDEs-recieved-and-actions&fy=All [https://perma.cc/R93G-JVU8] (last visited Aug. 12, 2020). 512 FOOD AND DRUG LAW JOURNAL VOL. 75
Currently in the EU, requests for authorization to conduct a clinical trial are reviewed by each Member State in which the trial will be conducted,92 and therefore EMA does not disclose information on these applications.93 While the authorization decision still lies with the Member States where the scientific assessment is led by the Reporting Member State, the regulation also requires registration of all clinical trials in a new publicly accessible, searchable EU Clinical Trial Database (EudraCT) after approval of the request to conduct the trial.94 Further, the regulation requires that any data and documents submitted to the EudraCT be held in the Database and publicly accessible unless the data (or part of the data) is protected as personal data, commercially confidential information (unless an overriding public interest in disclosure exists), confidential communications between Member States, or if the data should be withheld to ensure “effective supervision of the conduct of a clinical trial by Member States.”95 This disclosure only applies after the request has been authorized by a Member State (unless an overriding public interest exists),96 and does not apply to applications withdrawn by the sponsor before a decision is made. In the case of trials for which authorization is not given, application information will be made public when the refusal decision is made.97 The Clinical Trials Regulation, adopted in 2014, further will harmonize the assessment and supervise processes for clinical trials throughout a centralized EU process, via a Clinical Trials Information System (CTIS). CTIS will contain the centralized EU portal and database for clinical trials anticipated by the Regulation. The EMA will set up and maintain CTIS, in collaboration with Member States and the European Commission.98 However, the timing of the Clinical Trials Regulation depends on an independent audit confirmation of full functionality of the CTIS. The regulation will then become applicable six months after the European Commission publishes notice of this confirmation. Currently, it is hoped that the CTIS will be operational by December 2021.99 To help harmonize the system, the regulation sets up a new centralized process in which sponsors request authorization to conduct a clinical trial from the relevant
92 Council Directive 2001/20, art. 9(2), 2001 O.J. (L 121) 11 (EC) [hereinafter Council Directive 2001/20]; See also Communication from the Commission—Detailed guidance on the request to the competent authorities for authorization of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1), 2010 O.J. (L 121), https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2010:082:0001:0019:EN:PDF [https://perma.cc/TY34-LW3N]. 93 See Clinical Trial Regulation, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human-regula tory/research-development/clinical-trials/clinical-trial-regulation [https://perma.cc/TR57-6MNY] (last visited Aug. 12, 2020). 94 Id.; see also Appendix, on disclosure rules, to the “Functional specifications for the EU portal and EU database to be audited – EMA/42176/2014,” EUR. MEDS. AGENCY (2015), https://www.e ma.europa.eu/en/documents/other/appendix-disclosure-rules-functional-specifications-eu-portal-eu-databa se-be-audited_en.pdf [https://perma.cc/TYS5-NXRF] [hereinafter Appendix, EUR. MEDS. AGENCY]. 95 Appendix, EUR. MEDS. AGENCY, supra note 94. 96 Article 81(5) of the Regulation (EU) No 536/2014; Clinical Trial Regulation, supra note 93. 97 Appendix, EUR. MEDS. AGENCY, supra note 94. 98 Council Directive 2001/20, supra note 92; Clinical Trial Regulation, supra note 93. 99 Clinical Trial Regulation, supra note 93. 2021 REGULATORY AGENCY TRANSPARENCY 513
Member States by submitting a single application through a centralized entry portal for submission.100 Once the CTIS is in effect, there will be a three-year transition period to the new system. During the first year, clinical trial sponsors may submit to either the EudraCT system or the CTIS system. In the second and third years, clinical trial sponsor must submit new clinical trial applications via the CTIS. Trials authorized via EudraCT, however, may continue but must be transferred to the CTIS by end of the three-year transition period.101 While HC does not release information about requests (e.g., company, product, indication), it does publish the number of clinical trial applications102 received per year and the decisions made on those applications in its Therapeutic Products Directorate Drug Submission Performance Annual Reports.103 B. Attainment of Product Designations FDA, EU, and HC have a myriad of product designation programs to either incentivize development or expedite the development and review of certain products. Designations such as breakthrough therapy, advanced therapy medicinal product, and orphan drug serve as examples of these programs. FDA regulations forbid the agency from disclosing the existence of a request for orphan designation (unless it has been previously publicly disclosed or acknowledged).104 However, the FDCA requires FDA to make the orphan designation of a drug publicly available.105 The agency meets this requirement through its searchable orphan drug designation database.106 In addition, agency determinations of orphan designation may be referenced in the summary review documents released after a drug is approved, but the actual orphan drug designation requests, determinations, and exclusivity determinations must be requested separately under FOIA.107 Following drugs approved in August 18, 2017, FDA has made public demonstrations of clinical superiority, which has permitted same drug (i.e., active moiety for the same indication) products to be marketed either during a previous same drug’s orphan drug exclusivity or following such exclusivity for its own seven-year
100 The EU Clinical Trial Portal and Database, EUR. MEDS. AGENCY (2016), https://www.ema.europa.eu/en/documents/leaflet/eu-clinical-trial-portal-database_en.pdf [https://perma.cc/MQ5J-8FMJ]. 101 EU, ICH and Brexit Pharma Regulatory Update - July 2020 to January 2021, 48 HEALTH SCIS. J., Feb. 2021, https://www.nsf.org/periodicals/health-sciences-journal/issue-48/eu-ich-brexit-pharma- regulatory-update [https://perma.cc/ULB7-6PV3] (last accessed Feb. 24, 2021). 102 Food and Drug Regulations, C.R.C., c 870, c.05.005 (Can.); see also Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications, HEALTH CANADA (2013), https://www.canada.ca /content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/prodpharma/applic-demande/guide-ld/clini/ ctdcta_ctddec-eng.pdf [https://perma.cc/V2P5-F5MH]. 103 See, e.g., Therapeutic Products Directorate: Drug Submission Performance Annual Report, HEALTH CANADA (2019), http://publications.gc.ca/collections/collection_2019/sc-hc/H166-2-2019-eng.pdf [https://perma.cc/NUT9-6GUN]. 104 21 C.F.R. § 316.52(a) (2020). 105 21 U.S.C. § 360bb(c) (2020); 21 C.F.R. § 316.28 (2020); 21 C.F.R. § 316.52(d) (2020). 106 Search Orphan Drug Designations & Approvals, U.S. FOOD & DRUG ADMIN., https://www.accessdata.fda.gov/scripts/opdlisting/oopd/listResult.cfm [https://perma.cc/KF53-LD6M] (last visited Jan. 7, 2021). 107 21 U.S.C. § 355(l); 21 C.F.R. § 314.430; 21 C.F.R. § 601.51 (2020). 514 FOOD AND DRUG LAW JOURNAL VOL. 75 period of exclusivity. Such reporting was required in the FDA Reauthorization Act of 2017 in section 527(e)2 of the FDCA.108 However, prior to this date, clinical superiority findings were not reported and had to be discerned by same drug listings in the orphan drug designation database for products with indicated marketing approvals. Similarly, FDA does not disclose when a product requests or receives a designation or entry into the four expedited programs for serious conditions109: (1) breakthrough therapy designation (BTD);110 (2) fast track;111 (3) priority review;112 or (4) accelerated approval113 (or determinations of eligibility) unless and until the product is approved and this information may be included in the summary review documents released (or an Advisory Committee meeting occurs).114 The same applies to other programs aiming to incentivize or accelerate development such as the regenerative medicine advanced therapy (RMAT) designation,115 the qualified infectious disease product (QIDP) designation,116 and the limited population pathway for antibacterial and antifungal drugs.117 However, FDA does track and release the number of BTD requests, approvals, and withdrawn designations.118 In addition, FDA discloses the number of products receiving fast track119 and priority review,120 and the number of RMAT designation requests received, granted, denied, and withdrawn.121
108 Clinical Superiority Findings, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/ industry/designating-orphan-product-drugs-and-biological-products/clinical-superiority-findings [https:// perma.cc/Q22A-A72C] (last visited Jan. 7, 2021). 109 See Guidance for Industry: Expedited Programs for Serious Conditions, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/media/86377/download [https://perma.cc/3T8E-AKSD] (last visited Jan. 7, 2021). 110 21 U.S.C. § 356(a) (2018). 111 21 U.S.C. § 356(b). 112 Prescription Drug User Fee Act of 1992, 21 U.S.C. § 379g (2018). 113 21 U.S.C. § 356(c); 21 C.F.R. pt. 314, subpt. H (2020); 21 C.F.R. pt. 601, subpt. E (2020). 114 21 U.S.C. § 355(l)(2); 21 C.F.R. § 314.430; 21 C.F.R. § 601.51. 115 21 U.S.C. § 356(g). 116 21 U.S.C. § 355f; see also Draft Guidance for Industry, Qualified Infectious Disease Product Designation Questions and Answers, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/media/111091/download [https://perma.cc/U7XW-GB3X] (last visited Jan. 7, 2021). 117 21 U.S.C. § 356(h). 118 Frequently Asked Questions: Breakthrough Therapies, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act- fdasia/frequently-asked-questions-breakthrough-therapies [https://perma.cc/84GJ-G7YN] (last visited Jan. 7, 2021).
