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Mar2016

Though not a new issue, clinical trial data sharing has over the past several months taken center stage within the medical research community. In December 2015, a STAT article showed there was substantial under-reporting to ClinicalTrials.gov. One month later, a French clinical trial left one man dead and European scientists calling for more data transparency. Five days after the deadly incident, the International Committee of Medical Journal Editors (ICMJE) issued new proposed clinical trial data sharing requirements. While many agree that increased data sharing is an ethical imperative given the risks that clinical trial participants are asked to undertake, the question many institutions are now struggling with is how they can meet that imperative with their current resources and while protecting the privacy of study subjects.

In January 2016, one man died and five other subjects were sent to the hospital after taking a drug during the phase I portion of a French clinical trial sponsored by Bial. In response, the British Pharmacological Society called for "improve[d] early access to data from catastrophic clinical trials." The Society pointed out that with respect to the drug used in the French clinical trial, "A better understanding amongst the scientific community of the nature of the drug, and the way in which it was dosed, would be helpful, even at this early stage, in preventing further harm to volunteers in other clinical trials."

One month earlier, in the United States, STAT released their findings that academic institutions and companies frequently violate a federal law that requires trial results be reported to ClinicalTrials.gov. ClinicalTrials.gov, which was created in 1997, is run by the National Institutes of Health (NIH). The FDA Amendments Act of 2007 (FDAAA) expanded the registration requirements and led to the creation of the ClinicalTrials.gov results database for the public. The database includes study outcomes and adverse events that were reported during the course of a trial.

It is important to note that while FDAAA covers all clinical trials that meet its requirements, irrespective of funding source, FDAAA does not apply to phase 1 trials. FDAAA also does not apply to trials overseas if they were not conducted under an Investigational New Drug (IND) Application or Investigational Device Exemption (IDE) or if the product was not manufactured domestically and exported for the trial.

In 2014, the Department of Health and Human Services (DHHS) issued a Notice of Proposed Rulemaking (NPRM) to expand "the scope of clinical trials required to submit summary results (under FDAAA) to include trials of unapproved, unlicensed, and uncleared products." DHHS noted that expanding the submission requirements would provide additional information to future research subjects and reduce the number of clinical trials being inadvertently duplicated.

In 2014, NIH also proposed a policy on ClinicalTrials.gov registration and results submissions that would apply to any NIH-funded clinical trial, regardless of study phase, type of intervention, or whether they are subject to the applicable FDAAA registration and results submission requirements. The proposed policy states "there is an important ethical dimension to dissemination of clinical trial results because individuals who volunteer to participate in such studies, and who may assume risks, trust that what we learn will contribute to generalizable knowledge about human health."

FDAAA has monetary penalties for non-compliant entities and the law directs the NIH to withhold funding if federal grantees are not complying with the law. However, the responsible agencies (FDA and NIH) have never penalized researchers or institutions for not posting data. Four years ago, Congressional representatives wrote to FDA and NIH citing their concern with a study that found substantial under-reporting to ClinicalTrials.gov. The lawmakers also asked if NIH had adequate resources and authority to enforce the reporting requirements. In April 2012, NIH responded that it did.

In their analysis, STAT found that industry had a better reporting rate than nonprofits and universities: "Results from academic institutions arrived late or not at all 90 percent of the time, compared with 74 percent for industry." These findings were confirmed in a more recent BMJ study as well.

Several university officials told STAT that they lacked the time and administrative funds to fully comply with the law. In a March 2015 NEJM article that also reported low rates of results reporting to ClinicalTrials.gov, the authors noted one estimate that preparing results summaries for a single trial for ClinicalTrials.gov took between four and sixty hours. The authors also note that "it is possible that the NIH and other funders have been unable or unwilling to allocate adequate resources to ensure timely reporting."

Despite under-reporting and enforcement problems, ClinicalTrials.Gov seems to be popular with the public. As of October 2015, the website received approximately 65,000 visitors each day and 207 million page views each month.

