Publication and reporting of clinical trial results
Objective: To estimate the frequency with which results of large randomized clinical trials registered with ClinicalTrials.gov are not available to the public.
Design: Cross sectional analysis
Setting: Trials with at least 500 participants that were prospectively registered with ClinicalTrials.gov and completed prior to January 2009.
Data sources: PubMed, Google Scholar, and Embase were searched to identify published manuscripts containing trial results. The final literature search occurred in November 2012. Registry entries for unpublished trials were reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database.
Main outcome measures: The frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database.
Results: Of 585 registered trials, 171 (29%) remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299 763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. Non-publication was more common among trials that received industry funding (150/468, 32%) than those that did not (21/117, 18%), P=0.003. Of the 171 unpublished trials, 133 (78%) had no results available in ClinicalTrials.gov.
Conclusions: Among this group of large clinical trials, non-publication of results was common and the availability of results in the ClinicalTrials.gov database was limited. A substantial number of study participants were exposed to the risks of trial participation without the societal benefits that accompany the dissemination of trial results.
The FDA has put few measures in place to ensure that drugs that are approved based on limited populations are only marketed to those limited groups
New drugs that receive expedited review by the Food and Drug Administration are being tested on fewer patients, leaving many safety questions unanswered even after they are approved, a study released on Monday in the Journal of the American Medical Association found.
It found that expedited drugs underwent a median of 5.1 years of clinical testing before being approved, compared with 7.5 years for those that underwent a standard review. But in many cases safety monitoring trials that were supposed to be conducted after the products were approved were either not conducted, not completed, or not submitted to the FDA.
“The testing of new drugs has shifted from a situation in which most testing was conducted prior to initial approval to a situation in which many innovative drugs are more rapidly approved after a small trial in a narrower patient population with extensive additional testing conducted after approval,” the authors said.
At the urging of patient groups, Congress and the drug industry, the FDA over the past decade has introduced multiple mechanisms for speeding new products to the market. While patient groups and drug companies applaud these measures, saying they get much-needed medication into the hands of patients more quickly, critics say the agency is approving products before they have been fully vetted.
Of the drugs studied by Moore and Furberg in 2008, the FDA required 85 follow-up trials to monitor for safety. By 2013, only 40 percent of those studies had been completed.
The FDA said in a statement that it will review the article in more detail but that on the surface “it shows that the expedited development programs are working as intended by getting promising new drugs to patients more quickly.”
The FDA has traditionally required two controlled clinical trials to prove that a drug is safe and effective. Over time the agency has relaxed the evidence it is willing to accept for certain products.
In some cases the FDA will accept data from a single trial and success may be judged on the basis of a surrogate measure – such as tumor shrinkage – that may or may not translate into a concrete measure such as increased survival.
“In situations of serious and life-threatening diseases with unmet medical need, patients and physicians who treat them have told us repeatedly that they are willing to accept greater uncertainty about risk in order to have access to the hope of improved treatment today,” the FDA said in its statement.
The FDA is discussing additional measures to speed the drug development process, including the use of “enriched” trials that would select patients based on certain demographic or genetic characteristics in order to increase the chance of a trial’s success.
The idea is to direct treatment to patients for whom it will be most effective or who are most likely to respond.
But in a commentary published alongside the study, Daniel Carpenter, a professor of government at Harvard University, said the FDA has put few measures in place to ensure that drugs that are approved based on limited populations are only marketed to those limited groups.
“The current system of accelerating drug approval in the United States can be described as a growing hodgepodge of exceptions to the rule of rigorous premarket review,” he said.
The FDA said it has a “robust program for postmarketing surveillance and ensuring the completion of required post-approval trials.”
“We believe that we have set the bar for the balance between pre-approval testing and early availability of promising new drugs to treat serious and life-threatening diseases in the right place.”
Clinical trial registration, reporting, publication and FDAAA compliance: unacceptably low
In an effort to understand how results of human clinical trials are made public, researchers analyzed 8907 clinical trials completed in 2006-2009 and registered at ClinicalTrials.gov, the world’s largest clinical trial registry.
Only 47% of trials analyzed in their large sample provided linked publications or basic results. Despite availability of several information channels, trial record managers do not sufficiently meet the mandate to inform the public about results of clinical trials either via a linked result publication or basic results submission, although there is a temporal trend showing an increasing rate of submission of basic results.
House of Commons, Science and Technology Committee, 2013
Clinical trials are the experimental foundation on which modern medicine is built. Trials also make a significant contribution to the UK economy and can provide patients with an important means of accessing the most exciting and innovative new treatments, before they reach the market.
Here you can browse the House of Commons Science and Technology Committee report together with the Proceedings of the Committee.
” 3.9 – I hope that the Science and Technology Committee will agree with Jeremy Paxman that the current situation is indeed “nuts”—unethical, unscientiﬁc and uneconomic nuts. “ ” 3.10 – My efforts to prompt improvement in clinical trial transparency over most of the past 30 years have manifestly failed. However, it is becoming clear that Sense about Science’s recently launched public campaign (www.alltrials.net) and Ben Goldacre‘s bestselling book Bad Pharma may be “game changers”. For the ﬁrst time in over 30 years I feel that there is reason to hope for substantive progress. I think that those who continue not to take under-reporting of research seriously will ﬁnd themselves on the wrong side of history. I hope that the Committee will see to it that, after decades of inadequate action, something substantial will be done to deal with the current, indefensible situation. ”
Leaked memo from industry bodies reveals strategy to combat calls by regulators to force companies to publish results
The pharmaceutical industry has “mobilised” an army of patient groups to lobby against plans to force companies to publish secret documents on drugs trials by asking them to express concern about the risk to public health by non-scientific re-use of data.
That means patient groups go into bat for the industry by raising fears that if full results from drug trials are published, the information might be misinterpreted and cause a health scare.
” It’s the Catch-22 of clinical trials: to protect pregnant women and children from the risks of untested drugs….we don’t test drugs adequately for them. In the last few decades, we’ve been more concerned about the harms of research than of inadequately tested treatments for everyone, in fact. But for “vulnerable populations,” like pregnant women and children, the default was to exclude them. And just in case any women might be, or might become, pregnant, it was often easier just to exclude us all from trials. “