119 FDA-TRACK, Number of Fast track designations granted in the quarter, U.S. FOOD & DRUG ADMIN., https://www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cber&status=public&i d=CBER-All-Number-of-Fast-Track-designations&fy=All [https://perma.cc/DJ3M-MYAJ] (last visited Jan. 7, 2021); see also Fast Track Designation Requests, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/drugs/ind-activity/fast-track-designation-requests [https://perma.cc/CA5G-GY4Y] (last visited Jan. 7, 2021). 120 FDA-TRACK, Number of priority reviews in the quarter, U.S. FOOD & DRUG ADMIN., https://www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cber&status=public&id=CBER- All-Number-priority-reviews&fy=All [https://perma.cc/QT8E-BVH2] (last visited Jan. 7, 2021). 121 Cumulative CBER Regenerative Medicine Advanced Therapy (RMAT) Designation Requests 2021 REGULATORY AGENCY TRANSPARENCY 515
In the EU, information on designated orphan medicinal products (orphan designation does not mean the product is granted a marketing authorization at this stage; the orphan-designated product will still need to follow usual procedures to obtain authorization)122 is published in the monthly meeting reports of the Committee for Orphan Medicinal Products (COMP).123 The meeting reports include lists of positive and negative opinions recommending or not recommending drugs as designated orphan medicinal products to the EC, as well as lists of products granted orphan designation by the EC.124 COMP meeting minutes outline information and discussion regarding drugs requesting designation as orphan medicinal products.125 And a public summary of the COMP’s opinion on orphan designation is published on EMA’s website about a month after the EC final decision.126 A full list of orphan- designated products can be found on the EC’s website.127 Designation as an advanced therapy medicinal product (ATMP; e.g., gene therapy, somatic cell therapy, tissue engineered product)128 follows a review by EMA’s Committee for Advanced Therapies (CAT), and their decisions are disclosed in summary reports.129 In addition, accelerated assessment provides marketing authorization applications for products of “major therapeutic interest” a shortened review timeline.130 EMA does
Received by Fiscal Year, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/vaccines-blood- biologics/cellular-gene-therapy-products/cumulative-cber-regenerative-medicine-advanced-therapy-rmat- designation-requests-received-fiscal [https://perma.cc/LD4V-8W8P] (last visited Jan. 7, 2021). 122 Orphan designation: Overview, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human- regulatory/overview/orphan-designation-overview [https://perma.cc/2EPG-HGVX] (last visited Jan. 7, 2021). 123 Committees COMP: Agendas, minutes and meeting reports, EUR. MEDS. AGENCY, https://www .ema.europa.eu/en/committees/comp/comp-agendas-minutes-meeting-reports [https://perma.cc/GCR3- WGEJ] (last visited Jan. 7, 2021). 124 E.g., COMP: Meeting report May 2019, EUR. MEDS. AGENCY, https://www.ema.europa.e u/en/documents/committee-report/comp-meeting-report-review-applications-orphan-designatoin-may-201 9_en.pdf [https://perma.cc/2FSQ-PRHE] (last visited Jan. 7, 2021). 125 E.g., Committee for Orphan Medicinal Products (COMP), EUR. MEDS. AGENCY, https://ww w.ema.europa.eu/en/documents/minutes/minutes-comp-meeting-19-21-march-2019_en.pdf [https://perma.cc/AC9J-XVMC] (last visited Jan. 7, 2021). 126 E.g., EU/3/10/749, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/medicines/human/ orphan-designations/eu310749 (last visited on September 15, 2019). In addition, orphan designations are reviewed when a marketing authorization is approved and that review is published with the EPAR and can be reviewed again within the first five years upon request of a Member State. See What EMA publishes and when, supra note 56. 127 Community Register of orphan medicinal products, EUR. MEDS. AGENCY, http://ec.eu ropa.eu/health/documents/community-register/html/reg_od_act.htm?sort=a [https://perma.cc/JTP9-7CE6] (last visited Jan. 7, 2021). 128 Commission Regulation 1394/2007, 2007 O.J. (324) 128 (EU). 129 Summaries of Scientific Recommendations on Classification of Advanced Therapy Medicinal Products, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human-regulatory/marketing- authorisation/advanced-therapies/advanced-therapy-classification/summaries-scientific-recommendations- classification-advanced-therapy-medicinal-products [https://perma.cc/5RCG-635G] (last visited Jan. 7, 2021). 130 Commission Regulation 726/2004, 2004 O.J. (136) 1, 20 (EU); see also Guideline on the scientific application and the practical arrangements necessary to implement the procedure for accelerated assessment pursuant to Article 14(9) of Regulation (EC) No 726/2004, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-scientific-application-practical-a 516 FOOD AND DRUG LAW JOURNAL VOL. 75 not disclose the Committee for Medicinal Products for Human Use (CHMP) decision on accelerated assessment until a final decision on the marketing authorization application is made and a summary of CHMP’s assessment will be included in the final CHMP assessment report of the marketing authorization.131 And finally, the PRIority MEdicines (PRIME) scheme exists to expedite the development of drugs that target an unmet medical need and “may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.”132 EMA publishes a list of all PRIME products by their international non- proprietary names or scientific names, updated monthly. Products are removed after a marketing authorization application is received by EMA or they have been otherwise withdrawn from the scheme.133 HC utilizes two expedited pathways for review of products intended to treat, prevent, or diagnose serious, life-threatening, or severely debilitating diseases or conditions that show “substantial evidence of clinical effectiveness” for a disease with no treatments or “a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.”134 Priority review135 status confers a shortened period for review—180 days from 300 days—for eligible drugs and Notice of Compliance with conditions (NOC/c)136 allows HC to grant a conditional approval to eligible products based on limited evidence such as a Phase 2 trial or surrogate endpoint (similar to FDA’s accelerated approval). When HC finds a request for NOC/c to qualify, it issues a Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) that outlines “the additional clinical evidence to be provided in confirmatory trials, post-market surveillance responsibilities and any requirements related to advertising, labelling, or distribution.”137
rrangements-necessary-implement-procedure-accelerated/2004_en.pdf [https://perma.cc/Y3LE-Y2J3] (last visited Jan. 7, 2021). 131 Id. 132 Enhanced early dialogue to facilitate accelerated assessment of Priority Medicines (PRIME), EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/enhanced- early-dialogue-facilitate-accelerated-assessment-priority-medicines-prime_en.pdf [https://perma.cc/N5HS- KL6P] (last visited Jan. 7, 2021); see also PRIME: priority medicines, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines [https://perma.cc/3RBB-DMRA] (last visited Jan. 7, 2021). 133 Id. 134 Administrative Corrections to Health Canada’s priority review documents, HEALTH CANADA (Feb. 6, 2009), https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/hpfb-dgpsa /pdf/prodpharma/priordr-eng.pdf [https://perma.cc/4ENR-NUEC]. 135 Id. 136 Food and Drug Regulations, C.R.C., c 870, § C.08.004 (Can.); see also Administrative Corrections, supra note 134. 137 Guidance Document: Notice of Compliance with Conditions (NOC/c), HEALTH CANADA, https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp-mps/alt_formats/pdf/prodpharma/applic-de mande/guide-ld/compli-conform/noccg_accd-eng.pdf [https://perma.cc/Y7XH-G55U] (last visited Jan. 7, 2021). 2021 REGULATORY AGENCY TRANSPARENCY 517
HC includes whether a product is being reviewed under priority review or NOC/c in its list of submission under review (SUR) list,138 described below. HC’s Therapeutic Products Directorate Drug Submission Performance Annual Reports includes the number of priority review status requests received per year and how many were denied or granted.139 The Annual Reports also include a list of new active substance approvals and whether they received priority review and/or received approval under Notice of Compliance with conditions.140 In addition, once a product is approved under NOC/c, a NOC/c-QN will be published (with proprietary information redacted)141 on HC’s “Notice of Compliance with conditions” webpage, which lists all products approved under NOC/c.142
III. MARKETING APPLICATION IN-REVIEW DISCLOSURES A. Application Submission As with an IND, FDA does not disclose the existence of a new drug application (NDA) or biologics license application (BLA) before an approval letter is sent to the applicant (unless previously disclosed or acknowledged) unless it is reviewed by an Advisory Committee.143 However, the agency does publish the number of NDAs and BLAs submitted per month.144 EMA publishes a list of new medicines (innovative, generic, and biosimilar) under evaluation for a centralized marketing authorization by EMA’s Committee for Medicinal Products for Human Use (CHMP) each month.145 It lists the international non-proprietary name (INN) (for generic and biosimilar medicines, active moiety only, with no information on salt, ester, or derivative) and therapeutic area(s) for each medicine. Once a product has received a positive or negative opinion from the CHMP or when the application is withdrawn, a medicine will be removed from this list. HC publishes a Submissions Under Review (SUR) List for New Drug Submissions (NDS) containing new active substances accepted for review on or after April 1, 2015 and new drug submissions and supplemental new drug submissions for new uses accepted for review on or after May 1, 2016 that are currently or formerly under
138 Drug and Health Product Submissions Under Review (SUR), HEALTH CANADA, https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/submissions-under -review.html [https://perma.cc/VPW6-RW5R] (last visited Jan. 7, 2021). 139 See supra note 134. 140 Id. 141 See supra note 103. 142 Notice of Compliance with conditions (NOC/c), HEALTH CANADA, https://www.canada.ca/ en/health-canada/services/drugs-health-products/drug-products/notice-compliance/conditions.html [https://perma.cc/8DVZ-8M6R] (last visited Jan. 7, 2021). 143 21 C.F.R. § 314.430(b); 21 C.F.R. § 601.51(b). 144 PDUFA Prescription Drug Applications and Supplements, U.S. FOOD & DRUG ADMIN. (2019), https://www.fda.gov/about-fda/fda-track-agency-wide-program-performance/pdufa-prescription-drug- applicarions-and-supplements [https://perma.cc/88FH-9KQC]; BsUFA Biosimilar Applications and Supplements, U.S. FOOD & DRUG ADMIN. (2019), https://www.fda.gov/about-fda/fda-track-agency-wide- program-performance/bsufa-biosimilar-applications-and-supplements [https://perma.cc/W284-7B4Y]. 145 Medicines Under Evaluation, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/medic ines/medicines-under-evaluation#2019-section [https://perma.cc/FNG2-RU4Y] (last visited Jan. 7, 2021). 518 FOOD AND DRUG LAW JOURNAL VOL. 75 review.146 Updated monthly, the list includes the drug, the month and year the submission was accepted, the therapeutic area, and (for submissions accepted for review on or after October 1, 2018) the company name and “class”147 of the submission.148 In addition, HC’s Therapeutic Products Directorate Drug Submission Performance Annual Reports includes a number of new drug submissions received annually (by fee category).149 B. Sponsor/Agency Meeting Minutes or Other Correspondence During Review FDA does not provide any sponsor/agency meeting minutes or other correspondence throughout the review process unless and until the product is approved, and then these materials may be included in the summary review documents posted publicly.150 If such materials are not included in the summary reviews, they may be requested by FOIA and will be disclosed following redaction of commercial confidential information, as previously discussed. Similarly, EMA and HC do not publish any sponsor/agency meeting minutes or other correspondence throughout the review process, but these materials may be referenced in the EPAR or Summary Basis of Decision issued after a decision on the application/submission has been made. C. Scientific/Advisory Committee Meeting Scheduling and Materials In the U.S., FDA can turn to outside experts to obtain their opinions on a specific product application and their non-binding recommendations on questions regarding approvability of the product.151 As required by the Federal Advisory Committee Act (FACA),152 these advisory committee meetings are public. In addition, FACA requires advance notice of upcoming meetings, opportunities for public attendance and input, sharing with the public of all materials (e.g., reports, studies, agenda) made available to or prepared for or by the committee (subject to FOIA exemptions), and the preparation of transcripts.153 FDA’s website includes an Advisory Committee Calendar,154 which includes meeting rosters, final questions and agenda, and both FDA briefing information
146 See supra note 125. 147 “The submission ‘class’ includes whether the submission is for a new active substance or a biosimilar, if it is being reviewed as per a formal expedited process, if review is taking place as part of an aligned process with a health technology assessment organization, and more.” Drug and Health Product Submissions Under Review (SUR), supra note 138; see also supra note 125. 148 See supra note 125. 149 Number of Original Investigational New Drug (IND) applications received in the quarter, supra note 91. 150 21 U.S.C. § 355(i)(2) (2020); 21 C.F.R. § 314.430 (2020); 21 C.F.R. § 601.51(b) (2020). 151 Human Drug Advisory Committees, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/advisory- committees/committees-and-meeting-materials/human-drug-advisory-committees [https://perma.cc/N6G6- 3SS9] (last visited Aug. 12, 2020). 152 Federal Advisory Committee Act (FACA), 5 U.S.C. app. II §§ 10–11 (1972). 153 5 U.S.C. app. II § 10–11; see also 21 C.F.R. § 14.60 (a)–(b) (2020); 21 C.F.R. § 14.61 (2020). 154 Advisory Committee Calendar, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/advisory- 2021 REGULATORY AGENCY TRANSPARENCY 519
(including information and data from the application at issue)155 and industry briefing information, which are shared prior to the meeting date. Transcripts of all Advisory Committee meetings are shared (added to the meeting website) after they are completed. EMA publishes the agendas and meeting minutes of its scientific committee (e.g., CHMP, CAT, COMP) meetings prior to approval of the marketing authorization application for a product.156 Agenda are published on EMA’s website for the specific committee prior to a meeting, and meeting minutes are published about a month after a meeting.157 For certain committees, including CHMP, EMA also releases highlights from meetings with “outcomes of major public interest” (including recommendations for approval or denial of a marketing authorization application) the Friday following a monthly plenary meeting.158 HC releases information on their scientific/expert advisory committee meetings159 and panel meetings160 on their website. This includes meeting announcements, agendas, and/or recordings of proceedings.161 D. Marketing Application Status FDA does not disclose information on the status of NDAs/BLAs during review.162 This includes user fee goal action dates, as governed by the Prescription Drug User Fee Act (PDUFA), which set out review deadlines for FDA to decide on an application to meet its user fee goal action dates.163 Nor does the agency disclose when and why
committees/advisory-committee-calendar [https://perma.cc/3V3F-WX45] (last visited Aug. 12, 2020). 155 Subject to FOIA exemptions. FDA can share that information based on the provision in 21 C.F.R. § 314.430(d)(1) (2020); 21 C.F.R. § 601.51(d)(1) (2020); see also FDA GUIDANCE FOR INDUSTRY ADVISORY COMMITTEE MEETINGS, supra note 17. 156 Commission Regulation 726/2004, art. 26, 2004 O.J. (L 136) 1, 11 (EC); Commission Regulation 726/2004, art. 80, 2004 O.J. (L 136) 1, 11 (EC); Council Directive 2001/83, art 126b, of the European Parliament and of the Council of 6 Nov. 2001 on the Community Code Relating to Medicinal Products for Human Use, 2004 O.J. (L 311); CHMP: Agendas, minutes and highlights, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/committees/chmp/chmp-agendas-minutes-highlights [https://perma.cc/2JRR-23RB] (last accessed Feb. 26, 2021); see also Principles for Publication of Agendas and Minutes of EMA Scientific Committees, EUR. MEDS. AGENCY (Dec. 17, 2013), https://www.ema.europa.eu/en/documents/other/principles-publication-agendas-minutes-ema-scientific- committees_en.pdf [https://perma.cc/792E-RJ3J]. 157 21 C.F.R. § 20.82 (2007). 158 See CHMP: Agendas, minutes and highlights, supra note 156. 159 Scientific/Expert Advisory Committees, HEALTH CANADA (Apr. 5, 2011), https://www.canada.c a/en/health-canada/services/drugs-health-products/drug-products/scientific-expert-advisory-committees.ht ml [https://perma.cc/QN39-GVSV]. 160 Id. 161 See, e.g., Respiratory and Allergy Therapies Scientific/Expert Advisory Committee, HEALTH CANADA, https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/scienti fic-expert-advisory-committees/respiratory-allergy-therapies.html [https://perma.cc/XQ5D-5D4X] (last visited Aug. 12, 2020). 162 See Harinder Singh Chahal, David Szeto, Anam H. Chaudhry, Daniel W. Sigelman, Stella Kim & Peter G. Lurie, Public Disclosure of the Filing of New Drug and Therapeutic Biologics Applications with the US Food and Drug Administration, 179 JAMA INTERNAL MED. 1144, 1146 (2019). 163 Prescription Drug User Fee Act of 1992, 21 U.S.C. § 301; see PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/media/99140/download [https://perma.cc/PJ6G-YFER] (last visited Aug. 12, 2020). 520 FOOD AND DRUG LAW JOURNAL VOL. 75
FDA extends the review period (e.g., for submission of a major amendment).164 In addition, FDA does not disclose when it places a hold on a clinical trial165 nor when it releases the clinical trial hold. Similarly, EMA and HC do not publish information on the status of a marketing authorization application/submission until a final decision takes place. Further, EMA does not publish if a clinical trial is suspended, as that is the decision of a Member State.166
IV. DECISION AND POST-DECISION DISCLOSURES A. Refuse to File Letter (U.S.)/Validation Supplementary Information Request (EU)/Screening Deficiency Notice (Canada) Within sixty days of receipt of a submitted NDA or BLA, FDA will accept (“file”) the application as “sufficiently complete to permit a substantive review”167 or send the applicant a “refuse-to-file” (RTF) letter informing the application that the application cannot be accepted in current form and why (e.g., it is deficient or incomplete).168 FDA does not disclose when it files an application or when it sends a refuse to file letter.169 Similarly, in the EU, after a marketing authorization application is submitted to EMA, the Agency validates it to ensure it is complete.170 If EMA finds that the application is not complete, it will issue a Validation Supplementary Information (VSI) request to the applicant asking for additional information, clarification or correction of information.171 If the application fails validation, EMA will send a
164 21 C.F.R. § 314.101(c); 21 C.F.R. § 314.60 (2020); 21 C.F.R. § 314.110(b)(1) (2020). 165 Clinical holds are considered administrative actions on an IND. See 21 C.F.R. § 312.42 (2020). 166 Council Directive 2001/20, supra note 92; see also Communication from the Commission— Detailed Guidance on the Request to the Competent Authorities for Authorisation of a Clinical Trial on a Medicinal Product for Human use, the Notification of Substantial Amendments and the Declaration of the end of the Trial (CT-1), 3.11, EUR. MEDS. AGENCY (Mar. 30, 2010), https://eur-lex.europa.eu/ LexUriServ/LexUriServ.do?uri=OJ:C:2010:082:0001:0019:EN:PDF [https://perma.cc/29KG-ETB2]. 167 21 C.F.R. § 314.101(a)(1); see also Refuse to File: NDA and BLA Submissions to CDER Guidance for Industry, Draft Guidance, U.S. FOOD & DRUG ADMIN. (DEC. 2017), https://www.fda.go v/media/109758/download [https://perma.cc/QV6A-KSZM] (“The FDA generally makes filing determinations for BLAs within the same time frame.”). 168 21 C.F.R. § 314.101(a)(3); 21 C.F.R. § 601.2; see also, e.g., Refuse to File: NDA and BLA Submissions to CDER Guidance for Industry, Draft Guidance, supra note 167; MAPP, supra note 11, 6025.4. 169 As official correspondence and part of the application, refuse to file letters are not disclosed per 21 C.F.R. § 314.430(c)–(d); see Refuse to File: NDA and BLA Submissions to CDER Guidance for Industry, Draft Guidance, supra note 167 (“[T]he review division will communicate an RTF action to the applicant by day 60 in the form of official correspondence.”).
