FDA Reform Debate Heating Up As Senate, House Propose Bills

House Propose Bills Companies, scientists, and patient-advocacy groups all applaud the ultimate objective of recently introduced legislation designed to get effective drugs to patients more quickly. However, not everyone agrees that the current versions of the Senate and House bills to reform the Food and Drug Administration are the way to accomplish the goal. DISSENTER: Edward Kennedy (D-Mass.) voted against the Senate bill. Proponents say the bills move reform in the right direction. Meanwhile, detractors worry that an emphasis on speeding drugs through approval could be harmful to patients and pharmaceutical research. They also believe that the proposed bills, which call for privatizing the FDA review process, pose conflict-of-interest problems and create disincentives for clinical investigations, especially for rare and life-threatening diseases. REVISIONIST: Nancy Kassabaum (R-Kan.) sponsor of the Senate FDA reform bill. In late March, the Senate Labor and Human Resources Committee approved the FDA Performance and Accountability Act, which was sponsored by Sen. Nancy L. Kassebaum (R-Kan.). In the House, hearings on three bills covering drugs, medical devices, and food safety took place on May 1 and 2. These bills represent a culmination of an ongoing effort by Congress, prompted by pressure from industry groups and others, to revise FDA procedures. Seeing opportunity in a movement toward regulatory reform in Congress, groups pushing for streamlining the FDA approval process are stepping up their efforts. Last February, in a letter presented to House Commerce Chairman Thomas Bliley (R-Va.), more than 330 health professionals, patients, research institutions, and business groups called for immediate action "to bring responsible reform" to the agency. The statistics of drug development are mind-boggling, and to many, indicate the need for reform. Documentation for a new drug application (NDA) can contain more than 80,000 pages of raw data, charts, and forms. A pharmaceutical company spends $359 million, on average, to get one drug from the test tube to the patient, according to statistics from the Washington, D.C.-based Pharmaceutical Research and Manufacturers of America (PhRMA). That same journey can take about 15 years from the time a promising compound is discovered to the date it becomes part of the growing pharmaceutical arsenal against disease. Both the House and Senate measures aim to expedite the drug-approval process, but they differ in how to achieve that goal. The Kassebaum plan dictates that FDA review and approve all NDAs in six months by 1998, after which outside groups such as contract research organizations could be called in to decrease the application backlog. The House bills would give drug, medical-device, and food companies the option of taking their initial NDAs to private reviewers from the outset. Both bills would also codify collaboration between agency officials and industry representatives on clinical-trial design and prioritization of drug approval for life-threatening conditions. CONCERNED: FDA chief David Kessler says his agency needs more resources to meet the bills' current provisions. The involved parties-even FDA commissioner David Kessler-agree that reform is necessary. In a March letter to Kassebaum, chairwoman of the Senate Labor Committee, and Sen. Edward M. Kennedy (D-Mass.), the ranking member of the committee, Kessler stated that he is "committed to working with [the Senate committee] to reach consensus on reform legislation that would accomplish our mutual goal of improving FDA's performance and accountability while at the same time preserving and strengthening the Agency's ability to protect and promote the public health." SEESAW: BIO president Carl Feldbaum figures observers will "go back and forth" on deadline issues. Representatives from industry trade organizations are pleased with the bills, but have minor quibbles on some of the details. "The Senate bill is very close to what BIO [the Biotechnology Industry Organization] would have drafted," notes Carl Feldbaum, president of the Washington, D.C.-based group. "The House bill goes somewhat beyond what BIO proposed [in its reform statements]." Patrick Korten, a PhRMA spokesman, says that his group views the bills "very favorably." Heightened interaction between industry and government on FDA reform issues spurred the recent legislation. A reform document proposed by industry last year, now known as the BIO-PhRMA bill, was used by the Senate and House committees in drafting the congressional bills. The BIO-PhRMA, House, and Senate versions are similar, barring a few provisions, in many respects, note industry representatives. These include the procedure for recognizing drugs already approved outside the United States. Representatives of patient-advocacy organizations differ in their initial reaction to the bills. The Patients' Coalition-a group of about 60 national health organizations formed to promote responsible FDA reform-in general is "dissatisfied" with the bills, comments Michael Langan, director of public policy