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EDITORIAL |
Dr. Yates is Vice President for Research, American Cancer Society, Atlanta, GA.
This article is available online at http://CAonline.AmCancerSoc.org
The Food and Drug Administration (FDA) serves many masters: the public, the academic and commercial research community, corporate drug developers, sister governmental agencies (National Institutes of Health, Centers for Medicare and Medicaid Services), and the legislative and executive branches of the government. The visibility of their decisions affects many constituencies, and this makes the FDA an easy target for unfair criticism. Their process of regulatory review and approval of new drugs, although a major service, is rarely appreciated. They are an "approval agency" and must selectively take negative positions and make decisions unfavorable to some petitioners. Over the years, their actions have been seldom praised and blamed often, even though they have demonstrated capability and responsiveness to suggestions.
Both patients and many health care professionals are often confused about the difference between two concepts: regulatory drug approval for marketing NDA (New Drug Application) and access through an IND (Notice of Claimed Investigational Exemption for a New Drug) to experimental agents by patients who have exhausted conventional therapies. These two different concepts are frequently misunderstood, particularly by some individuals and groups advocating open access to all promising experimental agents following completion of Phase I testing. Access under an IND to agents not approved for marketing by the FDA can occur for the following reasons: (1) as part of a clinical study generally in the context of drug development, (2) for a single patient or small numbers of patients if certain conditions are met, or (3) depending on the amount of data available, for larger numbers of patients in the form of a treatment IND or protocol.1 Access to these agents requires an Institutional Review Board (IRB)-approved protocol, a request to the manufacturer, and a physician who agrees to provide pertinent treatment information to the manufacturer in return for the desired drug. The physician must complete and submit treatment and toxicity information relevant to that patient. Documentation and submission of therapeutic outcomes, as well as expected and unexpected toxicities observed by the physician, must be collected.
Because most agents in Phase II (preliminary evidence of drug efficacy) and Phase III (new agent versus standard therapy) studies can be obtained from the manufacturer as a single patient IND (sometimes even larger series of patients get access), complaints about the FDA restricting access are erroneous. Complainants commonly confuse the concepts of access and approval either purposely or mistakenly to support their claim that the only solution to the "access problem" is to lower the drug approval standards. New and promising agents can be made available to treating physicians if they secure the drug from the manufacturer, follow an IRB-approved protocol, and provide the relevant patient and treatment information. Patients, through their physicians, can seek and gain access to new and promising agents that are in clinical trials when they themselves might not have access to or be eligible for a particular trial.
Before approval of a new therapeutic agent, the FDA requires (as stated in the Federal Food, Drug, and Cosmetic Act) well-designed and conducted clinical trials to adequately assess therapeutic benefit and toxicity. A comprehensive drug development plan through a collaborative effort between the manufacturer and the FDA is the optimal approach. The small margin between therapeutic benefit and toxicity for many chemotherapeutic agents used to treat cancer merits caution. Toxicities can range from minor annoyances to life-threatening events. Cosmetic (hair loss), disabling (neurotoxicity), and life-threatening (cardiac toxicity) side effects are legitimate concerns for patients, providers, and regulators in the FDA. The public deserves to know enough to weigh the relative risks from toxicity in comparison with the potential benefits and understand that they are protected whether participating in a clinical trial or taking a drug for an approved indication.
The FDA regulatory process is designed to protect patients while providing an avenue for drug developers to demonstrate efficacy, assess toxicity, and secure new drug approval. The Agency must also consider the potential late toxicities that become apparent only following extensive use after approval. Drugs with relatively low response rates are a particular challenge to evaluate with regard to the balance between efficacy and tolerable toxicity. The FDA may grant accelerated approval for drugs studied for serious and life-threatening conditions that offer a benefit over existing therapies. Under this regulation, the agent may also be approved based on studies that show it has an effect on an outcome that is not the ultimate benefit, but is reasonably likely to predict the drug's ultimate benefit—for example, a posttherapeutic drop in a pretreatment elevated tumor marker such as beta subunit of chorionic gonadotropin in testicular cancer. Approval under this provision requires continued study postmarketing to verify the agent's clinical benefit and safety. The postapproval collection of additional information is a reasonable expectation for drugs approved through the accelerated process and is a requirement. Although this system has functioned reasonably well in distinguishing investigational agents that improve patient outcomes from those that do not, it is understandable that many patients facing life-threatening diseases will become impatient with this process. It is not surprising that some patients and their loved ones are willing to substitute optimism for data when advocating for earlier access to experimental drugs that have only completed Phase I studies.2 Accelerated approval after Phase II testing has two serious consequences. First, limited and only short-term toxicity information may result in unsafe exposure to patients, resulting in adverse late effects; and second, the dependability of collection and reliability of efficacy and toxicity information may be compromised.
Contrary to some characterizations, the FDA is not a static agency, but is responsive to the changes in the oncology landscape. Indeed, the recruitment of a respected oncologist to head the Office of Oncology Drug Products in the Center for Drug Evaluation and Research is a reflection of this change in receptivity. Quality leadership and strong scientific management will protect the public and continue to earn the respect of leaders in drug development, both in academia and industry.
Critics of the Agency often complain about the irregular approval process and then propagate claims about FDA-imposed inadequate access to unapproved substances. Deliberate distortion of this access and approval issue, the promotion of historical controls for efficacy trials, the demonization of randomization and statistics, and finally, the promotion of anecdotal medicine all work to undercut the quality and strength of cancer research and care. Claims and counterclaims supported by poorly designed trials and the collection of poor data supports an environment for exploitation by medical charlatans. Self-promotion, commercial exploitation, and unreasonable criticism of the FDA are distractions that are generally not in the public interest. The FDA is to be commended and should receive increased support from Congress to assure its ability to monitor late effects. Such support will enable it to continue to serve the public and scientific community. With new senior leadership, a mutual respect among industry, academia, and other governmental agencies will continue to improve a process that has served this country well.
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