170 Marketing Authorisation, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human- regulatory/marketing-authorisation [https://perma.cc/98FZ-ZSDH] (last visited Sept. 17, 2019); see also European Medicines Agency Pre-Authorisation Procedural Advice for Uses of the Centralized Procedure, EUR. MEDS. AGENCY (Jan. 11, 2021), https://www.ema.europa.eu/en/documents/regulatory-procedural- guideline/european-medicines-agency-pre-authorisation-procedural-advice-users-centralised-procedure- document_en.pdf [https://perma.cc/DG5F-EJXH]. 171 European Medicines Agency Pre-Authorisation Procedural Advice for Uses of the Centralized Procedure, supra note 170. 2021 REGULATORY AGENCY TRANSPARENCY 521
“negative validation letter” to the applicant, who must then submit a new marketing authorization application.172 EMA does not publish VSIs or negative validation letters.173 For a Canadian submission to HC, applications go through a ten-day processing period to ensure the submission includes all necessary information,174 followed by a screening period to verify that the application type, class, and fee is correct, and information regarding the type and class of information has been provided.175 Sponsors of applications that pass this screening and are accepted for review will receive a Screening Acceptance Letter, while sponsors of applications that fail this screening will receive Clarification Request asking for an expansion or clarification of specific information or re-analysis of existing information (not requests for new data).176 If a sponsor’s response to the Clarification Request is inadequate, HC will send a Screening Deficiency Notice (SDN) identifying the deficiencies in the submission.177 HC does not publish Clarification Requests or SDNs. B. Positive Marketing Application Decisions In the U.S., after FDA approves an NDA or BLA it will add the application to the Drugs@FDA178 database on its website and for new drugs will upload an action package179 consisting of a set of FDA-generated documents related to the review of the drug (redacted for trade secrets and confidential commercial or financial information), including “a summary review that documents conclusions from all reviewing disciplines about the drug, noting any critical issues and disagreements with the applicant and within the review team and how they were resolved, recommendations for action, and an explanation of any nonoccurrence with review conclusions.”180 In addition, the product’s approval letter will be posted that lists any post-marketing commitments (PMCs) or post-marketing requirement (PMRs) studies the sponsor will conduct.181
172 Id. 173 Id. 174 Incomplete packages are put on an administrative hold until the hold is resolved. See Guidance Document: Management of Drug Submissions and Applications, HEALTH CANADA, para. 10.2.3.1 (Nov. 8, 2019), https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applicati ons-submissions/guidance-documents/management-drug-submissions/industry/document.html#a1 [https: //perma.cc/TJ8S-VP47]. 175 See id. para. 10. 176 See id. para. 10.2. 177 See id. para. 10.2.3. 178 Drugs@FDA: FDA Approved Drug Products, U.S. FOOD & DRUG ADMIN., https://www.a ccessdata.fda.gov/scripts/cder/daf/ [https://perma.cc/5LS3-364K] (last visited Aug. 12, 2020). 179 21 U.S.C. § 355(l)(2) (2020); 21 C.F.R. § 314.430(e) (2020); Complete List of Licensed Products and Establishments, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/vaccines-blood-biologics/complete- list-licensed-products-and-establishments [https://perma.cc/4B96-KRYD] (last visited Aug. 12, 2020); see also supra note 8; MAPP, supra note 11, at 6020.8 Rev.1; MAPP, supra note 11, at 4520.1 Rev.2. 180 21 U.S.C. § 355(l)(2)(C). 181 Postmarketing Requirements and Commitments: Reports, U.S. FOOD & DRUG ADMIN. (NOV. 25, 2020), https://www.fda.gov/drugs/postmarket-requirements-and-commitments/postmarketing-requiremen ts-and-commitments-reports [https://perma.cc/MH3M-TRGC]. 522 FOOD AND DRUG LAW JOURNAL VOL. 75
Ideally, FDA is to publish an action package for a new drug within thirty days of approval,182 but has developed a priority scheme to redact and post action packages for various drug approvals.183 Some drugs, for example NDAs approved under Section 505(b)(2) of the FDCA or abbreviated NDAs (ANDAs) approved under Section 505(j) of the FDCA, may not be routinely posted. For a previously approved drug, FDA will post the action package within thirty days of a third request for the action package for approval received by a FOIA request.184 The statute requires FDA to publish the summary review within forty-eight hours after approval of a new drug, unless the materials require redaction.185 FDA does not disclose an action package for withdrawn/rejected applications.186 As a practical matter, FDA inconsistently posts such action packages, which have been modified in content as discussed above to have integrated reviews, and if not timely posted, may be requested under FOIA. Such FOIA requests, especially if not prepared by FDA in advance, may take several years to complete, even if requested by the drug manufacturer for its own application’s action package. Similarly, EMA posts on its website187 a European Public Assessment Report (EPAR) for each decision on a marketing authorization application.188 EC regulations require that:
The Agency shall immediately publish the assessment report on the medicinal product for human use drawn up by the Committee for Medicinal Products for Human Use and the reasons for its opinion in favour of granting authorisation, after deletion of any information of a commercially confidential nature. The European Public Assessment Report (EPAR) shall include a summary written in a manner that is understandable to the public. The summary shall contain in particular a section relating to the conditions of use of the medicinal product.189
EPARs include the bases for the committee’s decision to recommend (or not, see below) the drug for approval.190 As such, they can become significantly technical in nature, and therefore an EPAR summary (medicine overview) written specifically for
182 21 U.S.C. § 355(l)(2)(A)(i). 183 MAPP, supra note 11, at 4520.1 Rev.2. 184 21 U.S.C. § 355(l)(2)(A)(ii). 185 21 U.S.C. § 355(l)(2)(B). 186 See 21 U.S.C. § 355(l) and 21 C.F.R. § 314.430(f) (2020). 187 Medicines, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/medicines/field_ema_we b_categories%25253Aname_field/Human/ema_group_types/ema_medicine_en [https://perma.cc/QP8H- ZGMA] (last visited Aug. 12, 2020). 188 The Public Assessment requirements apply to nationally authorized products through the Mutual Recognition and Decentralised procedures. Commission Regulation 726/2004, art. 13(3), 2004 O.J. (L 136) 1, 11 (EC); see also European Public Assessment Reports: Background and Context, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/medicines/what-we-publish-when/european-public-assessment-reports-bac kground-context [https://perma.cc/T6WT-C7N7] (last visited Aug. 12, 2020). 189 Council Regulation 726/2004, art. 13(3), 2004 O.J. (L 136) 1, 11 (EC); see also European Public Assessment Reports: Background and Context, supra note 188. 190 See European Public Assessment Reports: Background and Context, supra note 188. 2021 REGULATORY AGENCY TRANSPARENCY 523 a public audience is also posted.191 EPARs are published (or updated) within weeks after an EC decision regarding the application and prior to the EC decision, a summary of opinion is included in the relevant committee meeting highlights.192 Similarly, HC publishes Regulatory Decision Summaries (RDS) for new drug submissions and supplemental new drug submissions for new uses approved after April 1, 2015.193 For approvals issued on or after October 1, 2018, RDSs are published for supplemental new drug submissions for new routes of administration, new dosage forms, and new strengths.194 RDSs provide a brief overview of the purpose of the submission, HC’s decision, and the reason for the decision.195 A more detailed description of the basis for approval can be found in the Summary Basis of Decision (SBD).196 These documents include information on the steps that led to the approval, what follow-up measures the company will take, and the scientific (clinical, nonclinical, and quality) bases for the decision.197 SBDs are posted for approvals of new drug submissions for new active substances198 and new drug submissions for biosimilars approved after September 1, 2012.199 C. Negative Marketing Application Decisions After FDA “files” or accepts a complete NDA or BLA, the review cycle “clock” starts and when that review cycle ends (six months from filing for priority review applications and ten months from filing for standard review applications, i.e., user-fee- goal-action dates), the agency will either approve the application or send a “complete
191 Reflection Paper: EPAR Summary for the Public, EUR. MEDS. AGENCY (Jan. 26, 2006), https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-paper-european- public-assessment-report-summary-public_en.pdf [https://perma.cc/VPA3-VLJQ]. 192 Id.; see also What We Publish on Medicines and When, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/medicines/what-we-publish-medicines-when [https://perma.cc/TA7G- ZDU8] (last visited Aug. 12, 2020). 193 Regulatory Decision Summaries, HEALTH CANADA (Dec. 13, 2019), https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/regulatory-decisio n-summary.html. In addition, a list of approved products (Notice of Compliance) database is available at: Notice of Compliance Search, HEALTH CANADA, https://health-products.canada.ca/noc-ac/index-eng.jsp [https://perma.cc/Q2DN-5LXA] (last visited Aug. 12, 2020). 194 Regulatory Decision Summaries, supra note 193. 195 The Drug and Health Product Register contains a database of Regulatory Decision Summaries. The Drug and Health Product Register, HEALTH CANADA (Nov. 13, 2020), https://hpr-rps.hres.ca/reg- content/regulatory-decision-summary.php [https://perma.cc/7EZ7-872Z]; see, e.g., Regulatory Decision Summary – Humira – Health Canada, HEALTH CANADA (Nov. 13, 2020), https://hpr-rps.hres.ca/reg- content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00495 [https://perma.cc/PW7Q- YMZE]. 196 The Drug and Health Product Register, supra note 195. 197 See, e.g., Summary Basis of Decision – Lorbrena – Health Canada, HEALTH CANADA (Nov. 13, 2020), https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD 00438 [https://perma.cc/WGB8-FC5N]. 198 Regulatory Decision Summaries, supra note 193 (“New active substances contain a medicinal ingredient not previously approved in a drug in Canada (and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate, or polymorph).”). 199 Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II, HEALTH CANADA (July 24, 2018), https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/summary-basis-decision/frequently-asked-questions-summary-basis-decision-project-phase-2.ht ml [https://perma.cc/TB5B-PFK2]. 524 FOOD AND DRUG LAW JOURNAL VOL. 75 response letter” stating that the application is not yet ready for approval and outlining reasons that FDA cannot approve the application at this time, i.e., specific deficiencies,200 and “where appropriate, the actions necessary to make the application potentially suitable for approval.”201 FDA does not disclose the existence or content of complete response letters. Unlike FDA, EMA does publish the results of a negative marketing authorization application review.202 In addition to a negative opinion questions and answers document outlining why the drug was not recommended for approval published in the highlights of the CHMP meeting (see above),203 EMA makes available refusal public assessment reports on its website after the EC’s decision refusing the marketing authorization.204 HC publishes RDSs for some but not all rejected submissions. RDSs are posted for final negative decisions for new drug submissions for new active substances205 accepted for review on or after April 1, 2015 and for new drug submissions and supplemental new drug submissions for a new use accepted for review on or after May 1, 2016.206 D. Withdrawn Marketing Applications FDA does not disclose information about why NDAs or BLAs are withdrawn but may affirm that an NDA was not withdrawn for reasons of safety or efficacy.207 EMA also publishes EPARs for withdrawn marketing authorization applications (MAA).208 If the applicant withdraws the MAA before an opinion on the application is decided, EMA will publish the applicant’s withdrawal letter stating the reasons they
