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Review But many critics are urging still other changes, including easier approval of 'off-label' uses DÉJÀ VU: NCI's David Parkinson sees parallels with AIDS drug testing. By Oncologists, industry officials, and cancer-patient advocacy organizations are applauding recently announced policy changes at the Food and Drug Administration (FDA) that speed up the approval process for cancer drugs. The plan, announced on March 29 by President Bill Clinton, aims to immediately streamline the drug-approval process and broaden availability of cancer treatments. Proponents of the changes contend they will expedite patients' access to potentially life-saving medications. STEPPING UP: Jefferson University's Robert Comis supports reform. "There's always been a concern about the time for getting a drug approved to go from development to the marketplace," says Robert L. Comis, Ludwig A. Kind Professor of Medicine and director of clinical programs at Philadelphia-based Thomas Jefferson University's Kimmel Cancer Center. Comis, who attended the White House announcement, views the new policies as "a major step forward." But not everyone is sanguine about the details and the implementation of the new policies. Some argue that FDA didn't go far enough. "They [policy changes] are a considerable but incremental first step," says Robert Young, president of Fox Chase Cancer Center in Philadelphia. Critics such as Young complain that the changes don't address a major problem in oncology: the FDA requirement that companies submit new drug applications for so-called off-label uses of already approved drugs. Perhaps as many as half the cancer drugs on the market today are found useful in treating diseases other than for those originally approved by FDA. Currently, FDA-approved supplemental use of a drug requires new testing. The new policies give FDA the authority to sanction drugs based on partial responses, such as a therapy's effectiveness in shrinking tumors. Until now, a cancer drug had to both extend and improve the quality of a patient's life. These both took much longer to evaluate. FDA hopes the changes slash its review times for so-called breakthrough therapies for life-threatening illnesses in half, from a little more than a year to roughly six months. Overall, cancer-drug development can last from three to as long as 20 years. By some estimates, as many as 100 cancer drugs currently under development in the United States could get earlier approval under the new policy. The revised policies also broaden drug availability. In the expanded-access program, physicians can get an experimental cancer drug from its maker by promising to provide information on the outcome of the treatment. In addition, FDA will accept evidence of a drug's effectiveness from other countries that have reviewing and approval systems. GOOD AND BAD: Mark Ratain of the University of Chicago predicts some "me-too" drugs may be approved, upping the competition and cutting costs. More physician education will be needed, he says. Mark Ratain, a professor of medicine at the University of Chicago, calls the new FDA policies "both good and bad." He comments: "It's good in that companies won't have to do as much testing as in the past, it won't cost as much money, and [drugs] will get to the patients more quickly. "The down side is that it lowers the bar," he notes. "The consequence is also good and bad. More drugs will be approved that will be of modest, if any, improvement-'me-too' drugs. Some drugs approved in other countries that are not approved [in the U.S.] are of little value from the standpoint of an individual's tumor. But from an economic standpoint, having more drugs that are the same may help with pricing pressures." While copycat drugs wouldn't help much medically, he maintains, the competition would help keep prices down. However, he notes, "we're creating a way for potentially ineffective drugs to be approved, and that creates complications. "The issue will be to educate physicians on the differences among various me-too drugs," he predicts. "It will force more physicians' education because there will be less [drug] screening by the FDA." Though the new FDA policies are designed to speed drug development, Ratain thinks the rule changes may in some cases slow things down. "Unfortunately, the new policy will not help novel compounds in early clinical trials. Many of these are not predicted to produce responses," he explains. Instead, they stabilize cancer growth. Such compounds include drugs that block cell communication, angiogenesis (the growth of new blood vessels), and metastasis (cancer spread). The traditional clinical-trial rules don't apply, Ratain says: "These will need more rigorous, controlled clinical trials with different end points, such as time to disease progression rather than survival." These differences may dissuade corporate investment in developing such drugs, he notes, because of the difficulty in securing FDA approval. In the planned expanded access, experimental therapies approved in other countries could be widely available in the U.S. even if they are early in the FDA approval process. Expanded-access protocols would allow many more patients to receive experimental therapies, with the criteria for entering a trial less restrictive than usual. President Clinton, in announcing the new policy, said: "Dozens of [drugs] will get to the market sooner, and that means they can help Americans suffering from cancers of the breast, lung, ovary, prostate, and colon, among others." David Parkinson, acting associate director of the cancer therapy evaluation program at the National Cancer Institute (NCI), supports FDA's moves. "The ultimate result will be a net clinical benefit," Parkinson notes. "A number of drugs that show early clinical benefit ultimately find a niche for certain patients." But the new FDA policies may complicate carrying out clinical trials. According to the University of Chicago's Ratain, patients who already have access to various drugs would be less likely to want to participate in time-consuming trials. Tim Whitten, vice president for marketing in oncology/immunology at Bristol-Myers Squibb Co., headquartered in New York, agrees that most patients wouldn't see a need to enter trials if they already had access to a drug. "It's relatively easy to get patients on those expanded-access trials. A patient can get access to a drug much easier than through trials designed to show whether the drug is effective in a specific patient population." As a result, "expanded-access [trials are] usually not a good source for data," he says. "We can't monitor patients adequately, and