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Post-marketing phase IV studies create opportunities for clinical research sites
It's a double-edged sword for industry
The FDA, pharmaceutical companies, and clinical research sites all have vested interest in post-marketing studies, but despite buy-in for this process and its recent growth, problems remain, experts say.
"It's a double-edged sword," says Christopher Milne, DVM, MPH, JD, an associate director of the Tufts Center for the Study of Drug Development in Boston, MA.
"Both industry and FDA are sticking to their guns that pre-approval research is not the problem and that enhancing the post-approval process is where you could get more bang for your buck," Milne says.
However, Milne found in a recent analysis published in the Tufts Center's Impact Report that post-marketing studies have had problems with delays, variable costs, and little improvement in product profile.1
Since 2001, the FDA has required drug sponsors to provide annual reports on certain phase IV post-marketing studies, and some post-marketing studies are mandated by law or part of a post-marketing commitment (PMC) with sponsors when more information is necessary about a drug to improve its use or quality.1
"We saw the FDA saying, by and large, that what they got out of the post-marketing studies with regards to improving what they knew [about a drug] was less than what they would have hoped for, or, less than the optimum," Milne notes.
Also called post-approval studies, phase IV research looks at how the drug is going to react in the market place in a larger subgroup of a patient population, says Joan A. Chambers, BS, director of strategic marketing and development for the Tufts Center for the Study of Drug Development.
"Once a drug has been approved, you can reach out to a larger group of patients and track other data that may not have been collected," Chambers says. "You might find that the drug helps patients for another ailment that it wasn't originally tested for in the clinical trial phase II or III."
Post-approval studies are becoming more common because of PMCs with sponsors and the FDA, Chambers notes.
Also, post-approval studies are growing because of changes in the industry's drug pipeline, which is not as robust as it once was, she says.
"You're seeing new strategies that need to be planned by sponsor companies," Chambers explains. "The numbers of new molecular entities are kind of dropping a little, or they're staying pretty status quo."
A lot of companies have brand name drugs that are coming off patent protection soon, and so there are indications of more interest and growth in late phase or post-approval studies, she adds.
"And there are increasing research and development costs, so sponsor companies are looking for new and innovative ways to produce a drug that may be more cost-effective," Chambers says.
An example of this would be to take an existing drug approved for one indication, and through a post-approval activity trial, identifying a potential new treatment for that drug, she says.
Milne's analysis of post-marketing research found that about 45 percent of such studies were delayed because of slow enrollment, technical difficulties, and other problems.1
Also, most drug sponsors said the study results changed little in their understanding of a drug's safety, efficacy, or quality.1
That's not necessarily bad news, Milne notes.
"Theoretically, if a lot of drug sponsors said, 'We found this and this and this in post-marketing studies,' and if they said the studies were expanding what they knew about their products, then that would be worrisome," Milne says.
The Tufts analysis also found that between 1998 and 2005 sponsors spent an average of $5.3 million per clinical post-marketing study, and the range of study costs were from $100,000 to $33 million, with the variability related to patient numbers (ranging from nine to 10,071).1
"Some of these studies are fairly limited, looking at smaller populations, perhaps specialized populations and populations with comorbidities," Milne says. "Paying $5 million for a study today is not huge, but this is obviously research funding that could go into clinical development if it weren't being spent looking at possible risks, and some don't pan out to be real risks."
Post-approval clinical trials often serve another purpose of increasing product awareness and penetration and expanding product demand, Chambers says.
"Hopefully, they'll establish a positive relationship with prescribing physicians," Chambers adds. "And if you get more physicians prescribing the drug, then ultimately you'll reach your goal of market penetration."
Sponsors sometimes want to spread out post-marketing studies among more physicians who have the intended population for a specific drug, and this goal creates opportunities for new investigators, Chambers says.
"Post-approval studies are a nice entry into clinical trials for investigators," she notes.
This is why post-approval studies have both clinical and market objectives and provide benefits to both the sponsor and the physician and patient, she says.
The studies also have benefits for clinical trial sites, which conduct about one-quarter of all post-marketing studies. Three-quarters of these studies are conducted in-house.1
"For every mandatory [post-marketing] study that's done, there are probably three to four studies that are done for marketing purposes, and these could be for anything," Milne says. "They could be looking for a new indication for the product and a new disease population."
These are the voluntary studies that the sponsoring company does to better manage the product application to a new patient population and to increase market penetration, he adds.
"This definitely is a growth area because as more of the emphasis of the market is on the global market, and you get multi-country applications where you're actually launching in more than one country pretty much simultaneously, then you're going to want to do post-approval studies in the country where you will market the product," Milne explains. "The condition of use is different from country to country."
The benefit of doing post-marketing studies is that the drug is being prescribed under a controlled situation, and a sponsor can look at actual use and other factors, including dietary, prescribing, and follow-up differences, he adds.
To clinical research organizations in the United States, these goals are an obvious benefit: the U.S. accounts for maybe 45 percent of the drug market and possibly as much as 60 percent of the profits, which means sponsors are motivated to conduct post-marketing trials here, Milne adds.
It's likely post-marketing studies will increase for other reasons, as well, Milne says.
"You'll have more mandatory studies, and payers are going to want to see it more," Milne says. "There also will be comparative effectiveness trials, and you now have to prove to a number of different audiences that your product works in different situations."