200 21 C.F.R. § 314.110 (2020); see also Complete Response Letter Final Rule, U.S. FOOD & DRUG ADMIN. (Feb. 9, 2018), https://www.fda.gov/drugs/laws-acts-and-rules/complete-response-letter-final-rule [https://perma.cc/68F8-H2W4]. 201 MAPP, supra note 11, at 6020.8 Rev.1. 202 Council Regulation 726/2004, arts. 12(3), 80, 2004 O.J. (L 136) 1, 17, 64 (EC); see also European Public Assessment Reports: Background and Context, supra note 188; Procedural Advice on Publication of Information on Negative Opinions and Refusals of Marketing Authorisation Applications for Human Medicinal Products, EUR. MEDS. AGENCY (May 2, 2013), https://www.ema.eu ropa.eu/en/documents/regulatory-procedural-guideline/procedural-advice-publication-information-nega tive-opinions-refusals-marketing-authorisation_en.pdf [https://perma.cc/HU75-XTDK]. 203 See European Public Assessment Reports: Background and Context, supra note 188. 204 Id. 205 Regulatory Decision Summaries, supra note 193 (“New active substances contain a medicinal ingredient not previously approved in a drug in Canada (and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate, or polymorph).”). 206 Id.; Summary Basis of Decisions are not currently created for negative decisions, nor are screening rejection letters or notices of non-compliance (deficiencies identified during scientific review) made public. 207 See 21 C.F.R. § 314.65 (2020); U.S. Food & Drug Admin., Draft Guidance: Updating ANDA Labeling After the Marketing Application for the Withdrawn Reference Listed Drug has been Withdrawn (July 2016), https://www.fda.gov/files/drugs/published/Updating-ANDA-Labeling-After-the-Marketing- Application-for-the-Reference-Listed-Drug-Has-Been-Withdrawn-Guidance-for-Industry.pdf [https://per ma.cc/2JDA-JD7R] (last accessed July 26, 2021); U.S. Food & Drug Admin., Guidance for Industry: Marketing Status Notifications Under Section 506I of the Federal Food, Drug, and Cosmetic Act; Content and Format (Aug. 2020), https://www.fda.gov/media/120095/download [https://perma.cc/M2UN-FNQ5] (last accessed Feb. 26, 2021). 208 Council Regulation 726/2004, arts. 11, 80, 2004 O.J. (L 136) 1, 17, 64 (EC); What EMA publishes and when, supra note 56. 2021 REGULATORY AGENCY TRANSPARENCY 525 withdrew the application.209 In addition, EMA will publish a Q&A document on its website following the CHMP meeting describing (in lay language) the scientific assessment of the product up to the time of the withdrawal.210 Additional documents that make up an EPAR will be published within three months of the withdrawal letter.211 HC publishes RDSs for canceled submissions for new drug submissions for new active substances212 accepted for review on or after April 1, 2015 and for new drug submissions and supplemental new drug submissions for a new use accepted for review on or after May 1, 2016.213 E. Appeals of Marketing Application Decisions In the U.S., a drug sponsor may appeal a decision denying approval (an RCT letter) by requesting a hearing on the question of whether the NDA or BLA is approvable.214 In addition, other formal dispute resolution avenues exist.215 FDA does not disclose the existence or appeal decision unless and until the application is approved or a public advisory committee meeting is held. Similarly, an applicant in the EU may request a reexamination of a negative opinion from CHMP within fifteen days after receiving the opinion.216 EMA discloses the appeal decision upon completion of the re-examination procedure as it would ordinarily do for any other opinion (see above), with EMA updating the initial negative opinion Q&A document and other EPAR documents to reflect the reexamination outcome.217 In addition, if the re-examination is positive, EMA will publish a new positive opinion Q&A document outlining the reasons for its recommendation.218 In Canada, applicants can follow the reconsideration process to dispute a negative decision on their submission.219 In this process, applicants must file a Letter of Intent
209 Procedural Advice on Publication of Information on Withdrawals of Applications Related to the Marketing Authorisation of Human Medicinal Products, supra note 202. 210 Id. 211 Id. 212 Regulatory Decision Summaries, supra note 193 (“New active substances contain a medicinal ingredient not previously approved in a drug in Canada (and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate, or polymorph).”). 213 Id. 214 21 U.S.C. § 360bbb-1; 21 C.F.R. § 314.125 (2020); see U.S. FOOD & DRUG ADMIN., GUIDANCE FOR INDUSTRY FORMAL DISPUTE RESOLUTION: APPEALS ABOVE THE DIVISION LEVEL (Feb. 2000), https://www.fda.gov/media/71887/download [https://perma.cc/J8RK-PHXF]. 215 21 C.F.R. §§ 10.75, 312.48(c), 314.103(c) (2020); see also U.S. FOOD & DRUG ADMIN., FORMAL DISPUTE RESOLUTION: SPONSOR APPEALS ABOVE THE DIVISION LEVEL: GUIDANCE FOR INDUSTRY AND REVIEW STAFF 1, 2 (Nov. 2020), https://www.fda.gov/media/126910/download [https://perma.cc/HG2Z- N3PX]. 216 Commission Regulation 726/2004, art. 9(2), 2004 O.J. (L 136) 14, 15; see European Public Assessment Reports: Background and Context, supra note 188. 217 Commission Regulation 726/2004, art. 9(2), 2004 O.J. (L 136) 14, 15; see European Public Assessment Reports: Background and Context, supra note 188. 218 What EMA publishes and when, supra note 56. 219 Guidance Document: Reconsideration of Decisions Issued for Human Drug and Natural Health Product Submission, HEALTH CANADA 1, 8 (Apr. 1, 2019), https://www.canada.ca/content/dam/hc- sc/migration/hc-sc/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/Guidance-Reconsideration_Decision s-2019.pdf [https://perma.cc/BX2Y-S9VN]. 526 FOOD AND DRUG LAW JOURNAL VOL. 75 within thirty days of receiving the negative decision letter.220 The reconsideration process can result in one of three outcomes: (1) the original decision is upheld; (2) the original decision is partially amended but the submission remains refused; or (3) the original decision is amended.221 HC does not disclose the existence of a reconsideration or make the final decision (i.e., the reconsideration letter) public, but will revise the RDS and/or SBD, as needed. F. Clinical Trial Results Summaries While FDA does release information about the clinical trials supporting an approved NDA or BLA in the review summaries and action packages for new drugs, the agency does not create or share sponsor-generated technical clinical trial summaries (clinical study reports or CSRs) or “lay summaries” of clinical trial results written in lay language and intended for the wider public. In addition, while FDA lists the current post marketing requirements and post marketing commitments (PMRs/PMCs) of products and their current status on its website,222 the agency inconsistently discloses the final summary reports of these clinical trials and usually in a very brief fashion indicating whether the study and reports met a post-approval requirement or not.223 However, in January 2018, FDA’s Center for Drug Evaluation and Research (CDER) began its Clinical Data Summary Pilot Program, intending to release (with the action package) portions of the CSRs from the sponsor’s NDA as a potentially more useful format for this information than what is currently included in the action package.224 The portions of the CSRs posted include information from the study report body, the protocol and amendments, and the statistical analysis plan for each study (no raw data).225 This voluntary pilot program sought to feature up to nine NDAs for release, but only the drug clinical data summaries for one product—Janssen’s Erleada®—were published.226 FDA asked for comments on partial disclosure of the CSRs, as well as a new Integrated Review Process and documentation template, which was implemented on June 24, 2019 for the product Dovato® (dolutegravir, lamivudine), replacing the current documentation where each discipline provides a separate application review document.227 This new template provides instead a collaborative document with input
220 Id. 221 Id. at 16–17. 222 See Postmarket Requirements and Commitments, U.S. FOOD & DRUG ADMIN., https://www.accessdata.fda.gov/Scripts/cder/pmc/index.cfm [https://perma.cc/7W7C-ZWNV] (last visited Aug 12, 2020). 223 See Postmarketing Requirements and Commitments: Frequently Asked Questions (FAQ), U.S. FOOD & DRUG ADMIN., https://www.fda.gov/drugs/postmarket-requirements-and-commitments/postmar keting-requirements-and-commitments-frequently-asked-questions-faq [https://perma.cc/AY7M-TMKD] (last visited Aug 12, 2020). 224 Clinical Data Summary Pilot Program, U.S. FOOD & DRUG ADMIN., https://www.fda. gov/drugs/developmentapprovalprocess/ucm589210.htm [https://perma.cc/M9YJ-Z8VG] (last visited Aug. 12, 2020). 225 Id. 226 Drug Approval Package: ERLEADA (apalutamide), U.S. FOOD & DRUG ADMIN., https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm [https://perma.cc/24NE-JSXK] (last visited Aug. 12, 2020). 227 New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and 2021 REGULATORY AGENCY TRANSPARENCY 527 from clinical, clinical pharmacology, biostatistics, toxicology reviewers, and other disciplines based upon the issues raised by the application.228 The comment period for the June 27, 2019 Notice closed on August 26, 2019, with twenty-one comments filed.229 Comments varied, from the Pharmaceutical Research and Manufacturers of America (PhRMA) supporting the integrated template and criticizing the need to release CSRs.230 A not-for-profit data transparency group, PhUSE Data Transparency Working Group, identified concerns with FDA redacting the CSRs without consulting sponsors, potentially leading to FDA disclosing commercial, confidential information.231 Editors of two medical journals that use FDA’s action packages on the Drugs@FDA website, the British Medical Journal and an open-access journal, PLOS Medicine, were concerned that individually attributable reviews would be replaced by a more anonymous group integrated review, where it would be less possible to discern internal differences of opinion and hence understanding of the approval process.232 A group of researchers filed comments supporting more thorough mandatory disclosure of CSRs to learn more about the safety and efficacy evidence supporting product approvals as well as to unify disclosure of CSRs as in Canada and Europe.233 And some consumers voiced concern for FDA integrating reviews rather than providing them separately and also asked for CSR disclosure to the fullest extent rather than certain sections identified by FDA.234 Given how HHS, NIH, and FDA have handled ClinicalTrials.gov, it may be unlikely the CSR disclosures will be disclosed with any frequency without a statutory mandatory disclosure requirement. In the EU, sponsors currently must submit clinical trial result summaries (including for post-authorisation safety studies (PASSs)235 and post-authorisation efficacy studies
Communication, 84 Fed. Reg. 30,733 (June 27, 2019). 228 Modernizing FDA’s New Drugs Regulatory Program, U.S. FOOD & DRUG ADMIN. (Jan. 2020), https://www.fda.gov/drugs/regulatory-science-research-and-education/modernizing-fdas-new-drugs- regulatory-program [https://perma.cc/74TJ-CC9K]; New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication, Notice, 84 Fed. Reg. 30,733 (June 27, 2019). 229 New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication, Notice, 84 Fed. Reg. 30,733 (June 27, 2019). 230 Comment from Pharmaceutical Research and Manufacturers of America PhRMA, Regulations.gov, Docket FDA-2019-N-2012-0022, https://www.regulations.gov/comment/FDA-2019-N- 2012-0022 [http s://perma.cc/VQQ5-YDBK] (last accessed Feb. 26, 2021). 231 Comment from PhUSE Data Transparency Working Group, Regulations.gov, Docket No. FDA- 2019-N-2012-0013, https://www.regulations.gov/comment/FDA-2019-N-2012-0013 [https://perma.cc/ B5FR-JQTK] (last accessed Feb. 26, 2021). 232 Comment from The BMJ and PLOS, Regulations.gov, Docket FDA-2019-N-2012-0018, https://w ww.regulations.gov/comment/FDA-2019-N-2012-0018 [https://perma.cc/LXY8-K9TP] (last accessed Feb. 26, 2021). 233 Comment from Peter Doshi et al., Regulations.gov, Docket No. FDA-2019-N-2012-10, https://w ww.regulations.gov/comment/FDA-2019-N-2012-0010 [https://perma.cc/JNV6-SW3U] (last accessed Feb. 26, 2021). 234 New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication, Notice, 84 Fed. Reg. 30,733 (June 27, 2019).
