Recent regulations are designed to restore public trust and improve healthcare.
The past decade has seen heightened awareness of a need to restore public trust in the pharmaceutical industry. Regulatory agencies and the public have expressed concern that inconsistent, incomplete, and delayed reporting of data from clinical trials obscures the results of pharmaceutical research, imperiling public safety. The public’s doubts about industry motives are largely attributable to the practice of selective reporting of clinical trials and results, which has led to increased scrutiny from regulatory agencies. Resulting regulations—such as clinical trial registration and public disclosure of results—were developed to restore public trust in the industry while improving healthcare through increased transparency and decreased information selection or bias.
Clinical trial registration
Paralleling widespread increase in the public’s access to information via the Internet, key legislation and events began in 1988 with the U.S. Omnibus Drug Act, which provided the first registration requirements. The Food and Drug Administration Modernization Act of 1997 tasked the National Library of Medicine and the National Institutes of Health (NIH) with managing one of the largest registries (ClinicalTrials.gov).1 In the 2000s, global clinical trial disclosure increased with the European Union’s Clinical Trials Directive 2001/20/EC, which created EudraCT and EudraPharm, followed by the World Health Organization’s (WHO) International Clinical Trials Registry Platform (ICTRP) in 2006.2,3 Sponsors have also initiated registries, for example, GlaxoSmithKline and AstraZeneca databases.4,5 These registries have greatly increased public awareness, allowed patients and clinicians to identify new treatment options, and fostered enrollment in clinical trials.
United States. The NIH registry contains more than 115,000 trials from over 170 countries.6 Regulations ensure that ClinicalTrials.gov includes valid, accurate, and timely information. The sponsor or principal investigator (PI) must register new clinical trials or update continuing trials within 21 days of the first subject’s enrollment. The requirement applies to all trials of drugs, biologics, and devices, except Phase 1, small feasibility, and behavioral intervention trials and observational studies. Noncompliance can result in monetary penalties or withholding of grant funds.7
European Union. The European Economic Area (EEA) is steadily progressing public data disclosure. Clinical trial information from the European Medicines Agency (EMA)’s EudraCT database, formed through Directive 2001/20/EC, was not publicly accessible until the EU Clinical Trials Register—a part of EudraPharm—was launched in 2011.8 This registry provides public access to clinical trial extracts authorized in the EEA or those that are part of pediatric investigation plans.9,10 Since EudraCT registration is required for clinical trial applications, there are no fines for noncompliance. Additionally, some EU countries have local registration requirements, for example, France’s mandatory national registration within 60 days and Italy’s voluntary local registration.
WHO and Other Registries. In hopes of providing a single access point to publicly accessible clinical trial information, the WHO launched the ICTRP in 2006 to compile local registries into one database.11 Many countries are using ICTRP registration as part of their local regulations, for example, Dutch mandatory registration in ICTRP. In an effort to decrease the redundant registry information, the EU announced in 2002 that EU Clinical Trials Register information will be electronically transmitted to WHO’s ICTRP.12
Emerging Markets. Emerging markets have varying regulations regarding clinical trial registration. Mexico, for example, has no formal registration requirements; China’s health authority manages a voluntary registry; and Chile requires local registration in a recently created Web-based database. Other countries have implemented (e.g., India) or are striving to implement (e.g., Peru) registration in ICTRP.
Clinical trial result disclosure
Registries alert the public to clinical trial activity, but many do not provide public access to results. Concerns over this lack of access have led various legislative bodies to enact disclosure regulations, such as Maine’s legislation requiring data disclosure on ClinicalTrials.gov if studies are conducted under state jurisdiction. Other developments include implementation of the Food and Drug Administration Amendments Act (FDAAA) and EudraCT public disclosure of clinical trials.
