In August 2008, the FDA implemented drug regulations that could slow down a fifteen-year trend toward faster drug approval.
“We’re becoming much more diligent and tighter controlled,” said Elizabeth Coyle, University of Houston pharmacy professor and infectious disease specialist at M.D. Anderson Hospital. “It’s become more difficult to get drugs to market.”
The trend of faster drug approvals began after the implementation of the Prescription Drug User Fee Act in 1993. The act required pharmaceutical companies to pay a fee for every drug application submitted and set quotas on the number of drugs the FDA had to review within a 10-month period.
In fiscal years 1993 to 2007, the agency reviewed drugs in record numbers.
During the fourteen-year period, the average number of drug applications reviewed increased to 124 from 109 and, from 1997 to 2005, an average of 63 percent of submitted drug applications was approved, a 2007 commissioner’s report to Congress showed. According to the Tufts Center for the Study of Drug Development, the average time for the FDA to approve new drugs declined to 13 months in 2007.
In the first year of the act, the median drug approval time was 17 months. In 1987, before the act, the median drug approval time was 29 months.
Indeed, in his annual Performance and Financial Report, the FDA commissioner told Congress that median review time for drug applications dropped to 10 months in fiscal year 2006.
However, after investigators found that FDA approved medications had killed people, the agency increased regulation.
The FDA also had less regulation for committees evaluating drugs for safety. Committee members with financial conflicts of interest could serve on committees as long as they registered their conflict with the FDA.
Despite the potential bias, the Eastern Research Group, a consulting firm hired by the FDA offering services in the occupational health and safety field said, “Under the current system, FDA advisory committee members with financial conflicts of interest can be granted waivers for participation.”
The group concluded that waivers are necessary because leading experts are often involved or have a connection with private industries.
However, the new regulations require the FDA to reduce the number of waivers granted to advisory committee members by five percent each year. By 2012, the number of granted waivers should be 75 percent of the 2007 number. Individuals with more than a $50,000 financial conflict of interest cannot receive a waiver.
Advisory committee members act as technical experts to the agency. The FDA secretary appoints members from universities, colleges, research centers, professional and medical societies and patient and consumer groups to review clinical trial data used to support new drug applications.
The regulations came after David Graham, Associate Director for Science and Medicine in the FDA’s Office of Drug Safety testified in 2004 before the Senate that the FDA pressured scientists to approve unsafe drugs for marketing because of financial conflicts of interest.
He said that the FDA approved Vioxx despite clinical trials indicating a 7-fold increased risk of heart attacks in patients taking low-dose Vioxx and a 5-fold increased risk in patients taking high-dose Vioxx.
He also cited a 2004 article published in the New England Journal of Medicine by Dr. Eric Topol who estimated that Vioxx caused 160,000 cases of heart attacks and strokes.
In response to Congressional pressure, the FDA hired the ERG to conduct a study December 2005 through October 2006. The study focused on committee meetings regarding the drugs Vioxx, Levaquin, Provigil and Tysabri and found that the FDA granted waivers to 21 percent of committee members with conflicts of interest.
The research group said that if individuals with financial ties to a certain drug were excluded, the outcome would have changed in 3 out of 74 meetings. The group concluded that that the results were not significant and did not demonstrate that individuals with financial conflicts voted in favor of their interest.
An investigative report by USA TODAY in September 2000 found 54 percent of committee members had financial conflicts in 159 FDA advisory committee meetings from Jan. 1, 1998, through June 30, 2000.
Michael Walls, a nephrologist who works in Houston hospitals, said the FDA should not rely on any committee members with financial conflicts of interest.
“There’s tremendous pressure for drug companies to develop a super drug,” he said. “A lot of the time they look the other way in terms of complications from the medications.”
Walls said he treated patients taking Vioxx who developed cardiovascular problems, and that Vioxx was unnecessary since Celebrex, a similar drug without Vioxx’s side effects, was already on the market.
However, UH pharmacist Coyle said all drugs have side effects. She denied that the FDA lacked stringency.
“If it’s on the market long enough problems will be found in certain patients,” she said. “It’s the pharmacist’s job to warn patients about risks that they might be susceptible to.”
Coyle said pharmaceutical companies don’t intentionally overlook side effects, but side effects increase as the population taking the medication increases.
“Vioxx was a live and learn thing,” she said.
Vioxx was developed to ease pain in patients with chronic pain who were at risk for gastrointestinal bleeds. Coyle said that, because patients with chronic pain tended to be older, they were more at risk for heart attacks.
She also said the FDA drug approval process has so many checks and balances that biased committees wouldn’t make a difference.
The study by ERG found that 17 percent of financial conflicts had a total dollar value above $50,000 while 39 percent of conflicts were valued under $10,001.
However, the new regulations may cause staff shortages in drug approval committees.
Tuft’s 2009 outlook predicted, “Continued shortages of experienced personnel, especially among upper level managerial staff, will continue to hamper the FDA’s ability to fulfill its mandate, as will advisory committees vacancies depleted by new conflict of interests.”
Sujit Sansgiry, a University of Houston pharmacy professor, said the FDA may not be able to comply with all the regulations because of staff shortages.
On average, according to the Pharmaceutical Research and Manufacturers of America, only five medicines out of every 5,000 are tested in clinical trials. The Tuft’s Center for the Study of Drug Development said that only one of the five drugs tested in clinical trials is eventually approved for patient use.
The average cost between when research begins to develop a new prescription medicine until it receives approval from the FDA to market the drug in the United States is $802 million in a period of 10 to 15 years, Tuft’s Center for Drug Development said in a 2006 report.
Considering that the FDA does not approve the majority of medications, companies must make the decision whether to continue with the approval process and possible lose more money, market the medication in less regulated countries or withdraw the medication completely from the market.
Many companies marketing high-risk, FDA approved medication, choose to remove medications from the market if they receive bad publicity.
After Graham’s testimony, Merck and Co. voluntarily removed Vioxx from the market.
After three patients died and four developed side effects, Genentech plans to withdraw the psoriasis drug, Raptiva, which has been on the market since 2003, by June 8, 2009. Health care professionals found that the drug caused progressive multifocal leukoencephalopathy, a rare brain infection, in patients using the drug.
Coyle said companies withdraw approval requests because of financial reasons or safety issues. Companies will often market drugs in less regulated countries if it’s not cost effective to release them in the United States.
Overall, consumers may be safer in the future from defective drugs, but they may also see slower drug approval rates.