235 Post-authorisation safety studies (PASS), EUR. MEDS. AGENCY, https://www.ema.europa.eu/ en/human-regulatory/post-authorisation/pharmacovigilance/post-authorisation-safety-studies-pass-0 [https://perma.cc/ZQQ7-A6B5] (last visited Aug. 12, 2020); The European Union electronic Register of 528 FOOD AND DRUG LAW JOURNAL VOL. 75
(PAESs)) to the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), managed by EMA, within twelve months after the end of the trial (for studies conducted in the EU) or six months after the end of a trial that include pediatric subjects.236 These clinical trial results summaries are available to the public through the EU Clinical Trials Register.237 As mentioned above, the current Clinical Trials Directive238 will be repealed by the Clinical Trials Regulation239 when the regulation comes into application (currently anticipated to be after completion of an audit of the system slated to begin in December 2020).240 The regulation will apply once the functionality of the EU portal and EU database is verified and published by the European Commission in an official notice. Thereafter, sponsors must submit clinical trial results summaries (including intermediate data analyses) into the centralized EU Clinical Trial Portal (within twelve months of a trial conducted within the EU and within six months of a trial with pediatric participants).241 In addition, sponsors must submit a summary written for a general audience (the “layperson’s summary”) and the clinical study report (CSR).242 The regulation lays out that:
For the purposes of this Regulation, in general the data included in a clinical study report should not be considered commercially confidential once a marketing authorisation has been granted, the procedure for granting . . . the marketing authorisation has been completed, the application for marketing authorisation has been withdrawn. In addition, the main characteristics of a clinical trial, the conclusion on Part I of the assessment report for the authorisation of a clinical trial, the decision on
Post-Authorisation Studies (EU PAS Register), EUR. NETWORK OF CENTRES FOR PHARMACOEPIDEMIOLOGY & PHARMACOVIGILANCE, http://www.encepp.eu/encepp_studies/ indexRegister .shtml [https://perma.cc/6HKY-GXU8] (last visited Aug. 12, 2020). 236 Council Directive 2001/20, supra note 92; see also Posting of Clinical Trial Summary Results in European Clinical Trials Database (EudraCT) to Become Mandatory for Sponsors as of 21 July 2014, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/news/posting-clinical-trial-summary-results-european- clinical-trials-database-eudract-become-mandatory [https://perma.cc/98SR-R35R] (last visited Sept. 24, 2019); Commission Guideline – Guidance on posting and publication of result-related information on clinical trials in relation to the implementation of article 57(2) of regulation (EC) No 726/2004 and article 41(2) of regulation (EC) No 1901/2006, EUR. MEDS. AGENCY 1, 8 (June 10, 2012), https://eur- lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:52012XC1006(01)&from=EN [https://perma.cc/ P74T-4W3F]; see generally Technical Guidance on the Format of the Data Fields of Result-Related Information on Clinical Trials Submitted in Accordance with Article 57(2) of Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006, EUR. MEDS. AGENCY, https://eur-lex.europa.eu/legal- content/EN/TXT/PDF/?uri=CELEX:52012XC1006(01)&from=EN [https://perma.cc/R6EJ-KWUP] (last visited Feb. 26, 2021). 237 Council Regulation 726/2004, art. 57, 2004 O.J. (L 136) (EC); Council Regulation 1901/20069, art.41, 2006 O.J. (L 378); see also Commission Guideline, supra note 236; About the EU Clinical Trials Register, EUR. MEDS. AGENCY, https://www.clinicaltrialsregister.eu/about.html [https://perma.cc/7MU3- PKUA] (last visited Sept. 24, 2019). 238 Council Directive 2001/20, supra note 92. 239 See Council Regulation 536/2104, 2014 O.J. (L 158) (EC). 240 Clinical trials – Regulation EU No 536/2014, EUR. COMM’N, https://ec.europa.eu/health/human- use/clinical-trials/regulation_en [https://perma.cc/Q9PV-LHLM] (last visited Aug. 12, 2020). 241 Council Regulation 536/2104, art. 82, 2014 O.J. (L 158) (EC). 242 Council Regulation 536/2104, art. 37, 2014 O.J. (L 158) (EC). 2021 REGULATORY AGENCY TRANSPARENCY 529
the authorisation of a clinical trial, the substantial modification of a clinical trial, and the clinical trial results including reasons for temporary halt and early termination, in general, should not be considered confidential.243
In addition, under EMA’s policy on the publication of clinical data (Policy 0070),244 the Agency posts clinical trial data on its website according to Phase 1 of the policy (Phase 2 is discussed below and relates to individual patient data).245 In force since January 1, 2015, Phase 1 sets out that EMA will publish clinical reports submitted to the Agency including those submitted as part of a marketing authorization application and as part of a new indication or line extension application for centrally authorized medicines (in addition, certain users can download the reports and the information can be accessed by third parties subject to the terms of use).246 Clinical reports usually include a (1) clinical overview; (2) clinical summary; and (3) clinical study report (i.e., modules 2.5, 2.7 and 5.3 of the common technical document).247 Clinical trial data is released after an EC decision on the MAA (for approved or rejected applications) or after receipt of a withdrawal letter for withdrawn applications.248 As of April 12, 2018, EMA has suspended publication of clinical trial data until further notice.249 In March 2019, new HC regulations came into force that allow public release of certain clinical trial information, including clinical overviews, clinical summaries, and clinical study reports250 after a drug receives a final decision on its marketing application.251 Prior to that change, clinical trial information was considered confidential business information (at all times) and could only be disclosed to certain individuals/organizations under specific circumstances related to protection and
243 Council Regulation 536/2104, 2014 O.J. (L 158) (EC) 68. 244 See European Medicines Agency Policy on the Publication of Clinical Data for Medicinal Products for Human Use, EUR. MEDS. AGENCY (Mar. 21, 2019), https://www.ema.europa.eu/en/documents/ other/european-medicines-agency-policy-publication-clinical-data-medicinal-products-human-use_en.pdf [https://perma.cc/Z4U7-6DU3]; see also Questions and Answers on the EMA Policy on Publication of Clinical Data for Medicinal Products for Human Use, EUR. MEDS. AGENCY, https://www.em a.europa.eu/en/documents/report/questions-answers-european-medicines-agency-policy-publication-clinic al-data-medicinal-products_en.pdf [https://perma.cc/53M3-ZTFY] (last visited Aug. 12, 2020). 245 Online Access to Clinical Data for Medicinal Products for Human Use, EUR. MEDS. AGENCY, https://clinicaldata.ema.europa.eu/web/cdp/home [https://perma.cc/SBL3-M7ZN] (last visited Aug. 12, 2020). 246 Id. 247 Clinical Data Available, EUR. MEDS. AGENCY, https://clinicaldata.ema.europa.eu/web/cdp/ background [https://perma.cc/9SEP-FMUA] (last visited Aug. 12, 2020). 248 Id. 249 Online Access to Clinical Data for Medicinal Products for Human Use, supra note 245. 250 Public Release of Clinical Information: guidance document, HEALTH CANADA, https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/profile-publicrelea se-clinical-information-guidance/document.html [https://perma.cc/RQM9-NTM5] (last visited Aug. 12, 2020). 251 Clinical information within drug submissions ceases to be CBI when Health Canada issues (1) a notice of compliance; (2) a notice of non-compliance-withdrawal; or (3) a notice of deficiency-withdrawal. Food & Drugs Act, R.S.C. 1985, c. 870, Section C.08.009.1-3; see also Regulations Amending the Food and Drug Regulations (Public Release of Clinical Information), HEALTH CANADA, http://gazette.gc.ca/rp- pr/p1/2017/2017-12-09/html/reg3-eng.html?source=post_page [https://perma.cc/C7BX-X5LP] (last visited Aug. 12, 2020). 530 FOOD AND DRUG LAW JOURNAL VOL. 75 promotion of human health and safety.252 As explained in the Canada Gazette notice, Regulations Amending the Food and Drug Regulations (Public Release of Clinical Information):
The following clinical information would cease to be treated as confidential following a final regulatory decision and would be released to the public: clinical summaries, reports and supporting data of clinical trials submitted in support of a drug submission, except: (a) Information that the manufacturer did not use in the drug submission to support the proposed conditions of use or purpose for the drug; or (b) Information that describes tests, methods or assays that are used exclusivity by the manufacturer.253
Recognizing that “[p]roviding public access to this clinical information can enable independent re-analyses of data, foster new research questions, and benefit Canadians by helping them to make informed decisions about their health,” HC issued guidance in March 2019.254 The guidance document sets out that:
Health Canada intends to publish on a proactive basis the information in drug submissions and medical device applications that receive a final regulatory decision following the coming into force of the regulations (new submissions). Proactive publication of this information will be phased in over four years, as described in section 3.3 of this guidance. Health Canada intends to make available on request the information in drug submissions and medical device applications that received a final regulatory decision prior to the coming into force of the regulations (past submissions).255
HC plans to release clinical information contained in eCTD modules 2.5 (Clinical Overviews), 2.7 (Clinical Summaries), and 5.3 (Clinical Study Reports), as well as clinical information in the following appendices to clinical study reports: 16.1.1 (Protocol and Protocol Amendments), 16.1.2 (Sample Case Report Forms), and 16.1.9 (Statistical Analysis Plan).256 This information can be found on HC’s clinical information portal257 for use in non-commercial purposes.258
252 Food & Drugs Act R.S.C., 1985, c. F-27, s.21.1(3)(c); Guidance Document – Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food & Drugs Act, HEALTH CANADA, https://www.canada.ca/content/dam/hc-sc/documents/services/drug-health-product-review-approval/cbi- gd-ld-ccc-eng.pdf [https://perma.cc/BYQ7-BWMF] (last visited Aug. 12, 2020). 253 Regulations Amending the Food and Drug Regulations (Public Release of Clinical Information), GOV’T OF CAN., http://gazette.gc.ca/rp-pr/p1/2017/2017-12-09/html/reg3-eng.html?source=post_page [https://perma.cc/C7BX-X5LP] (last visited Aug. 12, 2020). 254 Public Release of Clinical Information: guidance document, supra note 250. 255 Id. 256 Id. The decision to disclose clinical information regarding interim analyses will be decided on a case-by-case basis. 257 Search for Clinical Information on Drugs and Medical Devices, HEALTH CANADA, https://clinical- information.canada.ca/search/ci-rc [https://perma.cc/H65B-RTGT] (last visited Aug. 12, 2020). 258 See Public Release of Clinical Information: guidance document, supra note 250. “Non-commercial 2021 REGULATORY AGENCY TRANSPARENCY 531
HC’s implementation schedule follows a four-year phased-in approach starting in 2019 (we only include drugs here; the plan also includes devices):
Implementation Stage 1/Year 1: release clinical information for new active substance new drug submissions, supplemental new drug submissions with confirmatory trials following approval under a notice of compliance with conditions; submissions to switch an authorized medicinal ingredient to non-prescription status Implementation Stage 2/Year 2: adding all new drug submissions Implementation Stage 3/Year 3: adding all supplemental new drug submissions Implementation Stage 4/Year 4: adding generic drug submissions.259
HC “aims to upload a final redacted and anonymized clinical information package onto HC’s clinical information portal within 120 calendar days from initiation of the process.”260 For clinical information not planned for prospective release (e.g., from previous drug submissions), individuals can request this information through HC’s clinical information portal and HC will publish that information (as well as a list of requests).261 HC does not require or publish lay summaries of clinical trial results. G. Agency-Created Data Analysis FDA does not release agency-created data analyses prior to NDA or BLA approval, unless it is included as part of FDA’s briefing package for an Advisory Committee meeting discussing the application.262 After FDA approves an NDA or BLA, any agency-created data analyses may be disclosed in the action package.263 Similarly, EMA and HC do not release agency-created data analyses unless they are referenced and/or included in the published EPAR/RDS/SBD. H. Pharmacovigilance/Risk Mitigation Information In the U.S., the safety of drugs is followed after they are approved and enter the market through FDA’s Adverse Events Reporting System (FAERS) in which reports of adverse events are submitted to the database by manufacturers264 and individual
purpose” is defined as “the information will not be used to support a marketing authorization application anywhere in the world, or sold or traded to another person.” 259 Id. 260 Id. 261 Clinical Information on Drugs and Health Products, HEALTH CANADA, https://www.canada .ca/en/health-canada/services/drug-health-product-review-approval/clinical-information-drugs-health-prod ucts.html [https://perma.cc/6C8M-BLV7]. 262 Subject to FOIA exemptions. FDA can share that information based on the provision in 21 C.F.R. § 312.430(d)(1); 21 C.F.R. § 601.51(d)(1); see also FDA GUIDANCE FOR INDUSTRY ADVISORY COMMITTEE MEETINGS, supra note 17.
