Faced with noncompliance of required reporting of clinical trial information, the U.S. Department of Health and Human Services (HSS) issued a final rule last September that gave more specifics about registering certain clinical trials and submitting summary results information to ClinicalTrials.gov. The rule also expanded the legal requirements for submitting registration and results information for clinical trials involving FDA-regulated drug, biological, and device products. National Institutes of Health (NIH)-funded trials fell under reporting requirements, as well, as the NIH issued a complementary policy at the same time. NIH-funded trials must register and submit summary results information to ClinicalTrials.gov even if the trials are not subject to the final rule. Although the enhancements add measures to improve the amount of clinical trial information on ClinicalTrials.gov, some researchers in favor of total transparency say that enforcement action and penalties still fall short.
Results of the first expansion
Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) mandated the expansion of ClinicalTrials.gov, the clinical trial registry and results data bank operated by NIH’s National Library of Medicine (NLM), to include more registration information for a broader set of clinical trials, as well as results information.1 Under the mandate, registration information for an applicable clinical trial had to be submitted no later than 21 days after enrollment of the first participant. Results of an eligible clinical trial of a drug, biologic, or device that is approved, licensed, or cleared by FDA had to be submitted to the database within 12 months of the completion date. Penalties for failing to comply with registration or results submission requirements included civil monetary penalties and, for federally funded studies, the withholding of grant funds.
A study by STAT in 2015, however, showed that compliance was low, with no penalties given to any researcher or institution for not reporting clinical trial data.2 Overall, research results were disclosed late or not at all at least 95% of the time since reporting became mandatory in 2008, according to STAT. Although pharmaceutical companies have been criticized for their lack of transparency, “major medical schools, teaching hospitals, and nonprofit groups did worse overall — many of them far worse,” says the author of the report. For example, results from academic institutions arrived “late or not at all 90% of the time, compared with 74% for industry.”
Former Vice President Joe Biden expressed his disapproval about the report to a cancer summit at Howard University in Washington, DC, on June 29, 2016. “Doc, I'm going to find out if it's true," he says. "And if it's true, I'm going to cut funding. That's a promise.”3
In November 2014, HHS issued a notice of proposed rulemaking (NPRM) describing the proposed requirements and procedures for registering and submitting the results, including adverse events, of clinical trials on ClinicalTrials.gov. It also considered regulations intended to provide more complete results information and enhance patients' access to the results of clinical trials, by proposing to expand the requirement for submission of results information for Applicable Clinical Trials of unapproved products (i.e., drugs, biological products, or devices that have not been approved, licensed, or cleared by FDA). HHS says it received nearly 900 comments during the 120-day public comment period, which closed on March 23, 2015. “Of the total comments received, about 60% were nearly identical in content, expressing support for clinical trial transparency efforts and the goals of the NPRM, and provided specific perspectives on a number of the proposals. Another large subset of comments also expressed support for clinical trial transparency and the NPRM goals, but did not comment on specific proposals. There were about 100 distinct comments that addressed specific NPRM proposals.”1 The effective date for the final rule was January 18, 2017, and the compliance date is April 18, 2017.
In November 2014, NIH also proposed a policy to ensure that every NIH-funded clinical trial is registered on ClinicalTrials.gov and has summary results submitted and posted in a timely manner. Public comments on the proposed rule were accepted until March 23, 2015, as well. NIH says it received approximately 240 public comments on the proposed policy, from a range of stakeholders including researchers, academic/research institutions, medical practitioners, patients, patient/disease advocacy groups, scientific/professional societies and associations, device manufacturers, trade associations, not-for-profit non-governmental organizations, and the general public.4 The policy took effect January 18, 2017.