In another sign of growing consensus around mandatory data sharing, the ICMJE, which counts many of the top-tier medical journals as members, released its proposed data sharing requirements in January 2016. ICMJE "proposes to require authors to share with others the de-identified individual-patient data (IPD) underlying the results presented in the article…no later than 6 months after publication" and "proposes to require that authors include a plan for data sharing as a component of clinical trial registration." ICMJE is accepting feedback on its proposals until April 18, 2016.

The ICMJE’s requirement to share data at the individual patient level has implications for IRBs and human research protections. For one thing, IRBs need to ensure that the informed consent process includes appropriate and understandable information about the data sharing plan and the conditions under which information will be shared. For another, the sharing of individual patient data, even de-identified, also entails that IRBs need to ensure there are adequate measures in place to protect individuals’ privacy and the confidentiality of their data.

Clinical trial data sharing serves to maximize research subjects’ contributions to science and enhances the chances that the risks they undertake are offset by future benefits. It also increases transparency around biomedical research and may, as a result, protect future potential subjects and serve to foster much-needed public trust in the research enterprise. There is no question that mandatory clinical trial data sharing poses significant operational issues for institutions, investigators, and IRBs. It may also raise additional ethical questions around adequate protection of subject privacy. The work it will take to address these issues should not be diminished. But there is also no question that data sharing is an idea whose time has come.

I invite you to share your perspective on clinical trial data sharing. Has the news of the French clinical trial and under-reporting to ClinicalTrials.gov changed your views on data sharing? How?

Should there be federal funding to help institutions report to ClinicalTrials.gov?

What other issues does mandatory data sharing raise?

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9 thoughts on “From the Director: Clinical Trial Data Sharing, the Law, and Reality

  1. Pingback: From the Director: Clinical Trial Data Sharing, the Law, and Reality - Bioethics Research Library

  2. Laurel Evans

    With increasing ability to re-identify “de-identified” individual level patient data, there are risks of privacy and confidentiality related to mandatory data sharing,. In Canada, we are struggling with the coercion aspect. That is, if a clinical trial is of potential therapeutic benefit and you MUST agree to sharing your individual patient level data for future research as a pre-condition to participating in that clinical trial are you really giving truly free and voluntary consent?

    Reply
    1. Elisa Hurley

      Thanks for your comment, Laurel. To be sure, mandatory data sharing raises the stakes with regard to privacy and confidentiality. I’m not sure I agree with your coercion point, however. It would be coercive, with respect to participating in a clinical trial, if a potential subject was faced with a threat if she did not enroll — for example, if there was a threat that she would not receive care from her physician if she does not volunteer for the trial. But if a potential participant is told that one of the conditions of enrolling in a trial is that her data will be shared (and here are the protections in place with respect to your privacy — that is important), then I don’t believe that person is coerced into participating in the trial. That person might not like those terms, but he or she has every opportunity to freely consent, or not consent, to participation, given the terms.

      Reply
  3. Jerilynn C. Prior, MD, FRCPC

    I agree that transparency in research is crucial as a disincentive to fraud. However, if the effort is to increase knowledge translation, there are many more effective ways to reach the public than http://www.clinicaltrials.gov.
    In my world, where all the research I do is underfunded (even if it is a Canadian Institutes for Health Research-funded study), the hours needed to report de-identified individual participant data (IPD should be understood as participant not patient!) are simply not available.
    At a minimum, Clinical Trials.gov needs to make the whole process of registering and reporting easier. (Currently it is cumbersome, must be approved by an institutional person, and the website is complex),

    Are there protections so that another researcher could not slice and dice and publish results for their own purposes?

    Are there plans to increase IRB funding to cover the added costs?

    If the idea is to transform research results into clinical practice, the barriers are habit, pharmaceutical marketing and the current training of health care providers (that doesn’t keep up with the research).

    This idea needs very careful thought and provisions for funding before it could improve research participant safety, scientific integrity or knowledge translation.