263 21 U.S.C. § 355(l)(2) (2018); 21 C.F.R. § 314.430(e) (2020); see also U.S. FOOD & DRUG ADMIN., SOPP 8401.7: ACTION PACKAGE FOR POSTING (Dec. 11, 2020), https://www.fda.gov/media/ 82426/download [https://perma.cc/6C57-VNYZ]; MAPP, supra note 11, at 6020.8 Rev.1. 264 21 C.F.R. § 314.80 (2020). 532 FOOD AND DRUG LAW JOURNAL VOL. 75 healthcare providers and/or patients (through MedWatch reports265). In addition, FDA conducts some active surveillance of drugs through its Sentinel Initiative,266 which on its website publishes reports and other information about its surveillance projects.267 The FAERS public dashboard268 allows anyone to search for information about adverse events reported for drugs and includes certain metrics (e.g., reports per year, reports by type, reports by reporter, reports by seriousness). In addition, the latest quarterly files (raw data) are available for download.269 FDA also publishes MedWatch safety alerts270 to notify the public on recalls and risks of adverse reactions, and potential signals of serious risks/new safety information identified from its bi- weekly screening of FAERS.271 In addition, after an NDA or BLA is approved, FDA publishes any approved Risk Evaluation and Mitigation Strategy (REMS) for that product on FDA’s website,272 usually within three business days of approval.273 These REMS are drug safety programs274 that include requirements meant to ensure the safe use of a drug and can include medication guides, educational requirements, and restricting prescribing only to certified prescribers.275 In the EU, EMA coordinates the pharmacovigilance of medicines.276 Product manufacturers, healthcare providers, and patients submit individual case safety reports
265 MedWatch: The FDA Safety Information and Adverse Event Reporting Program, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/safety/medwatch-fda-safety-information-and-adverse-event-reporting -program [https://perma.cc/CJB7-AHA9] (last visited Aug. 12, 2020). 266 FDA’s Sentinel Initiative, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/safety/fdas-sentinel- initiative [https://perma.cc/UTU3-R6Y4] (last visited Aug. 12, 2020). 267 SENTINEL, https://www.sentinelinitiative.org/ [https://perma.cc/F2TW-TA2K] (last visited Aug. 12, 2020). 268 FDA Adverse Events Reporting System (FAERS) Public Dashboard, U.S. FOOD & DRUG ADMIN., https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa- 6d3021737452/state/analysis [https://perma.cc/H9Y8-ADRJ] (last visited Aug. 12, 2020). 269 FDA Adverse Event Reporting System (FAERS): Latest Quarterly Data Files, U.S. FOOD & DRUG ADMIN., https://www.fda.gov/drugs/fda-adverse-event-reporting-system-faers/fda-adverse-event-reporting -system-faers-latest-quarterly-data-files [https://perma.cc/3VY9-UKX8] (last visited Aug. 12, 2020). 270 See MedWatch: The FDA Safety Information and Adverse Event Reporting Program, supra note 265. 271 21 U.S.C. § 355(k)(5) (2020). See Potential Signals of Serious Risks/New Safety Information Identified from the FDA Adverse Event Reporting System (FAERS), U.S. FOOD & DRUG ADMIN. (Oct. 5, 2020), https://www.fda.gov/drugs/fda-adverse-event-reporting-system-faers/potential-signals-serious-risks new-safety-information-identified-fda-adverse-event-reporting-system [https://perma.cc/FN39-9CA8]. 272 Approved Risk Evaluation and Mitigation Strategies (REMS), U.S. FOOD & DRUG ADMIN., https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm [https://perma.cc/FZ6B-NTXG] (last visited Aug. 12, 2020). 273 MAPP, supra note 11, at 4520.1 Rev. 2. 274 The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require REMS. Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, 121 Stat. 823. 275 Risk Evaluation and Mitigation Strategies, U.S. FOOD & DRUG ADMIN. (Aug. 8, 2019), https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems [ht tps://perma.cc/C5EW-4RU5]; What’s in a REMS?, U.S. FOOD & DRUG ADMIN. (Jan. 26, 2018), https://www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/whats-rems [https://perma.cc/ HV35-Y6RM]. 276 Council Regulation No. 1027/2012, 2012 O.J. (L 316/38) (EU); Council Directive 2012/26, 2012 O.J. (L 299/1) (EU); Council Directive 2010/84, 2010 O.J. (L 348/74) (EU); Council Regulation No. 2021 REGULATORY AGENCY TRANSPARENCY 533 of adverse events to the EudraVigilance Database.277 EMA publishes data from EudraVigilance in the European database for suspected adverse drug reaction reports.278 In addition, product manufacturers submit periodic safety update reports (PSURs) to a central repository.279 PSURs “present a comprehensive and critical analysis of the risk-benefit balance of the product, taking into account new or emerging safety information in the context of cumulative information on risk and benefits.”280 EMA and Member States assess the PSURs for each active (or combination of) active substances to determine if the benefit risk balance has changed and if the marketing authorization should be updated.281 These assessments (called single assessment of related PSURs or PSUSAs) may result in an update of the relevant EPAR documents and, when a change to the product information is required, EMA publishes a document titled “The scientific conclusions and grounds recommending the variation to the terms of the marketing authorisation” on the product’s EPAR page (for nationally authorized medicines the information can be found on EMA’s “Outcomes of periodic safety update report single assessments” webpage).282 For assessments resulting in no change to the marketing authorization, EMA publishes a list of medicines assessed.283 Similarly, EMA assesses the results of post-authorization safety studies (PASSs)284 and they may result in updating EPARs, publishing scientific conclusion documents, or listing the medicines as assessed if no changes to the marketing authorization are warranted.285 After approval, certain medicines, including all new active substance products and all biological medicinal products, are watched more intensely under EMA’s
1235/2010, 2010 O.J. (L 348/1) (EU); Commission Implementing Regulation No. 520/2012, 2010 O.J. (L 159/5) (EU); see also Implementation of the Pharmacovigilance Legislation, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human-regulatory/overview/pharmacovigilance/legal-framework/impleme ntation-pharmacovigilance-legislation [https://perma.cc/DPP2-JG2Y] (last visited Aug. 12, 2020); Legal Framework: Pharmacovigilance, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human-regulatory/ overview/pharmacovigilance/legal-framework-pharmacovigilance [https://perma.cc/FP49-Z2RZ] (last visited Aug. 12, 2020). 277 Council Regulation No. 1235/2010, 2010 O.J. (L 348/1) (EU); EudraVigilance, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human-regulatory/research-development/pharmacovigilance/eud ravigilance [https://perma.cc/6YFS-TPRC] (last visited Aug. 12, 2020). 278 EudraVigilance – European Database of Suspected Adverse Drug Reaction Reports, EUR. MEDS. AGENCY, http://www.adrreports.eu/ [https://perma.cc/CRW2-48U9] (last visited Aug. 12, 2020). 279 Commission Implementing Regulation No. 520/2012, 2012 O.J. (L 159/5) (EU); Council Regulation No. 1235/2010, 2010 O.J. (L 348/1) (EU); Council Directive 2010/84, 2010 O. J. (L 348/74) (EU); see also Periodic Safety Update Reports (PSURs), EUR. MEDS. AGENCY, https://www .ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/periodic-safety-update- reports-psurs [https://perma.cc/3MNW-938M] (last visited Aug. 12, 2020). 280 Periodic Safety Update Reports (PSURs), supra note 279. 281 Download Medicine Data, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/ medicines/download-medicine-data [https://perma.cc/M7TL-FSY4] (last visited Aug. 12, 2020). 282 Id. 283 See MedWatch: The FDA Safety Information and Adverse Event Reporting Program, supra note 265; see also 21 C.F.R. § 20.82 (2005). 284 Council Directive 2001/83, art. 1(15), 2004 O.J. (L 311) (EC). 285 See 21 C.F.R. § 20.82 (2005). 534 FOOD AND DRUG LAW JOURNAL VOL. 75
“additional monitoring” program for five years (or longer, as decided by the Pharmacovigilance Risk Assessment Committee (PRAC)), and must carry a black symbol in its package leaflet and the summary of product characteristics to denote its additional-monitoring status and to encourage reporting of adverse events.286 A list of all medical products currently being followed under additional monitoring can be found on EMA’s website.287 Risk management plans (RMP) include information on plans to prevent or minimize the product’s risk in patients and safety and efficacy studies to be conducted post- marketing.288 All product sponsors are required to submit an RMP to EMA in their MAA.289 Summaries of risk management plans are publicly available on EMA’s website, and are required to include “key elements of the risk management plan with a specific focus on risk minimisation activities and, with regard to the safety specification of the medicinal product concerned, important information on potential and identified risks as well as missing information.”290 In addition, the pharmacovigilance referral process exists to resolve concerns about safety or the benefit-risk balance of a medicine or class of medicines.291 When requested by the EC, a Member State or the manufacturer of the medicine, EMA conducts a scientific assessment (safety-related referrals are conducted by the PRAC and then assessed by CHMP for nationally authorized medicines).292 Information
286 Commission Implementing Regulation 198/2013, 2013 O.J. (L 65/17) (EU); Commission Implementing Regulation No. 520/2012, 2012 O.J. (L 159/5) (EU); Council Directive 2012/26, 2012 O.J. (L 299/1) (EU); Council Regulation No. 1027/2012, 2012 O.J. (L 316/38) (EU); Council Regulation No. 726/2004, art. 23, 2004 O.J. (L 136) (EC); Council Directive 2001/83, art. 11, 2004 O.J. (L 311) (EC). See also Medicines Under Additional Monitoring, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human- regulatory/post-authorisation/pharmacovigilance/medicines-under-additional-monitoring [https://perma.cc/ CU86-74YU] (last visited Sept. 24, 2019); Guideline on Good Pharmacovigilance Practices (GVP): Module X – Additional monitoring (2013), EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/docume nts/scientific-guideline/guideline-good-pharmacovigilance-practices-module-x-additional-monitoring_en .pdf [https://perma.cc/M7RK-HR87]. 287 Id. 288 Risk Management Plans, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human- regulatory/marketing-authorisation/pharmacovigilance/risk-management/risk-management-plans [https://p erma.cc/LMN2-9GCE] (last visited Aug. 12, 2020); see also Questions and Answers: Questions and answers on the risk management plan (RMP) summary, EUR. MEDS. AGENCY (Mar. 30, 2017), https://www.ema.europa.eu/en/documents/other/questions-answers-risk-management-plan-rmp-summary_ en.pdf [https://perma.cc/V8LH-9LAE]. 289 Council Regulation 1235/2010, 2010 O.J. (L 348/1) (EU); Council Directive 2010/84, 2010 O.J. (L 348/74) (EU). 290 Council Regulation 1235/2010 of 15 December 2010 amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products, 2010 O.J. (L 348/1) (EU) https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L: 2010:348:0001:0016:EN:PDF [https://perma.cc/P823-LDSH] (last accessed Feb. 26, 2021). 291 Referral Procedures, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/human- regulatory/post-authorisation/referral-procedures [https://perma.cc/HKS5-YN4Z] (last visited Aug. 12, 2020); see, e.g., Questions & Answers on Urgent Union Procedures (Article 107i of Directive 2001/83/EC), EUR. MEDS. AGENCY (Jan. 31, 2019), https://www.ema.europa.eu/en/documents/regulatory-procedural- guideline/questions-answers-urgent-union-procedures-article-107i-directive-2001/83/ec_en.pdf [https://perma.cc/EP6V-RP37]. 