Major provisions of the HHS final rule
The HHS final rule specifies how data that were collected and analyzed in accordance with a clinical trial’s protocol are to be submitted to ClinicalTrials.gov. Important provisions of the rule include:5
Applicable clinical trial. The final rule clarifies which clinical trials of FDA-regulated drug products (including biological products) and device products and which pediatric postmarket surveillances of a device product are applicable clinical trials for which information must be submitted to ClinicalTrials.gov. A checklist for evaluating which clinical trials are subject to the regulations is available at https://prsinfo.clinicaltrials.gov/ACT_Checklist.pdf. The requirements do not apply to Phase I trials of drug and biological products or small feasibility studies of device products. “In general, to be considered an applicable clinical trial, one or more of the following criteria also must be met. The clinical trial must include one or more sites in the United States; study a drug, biological, or device product that is manufactured in the United States or its territories and is exported for use in a clinical trial outside the United States; or be conducted under an FDA investigational new drug application (IND) or investigational device exemption (IDE).”6 The final rule considers all interventional clinical trials with one or more arms and with one or more pre-specified outcome measures to be controlled clinical trials. The final rule does not consider any expanded access use to be an applicable clinical trial.1
Responsible party. A responsible party is the sponsor of the clinical trial or a designated principal investigator. The responsible party could be an organization (such as a drug or device manufacturer, a university or academic medical center, or a government research organization such as the NIH), or an individual. The final rule specifies the approach for determining who is the sponsor of a clinical trial and explains how a sponsor can designate a principal investigator as the responsible party.6
Registration. The final rule requires that, in general, a responsible party register an applicable clinical trial at ClinicalTrials.gov no later than 21 days after enrolling the first participant. Registration consists of submitting four categories of data elements: 1) descriptive information, 2) recruitment information, 3) location and contact information, and 4) administrative information.6 If a drug or biological product studied in an applicable clinical trial is available under expanded access, the final rule requires the responsible party, if both the manufacturer of the drug product or biological product and the sponsor of the clinical trial, to also submit a separate expanded access record (or link to an existing expanded access record) containing certain details about how patients may obtain access to the investigational product.
Submitting results. The clinical trial results information submission requirements in the final rule apply to an applicable clinical trial with a primary completion date on or after the effective date of the final rule. In general, results information must be submitted no later than one year after the primary completion date of the applicable clinical trial. Primary completion date is the date that the final subject was examined or received an intervention for the purpose of collecting the data for the primary outcome measure. Results information submission may be delayed for as long as two additional years if the responsible party submits a certification to ClinicalTrials.gov that either: 1) a drug, biological, or device product studied in the clinical trial is not yet approved, licensed, or cleared for marketing by FDA and is still under development by the manufacturer; or 2) that the manufacturer is the sponsor of the clinical trial and has sought or will seek approval, licensure, or clearance for a new use of a product studied in the trial within one year. The final rule also permits responsible parties to request extensions to the results information submission deadline for “good cause.”6
The results information should consist of tables of information summarizing: 1) participant flow information, 2) demographics and baseline characteristics of the enrolled participants, 3) primary and secondary outcomes, including results of any scientifically appropriate statistical tests, and 4) adverse events (anticipated or unanticipated).6 Adverse event information consists of one table that summarizes all serious adverse events experienced by participants enrolled in the clinical trial, and a second table that summarizes other adverse events that exceed a frequency of 5% in any arm of the clinical trial. The final rule adds a third table for summarizing all-cause mortality, with the number and frequency of deaths due to any cause by arm. All results information is aggregated, summary level data. In addition, this rule requires responsible parties to provide the time frame for adverse event data collection and specify whether the collection approach for adverse events was systematic or non-systematic. The final rule does not require a responsible party to collect adverse event information that is not specified in the protocol.1 The final rule also adds a requirement to submit the clinical trial protocol and statistical analysis plan at the time of results information submission. Section 11.48 provides a listing of all required results information data elements. Narrative summaries do not need to be submitted.
Updates and other requirements. All submitted information must be updated at least once a year, maybe more for some data elements to help ensure that users of ClinicalTrials.gov have access to accurate, up-to-date information about important aspects of a clinical trial. The responsible party also must address any apparent errors, deficiencies, and/or inconsistencies identified by NIH as part of the quality control review process and any other errors identified by the responsible party within the timeframes set forth in the final rule.
Results posting. According to the final rule, NIH generally will post registration and results information no later than 30 days after it is submitted to ClinicalTrials.gov. However, the posting provisions differ for trials of unapproved and uncleared device products. NIH is prohibited from posting registration information for those trials unless the responsible party authorizes NIH to do so.
