September 28, 2019

Global Developments in Clinical Trial Transparency

By Darshan Kulkarni, PharmD, MS, Esq., The Kulkarni Law Firm, Philadelphia, PA; Reema Butala, Overland Park, KS; Dan Benau, PhD, University of the Sciences, Philadelphia, PA

In his keynote address in 2018, Scott Gottlieb, the Food and Drug Administration (FDA) Commissioner, announced new initiatives towards greater transparency of clinical trials and making trial data more readily available to the public.1 

While some dissenting parties fear that information sharing can hurt commercial interests, there has been a growing consensus among stakeholders about the usefulness of clinical trial transparency to public health because it leads to open science with more data sharing than ever before.2 Increased transparency and data sharing ensures research integrity, drives innovation and potentially prevents unnecessary spending on pointless clinical trials by utilizing the existing data more thoroughly.3

Current Situation

In the past, transparency simply meant “publishing results in peer-reviewed journals.” However, because publishing is often time-consuming, many studies never end up being published in a journal. In some cases, results are selectively reported, or there may be a delay in the release of important new findings.4

In modern times, the insufficient reporting of clinical trial results has become increasingly unacceptable, as it can compromise research integrity and endanger patients. There is also a growing sentiment that patients should be informed of the studies they participate in.5 Since it is becoming increasingly feasible to share data, the expectation of “full clinical trial transparency” requires not just “prospective trial registration,” but even “publication of trial results” as well as “access to deidentified individual participant data.”6

Global health authorities of the United States, the European Union (EU), and a few other countries are taking significant steps to mitigate the problems associated with the opacity of clinical trials by making clinical trial data and results more available. 

FDA and Clinical Study Transparency

As part of an overall effort towards transparency, the FDA set up a Transparency Taskforce in 2010. Projects such as the ”Data Dashboard” and “openFDA” made large datasets on compliance actions, adverse events, and other information publicly accessible for the very first time. These projects were an opportunity for the public to not only access agency data, but to also monitor the FDA’s performance.7

Specifically, with regard to clinical trials transparency, the Food and Drug Administration Modernization Act of 1997 and its amendments require mandatory registration for all clinical trials conducted for serious or life-threatening conditions.8 The disclosure requirements further expanded in 2007 with the implementation of the Food and Drug Administration Amendments Act (FDAAA) that required all clinical trials to be registered, irrespective of the type of condition.9 A new policy (NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information) implemented in 2017 required all studies sponsored by the National Institutes of Health (NIH) to register and publicly report the study results on ClinicalTrials.gov, NIH’s clinical study database.10

Another new initiative announced in 2018 “to increase transparency around clinical research posted on ClinicalTrials.gov” used unique identifier numbers called the NCT number to “track clinical research from a drug’s development throughout the regulatory process.” In early 2018, the FDA launched “a pilot to evaluate whether disclosing certain summaries of clinical information -- called Clinical Study Reports or CSRs -- following the approval of a New Drug Application (NDA), can improve the public’s access to drug approval information.”11  The program recruited industry volunteers to post CSR information on the FDA’s website. Only one volunteer agreed to post CSR information publicly. As of June 2019, the FDA had ceased recruiting sponsors for the program and was collecting feedback from the public on this initiative.12

A “layperson summary " is another plain-language document explaining clinical trial results to a lay audience. The main objective of the summary is to enhance the public’s understanding of clinical trials data.17 These layperson summaries are not a mandatory requirement by the FDA.18 The layperson summaries are highly technical content which are simplified and written in a consumer-friendly language using “large color pie and bar charts and simple tables” to aid patients in understanding the material.15 They often utilize a “question and answer” format to explain information, such as the number of participants in the study with a breakdown by sex, age, and race.16  The FDA forayed into plain-language writing back in 2014 when it began releasing the “drug snapshots” document. As part of the FDA’s efforts to promote transparency of clinical trial demographic data, the FDA created the snapshots document to explain the benefits/risks associated with the drug to patients.  An individual document is typically released within 30 days of drug approval.13 By looking at these snapshots, consumers can see who participated in a clinical trial for a particular drug, as well as the results of the safety and efficacy studies in those participants.  Consumers can then use these results as a tool to talk to their doctor about a particular drug.14

The European Union and Clinical Study Transparency

The EU is engaged in similar transparency efforts. Even though the EU had a more “reactive” policy with regards to data disclosure and clinical trial transparency in the past with information only released on request (as seen in what is commonly referred to as Policy 0043),19 things have been changing since the European Medicines Agency (EMA), the EU’s version of the FDA, adopted Policy 007020 in 2014.21   A long-drawn effort by the EMA and multiple stakeholders resulted in Policy 0070 pertaining to the “publication of clinical data for medicinal products for human use.” The scope of Policy 0070 “relates to proactively sharing study-level and patient-level clinical data, i.e., clinical reports (clinical overviews, clinical summaries, clinical study reports, protocol and protocol amendments, sample case report forms, documentation of statistical methods) and individual patient data (IPD), submitted under the centralized marketing authorization procedure after Jan. 1, 2015.”22

