Increasing transparency of clinical trial data in the United States and the European Union.

• Published date: 22 September 2015
• Author: Choi, Rebecca
• Date: 22 September 2015

I. THE STATUS OF CLINICAL TRIALS DATA

The Internet is becoming "the greatest source of health information" for most consumers, which reinforces the importance of making online information about clinical trials accessible in a reliable, unbiased format. (1) Non-reporting and distorted reporting of clinical trials impede the betterment of scientific knowledge and public health. (2) Therefore, proper reporting of clinical trial results on the Internet is an essential step to ensure the research community and providers "... fully understand the benefits ... [and] potential consequences of taking a certain drug." (3)

There have been increasing demands for public transparency, such as the Declaration of Helsinki, which states the need for complete disclosure of clinical trial data. (4) Clinical trial data is research meant to "contribute to generalizable knowledge" as set forth in the Belmont Report, (5) and the research community has an obligation to share that data with trial participants. (6) Hoarding data will cause researchers to "duplicate efforts, repeat mistakes, and potentially cause avoidable injuries or deaths to research subjects." (7) Changes in the administration of clinical trials is necessary to safeguard public health and maximize effective use of clinical trial data. (8) A possible reform is inclusion of independent entities in the process currently dominated by pharmaceutical companies who sponsor, fund, and conduct their own clinical trials. (9) The present arrangement makes it possible for these companies to publish trial results that favor the company's product and suppress results that are unfavorable. (10) Glenis Willmott, an advocate of the new European Union (EU) clinical trials legislation, contends, "When a patient makes the decision to take part in a clinical trial, they do so to help advance medicine, to improve treatment ... They do not do it to help a particular company promote a particular drug." (11) People have a "right to health" and a critical element of the right to health is "shared public access to clinical trials data." (12)

Since the funds for many clinical trials are supplied by drug manufacturers, who in turn receive large public subsidies, clinical trial data should be considered a "public good" (13) Yet chug manufacturers continue to assert ownership and proprietary rights to clinical trial data including clinical study reports (CSRs). They classify CSRs as a trade secret (14) and argue a policy of CSR release advantages the competition. (15) Even if this was the case, "patent laws and exclusive marketing periods protect the sponsor's investment." (16) In fact, such protections may have a detrimental impact on consumers by placing affordable drugs beyond their reach. (17) More openness could help improve the image of drug companies; there have been calls to ban industry-sponsored research. (18)

Given the climate of public distrust toward "Big Pharma," (19) clinical data transparency is becoming a higher priority item on the agenda of the international community. (20) Part II of this Note provides specifics on the recent developments propelling clinical trial registration and reporting. Part III covers the FDA's stance on clinical trial disclosure in the U.S. Part IV explains the EMA's initiative to increase transparency in the EU's newly passed Clinical Trials Regulation. Part V focuses on public release of CSRs. Part VI sets forth proposed models for access to clinical trial data that address issues of patient privacy and proprietary information. Part VII discusses the need to strike a balance between the conflicting interests of drug manufacturers and public health proponents.

II. REPORTING AND REGISTRATION OF CLINICAL TRIALS

Access to health data, clinical trials in particular, is a growing concern among consumers since some pharmaceutical companies develop drugs with no more benefit than drugs currently on the market and even fail to adequately disclose drug use risks. (21) Big Pharma has faced hefty fines for withholding negative findings from clinical trials, but the fines imposed do not seem to constitute sufficient deterrence. (22) Such incidents indicate a more exacting framework is needed to discourage selective reporting.

In 2006, international attention centered on trial registration when the World Health Organization (WHO) established the International Clinical Trial Registry Platform (ICTRP). (23) Regrettably, the ICTRP did not include a means of enforcement. (24) Not long afterward, improvements in trial protocols and design were considered to address "biased reporting of outcomes within studies," a correlative problem to "biased reporting of whole studies." (25)

The U.S. was the first to enact clinical trials transparency legislation and Europe followed shortly thereafter. (26) Congress mandated trial registration on a public database (ClinicalTrials.gov) in the Food and Drug Administration Modernization Act of 1997 (FDAMA). (28) The European Parliament required registration on a European database (European Union Drug Regulating Authorities Clinical Trials (EudraCT)) (29) in the Clinical Trials Directive (Directive 2001/20/EC). (30) In 2009, the move toward transparency accelerated when Peter Doshi uncovered data on the limited efficacy of the anti-flu drug Tamiflu and began pushing for release of clinical trial data. (31)

