Unapproved Drugs and Unproven Off-Label Prescriptions
By Rachel Walden
Last November, a pair of Associated Press (AP) reporters conducted an investigation which found that Medicaid paid nearly $200 million from 2004--2007 on more than 100 unapproved drugs  which never went through the Food and Drug Administration’s (FDA) review and approval process. The drugs entered the market prior to 1962, when the FDA began requiring safety and effectiveness reviews for new drugs. Many manufacturers consider the drugs, estimated to account for around 2% of prescriptions annually, to be “grandfathered” in and not to need further review. The FDA has neither systematically reviewed nor removed from these drugs from the market since implementing the new standards. Worse, AP reported that the FDA does not even keep a comprehensive list of unapproved drugs currently on the market.
As a watchdog over health claims made by drug manufacturers – especially for products targeted at women, the Network is concerned about the safety and efficacy of unapproved products — such as the drugs described above. In 2006, the Network petitioned the FDA to halt the marketing of Estratest and Syntest, two estrogen/testosterone products that are labeled for treatment of vasomotor symptoms of menopause (e.g., hot flashes) that do not respond to estrogen alone —neither of which has been approved by the FDA for this purpose or fully reviewed for safety. While the FDA has acknowledged the known risks and unanswered safety questions associated with these products, in 2003 the agency concluded that there is not substantial evidence that they work to treat hot flashes that don’t respond to estrogen alone – the claim made on the label.
In the citizen’s petition submitted to the FDA, the Network asked that the FDA “act immediately to halt this marketing of estrogen/testosterone products for an unapproved, unproven indication,” and noted that the risks associated with the use of the products are unacceptable given the lack of substantial evidence for their efficacy. The problem is far bigger than these specific drugs, however: the FDA itself estimates that, “in the United States today, perhaps as many as several thousand drug products are marketed illegally without required FDA approval.”
In addition to the problem of unapproved drugs, many drugs approved by the FDA for one purpose are prescribed for other purposes for which they have not been approved and which may not have been thoroughly studied. This practice is called "off-label" use, and is estimated to account for about 20% of prescriptions. While the FDA does not regulate off-label use — leaving it up to providers’ clinical judgment to prescribe medicines appropriately — it does prohibit pharmaceutical companies from marketing drugs for unapproved purposes such as off-label use.
In a study published in Pharmacotherapy, researchers identified 25 drugs that are commonly prescribed off-label with inadequate supporting evidence, particularly antidepressants, antipsychotics, and some sedatives. The authors suggest that the list should be used to prioritize research into common off-label uses, and concluded: “the policy implication of our finding may include a requirement for comparative effectiveness studies, greater scrutiny of marketing for particular off-label drugs, efforts by payers to require physician justification of off-label uses, and a range of post-market pharmacovigilance activities, as appropriate.”(5)
Although these drugs were largely for mental health concerns affecting both men and women, other common off-label uses exist that affect women exclusively, such as the use of misoprostol (Cytotec) to induce labor and drugs that are used to treat infertility, menopause, and reproductive cancers. Off-label use may seem to safe, and clinicians may have observed that a specific drug seems to work for its off-label use. But, this observation does not provide the gold standard of evidence for drug approval: results from well-designed, randomized, double-blinded controlled trials. It is important for consumers to be able to rely on evidence that a drug's side effects are likely to be outweighed by its efficacy in treating their specific condition, information that is less readily available when a drug is being prescribed for an off-label, perhaps unstudied, use.
Asking for Change
The FDA currently does not require providers to inform patients when prescribing an unapproved or off-label product. As noted in the Estratest petition, women may believe a product is safe and FDA-approved simply because their health care practitioners have prescribed it, without informing them of the lack of evidence supporting the drug or a specific use. As noted by the AP analysis and suggested by the Pharmacotherapy study, substantial amounts of money are being spent (by both individuals and the Federal government) on these drugs without compelling evidence that they are safe or effective for the prescribed purpose. The NWHN believes that patients should be explicitly informed when a product is not FDA-approved for the purpose for which it is being used. While the Network will continue to respond to specific situations with advocacy efforts such as the Estratest petition, broader regulatory change is required in order to ensure that patients will know when they are taking a drug for a use that the FDA hasn’t reviewed or approved. The Network also urges reforms requiring the FDA to exercise greater scrutiny of marketing for off-label drugs, requiring clinicians to justify off-label uses, and investing resources in research to determine whether common off-label uses are safe and effective.
1. Alonso-Zaldivar R, Bass F. AP analysis: Medicaid pays for risky, unapproved drugs. November 24, 2008. Available from: http://seattletimes.nwsource.com/html/politics/2008426220_apunapproveddr...
2. NWHN, Estratest Citizens Petition, Washington, DC: NWHN, August 21, 2006. Available from: http://www.nwhn.org/UserFiles/File/EstratestCitizensPetition%281%29.pdf
3. Food and Drug Administration, Guidance for FDA Staff and Industry: marketed Unapproved Drugs Compliance Policy Guide, FDA: Silver Spring, MD, June 2006. Available from: http://www.fda.gov/cder/guidance/6911fnl.pdf
4. FDA. “FDA Takes Action Against Compounded Menopause Hormone Therapy Drugs” FDA: Silver Spring, January 9, 2008. Available from: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01772.html
5. Walton SM, Schumock GT, Lee KV et al., “Prioritizing future research on off-label prescribing: results of a quantitative evaluation,” Pharmacotherapy 2008; 28(12):1443-52.
Rachel R Walden, MLIS is a medical librarian and blogger for Women's Health News and Our Bodies Our Blog.