April 01, 2018

Aiming for Transparency: Clinical Trial Disclosures in the United States and European Union

Darshan Kulkarni, Synchrogenix, Philadelphia, PA, Ashley Thomas, Baker Donelson, Washington, DC and Andrea Tunnard, MS Candidate 2019, University of the Sciences, Philadelphia, PA

The disappointing results of a new tuberculosis vaccine booster in clinical studies have raised questions about the transparency of data used to make regulatory and patient decisions.1 In a trial conducted by Oxford University researchers, parents of the infant trial participants in an impoverished South African population gave informed consent for administration of the experimental vaccine after they were told that the drug was demonstrated to be safe in animal trials. Unfortunately, it is alleged that the information provided was misleading at best and false at worst since the researchers withheld or “played down” information that was unsupportive.1  This, the latest in a salvo of concerns around a lack of transparency in clinical research, in combination with the empowered patient movement2 has forced a tipping point with  regulatory organizations like the Food and Drug Administration (FDA) and European Medicines Agency (EMA)3 requiring companies engaged in research to be more transparent with their processes and findings.

Accordingly, lawmakers and regulators have deemed it necessary that more data be available to help patients make informed decisions about whether to participate in studies and to help regulators evaluate if there is incomplete information available to patients.4  Additionally, to protect clinical trial participants and potential patients, it is important that there be transparency of data throughout the drug discovery continuum regardless of the result of the clinical trial. Regulators as well as other stakeholders have already begun taking steps in this direction. This article examines the current discussions associated with clinical trial data disclosures in the United States and Europe.

Background

While patients accept some risk when deciding to participate in a clinical trial, they do so in good faith that the researcher has disclosed all known results of the previous research.  Failure of scientists to provide complete disclosure may constitute a violation of several ethical, and potentially legal, principles including the Declaration of Helsinki 5 and the Belmont Report.6  Medical history is rife with tragedies that highlight the importance of obtaining “true” informed consent.  The Tuskegee syphilis study7 which concluded in 1972 and the 1996 Pfizer meningitis study8 are examples of tragedies in which “true” informed consent was never obtained because of deficient transparency.  While incremental changes around transparency have since occurred, there is a relative consensus that there has been an inadequate response which has resulted in current problems related to incomplete information, leading to flawed clinical decision making. These inappropriately conducted studies, and the lack of transparency around their protocol and results, will impact future research.   Patients will refuse to participate in clinical trials if they do not trust researchers to be transparent.  

Current Rules Governing Disclosure

United States

Prior efforts to improve clinical trial results disclosure had limited success. ClinicalTrials.gov9 was initially created in response to the Food and Drug Administration Modernization Act (FDAMA) of 199710 and was intended to create a public registry to include information about federally or privately funded clinical trials conducted under investigational new drug applications to test the effectiveness of experimental drugs for patients with serious or life-threatening diseases or conditions. The limited scope of the initial registry limited its applicability and resulted in calls for more transparency, which eventually expanded the scope of trials that had to be registered. The registration requirements of clinicaltrials.gov were expanded in 2007 after Congress passed the FDA Amendments Act (FDAAA).11 These updates require that more types of trials be registered and additional trial registration information to be submitted. The law also requires the submission of results for certain trials. Nevertheless, a 2014 meta-analysis12 found that 29 percent of 400 randomly selected clinical trials did not publish results on clinicaltrials.gov within four years of completion of the trial.  Patients, caregivers and healthcare practitioners have been clamoring for more data and protesting the seeming lack of transparency.13 Accordingly, agencies which fund and oversee biomedical research are getting tougher on clinical trial disclosure.14  

The Department of Health and Human Services (HHS)15 and the National Institutes of Health (NIH)16 jointly changed their regulations, effective 2017.17  They have begun requiring additional disclosures, through expanded registry and results data banks, for research conducted on human participants. Under these recently enacted regulations, companies must proactively register sooner and make additional disclosures relating to statistical plans. These trials must be registered within 21 days of initiating the recruitment process.  The regulations aim to prevent companies from “gaming” the system by changing statistical plans after the study data is received. Failure to adhere to requirements may result in researchers losing NIH funding.  