for the National Organization for Rare Disorders (NORD) Inc., a nonprofit patient-advocacy group based in New Fairfield, Conn. The coalition was brought together by NORD, the Atlanta-based American Cancer Society, and the American Foundation for AIDS Research (AmFAR) in New York. The bills "lower the standards that we currently have for safety and efficacy in the [U.S.], and they will undermine incentives for research," maintains NORD's Langan. However, Neil Kahanovitch, a practicing physician and president and founder of the Center for Patient Advocacy, a nonprofit group in Arlington, Va., maintains that "the quicker [applications] get reviewed, the more applied science, if you will, can be put into clinical use. The longer it takes FDA to do their job, the less money is available for research and development [of new drugs]." Although Kahanovitch's group supports FDA overhaul, his group is not a member of the coalition. THE RIGHT PATH: Tuft's Louis Lasagna maintains that the bills move reform "in the right direction." Biomedical scientists familiar with FDA reform, like Louis Lasagna, dean of the Sackler School of Graduate Biomedical Sciences at Tufts University, view the bills positively. "I think there's a lot in the bills that move reform in the right direction," Lasagna comments. Some leading politicians have come out against the proposals. In a statement issued in late March, Kennedy said that the Senate bill will "cripple the FDA and turn many of its functions over to private industry." Kennedy was one of the four members of the 12-senator committee who voted against the bill. He also wrote that "the basic theme" of the bill is "privatization," returning the country to the "days when drug manufacturers decided what was safe and effective." Lasagna, who is also the director of Tufts' Center for the Study of Drug Development, calls Kennedy's claims "shameful." He asserts: "I don't think anyone wants to go back to the days where we didn't demand convincing data on clinical efficacy." The Senate's timetable for approving drugs concentrates on the review phase of the process, the time it takes FDA officials to review and approve an NDA (see figure). The drug-development phase comes before an NDA can be filed, however. This is the period from discovery of a promising compound to the end of Phase III clinical trials, which can take almost 13 years. Feldbaum hopes that the Senate's 1998 deadline is attainable, adding that it's essential to maintain standards of safety and efficacy. "The FDA should be the gold standard around the world." But he figures the involved parties "will go back and forth" on this and other key issues before the FDA-reform debate is over. In his letter to the Senate Committee, Kessler contended that FDA cannot "meet the time frames set forth in the [Senate] bill using existing resources," noting that the agency "would be required to review the complex scientific submissions for novel products such as the fat substitute Olestra, the synthetic animal hormone bovine somatotropin (BST), and vaccines for communicable diseases that could threaten thousands of persons, in six months." He fears that with the way the bill is now worded, failure to meet the deadline could result in "all future applications in the same product category [being] contracted out to private companies." PhRMA's Korten says that the six-month objective has been on the books for about 30 years. The Senate bill would codify that, he explains. The 1962 Kefauver Amendment to the Food, Drug, and Cosmetic Act of 1938 first set the goal of a 180-day clock for FDA to approve NDAs. Thirty years later, prompted by the 1992 User Fee Act, commissioner Kessler set forth new goals: FDA aimed to review all NDAs in 12 months and review priority NDAs in six months by 1997. All parties concede that FDA is well on its way to meeting its own objectives. According to a 1995 report from the General Accounting Office, FDA has slashed its time for reviewing NDAs from 33 months in 1987 to 19 months in 1992 (K.S. Brown, The Scientist, Jan. 22, 1996, page 1). Most recently, in an effort to expedite cancer-drug approval, President Bill Clinton announced in March that FDA could accept less data from a company studying a drug's cancer-fighting potential (S. Benowitz, The Scientist, April 29, 1996, page 1). "If FDA wants to [approve drugs quickly], they can," Korten maintains. "They've cleared three AIDS drugs in the last six months in record times." Adds Lasagna: "For life-threatening illnesses for which nothing is available, I think one could demand less data than for the 23rd non-steroidal anti-inflammatory drug that isn't very much different than the 22nd. The FDA has moved in this direction," especially in the areas of AIDS and cancer. Still, Spencer Cox, director of the antiviral project for the Treatment Action Group (TAG), a nonprofit AIDS treatment and research group based in New York, says his organization opposes the bills because they "tie FDA's hands" and "limit" the agency's capacity to deal with serious and life-threatening diseases. "It limits the abilities to triage very promising therapies and rush