New rules released today by the Department of Health and Human Services (HHS) and the National Institutes of Health (NIH) will improve the availability of information about clinical trials posted on the ClinicalTrials.gov register, but still fall short of global best practices and lack teeth, a preliminary analysis by AllTrials suggests.
Dr Till Bruckner, campaign manager at Sense about Science which runs the AllTrials campaign said
The new rules improve the situation on paper, but unless they are backed up with effective monitoring and sanctions, they are unlikely to change much in practice. It’s clear that the many good and committed people working in the HSS and NIH have done their best to promote transparency, but the political will to put patients’ interests first and effectively enforce these rules is evidently still lacking. Not a single company has been fined for breaking these rules so far, at a direct cost of $25 billion to American taxpayers. Researchers, doctors and patients don’t need partial solutions and paper tigers, they need all trials to be registered and reported, starting today.
Trevor Butterworth, director of Sense about Science USA which runs AllTrials USA said
Patients and medical practitioners have watched study after study document widespread noncompliance with the law to the profound detriment of medicine. We are relieved that the exhausting pace of enactment has reached this milestone; please HHS, don’t stop.
Based on summaries of the long-awaited HHS regulation and a parallel new NIH policy previewed by AllTrials, both institutions have strengthened their reporting requirements, but have failed to back them up with effective sanctions. At the same time, the NIH does seem to have taken a big step forward by going above and beyond the minimal requirements set out by the HHS today.
Dr Ben Goldacre, co-founder of the AllTrials campaign said
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. 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.
The publication of the rules comes only two days after the United Nations called on governments worldwide to pass legislation requiring clinical trials to be registered, and their methods and results to be fully reported. Last month, researchers discovered that medical trials involving tens of thousands of children had not posted their results, in many cases in breach of US law. An investigation by STAT news last year documented widespread violations of existing legal requirements to report trial results by pharma companies and universities; federal agencies have yet to impose a single fine. In response, US Vice President Joe Biden threatened to cut funding to researchers who fail to report trial results.
The new rules do not affect the design or conduct of clinical trials or define what type of data should be collected during a clinical trial. Rather, they set out what information about clinical trials and their results will be made public.
Below is a summary of the most important new rules, with preliminary comments by AllTrials.
New HHS Regulation
Rule: Phase I trials are not covered by the regulation, so they do not have to be registered nor reported.
AllTrials comment: This is disappointing. The UK government said in its inquiry into the disastrous TGN1412 Phase I trial which nearly killed six participants that phase 1 trials should be shared more widely: this has not yet happening. If trial sponsors are not required to register and report Phase I trials, other researchers won’t know about any negative reactions to new compounds, and may unwittingly harm people. Only two days ago, the UN called for all trials to be made transparent. The best interests of patients require that all trials be registered and fully reported, not just some of them.
Rule: Clinical trials must be registered no later than 21 days after enrolling the first participant.
AllTrials comment: Trials should have to be registered before the first participant enrols.
Rule: From 2017 onwards, summary results information must be submitted regardless of whether the drug, biologic, or device in the study has been approved, licensed, or cleared for marketing by the FDA.
AllTrials comment: This is a great step forward, removing previous caveats to summary results posting requirements.
Rule: Results information must be submitted no later than one year after the primary completion date of the applicable clinical trial, with exceptions.
AllTrials comment: The one year deadline corresponds to global best practices, and should be applied without exceptions.
Rule: At the time the results are submitted, the clinical trial protocol and statistical analysis plan also have to be submitted. Personally identifiable information and trade secret and/or confidential commercial information may be redacted from the protocol.
AllTrials comment: This is a good step forward towards internationally recognised best practice. Researchers and regulators worldwide also need access to Clinical Study Reports, not just summary results and protocols, to ensure patient safety. Researchers recently flagged a case in which a pharmaceutical company seemed to have tried to hide harmful side effects in its summary results and protocols.
Rule: For federally funded trials, grant funding can be withheld if the rules outlined above are broken. Civil monetary penalties of up to $10,000 per day can be imposed for post results late on Clinicaltrials.gov, with this amount to be adjusted going forward.
AllTrials comment: Will these sanctions ever be enforced? To date, not a single fine has been imposed under the 2007 FDA Amendment Act despite routine violations of the act by trial sponsors, costing US tax payers an estimated $25 billion in lost revenue. The new wording effectively perpetuates the current bizarre situation in which legal compliance is treated as an option, not an obligation.
New NIH Policy
Rule: From 2017 onwards, all clinical trials funded wholly or partially by NIH have to be registered and reported. This includes Phase I trials and trials that do not involve any regulated product such as trials involving only behavioural interventions. Reporting rules are the same as those set out by the HHS (see above) in terms of data requirements and time frames.
AllTrials comment: It’s excellent to see that NIH will in future require all trials it wholly or partially funds to be registered. The HHS, as well as other trial funders all around the world, should take note and follow NIH’s good example in this regard.
Rule: Noncompliance “may” lead to suspension or termination of grant or contract funding and “can” be considered in future funding decisions.
AllTrials comment: This is disappointingly weak. All the good elements in NIH’s policy may come to nothing if these rules are not consistently and effectively enforced. Both patients and tax payers deserve better.
In an article published in Lexicology on November 15th, the law firm Hogan Lovells explained that:
The Final Rule requires an unprecedented level of transparency in reporting… The NIH Policy extends to phase 1 drug and biological product trials, feasibility studies of device products, and behavioral, surgical, and other medical interventions not regulated by the Food and Drug Administration (FDA). Applicants for NIH funding must submit a plan describing how obligations under this Policy will be met.
NIH acknowledged the costs of complying with this Policy and suggested that the salaries of administrative and clerical staff that facilitate compliance could be permissible direct charges to an award, but only if these costs otherwise meet the OMB Uniform Guidance test for direct charging of administrative and clerical salaries.
Notably, noncompliance with the NIH Policy “may provide a basis for enforcement actions, including termination” and jeopardize future grant funding. NIH also says it may publicly post on the clinical trial record an awardee’s omission to submit information that the Policy requires.