Compliance. The final rule has a compliance date of 90 days after January 18, 2017. NIH also is required to make a responsible party’s non-compliance public through a posting on the clinical trial record. If the applicable clinical trial is funded in whole or part by HHS, failure to submit all required registration and results information can jeopardize grant funding and future funding to the grantee.6
The final rule provides a list of potential legal consequences for non-compliance. FDA has the authority to issue a Notice of Noncompliance to a responsible party who has failed to comply with the requirements for registering and submitting results information for an applicable clinical trial. FDA also may impose civil monetary penalties for such violations. Additionally, a responsible party who commits a prohibited act(s) may be the subject of an injunction action or criminal prosecution brought by the Department of Justice.6
Provisions of the NIH policy
The most important thing to note about the final NIH policy is that it applies to all clinical trials funded in whole or in part by NIH, regardless of study phase, type of intervention, or whether they are subject to the HHS final rule. The NIH policy applies to clinical trials that are defined as “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.”6 In addition to the types of trials covered by the final rule, the NIH policy applies to all other trials funded by NIH, including Phase I trials of drug and biological products, small feasibility studies of device products, and clinical trials of behavioral, surgical, and other types of health and medical interventions. Clinical trials that use NIH-supported infrastructure, but receive no other NIH funds for the conduct of a specific clinical trial, are not subject to the NIH policy.
Researchers who apply for NIH funding are required to submit a plan outlining how they will comply with the clinical trial information dissemination expectations of the policy.6 “Consistent with the terms and conditions of their NIH funding, awardees undertaking clinical trials covered by the NIH policy must ensure the submission and updating of the same type of registration and results information, and in the same timeframes, as responsible parties whose trials are subject to the final rule. An NIH-funded clinical trial that is also subject to the final rule should only have one entry in ClinicalTrials.gov containing its registration and results information.” The policy takes effect on the effective date of the final rule, and applies to applications and proposals received and intramural clinical trials submitted for institutional review board review on or after that date.6
Compliance with the NIH policy will be via the terms and conditions of the NIH award. Failure to comply with the terms and conditions of an NIH funding award could lead to grants enforcement actions, including termination of funding.
NIH statement on final rule
Francis S. Collins, NIH Director, with the assistance of Kathy L. Hudson, Deputy Director for Science, Outreach, and Policy for the NIH, wrote a blog post after the publication of the HHS regulation and NIH policy to reflect on how the new regulation and policy “fit into our overall efforts to improve clinical trials and data sharing.”7 “Clinical trials are essential for the translation of research advances to new approaches to prevention and treatment,” he says. “Volunteers who take part in clinical trials often do so with no assurance of personal benefit, but with the expectation that their involvement will add to the growing body of knowledge about health and disease, and thus may help others someday. For that to be realized, all trial results information needs to be publicly reported in a timely fashion — and yet we know that doesn’t always happen. Today’s announcements aim to change that.”
He acknowledges that data sharing is not always easy. “I learned this firsthand, when as part of a test of the new system some time ago, my senior team and I tried to enter sample data from a trial into ClinicalTrials.gov — it is not a trivial task,” he writes. “Registering a trial and submitting results information should not cause researchers to pull their hair out, nor should it take an inordinate amount of time away from valuable research. That is why we will be doing all we can to make submitting information to ClinicalTrials.gov as frictionless as possible for the regulated community.”
The final rule sets forth remarkable initiatives for sharing summary level clinical trials information, he says. “But we still have a long way to go. Sharing individual patient level data from trials is still on the list. The NIH has evaluated various models for making the sharing of these data feasible and useful to researchers. We are also exploring ways to support large scale sharing of research data and other information through the development of a cloud-based data commons.”
For sponsors and others responsible for trials subject to the FDAAA or covered by the NIH policy, the days of deciding whether or not summary results are worth reporting are over: All such trials will have summary results information posted publicly on ClinicalTrials.gov, say scientists from the National Library of Medicine and NIH’s Office of Science Policy.8 “The time to decide whether a trial is worth doing is before the trial is started, not after participants have been put at risk.”
“The FDAAA and the NIH policy hold all parties responsible for clinical trials — not just the individual investigators — accountable,” they continue. “Organizations will need to ensure that their systems, procedures, and organizational values all promote complete and timely clinical trial reporting. In the end, the parties responsible for clinical trials will be held accountable by the public. We hope that sponsors and other relevant entities will go considerably above and beyond the minimum requirements and expectations, making an effort to honor the contributions of all study participants and ensure that others in the scientific community have access to complete and high-quality information about every clinical trial under their stewardship.”