As part of this effort to encourage public disclosure of data, the International Committee of Medical Journal Editors (ICMJE) has stated clinical trial information must be disclosed in a public clinical trial registry to be considered for publication in a member journal.13
United States. Enacted in 2007, the FDAAA (section 801) mandates that ClinicalTrials.gov includes results for completed trials.14 Trial results from approved products in approved indications must be posted within 12 months of the trial’s actual or estimated completion. Deadline extensions for results submission are granted by the director of the NIH if the sponsor or PI has delivered a written request, has reasonable cause, and has estimated the date the results will be submitted.15
The sponsor or PI may request deferred submission of results by completing a certification, submitted through the Protocol Registration System, verifying that the trial was completed before initial approval, licensure, or FDA clearance, then the submission deadline is within 30 days of approval, licensure, or clearance.14 A deferral is also possible if the trial studied a new indication of an approved drug, biologic, or device, and the application for the new indication is filed within one year. Then the submission deadline is within two years of the submitted certification date or within 30 days of the following (whichever occurs first):
• FDA provides approval, licensure, or clearance for the new indication;
• FDA issues a letter for the new indication;
• Sponsor withdraws, for no less than 210 days, the application or premarket notification for the new indication, without resubmission.
The FDAAA-expanded results disclosure database rule, originally planned for 2010, would have required disclosure of detailed clinical trial results as well as the full protocol. At the time of this publication, a final rule for expanded results disclosure has not yet been promulgated. In addition, as of September 2012, the authority to monitor industry compliance and pursue information was transferred from the NIH to the FDA in hopes of enforcing registration and disclosure compliance.16
European Union. Because of increasing pressure for transparency, the EMA is pushing forward with plans to include results. Early in 2012, EMA guidance was adopted that permitted post-approval release of directly requested dossier data. Select data will be made available through EuDRAPHARM, and the actual data points will be discussed at an EMA workshop in November 2012.
Other Registries. Emerging market countries have varying regulations regarding results disclosure: Argentina and Venezuela require disclosure within one year, while it is voluntary in South Africa. The industry has followed with its own clinical trial result disclosure; for example, GlaxoSmithKline’s transparency pledge in October 2012 gave an independent group authority to control public access to all results regardless of their outcome.17
Practical challenges and opportunities
The expansion of registration and disclosure requirements has caused multiplicity and regional variances worldwide, introducing a new set of regulatory challenges. Stakeholders struggle to keep abreast from myriad registries, including not only the data points that must be disclosed, but also data protection standards and even formatting requirements. In an already dynamic regulatory landscape, the inconsistency has complicated industry attempts to maintain compliance. Harmonization of registry structure and local requirements for disclosure would provide necessary clarity.
The corporate burden of information management and competitive loss of information may hinder innovation and clinical development. Data disclosure has led to debate about whether any sponsor-produced information can remain proprietary and whether mandatory results disclosure has unintended business consequences—such as financial impact and loss of intelligence to competition—and interferes with publication potential or marketing plans. Sponsors also must balance nonregulatory requirements, such as potential conflicts between clinical trial disclosure and journal publication. Meanwhile, the data-reporting responsibilities of third parties in pharmaceutical research, such as CROs and consultants, remain ambiguous.
Disclosure of positive and negative results will aid in planning for future trials. Furthermore, concern over lack of publication of some clinical trials is well founded. A recent publication found that a significant number of cancer trials with potential effects on treatment practices were published only after significant delay, or not at all.18 Results disclosure has the potential to improve patient care by providing timely trial results—whether positive and negative.
However, stakeholders may not be best served with a single interface. Clinical trial data elements could be regionally coordinated by country regulators—such as the Pan African Clinical Trials Registry—to minimize the number of registries, while maintaining regionally important variables (for example, ethnic and environmental) that may affect the clinical utility of products in development. To best meet the needs of stakeholders ranging from the public to specialized researchers, registries may need to tailor their access points to accommodate, for example, uncommon diseases or patient populations with unusual characteristics.
In parallel, pharmaceutical companies may continue to develop sponsor-specific clinical trial data access. This new business model—to self-regulate the open release of once-proprietary data—may evolve into an industry standard to increase transparency of data, providing independent analysis to improve research strategies, normalizing competitive intelligence, and potentially avoiding hefty nondisclosure fines, while improving the public’s perception of industry.
