When I started writing about all this PHARMA/Clinical Trial stuff a year or so ago, I was essentially an illiterate, embarrassingly naive. I didn’t know what clinicaltrials.gov was, how drugs were approved by the FDA, what the Clinical Research Industry or Clinical Research Organizations [CROs] were. All I knew was that there was something very wrong in the state of psychiatry – something that wasn’t there in the past when I was teaching and doing general psychiatry. It was after retirement when I needed to catch up for a couple of volunteer clinic jobs when I realized that I was, indeed, a stranger in a strange land.
As I cycled through the available data on the clinical trials, I’ve been stunned at how much graphmanship and statistical manipulation has gone on – outright deceit. This Study 329 business is particularly shady, but in the psychopharmacological clinical trials, finding some kind of data massage and deception is regular enough to almost be expected, at least in the industry-funded studies. I’ve convinced myself that the answer is to require the raw data to be publicly available. Apparently, I’m not the only one that thinks that’s the answer. I read this earlier and bookmarked it, but at the time, I was
obsessed engaged with psychopharmacological evangelism: and matters translational:
US bill seeks tighter reporting requirements for ClinicalTrials.gov
by Peter Mansell
August 07, 2012
A new bill introduced in the House of Representatives is looking to tighten up reporting requirements for ClinicalTrials.gov, the public online registry run since October 2008 by the US National Institutes of Health [NIH]. H.R. 6272, the Trial and Experimental Studies Transparency [TEST] Act of 2012, was introduced by Congressman Edward Markey [Democrat, Massachusetts], senior member of the House Energy and Commerce Committee, and referred to that committee last week. It is co-sponsored by Congressional Democrats Rosa DeLauro, Janice Schakowsky and Henry Waxman, and has the support of the Patient, Consumer and Public Health Coalition and Consumers United for Evidence-Based Healthcare.
Among the TEST Act’s provisions are to strengthen reporting requirements so that results from all eligible clinical studies are posted on ClinicalTrials.gov within one year of the trial being completed. It would also seek legislation obliging sponsors of trials studies conducted outside the US, yet used to support an application for marketing in the US, to comply with the registration and reporting requirements of the NIH database. The TEST Act’s other provisions include:
- Requiring all interventional biomedical studies on humans to be registered on ClinicalTrials.gov before the first participant is enrolled in the trial.
- Delayed submission of results [up to two years after trial completion] for studies on medical interventions that have never before been approved for any use.
- Instructing the NIH and the US Food and Drug Administration to report to Congress on implementation of, and compliance with, the new database standards.
Early this year, an editorial in the BMJ called on professional associations to take disciplinary action against clinical researchers who failed to disclose data from clinical trials, arguing that lack of transparency risked undermining clinical decision-making, harming patients and wasting public money invested in health systems. As the editorial pointed out, the US Food and Drug Administration Amendments Act of 2007 made publication within 12 months of a results summary on ClinicalTrials.gov mandatory for all eligible trials in the US “initiated or ongoing as of September 2007”. However, a review by Prayle et al published in the same issue of the BMJ found that only 22% of trials subject to mandatory reporting under the 2007 Act had results available within one year of completion. In another linked article, a survey by Ross et al of US research conducted between 2005-2008 and primarily or partially funded by the National Institutes of Health showed that in less than half of the sample were the summary reports of trials registered with ClinicalTrials.gov published in a peer-reviewed, MEDLINE-indexed biomedical journal within 30 months of completion. Moreover, one third of the trials remained unpublished 51 months after completion, the authors found.
Many clinical trials involving human subjects are not registered in a publicly accessible federal database and are not reporting critical study results, the TEST ACT sponsors said. The ACT is designed “to close these clinical trial loopholes and bring certainty and transparency to life-saving research studies”. Moreover, the sponsors noted, 80% of the drugs entering the US market in 2008 were clinically tested overseas, while a growing number of medical device trials are moving abroad. “Many of these trials are not required to be registered with the clinical trials database,” they added.
Transparency for Clinical Trials — The TEST Act
by Jeffrey M. Drazen, M.D.