The FDA is also making strides toward increased clinical data transparency.  In January 2018, FDA Director Scott Gottlieb announced that the FDA will launch a pilot program to make more data available to the public.  Currently, the FDA makes New Drug Applications available to the public when a drug is approved.  However, Gottlieb said in a press release that he wants to begin releasing Clinical Study Reports (CSR).18  Since CSRs contain the results of the clinical study, the public will have more granular access to clinical data, including the adverse events.  Furthermore, as described in Dr. Gottlieb’s press release,18 future clinical trials registered on ClinicalTrials.gov will be associated with an identifying number that will make it easier to search the database for all trials of a specific drug.  Based on these changes, patients will have access to more information about the results of clinical studies and will empower patients in making healthcare decisions.  

Europe

Unlike the U.S. Government, which through the FDA has primarily limited its focus to reporting results, the European Union (EU) and the EMA have gone further by requiring that raw data be made publicly available, and by insisting that the results be made available to patients via summaries in lay language.

The EMA is committed to ensuring the widest possible access to EMA documents concerning any matter related to the policies, activities and decisions falling within the agency’s remit and responsibilities.19  It is also committed to increasing its level of openness and transparency over its decision-making processes. Accordingly, in compliance with Regulation (EC) No 1049/200120 and pursuant to Article 73 of Regulation (EC) No 726/200421 the EMA is expected to make data disclosure mandatory relating to the efficacy of medical products for humans and animals. The EMA typically achieves its data disclosure policy using one of two complementary mechanisms:

(1) The Clinical Data Publication Policy,22 which applies only to centrally authorized products and applies to studies submitted to the EMA in the context of a Marketing Authorization Application (MAA) where clinical data and an anonymization report will need to be provided.

(2) The Clinical Trial Regulation,23 which applies to all clinical trial related information generated during the life cycle of a clinical trial and applies to all investigational medicinal products regardless of whether they have a marketing authorization.

While the Clinical Data Publication Policy limits itself to studies submitted to the EMA in the context of an MAA, the Clinical Trial Regulation applies to all clinical trials conducted in the EU and pediatric trials conducted outside the EU that are part of a pediatric investigation plan. These mechanisms manifest themselves in the form of Regulation 726/2004 and its counterpart, EMA Policy 43, and in Regulation 536/2014 and its counterpart EMA Policy 70, as described below. 

EMA Policy 43

The EMA is required to “provide the Member States and the Institutions of the Community with the best possible scientific advice on any question relating to the evaluation of the quality, safety and efficacy of medicinal products for human or veterinary use which is referred to it,” as described in Article 57 Regulation (EC) No 726/2004.24 As part of this goal of providing the widest possible access to EMA documentation, the EMA promulgated EMA Policy 43 in 2010. EMA Policy 4325  applies to medicinal products for human and veterinary use and broadly allows for the “widest possible access”26 to documentation submitted to the EMA related to human and veterinary use. This access is subject to a variety of limitations, including privacy of internal communications.  As part of this process, in appropriate cases, only part of the document may sometimes be made available since the redactions are necessary to protect legitimate privacy and commercial interests.

EMA Policy 43 thus provides for the use of an electronic registry27 of documents. This registry, available on the EMA Clinical Data website to any EU citizen via a simple login process, provides access to clinical data that has been submitted by pharmaceutical companies to support their marketing applications for human medicines under the centralized procedure. The registry hence provides more granular access to information than was previously available, including the protocol of the study and the statistical methods used to generate the data.

EU/536/2014

EMA Regulation EU/536/2014 was passed in 2014 as part of the focus on data transparency to increase harmonization of clinical data reporting28 within the EU and ultimately increase the number of studies conducted in EU countries. 536/2014, as it’s more commonly known, requires that data from a clinical trial only be submitted in support of a clinical trial application if that clinical trial has been recorded in a publicly accessible and free of charge database. Technical difficulties have delayed the implementation of the regulation to 2019.29 The upcoming relocation of the EMA from London to Amsterdam,30 following the United Kingdom’s withdrawal from the EU, may potentially cause further complications.  Additionally, while patients would ultimately benefit from access to raw data, the primary beneficiaries of the disclosure of raw data associated with clinical research would be researchers and potentially some clinicians. With patient centricity gaining traction in drug development,31 536/2014 requires sponsors to provide summary results of clinical trials32 in a format understandable to laypersons. These lay summaries will be made available in a new EU database once it becomes available.