Clinical trial registration requirements and evolving data disclosure regulations are methods to support the original purpose of helping patients identify available trials and increasing transparency of information. The United States, European Union, and WHO registries have transformed the clinical trial landscape and have provided valuable information to regulatory agencies, independent researchers, non-profit organizations, trade associations, the pharmaceutical and contract research industries, and to the public.
The public will eventually be able to track trials from start to finish. Results could then be disclosed on a predictable schedule, enhancing the credibility of the research community. Data disclosure requirements likewise continue to evolve and include disclosure of adverse events and results. These results will be available for independent analysis and interpretation to inform and improve public health decisions.
The needs and requirements of stakeholders and the emerging criteria for public registration will continue to vary, as the expectations and goals of the major registries continue to evolve. It is too soon to comment on best practices—other than vigilant monitoring to identify new regulations—as voluntary-to-mandatory requirements are emerging as quickly as new regulations are being released in this ever-changing global regulatory landscape.
1. ClinicalTrials.gov. Available at: www.clinicaltrials.gov.
2. EudraPharm Portal. Available at: http://eudrapharm.eu/eudrapharm/selectLanguage.do
3. International Clinical Trials Registry Platform Search Portal. Available at: http://apps.who.int/trialsearch/ .
4. GlaxoSmithKline Registry. Available at: http://www.gsk-clinicalstudyregister.com
5. AstraZeneca Registry. Available at: http://www.astrazenecaclinicaltrials.com
6. Thomas KB, Joergensen M, Lynch G, et al. Clinical trial disclosure: global overview and implications of new laws and guidelines. Drug Inf J. 2010;44:213-225.
7. Registration at ClinicalTrials.gov Factsheet. Available at: http://prsinfo.clinicaltrials.gov/s801-fact-sheet.pdf
8. EU Clinical Trials Register. Available at: www.clinicaltrialsregister.eu
9. European Commission, Enterprise and Industry Directorate-General. List of fields contained in the ‘EudraCT’ clinical trials database to be made public in accordance with Article 57(2) of Regulation (EC) No 726/2004 and its implementing guideline 2008/C168/02. Published February 4, 2009.http://ec.europa.eu/health/files/eudralex/vol-10/2009_02_04_guideline_en...
10. European Commission, Enterprise and Industry Directorate-General. List of fields to be made public from EudraCT for paediatric clinical trials in accordance with Article 41 of regulations (EC) No 1901/2006 and its implementing guideline 2009/C28/01. Published February 4, 2009. http://ec.europa.eu/health/files/eudralex/vol-10/2009_02_04_guidelines_p...
11. WHO International Clinical Trials Registry Platform (ICTRP). WHO Trial Registration Data Set (Version 1.2.1). Available at: http://www.who.int/ictrp/network/trds/en/.
12. World Health Organization. International Clinical Trials Registry Platform (ICTRP): Data Providers. Available at: http://www.who.int/ictrp/search/data_providers/en/index.html.
13. International Committee of Medical Journal Editors (ICMJE) Statement on Clinical Trial Results Disclosure. Available at: http://www.icmje.org/publishing_10register.html.
14. FDAAA 801 Requirements. Available at: http://www.clinicaltrials.gov/ct2/manage-recs/fdaaa#WhoIsResponsibleForR...
15. Office of Information and Regulatory Affairs, Office of Management and Budget. Expanded Registration and Results Reporting at ClinicalTrials.gov. Available at: http://www.reginfo.gov/public/do/eAgendaViewRule?pubId=201104&RIN=0925-A...
16. USA Federal Register. Available at: https://www.federalregister.gov/articles/2012/09/26/2012-23598/office-of...
17. GSK Pledge Announcement. Available at: http://www.gsk.com/media/press-releases/2012/GSK-announces-further-initi...
18. Tam VC, et al. Compendium of unpublished phase III trials in oncology: characteristics and impact on clinical practice. J Clin Oncol. 2011;10;29(23):3133-3139.