Approval Studies Do Not Have Enough Patients?

The clamor for additional or lengthier studies to detect safety signals often prompts rejoinders that such efforts would not only lengthen the amount of time before a medicine could hit the market, but also adds to the development cost, which would be passed along to purchasers. Just the same, a new study indicates the number of patients needed to study chronic use in the European Union is insufficient to evaluate safety and long-term efficacy.

Consequently, the researchers say that a "reevaluation" of both the number of patients participating in clinical trials and the long-term requirements for collecting pertinent data for regulatory approval of new medicines is merited. And this is especially true for drugs that are designed for long-term use.

The study analyzed data from studies submitted to the European Medicines Agency regarding 200 drugs that were approved between 2000 and 2010, and whether the number of patients was in sync with guidelines issued by the International Conference on Harmonisation E1. This is also followed by the US for determining trial sizes need for safety of drugs to be used on a long-term basis for illnesses that are not life-threatening (see this).

The study, which was published in PLos Medicine, found that the median number of patients studied before approval was 1,708 for standard medicines and 438 for orphan drugs. On average, chronic meds were studied in a larger number of patients - the median was 2,338 - than drugs for intermediate or short-term use - 878 and 1,315, respectively.

Also, the safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least six and 12 months in 46 percent and 58 percent of new medicines, respectively. Among the 84 medicines intended for chronic use, 68, or 82 percent, met the guideline recommendations for 6-month use, while 67, or roughly 80 percent, of the medicines met the criteria for 12-month patient exposure (here is the study).

And so, the researchers conclude that "the numbers of individuals studied before approval of new medicines in Europe from 2000 to 2010 are... generally adequate to assess only short-term efficacy. For most approved medicines intended for chronic use, the number of patients studied before marketing is insufficient to study safety and long-term efficacy... A discussion of the long-term exposure requirements for approval of medicines, particularly for medicines intended for chronic use, seems warranted." Whether any meaningful conversations will take place is unclear. Certainly, the findings underscore the ongoing tension between those who want more drugs to be available as fast as possible - a diverse group that can include most any type of stakeholder group - and those who maintain that haste makes waste, and also sometimes serious adverse events. But the findings suggest there is a price to pay when studies do not gather enough information for the long haul. In other words, short-term gain, but long-term pain.

confused pic thx to guudmorning on flickr

6 Comments

Mar 21, 2013 - 12:30pm
The PLoS article does not seem to mention the large safety studies that are typically ongoing at the time of approval and which continue for years afterwards. For example, Biogen's BG-12, which has a US PDUFA date next week, has an fully enrolled 1700 subject safety trial that will run for 5 years. Pradaxa, approved in 2010, had a 5800 patient extension trial ongoing at the time of approval that ended in December 2012. The pivotal trials for Stribild, approved in mid-2012, will continue to collect safety data until mid 2014.

The article leaves one with the impression that the only controlled safety testing for most drugs is 6 months in a few hundred people. This is generally not the case.

Mar 21, 2013 - 12:48pm
"A discussion of the long-term exposure requirements for approval of medicines, particularly for medicines intended for chronic use, seems warranted.”

Indeed. So does the risk/benefit ratio.

Interesting. I discussed this issue on my blog in 2011.

http://marilynmann.wordpress.com/2011/06/12/assessing-drug-safety-post-approval-lessons-from-vioxx-avandia-and-meridia-part-1/

http://marilynmann.wordpress.com/2011/06/26/assessing-drug-safety-post-approval-lessons-from-vioxx-avandia-and-meridia-%e2%80%93-part-2/

Mar 21, 2013 - 2:31pm
I clicked on the link & I'm afraid I'm a little confused. The guidelines first acknowledge that "available information suggests that most [adverse drug events] first occur, and are most frequent, within the first few months of drug treatment." It then says "usually 300-600 patients should be adequate" for assessing safety over 6 months. It continues by saying "some patients should be treated with the drug for 12 months" &, based on a lot of variables, "100 patients exposed for a minimum of one-year is considered to be acceptable to include as part of the safety data base."

So this threshold of 1000 patients that approved drugs are supposedly not meeting--Where's that coming from?

Very interesting. Thanks for posting.

Another factor to consider is undetected patient nonadherence (up to 30%) during clinical trials which can lead to approval of a dose that is too high and unexpected drug toxicities post-approval. With patient adherence increasing in the general population because of the major focus it has been given in the last 10 years, patients who are more adherent than those in the clinical trial are at risk of taking a toxic dose.

Maybe there isn't a need to extend the length of the clinical trial but rather to take a series of steps that will ensure patient adherence in clinical trials is at least 95% so that it is always higher than that of the general population?