reporting methods tend to differ from those trials intended for FDA approval." While Whitten worries that expanded access might create less pressure to get a drug approved, he still thinks a faster approval system will quicken the pace of drug development. "Getting [cancer drugs] to market quicker will get those additional trials under way in a more timely fashion, and patients will generally benefit faster than they would without such regulations." The streamlined approach seeks to give cancer drugs the same "fast track" treatment begun several years ago for promising AIDS medications, such as protease inhibitors. "It's been instructive to see what the AIDS community has gone through," Parkinson comments. He notes that initially, AIDS activists demanded immediate access to all new experimental drugs. Yet some harmful effects of early approvals caused the activists to change their tune. Now, "when drugs go through advisory committees, you see statements from AIDS activist groups about the need for careful evaluation. "I think we'll see the same thing from cancer advocates-they'll want responsible studies to really evaluate the usefulness of these drugs." Many advocates are paying close attention to the new policies. "The agency will have to monitor these quick access drugs very carefully," Sidney Wolfe, director of Public Citizen's Health Research Group in Washington, D.C., told the New York Times (P. Hilts, April 2, 1996, page A1). "The potential risk is that the drugs showing initial promise won't show the same effectiveness [when they are tested] in comparative studies," Parkinson points out. Though cancer medicine has shown that in general, tumor shrinkage and other partial responses are clear indicators-"surrogate markers"-for patient survival, drug companies will still be compelled by FDA regulations to complete standard long-term testing. REFORMER: Penn's John Glick urges further FDA changes. John Glick, director of the University of Pennsylvania Cancer Center, sees the reduction in approval times and expanded access as "great steps and positive for patients." Yet he believes FDA must go further. "We have to simplify and expedite the process of approval for new off-label uses of approved drugs," says Glick, who is president of the American Society of Clinical Oncology (ASCO), headquartered in Alexandria, Va. "We have to get an approval process in which supplemental new drug applications can be approved based on quality peer-reviewed literature and not having to do controlled trials over again." What's more, Glick contends, legislative reform of FDA is needed "so that the [FDA] restriction will be lifted on [pharmaceutical companies'] dissemination of peer-reviewed literature on off-label uses of approved drugs." Currently, FDA does not allow drug companies to spread information about off-label uses of approved medicines. This means that cancer physicians and patients are deprived of potentially important and life-saving information, he maintains. Fox Chase's Young agrees with Glick's concerns: "The FDA failed to devise a satisfactory mechanism to approve secondary indications. "Such drugs are on the market already, approved for a particular use," Young points out. "Oncology is moving so quickly-more than half of cancer patients are being treated by chemotherapy agents for off-label uses. "These are treatments that are considered state-of-the-art-it could be considered malpractice if you didn't use them. It's unreasonable for companies to have to reapply to the FDA and conduct new trials that could delay use for years. The failure to get secondary-indication approval hampers the ability of doctors and patients to know what is the best possible dose and schedule for a disease treatment." Ellen Stovall, a cancer survivor who is executive director of the National Coalition for Cancer Survivorship, based in Silver Spring, Md., is also concerned about the dissemination of information on off-label uses. "For cancer patients, that's a significant way that cancer is treated," she asserts. "With physicians' time being managed by the marketplace, this is a serious concern for us-doctors getting information in a timely fashion." She complains that "we were promised time and time again about the FDA becoming more supportive publicly about the off-label information dissemination, and they haven't been." Joseph Bailes, who heads the ASCO clinical practice committee, is dismayed that "appropriate dissemination of off-label uses via peer-reviewed articles should be such a problem to the FDA. "This is how doctors learn," he declares. "I'm at a loss that it's turned into such an issue. They should step up to the plate and revise this. These drugs have a long history of off-label use-this makes no sense. This is a policy in direct contradiction to the practice of oncology. "From the point of view of speeding up review and approval, it's long overdue. These are issues have been discussed for years-this isn't anything new. What you're seeing is a response to a changing political environment." Oncologist Michael Friedman is viewed by many as a key architect of the current FDA reforms. Friedman, former associate director for NCI's Cancer Therapy Evaluation Program, joined FDA in October as its deputy commissioner for operations. He sees "the more critical impact of these policy changes on drugs undergoing development now, in which companies can modify their development strategies and save time. That's where the biggest impact of the accelerated approval initiative will be felt." Business benefits from accelerated approval because companies "can get a drug approved much more quickly and a faster return on their investment. It could have tremendous impact on the industry." WAITING: Eli Lilly's Andrew Dorr wonders how FDA will interpret policies. But many wonder how FDA will implement the policy changes. "It remains to be seen how the FDA's various components-the cancer division, for example-interpret these guidelines, particularly in approving data with respect to response," says Andrew Dorr, medical research adviser to Eli Lilly and Co. of Indianapolis. He sees greater sharing between NCI-funded academic-based clinical trials cooperative groups and pharmaceutical companies in evaluating drugs, despite the traditional reluctance of industry-including Eli Lilly-to use such data. Cooperative groups and industry frequently differ on various testing and reporting guidelines. Both groups tend to want to control trial design and participation, Dorr says. Lilly is poised to take advantage of the revised

Industry Applauds FDA Plan For Faster Cancer-Drug Review

Apr 28, 1996

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