    Reply
    1. Elisa Hurley

      Thank you for your comments, Jerilynn. I agree with you that, as it stands, ClinicalTrials.gov is not especially user-friendly for either the public or those reporting trial results. PRIM&R has commented on this issue, in fact, in a letter to U.S. Representative Ed Markey in 2012. You also nicely articulate some of the operational hurdles that need to be addressed for ClinicalTrials.gov and mandatory data sharing initiatives more generally to realize their potential to improve science and the safety of clinical trials for human subjects.

      Reply
  4. Marc Levine

    The idea of sharing details of clinical trial protocols and sharing of the data in aggregate form along with the results of the analysis is a compelling one and can be justified on both scientific and ethical grounds.

    However, the requirement for the mandatory consent of patients for sharing of their data on an individual level (even though de-identified) poses at least two major ethical concerns:

    1. Since the data will/may be used by others for purposes other than answering the question posed by the study to which the participant is being consented, the principle of voluntariness of participation in research will be nullified.

    2. For clinical trials that offer potential benefit to the participant, the mandatory sharing of individual data with other researchers for other purposes, is potentially coercive. Participants will be conflicted by wanting to be in the study and in order to do so will need to agree to a use of their data for purposes to which they would otherwise not consent (for whatever reason). There are situations in which the risk of re-identification of participants is substantial, and this would seem to escalate the coerciveness of mandatory (as opposed to optional) data sharing.

    Moreover, current efforts by sponsors to mandate the sharing of individual level data also is coercive to REBs. RBEs may prefer, for the reasons above, to disallow research unless future sharing of data is made optional. However, to exclude research from their sites on ethics grounds would seem to undermine the autonomy of potential participants to make an informed choice to join a therapeutic clinical trial. Thus REBs are being compelled to approve studies involving mandatory data sharing that would otherwise be deemed unethical.

    Our REB takes the position that data sharing of the type referred to above should be optional, though we are getting strong resistance from sponsors. I believe this issue should be addressed on a national level as soon as possible. The interim approach we are taking is as follows:

    We work with PIs to try and make individual level data sharing optional (with an optional consent form). If the sponsor absolutely refuses and threatens to pull the study from our site, then we require the PI to have participants sign a notice from the REB informing them of the ethical concern of the board and indicating that the participant is aware of this issue and the attendant risks when deciding to participate in the clinical trial. This provides at least some assurance that participants are clearly made aware of the potential risk and the questionable ethics of this process.

    Reply
    1. Elisa Hurley

      Thank you for your thoughtful and thought-provoking comments, Marc. It’s very interesting to hear about how this issue is being discussed in Canada. In the U.S., we’ve had a lot of discussion about the importance of public education as an accompaniment to broad data sharing — my own view is that public education around research is an ethical imperative. I wonder if the concerns you raise about the quality of consent would be mitigated in a context in which there is a concerted effort to educate and engage patients and potential research participants in a public conversation about research and its benefits (and risks)?

      Reply
  5. Kuo-Hsing Kuo, MD, PHD

    To avoid negative impact on issues derived from patient confidentiality, ethical regulation, or even commercial sensitivity, the overarching principles of sharing should be aimed at the enhancement of patient safety through mechanisms of timely access and transparency on well-defined content, but not mandatory sharing on unrestricted information for all studies involving human subjects. The meaningful mechanisms should raise the threshold of actionable adaptations for future trials or similar class of drug developments within acceptable ethical considerations.

    The call, in 2006, from the British Pharmacological Society has recommended early release of the study protocol, the Product Dossier and the batch release data to maximize patient safety in the future. The International Committee of Medical Journal Editors, in 2016, also proposed the sharing of de-identified individual patient data on clinical trials that aim to gather the cause-and-effect relationship between health-related intervention and health outcomes. Both recommendations delineate well-defined sharing content in order to achieve the goals of patient safety and public confidence without compromising others.

    Reply
  6. Paul D Mullins

    Many thanks for this.
    Comment:
    A ‘one size fits all’ approach to data sharing for all clinical trials is inappropriate, for example in a non-interventional longitudinal observational clinical trial measuring variables in the investigation of the natural history of a disease.
    Best wishes,
    Paul

    Reply