In order to ensure published clinical trials contain correct and updated information, health care professionals need direct access to CSRs, not merely the filtered data of CSRs presented in journal articles; (32) however, transparency presents risks when taken to the extreme and should be pursued in a balanced manner. (33) If transparency is taken to the extreme, the "'seen' error of approving new medicines" may result in the "'unseen' error of blocking new medicines." (34)

Drug manufacturers present the greatest opposition to registration and reporting of clinical trials data. (35) They argue trial registration may provide competitors access to confidential information. (36) Therefore, some drug manufacturers argue that incentives, such as protection from mass tort litigation, should be exchanged for disclosure. (37) Though the need to foster a competitive environment in science is important, it is equally important to hold trial sponsors accountable for the accuracy of their clinical research in order to promote public confidence in drugs based on that research.

III. CLINICAL DRUG TRIALS IN THE UNITED STATES: THE FDA'S STANCE ON DISCLOSURE OF CLINICAL TRIAL DATA

Many drug manufacturers tend to selectively disclose data to ensure the commercial success of their drugs, resulting in drug scandals. (38) These scandals are complicated by the fact that some of the research studies relied upon are, in fact, "seeding trials." (39) Such studies "endanger human subjects" but fly under the radar of public knowledge. (40) Though institutional review boards (IRBs) serve as a safeguard, they do not check whether the studies they evaluate are seeding trials and their financial ties to the pharmaceutical industry may affect their evaluations. (41) The conflicts of interest manifest in clinical research and drug development bring to mind "the ancient question 'Who guards the guardians?"' (42)

Independent scrutiny of clinical trials is critical and must be paired with legislation that promotes transparency of such trials and access to the drugs tested by those trials. To facilitate access, Congress passed the Improving Access to Clinical Trials Act in 2010 (43) and introduced in 2012 the Transforming the Regulatory Environment to Accelerate Access to Treatments (TREAT) Act, which was ultimately not enacted. (44) To encourage transparency, Congress required posting of summary trial results on the Clinicaltrials.gov database in the 2007 Food and Drug Administration Amendment Acts (FDAAA); (45) however, the FDAAA contained exemptions for trials of drugs based on phase and approval status. (46) Its effect in increasing reporting was short-term, (47) resulting in efforts to pass the 2012 Trial and Experimental Studies (TEST) Act. (48) The TEST Act was more expansive in scope, (49) but the bill was not enacted and was reintroduced as H.R. 2031 in 2013 to bring "the U.S. closer toward reforms now underway in the EU." (50)

Though the TEST Act stalled, transparency remained at the forefront of the FDA's agenda as seen in its actions in 2014 to make available "demographic subgroup data[.]" (51) The Department of Health and Human Services (HHS) continued the transparency initiative by issuing a "Notice of Proposed Rulemaking (NPRM)." (52) The most significant change proposed in the NPRM is the requirement "to submit summary results to include trials of unapproved ... products." (53) A secondary proposal by the NIH suggests registration and reporting for all NIH-funded trials "regardless of study phase, type of intervention, or whether they are subject to the FDAAA requirements;" (54) however, as Jennifer Miller, a fellow at the Kenan Institute for Ethics at Duke University, observes, the impact of these initiatives may be limited since "oversight and enforcement by the FDA ... is weak." (55)

Moreover, in the drug evaluation process, the FDA gives drug manufacturers great leeway when it comes to determining the parameters of release for "confidential commercial information (CCI)," (56) which is often "information relating to risk and benefit" of a new drug. (57) Currently, the FDA approval process includes safeguards such as advisory committees and "approval contingent upon the sponsor's conducting of post-marketing studies." (58) Even with these measures in place, it remains difficult to ascertain the risks and actual clinical efficacy of drugs in clinical trials due to sponsor control. Should the industry retain input in the process, independent experts must be given the dominant role. (59) Alternatively, in order to ensure drugs meet the requisite criteria...