292 Certain referrals have been made through the Coordination Group for Mutual Recognition and Decentralised Procedures requiring changes to product labels and harmonization of the product labels 2021 REGULATORY AGENCY TRANSPARENCY 535 about safety (and other types of) referrals is available online in EMA’s database of referrals, including a Q&A format written for a lay audience and, for safety referrals, instructions on how the public can submit data for the assessment and information on whether and when a public hearing will be held.293 In addition, the PRAC meeting highlights announces the start of a safety-related referral, including the reasons why it was conducted, and, after the assessment, the meeting highlights include the PRAC’s recommendation to the CHMP. The CHMP’s decision is announced in the CHMP meeting highlights.294 HC’s post-market surveillance program is called Canada Vigilance,295 a part of the MedEffect program that “provides consumers, patients, and health professionals with easy access to: report an adverse reaction or side effect; obtain new safety information on drugs and other health products; and learn and better understand the importance of reporting side effects.”296 The Canada Vigilance online database297 contains publicly searchable information about suspected adverse reactions to health products based on adverse reaction reports reported by consumers, health care professionals, manufacturers, and distributors.298 In addition, advisories and recalls can be found in the Recalls and Safety Alerts Database.299 HC does not publish risk management plans.300 I. Patient-Level Clinical Trial Data FDA does not disclose any patient-level clinical trial data to protect individually identifiable information.301
(summary of product characteristics) for nationally approved products. See EudraVigilance – European Database of Suspected Adverse Drug Reaction Reports, EUR. MEDS. AGENCY, http://www.adrreports.eu/ (last accessed Feb. 26, 2021). 293 Council Regulation No. 726/2004, 2014 O.J. (L 136) (EC); Council Directive 2001/83, 2001 (L 311) (EC). See also Public hearing, EUR. MEDS. AGENCY, https://www.ema.europa.eu/en/about-us/how-we- work/public-hearings [https://perma.cc/AQ5X-J48X] (last visited Aug. 12, 2020). 294 PRAC: Agendas, minutes and highlights, EUR. MEDS. AGENCY, https://www.ema.eur opa.eu/en/committees/prac/prac-agendas-minutes-highlights [https://perma.cc/HA73-QRNN] (last visited Aug. 12, 2020). 295 Canada Vigilance Program, HEALTH CANADA (July 12, 2018), https://www.canada.ca/en/health- canada/services/drugs-health-products/medeffect-canada/canada-vigilance-program.html [https://perma.c c/24MR-SQ2N]. 296 MedEffect Canada, HEALTH CANADA (Dec. 15, 2020), https://www.canada.ca/en/health- canada/services/drugs-health-products/medeffect-canada.html [https://perma.cc/ZW6P-646Z]. 297 Canada Vigilance Adverse Reaction Online Database, HEALTH CANADA (Dec. 11, 2020), https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada/adverse-reactio n-database.html [https://perma.cc/J88T-M3SE]. 298 Id. 299 Recalls and Safety Alerts, HEALTH CANADA (Dec. 21, 2020), http://www.healthycan adians.gc.ca/recall-alert-rappel-avis/index-eng.php?cat=3 [https://perma.cc/B934-2UMD]. 300 Guidance Document - Submission of Risk Management Plans and Follow-up Commitments, HEALTH CANADA (June 26, 2015), https://www.canada.ca/content/dam/hc-sc/migration/hc-sc/dhp- mps/alt_formats/pdf/pubs/medeff/guide/2015-risk-risques_management-gestion_plans/2015-risk-risques _management-gestion_plans-eng.pdf [https://perma.cc/M52Y-3VL6]. 301 Any patient-level clinical trial data found in disclosable documents will be redacted under FOIA rules. 536 FOOD AND DRUG LAW JOURNAL VOL. 75
Currently, EMA does not disclose any patient-level clinical trial data.302 However, this will change when Phase 2 of EMA’s policy on the publication of clinical data (Policy 0070) comes into application (timeframe unknown). When it does, individual patient data (IPD) from a clinical trial will be publicly available for download and use for academic and non-commercial research purposes. Protected under various laws, personal data and commercially confidential information (CCI) will be redacted (in general, clinical trial data is not considered CCI).303 As explained in the policy: Before IPD can be made available, there is a need to first clarify:
the submission of IPD for subsequent scientific review by the Agency, and how to best provide access to such IPD, including the conditions to be fulfilled.
It is important to emphasize in this regard that the Agency will not request applicants/MAHs to submit IPD for the sole purpose of publication of IPD. The Agency will first undertake a targeted public consultation with all concerned stakeholders on the various aspects in relation to IPD to provide clarification. Subsequently, in consultation with the Agency’s Management Board, the policy will be amended to reflect the outcome of this targeted public consultation.304 HC does not release individual patient records.305 J. Pooled Data Sets FDA, EMA, and HC do not disclose any agency-pooled data sets (i.e., data pooled from across products). K. Supplemental Application (U.S.; Canada)/Extensions of Indication or Variation (EU) As for NDAs and BLAs, FDA does not disclose the existence of a supplemental application306 before an approval letter is sent to the applicant unless previously disclosed or acknowledged and unless it is reviewed by an Advisory Committee.307 However, the agency does publish the number of supplemental NDAs and supplemental BLAs (reviewed by the drug center) submitted per month.308
302 Subject to the legislative constraint under the EU General Data Protection Regulation. Council Directive 95/46, 1995 O.J. (L 281) (EC). 303 Council Regulation 2016/679, 2016 O.J. (L 119/1) (EU). 304 What EMA publishes and when, supra note 56. 305 Guidance: Public Release of Clinical Information: guidance document, HEALTH CANADA, https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/profile-public- release-clinical-information-guidance/document.html (last accessed Feb. 26, 2021) (“Researchers interested in obtaining individual patient records related to information for therapeutic products for the purpose of research or statistical analysis may do so under the Privacy Act in accordance with applicable provisions.”). 306 21 C.F.R. § 314.70 (2019). For biologics post-approval, see Efficacy Supplement Approvals, U.S. FOOD & DRUG ADMIN. (Oct. 10, 2020), https://www.fda.gov/drugs/nda-and-bla-approvals/efficacy- supplement-approvals [https://perma.cc/JQY7-4ED2]. 307 21 C.F.R. § 314.430(b) (2019); 21 C.F.R. § 601.51(b) (2019). 308 FDA-TRACK: Center for Drug Evaluation & Research – Pre-Approval Safety Review – Drugs and Biologics Dashboard, U.S. FOOD & DRUG ADMIN, https://www.fda.gov/about-fda/fda-track-agency-wide- program-performance/fda-track-center-drug-evaluation-research-pre-approval-safety-review-drugs-and- biologics-dashboard [https://perma.cc/VC3N-DZN7] (last visited Aug. 12, 2020). 2021 REGULATORY AGENCY TRANSPARENCY 537
While for new MAAs, EMA does not currently publish a list of an extension of indication or variation application.309 HC publishes a Submissions Under Review (SUR) List that includes supplemental new drug submissions for new uses accepted for review on or after May 1, 2016 that are currently or formerly under review.310 Updated monthly, the list includes the drug, the month and year the submission was accepted, the therapeutic area, and (for submissions accepted for review on or after October 1, 2018) the company name and “class” of the submission.311 In addition, HC’s Therapeutic Products Directorate Drug Submission Performance Annual Reports includes a number of supplemental new drug submissions received annually (by fee category).312
CONCLUSION
As this survey illustrates, FDA, EMA, and HC share many procedural commonalities, but also differ in significant respects. That said, each regulatory agency—FDA, EMA, and HC—has described its commitment to regulatory transparency in a similar way, focusing on benefits to public health, research and development, and patients. For example, as EMA explained:
The aim of the European Medicines Agency (‘the Agency’) is to protect and foster public health. Transparency is a key consideration for the Agency in delivering its service to patients and society. Although the Agency since its creation has launched several initiatives to increase transparency of information on medicinal products, there is growing demand from stakeholders for additional transparency, not only about the Agency’s deliberations and actions, but also about the clinical data on which regulatory decisions are based. The Agency is committed to continuously extend its approach to transparency and has, therefore, taken the initiative to develop a policy on publication of clinical data.313
Those seeking to increase transparency at home may look to other regulatory agencies to identify how and support arguments for change, and may look to their own regulatory agency to identify what barriers exist in rule and law. As many have argued, greater transparency may result in improved regulatory efficiencies, such as higher quality applications with fewer refusals to file or review cycles, as well as more indications being added to products rather than relying on off-
309 See 21 C.F.R. § 20.82. 310 Drug and Health Product Submissions Under Review (SUR), supra note 138. 311 “The submission ‘class’ includes whether the submission is for a new active substance or a biosimilar, if it is being reviewed as per a formal expedited process, if review is taking place as part of an aligned process with a health technology assessment organization, and more.” Drug and Health Product Submissions Under Review (SUR), supra note 138; see also Submission ‘Class’, HEALTH CANADA (Dec. 10. 2018), https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/submissi ons-under-review/submission-class.html [https://perma.cc/BBF3-EA7F]. 312 Drug Products, HEALTH CANADA, https://www.canada.ca/en/health-canada/services/drugs- health-products/reports-publications/drug-products.html [https://perma.cc/6JDW-FV6Z] (last accessed Feb. 26, 2021). 313 European Medicines Agency Policy on the Publication of Clinical Data for Medicinal Products for Human Use, supra note 244. 538 FOOD AND DRUG LAW JOURNAL VOL. 75 label use. In addition to accelerating research and development by minimizing costly duplication of effort and reducing regulatory uncertainty, enhanced transparency can help to build trust in, and understanding of, regulatory agency decisions, especially in uncertain times like the ones we find ourselves in today. Further, policymakers should consider the benefits of regulatory harmonization for disclosure policies and procedures for regulatory marketing applications and supplements, as having to create multiple, slightly different versions of such regulatory documents can result in significant, arguably unwarranted burdens. As FDA noted in March 2020, a lack of global harmonization is one barrier to clinical trial information disclosure due to the “transactional, administrative and redaction (because there are differing regional disclosure standards) costs, whether the costs are incurred by industry or a regional regulatory authority.”314 Additional research is recommended following this comparative survey to determine whether such efficiencies have been achieved or could be improved by increased regulatory agency transparency.
