Decline in New Drugs Raises Concerns
FDA Approvals Are Lowest in a Decade
By Marc Kaufman
Washington Post Staff Writer
Monday, November 18, 2002; Page A01
New drugs to treat and cure sick patients are coming onto the market in the United States at the slowest rate in a decade, despite billions invested by pharmaceutical companies on research and a costly expansion by the federal agency that reviews new medicines.
The decline in the number of new drugs is most pronounced in the category considered by the Food and Drug Administration to have the greatest promise for patients -- those listed as breakthrough "priority" drugs and "new molecular entities" that are different from any others on the market.
The slowdown is troubling to many because it is largely unexpected. The drug industry now invests three times as much money in research as it did a decade ago, and the FDA has already undergone a major revamping to become more efficient and prompt -- an expansion funded largely by user fees from the drug makers. Yet the number of industry applications for innovative new drugs is down significantly, and the average time needed by the FDA to review applications is moving up.
The net result of both trends is a steep drop in the number of new drugs coming to the market to help cure and treat illnesses, and growing disappointment among many patients and their families and advocates.
"We hear talk all the time from the drug makers of the great drugs waiting in line, but the reality doesn't seem to match the facts," said Ellen Stovall, director of the Cancer Leadership Council, a patients advocacy group. "There's been a lot of hope about new drug cures and treatments and we've seen some progress, but lots more disappointment."
The possible reasons for the decline -- whether it is a function of FDA caution after some high-profile drug withdrawals, industry shortcomings and strategies, or a troublesome combination of both -- is the subject of an increasingly urgent debate. Some believe the drop is a relatively short-term development that will resolve on its own, while others believe there is a deeper and more fundamental problem.
"Industry was trying to hit home runs, and it struck out a lot," Henry McKinnell, chief executive of the largest pharmaceutical company, Pfizer Inc., said in an interview. "Added to that, the [FDA] is giving greater scrutiny to each drug application. The result is that we are spending more time on each drug, spending much more on research, but seeing a definite drop in the number of new drugs."
Like many drug industry leaders, McKinnell still sees a "golden period" for new drug discovery ahead. But he acknowledges it may be further off than once predicted.
The newly confirmed commissioner of the FDA, Mark McClellan, has said that getting more drugs into and through the FDA review process is a top priority. McClellan was sworn in last week, filling a leadership void at the agency that had lasted 20 months.
The number of new drugs coming onto the market peaked in the mid-1990s, when the FDA approved more than 120 new drug applications in both 1996 and 1997 after being criticized for being too slow. Among the breakthrough drugs approved in that period are the cholesterol-lowering Lipitor, the novel osteoporosis medication Fosamax, and the protease inhibitors that revolutionized treatment of AIDS. But by 2001, the number of annual new drug approvals had dipped to 66, and for 2002 stood at 46 at the end of September.
But followers of the drug industry generally look to the smaller category of "new molecular entities" (NMEs) -- chemicals never before used as medications -- to assess how well the drug development and review process is working. In that group, the decline was even steeper. The annual number of NMEs approved went from an all-time high of 53 in 1996 to 24 approvals in 2001. By the end of this September, the number of NMEs approved was only 11 -- a pace that could result in the lowest yearly total of NME approvals since the 1980s.
Equally worrisome, the number of new drug industry applications for "priority" new drugs -- the ones that the FDA concludes are most likely to be breakthrough, potentially life-saving treatments -- has declined precipitously. Although there were 32 priority applications in 1997, there were only six in 2001. So far this year, there have been five.
Pharmaceutical industry officials say the slowdown can be at least partially explained by the fact that companies are making a major shift from developing new drugs through traditional chemistry to instead using cutting-edge biotechnology. Reflecting that change, a recent report from the Pharmaceutical Research and Manufacturers of America (PhRMA) found that a record 116 medicines made through biotechnology are now in the last phase of clinical testing or awaiting FDA review.
While the drug industry has been struggling with these research obstacles, many also believe the FDA has become notably more cautious in its review of new drug applications -- largely in response to the 10 drugs withdrawn from the market between 1998 and 2001 for safety reasons.
Most of those drugs had been approved by the FDA in the mid- 1990s, when the number of new drug approvals skyrocketed after the creation of an industry-funded program that expanded and streamlined the review process. None of the withdrawn drugs was life-saving, yet all proved fatal to some users and the agency was criticized for being too lenient in allowing new drugs on the market.
Although agency officials disagree with the assessment that there was a problem with drug approvals during the mid-1990s, they do acknowledge that they became more sensitive in recent years to some better understood potential problems with new drugs.
"As we identify safety concerns with one product or area, that can lead to a need to evaluate another new product more closely than we would have if we didn't have that knowledge," said John Jenkins, the director of the office of new drugs for the FDA's Center for Drug Evaluation and Research. "It would be irresponsible for us not to do that."
But Jenkins said the primary reasons there are fewer drugs being approved is that there are fewer applications from industry.
Nonetheless, Kenneth Kaitin, director of the Tufts University Center for the Study of Drug Development, said that FDA review was having an impact. "The FDA is clearly showing the stress of maintaining the torrid pace it set in the mid-1990s," he said.
But Kaitin said the FDA is not necessarily responsible for the low number of drug approvals. "It's ludicrous to say the FDA is making it too hard," he said. "The industry pipeline is dry."
And those that are being submitted are increasingly "me-too" versions of popular medications already on the market. The National Institute for Health Care Management, a nonprofit research group associated with the Blue Cross system, reported earlier this year that although the number of standard drugs being approved by FDA has remained relatively steady, the more innovative "priority" drugs have plummeted.
The last FDA commissioner, Jane Henney, said that she was concerned by the declining number of new drug applications when she was in office. She said it was a problem that needed to be addressed on a national, public-private basis.
She denied there was any conscious decision to slow down the review process during her tenure, though she acknowledged that the average review time for standard drugs was on the rise. She said, however, that reviews of exciting new drugs -- such as the recently approved cancer medication, Gleevec -- are still being regularly approved within six months, the time period allowed for review of a "priority" drug.
But McKinnell of Pfizer said the regulatory atmosphere clearly changed, and that it has had a chilling effect on drug makers.
He said, for instance, that drug companies may decide not to file an application for new drug approval even though they found a medication to be effective in their trials. He said that after the recalls of the late 1990s, the FDA began requiring more testing for drug-to-drug interactions, for potential liver toxicity and for cardiac risk, and that some companies "look at that burden and decide not to file."
Further complicating the FDA-drug industry relationship is the brain drain and employee burnout that has been widely reported at the agency. After Congress passed the Prescription Drug User Fee Act (PDUFA) in 1992 (and reauthorized it in 1997), the agency committed to performance standards that dictated how long a new drug application should take.
A recent GAO report concluded that PDUFA "has resulted in increased reviewer workload" and may be contributing to increased attrition among staff responsible for reviewing new drugs and biologics.
In an effort to further expedite the FDA drug review process, Congress passed a new PDUFA reauthorization this summer that will bring in $1.2 billion in industry user fees over five years. The stated goal was, again, to speed more drugs to the market.
washingtonpost.com |