Policy 70

EMA Policy 7033 is part of the EMA’s transparency initiative surrounding clinical research. Policy 70 is composed of two phases:  Phase 1 of Policy 70 was “entered into force” on January 1, 2015 and pertains to publication of clinical reports only. Phase 2, will be implemented at a later stage, pertains to the publishing of individual patient data (IPD).34 These disclosures are subject to various limitations concerning commercial confidential information and personal data. Accordingly, the EMA issued guidelines35 explaining certain techniques it will allow to obfuscate that information. These techniques include anonymization, redaction, and use of aggregated data so that those without advanced medical knowledge can benefit from access to clinical trial data.  This Policy also states that secondary analyses of clinical data by independent experts should be available to the public, and those who perform the analyses should disclose to the public any considerations that must be made for public health.18 The Policy is intended to allow for greater public scrutiny of clinical data, as well as to improve future trials through availability of information.  

Like in the United States with ClinicalTrials.gov, the EMA’s Policy 43, Policy 70 and 536/2014 represent important strides to improve data transparency. Yet it is important to balance the interest in transparency against both the need for privacy and the commercial interests of drug developers.  There have been several developments in the EU regarding this balance.

General Data Protection Regulation (GDPR)

The need for transparency is balanced in the EU using various mechanisms. Of particular note is the General Data Protection Regulation (GDPR)36 which becomes enforceable on  May 25, 2018 at the end of a two-year transition period. The GDPR will have significant impact not only in clinical research in general but also in transparency and disclosure in particular since it raises the bar to provide better privacy protection for individuals, places stricter limits on consenting requirements which can impact informed consent, impacts portability of data and affects international data transfers, all of which may be used in tracking and providing access to patient data. Penalties for violating the GDPR are quite steep.37 In the event of any non-compliance with key provisions of the GDPR, regulators have the authority to levy a fine in an amount that is up to the greater of €20 million or four percent of the company or organization’s global revenue, which is the maximum fine possible for serious infringements. GDPR violations could include non-adherence to the core principles of processing personal data, infringement of the rights of data subjects and the transfer of personal data to third countries or international organizations that do not ensure an adequate level of data protection.

Recent Court Decisions

The EMA’s rather broad directive to overhaul data transparency was challenged in the General Court of the EU. Pari Pharma,38 PTC Therapeutics International,39 MSD Animal Health Innovation and Intervet International40 each challenged the EMA on various aspects of disclosure, including that of a clinical study report and concerning a toxicology report via three separate court filings. The General Court ruled in favor of the EMA in all three cases in February 2018.  An EMA press release dated February 6, 2018 discussing the three separate court decisions stated that the General Court determined that the “companies failed to give any concrete evidence of how the release of the contested documents would undermine their commercial interests, and therefore it rejected their claims.”41 It therefore seems likely that the EMA’s push towards data transparency is here to stay.

Private Industry

Pharma Industry Associations

Outside of government, industry organizations and pharmaceutical companies are taking proactive steps to align themselves with the movement toward increasing data transparency.  Some major pharmaceutical industry organizations like the Pharmaceutical Research and Manufacturers of America (PhRMA)42 in the United States, the Association of British Pharmaceutical Industry (ABPI)43 in the United Kingdom, and the European Federation of Pharmaceutical Industries and Associations (EFPIA)44 in the EU have pushed their industries in the direction of transparency through leadership.  PhRMA and EFPIA jointly published a list of guiding principles45 for pharmaceutical companies in the United States and Europe.  These principles prioritize data sharing among researchers to improve clinical trials, as well as data transparency to serve public health.  The same guiding principles also state that “all company-sponsored clinical trials should be considered for publication in the scientific literature irrespective of whether the results of the sponsors’ clinical trials are positive or negative,”45 reaffirming the position of the NIH and HHS detailed earlier.  

ABPI has similar guidance on its website for British pharmaceutical companies, and has created a systematic method of clinical trial data disclosure through the creation of a Trial Disclosure Toolkit46 for researchers.  In the Toolkit, researchers will find forms to harmonize submissions for disclosure.  UK pharmaceutical companies may benefit from this tool, which help define exactly which documents need to be disclosed.

