never been imposed…

Posted on Friday 20 November 2015

We live in a time of meta-analyses [studies of studies]. This one selected the 15 new drugs approved during 2012 from large pharmaceutical companies [from among 48 new drugs approved that year]. They looked at all trials [from all phases] to see if they were registered, reported, published, or reported-or-published [public]. They also partitioned them in various ways [for ethical versus legal compliance], then created transparency criteria to rank the studies. Be warned – the text is dense. One reason it’s here is that it explains when public disclosure is required and quantifies the compliance rates:
by Jennifer E Miller, David Korn, and Joseph S Ross
BMJ Open 2015;5:e009758.

Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: [1] legal requirements and [2] the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge.
Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration [FDA] for drugs approved in 2012, sponsored by large biopharmaceutical companies.
Data sources: Information from Drugs@FDA,, MEDLINE-indexed journals and drug company communications.
Main outcome measures: Clinical trial registration and results reporting in, publication in the medical literature, and compliance with the 2007 FDA Amendments Acts [FDAAA], analysed on the drug level.
Results: The FDA approved 15 drugs sponsored by 10 large companies in 2012. We identified 318 relevant trials involving 99,599 research participants. Per drug, a median of 57% [IQR 32–83%] of trials were registered, 20% [IQR 12–28%] reported results in, 56% [IQR 41–83%] were published, and 65% [IQR 41–83%] were either published or reported results. Almost half of all reviewed drugs had at least one undisclosed phase II or III trial. Per drug, a median of 17% [IQR 8–20%] of trials supporting FDA approvals were subject to FDAAA mandated public disclosure; of these, a median of 67% [IQR 0–100%] were FDAAA-compliant. 68% of research participants [67,629 of 99,599] participated in FDAAA-subject trials, with 51% [33,405 of 67,629] enrolled in non-compliant trials. Transparency varied widely among companies.
Conclusions: Trial disclosures for new drugs remain below legal and ethics standards, with wide variation in practices among drugs and their sponsors. Best practices are emerging. 2 of our 10 reviewed companies disclosed all trials and complied with legal disclosure requirements for their 2012 approved drugs. Ranking new drugs on transparency criteria may improve compliance with legal [FDAAA] and ethics standards and the quality of medical knowledge.
These graphs give an overview – on the left, the number of trials for each drug; – on the right, the percentage of trials for each drug that meet the criteria listed on the abscissa. Like all of this genre of studies, the compliance rates are dismal. For example 20% of these approved drugs had no accessible Phase III trial information [neither reported on nor published in a journal]. But I’ll leave further exploration of that gloom in your hands, and get to my point. The last two sentences of the following section are the main reasons I posted this article:
Transparency by legal standards

There are at least three reasons why compliance with current disclosure laws might be suboptimal. First, legal requirements are perceived to be unclear or ambiguous, as a spectrum of interpretations of FDAAA has emerged…

Second, mergers, acquisitions, collaborations and licensing agreements may complicate compliance. Two companies in our sample acquired or licensed drugs initially developed by smaller companies, and another used a partner company for some trials, raising questions about whose responsibility it was to ensure trials complied with FDAAA.

Finally, compliance may be affected by a perceived lack of enforcement. FDAAA empowers the FDA to impose a $10,000 a day penalty for non-compliance. To date, this penalty has never been imposed.
Let me repeat those lines for emphasis: "FDAAA empowers the FDA to impose a $10,000 a day penalty for non-compliance. To date, this penalty has never been imposed." And while I’m at it, let me nominate suboptimal compliance and perceived lack of enforcement for understatements of the year. Like almost everything we’ve learned about these industry funded clinical trials, it’s an elaborate system that creates massive amounts of data, but it just doesn’t work. Since its inception in 1962, there have been many reforms – new procedures, new rules for reporting, etc. But they seem to only add more layers of bureaucracy and make little impact because there’s no real oversight or enforcement.  This group envisions repeating their analyses in an ongoing yearly surveillance effort and apparently has the funding support to do it:
Motivating transparency

Given the wide variation in compliance with both legal and ethical standards across drugs and companies, we propose continuing our clinical trials transparency monitoring, evaluations and scoring of new drugs approved by the FDA, along with their sponsors. These ongoing rankings— developed initially with support from Harvard University, Duke University, Susan G. Komen Foundation and the Raskob Foundation [for a full list of sponsors, see the Acknowledgements section] — will be conducted annually under the auspicious of Bioethics International, with grant support from the Laura and John Arnold Foundation.

This system will help identify best practices, incent better behaviours and standardise the industry’s practices and thereby contribute importantly to an enrichment of medical knowledge. Moreover, the scorecard and rankings have the potential to benefit consumers of clinical trial information by helping to assure them of the integrity and completeness of their data. Not least, full transparency of clinical trials would also strengthen the protection of human research participants by avoiding their unknowing recruitment into already failed experiments.
We’re about to have a new head of the FDA [likely Dr. Robert Califf]. While there’s an growing cadre of people focusing on Data Transparency, particularly with the industry funded trials, without the FDA’s full cooperation, it might be a hopeless endeavor. One would think that it’s the FDA Director’s job make this system function as intended, and we need to hold him to the task. The liberal imposition of some of these already approved fines would be a really great place to start…

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