The role of IRBs
This final rule does not impose requirements on the design or conduct of clinical trials or on the data that must be collected during clinical trials. Instead it specifies how data that were collected and analyzed in accordance with a clinical trial's protocol are submitted to ClinicalTrials.gov.1 A recent article in the Journal of the American Medical Association suggests that since institutional review boards (IRBs) are charged with “ensuring appropriate respect for research participants and ensuring that the risks participants face are justified,” wouldn’t IRBs then be a logical choice for ensuring the timely reporting of trial results?9 Samuel N. Doernberg and David Wendler from the NIH Clinical Center Department of Bioethics say that IRBs could require investigators to prospectively register trials prior to initial approval and before enrollment of the first study participant occurs. IRBs could also require the protocol to say how investigators plan to share the study results. This plan should include four elements, Doernberg and Wendler say. The elements are: nature of the results to be shared, location or registry for sharing results, timeline for sharing the results, and who is responsible for reporting the results.8 Third, IRBs can require information about the investigator’s prior compliance with sharing of study results. And finally, IRBs should require evidence that the results have been shared when deciding whether to approve the termination of a study. “If the research community is committed to maximizing the value of clinical trials, then IRBs should be engaged in this endeavor. Conditioning study approval on trial registration and sharing of data makes it likely that much more sharing of trial results will occur, thereby helping to realize the promise of clinical trials for improving health and well-being.”8
Just one part of plan
According to a recent article by NIH officials in the Journal of the Americal Medical Association, this new regulation and policy is part of a “multifaceted effort to improve the quality and efficiency of clinical trials, an effort that is focused on a variety of key points along the lifespan of a clinical trial.”10
These initiatives will reengineer the process by which clinical investigators develop ideas for new trials, how NIH reviews and selects clinical trials for support and oversees the progress of the research, and how results and aggregate data are shared broadly and rapidly. Specifically, these changes are aimed at enhancing the application and award processes, increasing NIH’s ability to assess the merits and feasibility of clinical trial applications; improving oversight and transparency; and increasing the sharing of clinical trial results. In combination, these initiatives are intended to ensure rigor and efficiency in the U.S. clinical trial enterprise.”
The NIH expects the “clarity” of the new regulation and NIH policy, together with their “comprehensive compliance and enforcement provisions,” to result in rapid increases in the percentage of trials that are registered and share aggregate data through ClinicalTrials.gov.10 “Investigators and sponsors who fail to comply with the regulation may be subject to civil monetary penalties assessed by FDA,” NIH officials say. “In addition, NIH will withhold clinical trial funding to grantee institutions if the agency is unable to verify adequate registration and results reporting from all trials funded at that institution. The availability of results will promote innovations in clinical trial design and avoid duplication of unsuccessful strategies, thereby avoiding unnecessary risks to research participants.”
Enforcement questions remain
But the question remains about the amount of resources available to enforce the new rules. In a press briefing NIH Director Collins says he believes researchers will want to avoid having their study listed in ClincalTrials.gov as being in violation of the law, according to STAT. “I don’t think anybody wants to be on the wall of shame,” he says. “We’re not going to have a vast army to pursue the compliance issues, but we really don’t think that (will be) necessary.”11
FDA Commissioner Robert M Califf said in a press conference call that neither FDA nor NIH would be adding enforcement staff. Instead the enforcement would be “folded” into the FDA’s bioresearch monitoring program, STAT reports.11
One advocate for full clinical trial disclosure was underwhelmed with the new regulation. “The announcement today was supposed to be about implementation. The FDA Amendment Act 2007 was passed nine years ago. At least two high impact academic journal publications have shown that this law is only being complied with by one trial in five. We have waited a decade to hear how the law will be enforced,” says Ben Goldacre, a fellow at the University of Oxford and cofounder of Alltrials.net, a project that advocates for total clinical trial transparency. “We now need to know who will be monitoring compliance; how they will share details of their deliberations and work; what principles and policies they will be following in making their decisions on whether to apply a fine, or any other form of censure; what institutions they sit in; how many of them there are; and so on. Doctors and patients cannot make informed decisions about which treatment is best for as long as the methods and results of trials on currently used treatments are still being routinely withheld. This is a serious public health problem: it needs a clear plan of action.”11
Collins said in the press briefing that both FDA and NIH will “automate compliance checks” to see if clinical trials are properly registered and that the results are reported, STAT says. Institutions will be contacted to make sure they “provide all the data required to bring their trials into compliance with the law.” Collins indicated that withholding funds could be a big deterrent. “We are serious about this,” Collins says. “It’s hard to herd cats, but you can move their food, or take their food away.”11
By Sue Coons, MA
This article was reprinted from Research Practitioner, Volume 18, Number 1, January-February 2017.