Boston Globe FDA rule changes in contention Benefits, dangers of shorter drug review at center of debate By Jeffrey Krasner, Globe Staff, 3/20/2002 Will faster drug approvals help Americans by giving them access to the newest and most effective medications? Or will speeding up approval let lethal drugs slip past regulators, exposing patients to undisclosed dangers? That debate is at the center of a fight brewing over the latest attempt to remake the rules that govern how drugs are approved by the federal government. Officials from the biotechnology and pharmaceutical industries worked with the Food and Drug Administration for six months to create a set of recommendations for the Prescription Drug User Fee Act, or PDUFA. The act, first passed in 1992, expires in September. The recommendations could form the basis for the next five years of drug review. But to some critics of PDUFA, the overhaul is just another step down a slippery slope that they claim has undermined the integrity of the FDA. ''This is basically the industry's wish list,'' said Dr. Sidney Wolfe, director of the Health Research Group at Public Citizen, the consumer advocacy nonprofit group founded by Ralph Nader, referring to the 20-page outline of new guidelines that awaits congressional approval. ''The past five or six years have been the worst ever in terms of drugs being approved that never should have been put on the market, or the number of employees who have left the FDA because of their disillusionment with the agency.'' Wolfe contends the PDUFA system, in which fees paid by companies seeking drug approvals contribute a big part of the FDA's budget, undermines the agency's integrity. ''The review of drugs is too important to be funded by anything other than taxpayer dollars,'' said Wolfe. ''Once the industry funds the process directly, they'll extract concessions and put strings on the money.'' Industry representatives defend the new recommendations. ''This is the result of a rigorous process looking at what had worked and what hadn't worked in the previous agreement,'' said Carl B. Feldbaum, president of the Biotechnology Industry Organization, a trade group. Others said the proposal represents a good balance between industry concerns and consumer needs. ''I'm fairly impressed with it as a compromise between feasibiltiy and addressing needed enhancements to the system of drug development and monitoring,'' said Chris Milne, assistant director of the Tufts Center for the Study of Drug Development. ''It's fixing a few things that needed to be fixed.'' The proposed overhaul comes against a backdrop of growing industry dissatisfaction with the FDA's performance. For the past two years, the time it takes to get a new drug approved has been increasing, according to the Biotechnology Industry Organization. Industry officials contend there is a growing backlog of applications for drugs and other therapeutics. Meanwhile, the FDA has operated without a commissioner for more than a year. Critics contend the agency is sluggish and lacks direction at a time when its work load is growing because of accelerating drug development. Under the proposed rules, the fee to submit a new drug for approval would increase from $311,000 last year to $576,000 in 2007, the final year of the new authorization. The total amount of money raised from the industry fees would nearly double from $133 million in 2001 to an estimated $259 million in 2003. ''From a small company perspective, the increase in the fee itself is steep,'' said Mark Skaletsky, chairman and chief executive of Essential Therapeutics Inc., an early-stage firm in Waltham developing antibiotics and cancer therapeutics. ''Still, if you get return on that investment, all of us will be happy.'' The priority for the industry is speed. The recommendations would ratchet up turnaround times. For instance, in 2003, the agency intends to issue a decision on 90 percent of certain resubmitted drug effectiveness studies within six months, and 30 percent within two months. By 2007, that goal changes to a decision on 90 percent within four months and 70 percent within two months. The recommendations would also create pilot programs under which companies would get early review of their drug testing data and additional feedback as research proceeds. Under one program, companies could submit their data to the agency in incremental units, rather than waiting until the end of clinical tests and submitting it all in one giant package. Under the other, the agency will try to provide ''frequent scientific feedback'' with the developers of certain drugs while clinical trials are still underway. If adopted widely after the pilot, such a system could help prevent situations in which drugs seemingly poised for approval are unexpectedly set back. For instance, Sepracor Inc. announced March 7 that its allergy drug Soltara - long expected to generate the Marlborough company's first profits - was going to be rejected by the FDA because of a lack of safety testing. Such unexpected derailments lead to dramatic reversals for biotechnology companies. Sepracor shares fell 59 percent, to $19.64 on the day of the announcement. Yesterday, the shares lost $1.47 to close at $20.41. The proposed agreement would also extend the use of industry fees to pay for the FDA to monitor the performance of drugs after approval, or so-called post-market surveillance. In the agreement, the agency could use the fees to monitor drugs ''with important safety concerns'' for three years after they are introduced to ensure ''these products are being used in a safe manner.'' That proposal also drew a polarized response. ''The idea is now the FDA can better fund its post-marketing surveillance,'' said Dr. Joseph Zammit-Lucia, president of Cambridge Pharma Consultancy, a British firm that advises pharmaceutical firms on regulatory issues. ''An important part of regulation is to keep monitoring drugs once people are using them in real life. It's a realization that this is an important thing that needs to keep improving.'' But Vera Hassner Sharav, president of the Alliance for Human Research Protection, a nonprofit that seeks to prevent dangerous drugs from hurting people during and after development, said the effort highlights deficiencies in testing before drugs are approved. ''They're speeding up the drug approval process knowing that there may be some safety hazards, and so they're post-facto allowing for some tracking of hazards that are likely to follow,'' she said. ''They're pretty much expecting problems because drugs are being approved too quickly.'' Another potentially divisive issue is a new rule under which the FDA could use outside experts to help it review the design of a company's clinical trials. The company could provide a list of experts for the agency to choose from. Feldman, president of the biotechnology trade group, said the proposal is only part of a needed FDA overhaul. He said the increased user fees are only part of the solution: Congress still needs to increase the agency's funding. ''We're concerned that FDA not become a choke point, especially for the large number of drugs in late-stage development.'' But the agreement forged between the agency and the industry still faces hurdles. Senator Edward M. Kennedy, Democrat of Massachusetts and chairman of the Committee on Health, Education, Labor and Pensions, where the PDUFA overhaul will face its first legislative test, last year asked the General Accounting Office to conduct a comprehensive study of the act. Among the issues raised by Kennedy are the impact of the act on drug safety and the turnover within the FDA. Kennedy declined to comment on the agreement pending further review by the committee. Jeffrey Krasner can be reached by e-mail at krasner@globe.com. Remember we are NOT Doctors and have NO medical training. 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