ICMJE

The International Committee of Medical Journal Editors (ICMJE) has been an early adopter of transparency initiatives. It has embraced its influence on disclosure of trial results by clinical researchers by issuing stringent guidelines47 for researchers seeking publication in affiliated journals. While ICMJE-imposed calls for data transparency were initially considered radical, they are now in line with those of various global databases48 since, among other criteria, they require that clinical researchers register with an acceptable clinical trials database such as ClinicalTrials.gov and include a data sharing statement for the granularity of data disclosure in their registration.  Companies that commit to meet ICMJE expectations will encounter fewer hurdles in the publication process. However, failure to meet these expectations can have significant impact once the ICMJE begins enforcing these requirements beginning in January 2019.

AllTrials

Like the ICMJE, the AllTrials initiative advocates strongly for greater disclosure of clinical trial data. The AllTrials49 initiative is a non-profit organization affiliated with the British Medical Journal Cochrane Collective and Dartmouth’s Geisel School of Medicine, among other prominent organizations, and led by Dr. Ben Goldacre, a British physician and a current fellow at Oxford University.50  The AllTrials initiative urges the public to become educated about the problems in clinical trial data disclosures, and to then help them “fix medicine”49 by affording greater transparency. As part of this initiative, AllTrials publishes a company ranking of the transparency of clinical trial disclosures by a pharmaceutical company based on registration, summary results, clinical trial reports and individual patient data. AllTrials’ tracking tool51 uses ClinicalTrials.gov’s data and identifies trials that are subject to the FDAAA as they reach 13 months from completion date. AllTrials is flagging this data and making it available to the public. The AllTrials’ list is updated each week and will rank those sponsors with the most trials that are out of compliance with the FDAAA, using a tool called the “FDAAA Trials Tracker.”52 It will also display an estimate of the total amount in fines that the FDA could levy in response to these compliance violations.

Unfortunately, the basis of the data for the AllTrials program in general and the FDAAA trials tracking tool in particular have been deemed to be flawed by the FDA.53 The FDA asserts that, among other concerns with the analysis of the data, the tool “lumps postmarket requirements in with postmarket commitments and doesn't account for justifiable delays.”54

The Good Pharma Scorecard

Unlike the AllTrials initiative, Bioethics International55 (BI), takes a less antagonistic position with pharmaceutical companies by working as a collaborator to help companies improve their scores and accounting for multiple factors that contribute to transparency. BI creates standards56 to measure transparency, benchmark performance, rank and audit companies, and research and advise pharmaceutical companies. The companies in question are informed of their ranking as well as the cause of their ranking, and given an opportunity to fix the problem before publication of the results on the “Good Pharma Scorecard.” 57 The BI program has a wider set of criteria than AllTrials, and judges companies based not only upon clinical trial transparency and data sharing, but also on clinical trial design, clinical trial conduct, pharmaceutical marketing practices and access to medicines.

Conclusion

The push for increased transparency in clinical data seems to be industry wide, as pharmaceutical companies are making changes driven by regulators and independent advocacy groups.  While the approaches vary considerably, the seemingly incremental progress shown by regulatory agencies and other stakeholders including the pharmaceutical industry, patients, healthcare providers and caregivers is a promising step toward improving data transparency and ultimately improving healthcare for patients.  

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Darshan Kulkarni

Synchrogenix

Darshan Kulkarni, Pharm.D., MS, Esq. is currently Vice President of Regulatory Strategy at Synchrogenix, a life sciences consultancy and services innovation platform, and is the Principal Attorney at the Kulkarni Law Firm. He is Visiting Professor in the Biomedical Writing Program at the University of the Sciences in Philadelphia, PA and continues to be a practicing pharmacist. Dr. Kulkarni currently serves as a Vice Chair of the Life Sciences Interest Group for the American Bar Association’s Health Law Section.  He may be reached at Darshan.Kulkarni@synchrogenix.com.

Ashley Thomas

Baker Donelson

Ashley Thomas, Esq. is an Associate in the Washington, D.C. office of Baker Donelson.  She provides counsel to a broad range of healthcare industry clients on a wide variety of regulatory compliance matters. She currently serves as the Vice Chair of the Web & Technology Committee for the American Bar Association’s Health Law Section.  She may be reached at AThomas@bakerdonelson.com.

Andrea Tunnard

MS Candidate 2019, University of the Sciences, Philadelphia, PA

Andrea Tunnard is an MS candidate in the Biomedical Writing program at the University of the Sciences in Philadelphia. She may be reached at atunnard@mail.usciences.edu.