them through the system by setting deadlines for approval," asserts Cox. "It means essentially that an antihistamine has to be treated in the same way as a new therapy for a very serious disease. The concern is to not tie up FDA in such a way that they can't be flexible to respond optimally to new developments." Deadlines for approval could get in the way of "good science," says Susan Polan, director of government relations for the American Cancer Society, which has not yet taken a stance on the bills. Swift approval is "clearly important," she states. "We want to make sure drugs are available as soon as possible without forgoing safety and efficacy." OBSTACLE: Development time is the "greatest barrier" in getting drugs to market, notes Ken Kaitin. "There is pressure from politicians, patients, and company stockholders now for firms to develop their products more quickly," remarks Kenneth Kaitin, associate director of Tufts' Center for the Study of Drug Development. "We've been fighting for that for a long time." But, he adds, "efforts placed solely on the review time miss the mark to some degree simply because it's the development time that's the greatest barrier to getting new drugs to market. "The FDA is never going to allow itself to be in the position where [it is] approving drugs that are unsafe just for the sake of getting them out," asserts Kaitin. He says that if the review and development process is made more efficient, scientists will see practical applications of their work in the clinic and on physicians' prescription pads more quickly. Although Kenneth Seamon, senior vice president for scientific development at Immunex Corp. in Seattle, says a "total revamping" of FDA is unnecessary, he does argue that some overall evaluation of the approval process is needed. What is really called for is "contracting the timeline at the discovery end," by having FDA officials work more closely with scientists at the discovery and early clinical end of the process, he maintains. Related to quickening FDA's process is the prickly notion of privatizing the review of NDAs. Korten says this potentially could be performed by specialists at university research centers, clinical-trial centers, or contract research firms such as the MITRE Corp., located in Mclean, Va. Both BIO and PhRMA suggest using nationally recognized researchers at medical centers for third-party review. For example, NDAs for arthritis drugs would be reviewed by medical centers whose faculty are renowned for their expertise in rheumatology. Another byproduct of this suggestion might be closer communication between basic researchers and clinicians. Kessler has serious concerns about proposals for third-party review, especially for medical devices. He stated in his March letter that the medical-device amendment would allow firms "to pay private companies to review applications to market devices ranging from heart valves to testing products that are used in protecting the blood supply." Kessler recognized that FDA would accredit these organizations and have a short period in which to review their decisions, but still expressed concern that "these safeguards are not sufficient to protect the public health." POTENTIAL CONFLICT: Provisions for outside review of new drug applications concern AmFAR's Ellen Cooper. And Ellen Cooper, AmFAR's vice president and director of clinical research and information, maintains that there's a difference between contracting out work FDA can't get to and privatizing whole functions. "Essentially, a sponsor could take their application to a private group that is 'accredited' by FDA at any time and negotiate their own fees," says Cooper. "There's just so much potential for conflict of interest, let alone [potential for] inconsistency in procedures and standards" among outside contractors in, for example, the number of required clinical trials. TAG's Cox agrees, adding that a move in this direction would "undermine" the authority of FDA. "Certainly the AIDS community has had our problems with FDA [over the speed of approval of anti-HIV drugs], but at the same time the agency fills a vital function in ensuring the products we use are safe and effective." But, notes Tufts' Kaitin, "With an adequate set of conflict-of-interest rules, I can't believe you can't get around those [types of] problems." PhRMA, in its mid-April statement entitled "The Need for FDA Reform: Problems with Current FDA Practices," calls for changes to the House bill's third-party review provisions. The association suggests that the legislative language should be clarified to ensure that third parties adhere to the same standards as FDA, and that new-drug applicants should not pay third parties to conduct reviews. According to the PhRMA document, FDA has "experimented" with the use of outside organizations to review portions of NDAs for the last two decades. Tufts' Lasagna finds it "interesting" that the bills suggest moving outside FDA for review and "applauds" this direction. Both he and Korten cite a pilot project conducted five years ago, in which MITRE Corp. reviewed five supplemental applications for other uses of