Articles 80 and 81 of the EU Clinical Trial Regulation 536/2014  (EU CTR536), released in 2014, stipulate the creation of an EU portal and database.23  This “publicly accessible” database will house data such as protocols, clinical trial summaries, and layperson summaries for all clinical trials conducted in the EU and its member states.24  Even though EU CTR536 was released in 2014, it is expected to completely supersede the previous regulations (Clinical Trials Directive 2001/20/EC (EU CTD))25 in 2020 only after this database has been established.26

Another requirement of the EU CTR536, specifically Article 37, is the submission of a layperson summary document to the EU clinical trial database. These summary documents were an EU effort to take a more patient-centered approach in its policies.27 Trial sponsors are required to submit these documents to the new EU database within one year of trial completion for all clinical trials conducted in the EU.28 Although EU has not released any formal guidelines regarding the writing of these summaries, an expert group put together recommendations in a guidance document, “Summaries of Clinical Trial Results for Laypersonsthat outlines some general principles.29

Canada and Clinical Study Transparency

To align with EMA Policy 0070, Health Canada, Canada’s version of the FDA, in 2018 released a draft guidance document called the “Public Release of Clinical Information” for public consultation.30 This document outlines the scope, policies, and implementation of the public release of clinical trial data. Similar to  EMA Policy 0043, the guidance document also contains information on how citizens can request access to information from past drug applications.31  In March 2019 Health Canada finalized the guidance document and launched a “Clinical Information Portal” which will act as a repository of the safety and efficacy information for all drugs and devices. Information will be uploaded to these two databases in multiple phases, and the proactive publication of drug data has already begun in 2019. Clinical information of devices is expected to be published in 2021.32

Ukraine and Clinical Study Transparency

To align Ukrainian regulations with that of the EU, the Ukrainian government passed an “Amendment of Article 9 of the Law of Ukraine ‘On Medicines’”33 in September 2018  mandating that trial results of all preclinical studies and clinical trials should be made publicly available. The main goal of this amendment was to give the public access to data that would enhance their understanding of the decision-making process for regulated medicines as well as give doctors “access to non-commercial information” about the drug to help them make better healthcare decisions. Per the new amendment, all clinical trial summary data will be publicly disclosed on the Ministry of Health of Ukraine (MoH) official website. The MoH has also committed to safeguarding “personal data of clinical trial participants” and “commercially confidential” data.34 This amendment modifies the current law that restricts access to data in regulatory filing documents. The MoH is working out the details of defining and implementing the new amendment.35

Conclusion

Health authorities are beginning to take significant steps toward achieving greater transparency in clinical trials. Building on this global momentum of open data, future clinical trials will take an even more patient-centered approach with more data sharing of “patient-level data to drive the development of medicines.”36

