The FDA's Fine Line
This past week, the Food and Drug Administration (FDA) came under fire from patient advocacy groups about a lack of access to unapproved, yet promising, cancer drugs. In a hearing conducted by its Oncologic Drugs Advisory Committee, the agency was lambasted for not forcing drug manufacturers to make promising new drugs more available to severely ill patients-even if these drugs are still in the clinical trial review process.
Expanding such "compassionate use" access might save the lives of thousands of people battling advanced disease, contend patient advocacy groups. However, drug industry spokesmen respond that expanding such unofficial access would severely limit their ability to enroll patients in clinical trials-already an extremely difficult task.
The Advisory Committee has until March to issue its recommendation, which will surely add further controversy to the already contentious debate.
In spite of such protests, however, the FDA continues to give its approval to a dizzying array of new treatments, treatment protocols, and even new uses for older treatments. In the past few months alone, the FDA has given the green light to dozens of new treatments just for breast cancer.
For example, the FDA gave its approval to Arimidex (anastrozole) as a first-line (initial) breast cancer treatment for post-menopausal women diagnosed with advanced disease. Arimidex had previously been approved by the FDA for use only after the drug Tamoxifen had failed to halt the cancer.
The FDA gave its approval to Ivax Corporation to market Paclitaxel, a generic version of Bristol-Myers Squibb's hugely successful drug Taxol, for the treatment for breast and ovarian cancers.
The FDA gave Bayer Diagnostics the go-ahead to market a test for monitoring patients with breast cancer that has spread. The test measures the blood levels of the HER-2/neu protein, a key indicator of aggressive disease in certain women.
Most recently, an advisory panel of the FDA voted unanimously to approve the drug Femara (letrozole) as a first-line therapy for women with advanced breast cancer. Femara was initially approved by the FDA in 1997 as a second-line treatment for women with advanced, estrogen-sensitive disease.
Such a slew of approvals is not uncommon for the FDA-and these are for only breast cancer drugs. The FDA also holds sway over food safety, veterinary medicines, cosmetics, medical devices, and so-called biologics-drugs derived from living (as opposed to chemical) sources. (These include serums, vaccines, blood derivatives, and biotechnology products, among others.)
In terms of cancer drugs, the FDA only gives its approval for a new treatment after clinical trials have demonstrated a minimum standard of effectiveness in treating a disease. And sometimes it gives a new approval for different dosages or applications of an already-approved drug. Recent examples include the newly-approved "first-line" uses of Arimidex and Femara mentioned above.
In addition, the FDA can give so-called "accelerated approval" when a new drug or treatment shows exceptional promise but has not completed the traditional set of clinical trials. Or the FDA can give "priority review," which means a decision will be forthcoming within six months.
Both of these rapid approval avenues are relatively new for the FDA, and were grudgingly undertaken by the agency only after intense pressure from patient advocate groups frustrated at a dearth of viable treatment options for cancer, AIDS, and other life-threatening illnesses.
Accelerated drug approvals by the FDA not only benefit patients with life-threatening illnesses, but also the manufacturers of the drugs themselves. The FDA has a crucial role to play in terms of attempting to guarantee product safety. Yet weighing the balance between safety and product availability has become an increasingly complex task, especially given the more liberal approval processes of many regulatory agencies in Europe and Latin America.
Bringing a new drug to market can sometimes take years to wind its way through the FDA approval bureaucracy-and decades overall if you take into consideration the research and development commitment that drug manufacturers undertake to bring a product to that final stage.
For a product to pass FDA scrutiny, it must first be submitted to an Advisory Panel of experts who review the results from clinical trials and other research. The panel then either recommends approval or rejection of the product and submits its finding to the FDA for final consideration. Although the panel's recommendation is not binding, the FDA usually follows its advice.
Typically, only about one in 1,000 new drug compounds that enter pre-clinical testing ever make it to Phase I clinical trials. And of these, only a handful demonstrate sufficient efficacy through the various clinical trial stages to warrant submission to the FDA.
Why do pharmaceutical companies invest so heavily in so many drugs, the vast majority of which will never earn a cent? Quite simply, a single successful drug, if proven effective, could be hugely profitable. It could mean life or death for a company, or enable it to fund other research and development efforts for years into the future.
When it comes to cancer research, the Food and Drug Administration (FDA) often makes headlines for its new approvals (and sometimes rejections) of treatments for the disease. But the FDA also plays an active role after treatments have gained its approval. It monitors their ongoing effectiveness and safety, and the agency doesn't hesitate to give very public warnings when expectations are not met, safety becomes a concern, or product promotions and labeling are misleading.
For example, earlier this year the FDA sent a warning letter to a researcher at a medical center in Boston for failure to report a death in a gene therapy clinical trial. In a second incident cited in the same warning, the FDA charged that a lung cancer patient was enrolled in that trial against the approved protocol.
The FDA required the researcher to submit a plan for corrective action and suspended a number of clinical trials pending completion of its investigation.
In another action, the FDA issued a warning letter to a New Jersey-based company, Celegene, which makes a drug Thalomid (thalidomide) to treat multiple myeloma and other cancers. The FDA alleged that sales representatives of the firm suggested that the drug instilled feelings of "well-being" in cancer patients and that its ability to block a tumor's blood supply may make it a treatment option for certain other cancers.
When it gave its approval to thalidomide in July 1998, the FDA imposed very strict prohibitions on its use, in part because of thalidomide's troubling past when it was taken by pregnant women and resulted in children being born with severe deformities.
Furthermore, while some preliminary studies have shown that thalidomide may be effective in blocking a tumor's blood supply, the FDA has yet to approve its use in certain cancer treatments except in extremely limited circumstances.
The FDA required the company to distribute its warning to relevant employees and directed the firm to submit a plan for corrective action.
In spite of such warning actions, the overriding objective of the Food and Drug Administration in terms of cancer and other treatments is clearly to promote the safest and most effective treatments in as timely a manner as possible. Sometimes that even includes taking the unusual step of supporting a product in the face of negative press-as was recently the case with Herceptin.
Herceptin was one of the first gene-based cancer drugs to be brought to market. It works by inhibiting the growth of the HER2 protein, which is often present in large amounts ("overexpressed") in women with metastatic breast cancer.
While Herceptin has been used to treat about 25,000 women since it was approved by the FDA in late 1998, the drug's manufacturer, Genentech, recently issued its own warning. The company said that 62 patients had serious problems with the drug; 15 patients eventually died.
All of the patients experienced allergic reactions to the drug after the initial dose, and some of the deaths may have been the result of other complications from their cancers. However, both Genentech and the FDA agree that Herceptin is one of the "least toxic" of the breast cancer drugs currently on the market, as well as one of the most promising.
The FDA publicly backed the continued use of Herceptin after the manufacturer's warning because it noted that such reactions to the drug are "rare" and occur at similar levels with other cancer drugs. Furthermore, the drug's promising results in breast cancer studies cannot be ignored. In one clinical trial, patients who had both chemotherapy and Herceptin demonstrated a 25 percent increase in survival compared with those taking chemotherapy alone.
The United States remains by far the largest market for pharmaceutical companies, and the aging of the baby boom generation will ensure that this demographic dominance remains. Increasing age means increasing illnesses-and an increasing need for drugs to combat them.
Therefore, regardless of any hurdles that must be overcome with the FDA, the pipeline of new drugs will continue unabated. The potential profits to drug companies-and the lives at stake-are simply too high to ignore.
U.S. Food and Drug Administration (http://www.fda.gov)
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