already-approved drugs. The firm "turned the [approvals] around sooner and at less cost than the FDA," says Korten. But he adds the agency was "dragged into that experiment kicking and screaming." "The biggest negative is that [the bills] simply reduce the incentive for a company to do research," says TAG's Cox. "Most company research is clearly targeted to marketing approval, which makes sense for a company whose primary obligation is to return a profit to their stockholders. If the standards for approval drop, the amount of research that's needed drops," he reasons. "That's simply not true," says PhRMA's Korten. "There's nothing in the proposed legislation that in any way reduces the requirement for determining safety." And NORD's Langan says the part of the Senate bill written by Sens. Bill Frist (R-Tenn.) and Connie Mack (R-Fla.) that calls for off-label promotion by drug makers will specifically affect research on cures for rare diseases. Companies sponsoring studies on treatments for rare diseases-so-called orphan drugs-receive seven years of marketing exclusivity. This essentially means a special patent that states that no other company can receive FDA approval to commercialize a similar product. "Under the Mack-Frist proposal, another company can market an off-label use of another product even though there's never been a single study on that secondary use," explains Langan. He does acknowledge the importance of off-label drugs for rare diseases, but suggests that the lack of research could mean forgoing fleshing out information such as proper dosages and combination therapies. "Frankly, information-dissemination provisions have no effect on [research] one way or another," counters PhRMA's Korten. "The Mack-Frist [proposal] seeks to allow individual companies to make available to practicing physicians copies of peer-reviewed articles in medical journals that discuss the value of an off-label use. That's especially important in the cancer field." More than half of all prescriptions for cancer treatment are off-label, according to Korten. Source: Pharmaceutical Research and Manufacturers of America, Washington, D.C. Because physicians don't have time to keep up with reading literature, "our companies think that they ought to at least have the right to simply send a [photocopy] to these folks so that they are aware of other off-label uses for which particular drugs have been shown to be effective," contends Korten. "We're not trying to put together marketing material to go on top of it." Langan argues that since the information would come from the pharmaceutical industry instead of an independent clearinghouse, for example, the articles might become "borderline promotional tools." Although he says TAG supports disseminating information, his group is concerned that companies might send out only positive studies. According to PhRMA's statement, "numerous blue-ribbon groups have found that FDA's burdensome requirements discourage early clinical research on new drugs." As a result, the organization claims loss of research funds by U.S. universities and nonprofit research centers to European clinics. Because of these concerns, FDA issued an Investigational New Drug Guidance last November, which deregulates early clinical research. The guidance allows companies to move ahead on Phase I trials based on preliminary toxicological findings and reduces the amount of manufacturing data needed to start human tests. The intent of these changes, according to FDA officials, is to make it easier for clinical researchers to start trials sooner, thereby lowering the regulatory hurdles for Phase I trials in the U.S. The House bill codifies the guidance and adds more reforms to this part of the drug-approval process. "For someone who treats patients, the last thing I want to do is prescribe drugs and products that are harmful. But then on the other hand, when some of those drugs that aren't available in the U.S. are in other countries, that's not right either," argues Kahanovitch. The Senate bill would give FDA 30 days to review drugs already okayed by the European Union. Watchdogs such as Sidney M. Wolfe, executive director of the Washington, D.C.-based Public Citizen Health Research Group, however, are critical of Europe's drug-approval standards, saying they are lower than in the U.S. (S.M. Wolfe, "Differences in the Number of Drug Safety Withdrawals: United States, United Kingdom, Germany, and France, 1970-1992," Washington, D.C., Public Citizen Health Research Group, Feb. 2, 1995). With majority leader Bob Dole (R-Kan.) promising to bring the Senate measure to the floor sometime this spring and House representatives receiving testimony on their bills this month, FDA reform deliberations have turned a corner. No matter what the various bills will look like at the end of the political debate, observers on both sides of the fence repeatedly state that safe and efficacious drugs shouldn't be sacrificed for the sake of expediency. "There's got to be a happy medium," stresses Kahanovitch.

FDA Reform Debate Heating Up As Senate, House Propose Bills

Interested in reading more?

Become a Member of