New England Journal of Medicine. 2012 367:863-864.
In the past few years, registration of clinical trials in a publicly accessible database has become routine. In the United States, much of the impetus for registration derives from the Food and Drug Administration Amendments Act of 2007 [FDAAA]. As a result of this law and other actions, most interventional clinical trials conducted in the United States have been registered at ClinicalTrials.gov, where, in most cases, the trial results must also be reported. The curators of the database have designed a simple tabular format in which the characteristics of the participants enrolled are reported in one table, the key primary and secondary outcomes in a second table, and adverse events in a third table. Journals adhering to the International Committee of Medical Journal Editors guidance for manuscripts submitted to biomedical journals3 have made it clear that reporting results in this fashion will not be considered prepublication of submitted manuscripts.4 One of the purposes of trial registration is to provide a third-party storehouse of trial designs and results. However, for this resource to be of value, it is important that the entire portfolio of clinical trials be in the database..
But there are loopholes in FDAAA that have made it possible for some entities to conduct clinical trials without registering them or reporting the results. On August 2, 2012, Representative Edward Markey introduced into the U.S. Congress the Trial and Experimental Studies Transparency [TEST] Act [H.R. 6272] to close these loopholes. The TEST Act expands reporting requirements under existing federal law by broadening the scope to include all interventional studies of drugs or devices, regardless of phase [i.e., including phase 1], design [i.e., including single-group trials], or approval status [i.e., making no distinction between trials of approved vs. unapproved products]; requiring all foreign trials that are used to support marketing in the United States to be registered; mandating results reporting for all trials within 2 years after study completion [including trials of unapproved drugs or devices]; and extending results reporting to include the deposition of consent and protocol documents approved by institutional review boards. This legislation is important. The bill requires that any trial that could be used to support an application for FDA approval be registered in ClinicalTrials.gov and that the results be reported in a timely fashion. It requires that early-phase trials [those in which a drug is initially tested in humans] be registered. Thus, these trials will become public knowledge..
The bill also requires that results be reported whether the drug is submitted for FDA approval by the manufacturer or not. For example, in a case in which a novel therapeutic strategy is associated with adverse outcomes, information about these outcomes would be in the database, even if the product were subsequently abandoned by the manufacturer. That way, if another entity pursued the same treatment approach with a different intervention, the trial designers would be aware of the potential dangers and could develop means for monitoring and mitigating the potential toxic effects.
Consider the disastrous results obtained when studies were conducted with an anti-CD28 antibody. All the healthy volunteers injected with the agent fell ill, some gravely ill, within minutes after receiving the treatment. Given that this trial did not need to be registered in a public database, would the data have become public knowledge if the volunteers had not been admitted to a public hospital? By requiring both registration and results reporting, the government would ensure that the data accrued became part of the public record and could guide further work in a given area.
Another provision of the TEST Act would require that trials conducted outside the United States, but used to support an application to the FDA, be registered and that their results be reported in the database in a timely fashion. This provision would ensure that the participants who put themselves at risk to test new treatments see the fruits of their altruism in the public domain. Simply put, a trial could be moved offshore but could not be hidden. We can make progress in medicine only if people are willing to put themselves at risk to test new diagnostic and therapeutic approaches. To recognize and reward these participants, and in keeping with the Declaration of Helsinki, clinical trials should be conducted in the open, with full public knowledge of the question asked, the intervention tested, and the results obtained. The TEST Act is another step toward this end, and we strongly support it.
Several other things worry me in my hopefulness. I think it really matters about the format and completeness that TEST will require for the posting of results. GSK posted "results" for the Paxil studies in 2004 [Paroxetine and pediatric and adolescent patients], but they were too opaque to use, until they posted the raw data of their computer readouts in the Appendices just last month [eleven years late]. That dovetails into another worry. There’s a lot of non-posting going on at clinicaltrials.gov and a lot of obfuscated posting. I want to go back and document the places where I’ve run into that, and am pleased to get the BMJ links above to see what others have found about non-compliance.