ABBREVIATIONS
ATMP Advanced therapy medicinal product BLA Biologics License Application BTD Breakthrough therapy designation CAT Committee for Advanced Therapies CBI Confidential business information CCI Commercially confidential information CDER Center for Drug Evaluation CHMP Committee for Medicinal Products for Human Use COMP Committee for Orphan Medicinal Products CSR Clinical study report CRL Complete response letter CTIS Clinical Trials Information System EC European Commission eCTD Electronic Common Technical Document EMA European Medicines Agency EPAR European Public Assessment Report EU European Union EudraCT European Clinical Trials Database FACA Federal Advisory Committee Act FAERS FDA’s Adverse Events Reporting System FDA U.S. Food & Drug Administration FDCA Federal Food, Drug & Cosmetic Act FDR Canada’s Food & Drugs Regulations FOIA Freedom of Information Act HC Health Canada IND Investigational New Drug
314 FDA Continues to Support Transparency and Collaboration in Drug Approval Process as the Clinical Data Summary Pilot Concludes, U.S. FOOD & DRUG ADMIN. (Mar. 26, 2020), https://www.fda.gov/news-events/press-announcements/fda-continues-support-transparency-and-collabora tion-drug-approval-process-clinical-data-summary [https://perma.cc/JG7W-DQS9]. 2021 REGULATORY AGENCY TRANSPARENCY 539
INN International non-proprietary name IPD Individual patient data MAA Marketing Authorization Application MAHs Marketing authorization holders NDA New Drug Application NDS List for New Drug Submissions NOC/c Notice of Compliance with Conditions NOC/c-QN Notice of Compliance with Conditions - Qualifying Notice PAESs Post authorization efficacy studies PASSs Post authorization safety studies PDUFA Prescription Drug User Fee Act PMCs Post-marketing commitments PMRs Post-marketing requirement PRAC Pharmacovigilance Risk Assessment Committee PRIME Priority Medicines PSURS Periodic safety update reports PSUSA Periodic safety update report single assessments QIDP Qualified infectious disease product RDS Regulatory Decision Summaries REMS Risk Evaluation and Mitigation Strategy RMAT Regenerative medicine advanced therapy RMP Risk management plans RTF Refuse-to-file SBD Summary Basis of Decision SDN Screening Deficiency Notice SUR Submissions Under Review TEU Treaty on European Union TFEU Treaty on the Functioning of the European Union VSI Validation Supplementary Information
Table 1: Comparison of Selected Regulatory Agency Disclosures
Disclosure FDA EMA HC Pre-Marketing Application Disclosures
Filing of an FDA does not Currently, a request While HC does Investigational disclose that an for authorisation to not release New Drug IND has been filed, conduct a clinical information Application (IND) accepted, or is trial is reviewed by about requests (U.S.) / Request for currently open the Member State (e.g., company, Authorisation to (unless already in which the trial product, Conduct a Clinical public). However, will be conducted, indication) it Trial (EU) / FDA does release and therefore EMA does publish the Clinical Trial the number of does not disclose number of Applications INDs filed information on clinical trial 540 FOOD AND DRUG LAW JOURNAL VOL. 75
Disclosure FDA EMA HC (Canada) quarterly. these applications. applications received per year After the Clinical and the decisions Trials Regulation made on those comes into applications in application, its Therapeutic information Products submitted in a Directorate Drug request for Submission authorisation to Performance conduct a clinical Annual Reports. trial will be publicly available in the EU Clinical Trial Database after approval or denial of the request unless the information is otherwise protected (e.g., commercially confidential). Attainment of any FDA does not EMA releases HC discloses designations or disclose the information on whether a participation in submission of a designated orphan product is being programs and/or request for medicinal products, review under rationale for designations a fully list of priority review granting (orphan, orphan designated or NOC/c, the designation breakthrough products, and a number of therapy, fast track, public summary of priority review priority review, the COMP’s status requests, accelerated opinion. and which new approval, active substance regenerative EMA discloses approvals advanced therapy designation received priority designation, the decisions for review or 2021 REGULATORY AGENCY TRANSPARENCY 541
Disclosure FDA EMA HC qualified infectious advanced therapy NOC/c. disease product medicinal products (QIDP) (ATMPs; e.g., gene designation, and therapy, somatic the limited cell therapy, tissue population pathway engineered for antibacterial product), and and antifungal publishes a list of drugs), but does all PRIME disclose drugs that products, updated receive an orphan monthly. designation and release the number EMA does not of recipients of the disclose the CHMP other designations. decisions on accelerated Designation assessment until a determinations may final decision on be available in the marketing summary review authorisation documents for application is made approved products and then summary or disclosed in a of CHMP’s public Advisory assessment is Committee released. meeting.
Marketing Application In-review Disclosures
Submission of a FDA does not EMA publishes a HC publishes a New Drug disclose the list of new Submissions Application (NDA) existence of an medicines under Under Review or Biologics NDA or BLA evaluation for a (SUR) List for License (unless previously centralised New Drug Application (BLA) disclosed or marketing Submissions 542 FOOD AND DRUG LAW JOURNAL VOL. 75
Disclosure FDA EMA HC (U.S.) / Marketing acknowledged) authorisation by (NDS). In Authorisation unless and until EMA’s Committee addition, HC Application approval of the for Medicinal reports the (MAA) (EU) / product (or an Products for number of new New Drug Advisory Human Use drug submissions Submission (NDS) Committee meeting (CHMP) each received (Canada) occurs). month. annually (by fee category). FDA does release the number of NDA/BLAs submitted by month. Sponsor/agency FDA does not EMA does not HC does not meeting minutes or provide any provide any provide any other meeting minutes or sponsor/agency sponsor/agency correspondence other meeting minutes or meeting minutes throughout the correspondence other or other review process throughout the correspondence correspondence review process throughout the throughout the unless and until the review process, but review process, product is these materials may but these approved, and then be referenced in the materials may be these materials EPAR after a referenced in the may be included in decision on the Summary Basis the summary marketing of Decision after review documents authorisation a decision on the posted publicly. application has submission has been made. been made. Scientific/advisory FDA’s website EMA publishes the HC releases committee meeting includes an agendas and information on scheduling and Advisory meeting minutes of their materials Committee its scientific scientific/expert Calendar, which committee advisory includes meeting meetings prior to committee rosters, final approval of the meetings and 2021 REGULATORY AGENCY TRANSPARENCY 543
Disclosure FDA EMA HC questions and marketing panel meetings agenda, meeting authorisation on their website. transcripts, and application for a This includes both FDA and product. For certain meeting industry briefing committees, EMA announcements, information. also releases agendas, and/or highlights from recordings of meetings with proceedings. “outcomes of major public interest”.
Status of marketing FDA does not EMA does not HC does not application during disclose disclose the status provide review information on the of a marketing information status of authorisation about the status NDAs/BLAs application until a of a product in during review, decision has been review. including user fee made. EMA does goal dates not publish if a /postponement of clinical trial is user fee goal dates suspended as that is and clinical the decision of a holds/release of Member State. clinical holds.
Decision and Post-Decision Disclosures
Refuse-to-file letter FDA does not EMA does not HC does not (U.S.) / Validation disclose the disclose the disclose the Supplementary existence or existence or existence or Information contents of a contents of contents of requests (EU) / refuse-to-file letter. Validation Clarification Application Supplementary Requests or deficiencies / Information Screening Screening requests or Deficiency 544 FOOD AND DRUG LAW JOURNAL VOL. 75
Disclosure FDA EMA HC Deficiency Notice negative validation Notices. (Canada) letters. Positive Marketing FDA provides a After the EC final HC publishes Application searchable database decision, EMA Regulatory Decisions: Action (Drugs@FDA) on publishes EPARs Decision Package (U.S.) / all approved NDAs (European Public Summaries European Public (and drug center Assessment (RDS) for new Assessment reviewed BLAs). Reports) online that drug submissions Reports (EU) / For new drugs, outline EMA’s and Summary Basis of FDA publishes an assessment of the supplemental Decision (Canada) action package marketing new drug with review authorisation submissions for documents application as well new uses outlining FDA’s as a lay summary approved after determination (on of approval. Prior April 1, 2015. Drugs@FDA). to the EC decision, For approvals EMA releases a issued on or after Q&A document October 1, 2018, after the committee RDS are decision to published for recommend the supplemental MAA. new drug submissions for new routes of administration, new dosage forms, and new strengths.
A more detailed description of the basis for approval can be found in the Summary Basis 2021 REGULATORY AGENCY TRANSPARENCY 545
Disclosure FDA EMA HC of Decision (SBD). Negative FDA does not After a negative HC publishes Marketing disclose the marketing Regulatory Application existence or authorisation Decision Decisions: contents of a application Summaries Complete response complete response decision, EMA (RDS) for final letter (U.S.) / letter. publishes a negative Refusal Public negative opinion decisions for Assessment Report Q&A document new drug (EU) / Regulatory after the meeting submissions for Decision and releases a new active Summaries Refusal Public substances (Canada) Assessment Report accepted for on EMA’s website review on or after an EC after April 1, decision. 2015, and for new drug submissions and supplemental new drug submission for a new use accepted for review on or after May 1, 2016. 546 FOOD AND DRUG LAW JOURNAL VOL. 75
Disclosure FDA EMA HC Withdrawn FDA does not EMA publishes the HC publishes marketing release an action applicant’s Regulatory applications package for withdrawal letter Decision withdrawn stating the reasons Summaries applications. they withdrew the (RDS) for application. In canceled addition, EMA submissions for publishes a Q&A new drug document submissions for describing (in lay new active language) the substances scientific accepted for assessment of the review on or product up to the after April 1, time of the 2015, and for withdrawal. new drug Additional submissions and documents that supplemental make up an EPAR new drug are published submission for a within three new use accepted months of the for review on or withdrawal letter. after May 1, 2016. Appeals of FDA does not EMA discloses the HC does not Marketing disclose the appeal decision as disclose the Application existence or appeal it would any other existence of a decisions decision unless and opinion (see reconsideration until the above), with EMA or make the final application is updating the initial decision (i.e., the approved or a negative opinion reconsideration public advisory Q&A document letter) public, but committee meeting and other EPAR will revise the is held. documents to RDS and/or reflect the SBD, as needed. reexamination 2021 REGULATORY AGENCY TRANSPARENCY 547
Disclosure FDA EMA HC outcome. In addition, if the re- examination is positive, EMA will publish a new positive opinion Q&A. Technical and lay FDA does not Clinical trial In March 2019, clinical trials release technical summaries new HC summaries clinical trial submitted to EMA regulations came summaries (clinical are available to the into force that study reports or public through the allow public CSRs) or “lay EU Clinical Trials release of certain summaries” for the Register (EU clinical trial broader public. In CTR). information, addition, while including clinical FDA lists the When the new overviews, current Clinical Trials clinical PMRs/PMCs of Regulation comes summaries, and products and their into application, clinical study current status on its sponsors will be reports after a website, the required to submit drug receives a Agency does not to the new EU final decision on disclose the final Clinical Trial Portal its marketing summary reports of clinical trial application. these clinical trials. summaries, “layperson’s HC does not summaries”, and require or release CSRs, which will lay summaries. all be available to the public.
EMA also publishes clinical reports submitted to the Agency for 548 FOOD AND DRUG LAW JOURNAL VOL. 75
Disclosure FDA EMA HC approved, rejected and withdrawn applications. Agency-created FDA does not EMA does not HC does not analysis of data release Agency- release Agency- release Agency- created data created data created data analyses, but after analyses unless analyses unless FDA approves an they are referenced they are NDA or BLA, any and/or included in referenced Agency-created the published and/or included data analyses may EPAR. in the published be disclosed in the RDS and/or action package SBD. and/or prior to approval disclosed as part of FDA’s briefing package for an Advisory Committee meeting.
Pharmacovigilance FDA publishes EMA publishes The Canada / Risk Evaluation information on data from Vigilance online and Mitigation adverse event EudraVigilance in database Strategy (REMS) reports through a the European contains publicly (U.S.) / Risk searchable public database for searchable Management Plan dashboard. FDA suspected adverse information (RMP) (EU) / Risk also issues safety drug reaction about suspected Management Plan alerts for recalls reports. adverse reactions (RMP) (Canada) and risks of to health adverse reactions, EMA publishes products. In and potential information about addition, signals of serious single assessments advisories and risks/new safety of related PSURs recalls can be information (PSUSAs) and found in the identified. updates EPARs as Recalls and 2021 REGULATORY AGENCY TRANSPARENCY 549
Disclosure FDA EMA HC necessary. In Safety Alerts After an NDA or addition, EMA Database. BLA is approved, publishes a list of FDA publishes any medicines assessed HC does not approved Risk in a PSUSA. publish risk Evaluation and management Mitigation Strategy EMA also plans. (REMS) for that publishes product on FDA’s information about website. assessments of the results of post authorisation safety studies (PASSs), updates EPARs as necessary, and publishes a list of medicines assessed. A list of all medical products currently being followed under additional monitoring can be found on EMA’s website, as well as summaries of risk management plans.
Information about safety (and other types of) referrals is available online. In addition, meeting highlights disclose the start of a safety referral and a committee’s 550 FOOD AND DRUG LAW JOURNAL VOL. 75
Disclosure FDA EMA HC recommendation or decision. Patient-level FDA does not Currently, EMA HC does not clinical trial data disclose any does not disclose release patient-level any patient-level individual clinical trial data. clinical trial data. patient records. However, this will change when Phase 2 of EMA’s policy on the publication of clinical data (Policy 0070) comes into application. When it does, individual patient data (IPD) from a clinical trial will be publicly available for download and use for academic and non-commercial research purposes. Agency pooled FDA does not EMA does not HC does not data sets release any release any release any Agency-pooled Agency-pooled Agency-pooled data sets. data sets. data sets. Supplemental FDA does not Unlike for a new HC publishes a application (U.S.) / disclose the MAA, EMA does Submissions Extension to existence of a not publish a list of Under Review Indication or supplemental NDA pending extension (SUR) List that Variation (EU)/ or BLA (unless to indication or includes Supplemental previously variation supplemental application disclosed or applications. new drug acknowledged) submissions for unless and until new uses 2021 REGULATORY AGENCY TRANSPARENCY 551
Disclosure FDA EMA HC approval of the accepted for product (or an review on or Advisory after May 1, Committee meeting 2016 that are occurs). currently or formerly under FDA does release review. In the number of addition, HC supplemental releases the applications number of submitted by supplemental month. new drug submissions received annually (by fee category).