 
Footnotes
  1. Fostering Transparency to Improve Public Health | FDA, https://www.fda.gov/news-events/speeches-fda-officials/fostering-transparency-improve-public-health (last visited Jul. 23, 2019).
  2. FDA to increase transparency in clinical trial data, https://www.pharmaceutical-technology.com/news/fda-transparency-clinical-trials/ (last visited Jun. 15, 2019).
  3. Daniel L. Shaw & Joseph S. Ross, US Federal Government Efforts to Improve Clinical Trial Transparency with Expanded Trial Registries and Open Data Sharing, 17 AMA J. Ethic 1152–1159 (2015), http://journalofethics.ama-assn.org/2015/12/pfor1-1512.html (last visited Jun. 15, 2019).
  4. Id.
  5. Id.
  6. Rafael Dal-Ré, Clinical Trials Transparency: Where Are We Today?, 4 Trends in cancer 1–3 (2018), http://www.ncbi.nlm.nih.gov/pubmed/29413417 (last visited Jun. 15, 2019).
  7. FDA, supra note 1.
  8. Food and Drug Administration Modernization Act of 1997, https://www.govinfo.gov/content/pkg/PLAW-105publ115/pdf/PLAW-105publ115.pdf (last visited Jul. 24, 2019).
  9. Food and Drug Administration Amendments Act of 2007, https://www.govinfo.gov/content/pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf#page=82 (last visited Jul. 24, 2019).
  10. NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information, https://grants.nih.gov/grants/guide/notice-files/not-od-16-149.html (last visited Jul. 24, 2019).
  11. FDA, supra note 1.
  12. Federal Register: New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication, https://www.federalregister.gov/documents/2019/06/27/2019-13751/new-drugs-regulatory-program-modernization-improving-approval-package-documentation-and (last visited Jul. 25, 2019).
  13. Peter Doshi, FDA drug summaries: a simplification too far?, 350 BMJ h3135 (2015), http://www.ncbi.nlm.nih.gov/pubmed/26070648 (last visited Jun. 15, 2019).
  14. CDER Conversations: Drug trials snapshots | FDA, https://www.fda.gov/drugs/news-events-human-drugs/cder-conversations-drug-trials-snapshots (last visited Jun. 15, 2019).
  15. Doshi, supra note 13.
  16. Drug Trials Snapshots | FDA, https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots (last visited Jul. 28, 2019).
  17. A. Ferrari MD PhD, E. Sala PhD, E. Ornago, M. Zaninelli, Transparency: The EU Prospective, http://www.appliedclinicaltrialsonline.com/transparency-eu-prospective (last visited Jun. 15, 2019).
  18. Namrata Singh, Writing lay summaries: What medical writers need to know,  www.emwa.org (last visited Jun. 15, 2019).
  19. European Medicines Agency, European Medicines Agency policy on access to documents (2018), https://www.ema.europa.eu/en/documents/other/policy/0043-european-medicines-agency-policy-access-documents_en.pdf (last visited Jul. 28, 2019).
  20. European Medicines Agency, European Medicines Agency policy on publication of clinical data for medicinal products for human use (2019), https://www.ema.europa.eu/en/documents/other/european-medicines-agency-policy-publication-clinical-data-medicinal-products-human-use_en.pdf (last visited Jul. 28, 2019).
  21. Ferrari, supra note 17.
  22. Id.
  23. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf (last visited Jul. 25, 2019).
  24. Ferrari, supra note 17.
  25. Directive 2001/20/EC of the European Parliament and of the Council, (2006), https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf (last visited Jul. 25, 2019).
  26. Liz Roberts, Clinical Trial Transparency and Disclosure: A Global View, https://www.phusewiki.org/docs/Deliverables/PhUSE White Paper- A Global View - FINAL v1.0.pdf (last visited Jun. 15, 2019).
  27. Ferrari, supra note 17.
  28. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014, https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf (last visited Jul. 25, 2019).
  29. Summaries of Clinical Trials Results for Laypersons Recommendations of the Expert Group on Clinical Trials for the Implementation of Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use (2018), http://health.gov/communication/literacy/quickguide/factsbasic.htm (last visited Jul. 31, 2019).
  30. Public Release of Clinical Information - Draft Guidance Document - Canada.ca, https://www.canada.ca/en/health-canada/programs/consultation-public-release-clinical-information-drug-submissions-medical-device-applications/draft-guidance.html (last visited Jul. 25, 2019).
  31. Roberts, supra note 26.
  32. Public Release of Clinical Information: guidance document - Canada.ca, https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/profile-public-release-clinical-information-guidance/document.html#s2.1 (last visited Jul. 30, 2019).
  33. Amendments to Article 9 of the Law of Ukraine on Medicines; On Access to the Results of Preclinical Study and Clinical Trials of Medicinal Products (2018), https://zakon.rada.gov.ua/rada/show/en/2519-19?lang=uk (last visited Jul. 25, 2019).
  34. Clinical trial results to be publicly available, http://en.moz.gov.ua/article/news/clinical-trial-results-to-be-publicly-available (last visited Jun. 15, 2019).
  35. Ukraine makes step to transparency of pre-clinical and clinical data | LinkedIn, https://www.linkedin.com/pulse/ukraine-makes-step-transparency-pre-clinical-clinical-borys-danevych/ (last visited Jun. 15, 2019).
  36. Hans-Georg Eichler & Fergus Sweeney, The evolution of clinical trials: Can we address the challenges of the future?, 15 Clin. Trials J. Soc. Clin. Trials 27–32 (2018), http://journals.sagepub.com/doi/10.1177/1740774518755058 (last visited Jun. 17, 2019).

About the Authors

Darshan Kulkarni, PharmD, MS, Esq. is the principal attorney of the Kulkarni Law Firm. He is currently Chair of the ABA Health Law Section's Life Science Interest Group, and advises life science companies on a variety of regulatory and compliance issues including clinical trial transparency issues.  He is also Visiting Professor at the University of the Sciences in Philadelphia. He may be reached at Darshan@kulkarnilawfirm.com

Reema Shetty Butala is a graduate of the Biomedical Writing program at University of the Sciences. She has worked in the pharmaceutical industry in various capacities and has an undergraduate and masters degree in Biomedical Engineering. She is a member of the American Medical Writers Association.  She may be reached at rbutala@mail.usciences.edu.

Dan Benau, PhD, is Professor of Biomedical Writing and Director of Biomedical Writing Programs at the University of the Sciences. He has been in the medical writing field for over 30 years. He may be reached at D.benau@usciences.edu.