Once approval to market a drug has been obtained, phase 4 begins. This constitutes monitoring the safety of the new drug under actual conditions of use in large numbers of patients. The importance of careful and complete reporting of toxicity by physicians after marketing begins can be appreciated by noting that many important drug-induced effects have an incidence of 1 in 10,000 or less and that some adverse effects may become apparent only after chronic dosing. The sample size required to disclose drug-induced events or toxicities is very large for such rare events. For example, several hundred thousand patients may have to be exposed before the first case is observed of a toxicity that occurs with an average incidence of 1 in 10,000. Therefore, low-incidence drug effects are not generally detected before phase 4 no matter how carefully phase 1, 2, and 3 studies are executed. Phase 4 has no fixed duration. As with monitoring of drugs granted accelerated approval, phase 4 monitoring has often been lax.
The time from the filing of a patent application to approval for marketing of a new drug may be 5 years or considerably longer. Since the lifetime of a patent is 20 years in the USA, the owner of the patent (usually a pharmaceutical company) has exclusive rights for marketing the product for only a limited time after approval of the new drug application. Because the FDA review process can be lengthy (300–500 days for evaluation of an NDA), the time consumed by the review is sometimes added to the patent life. However, the extension (up to 5 years) cannot increase the total life of the patent to more than 14 years after approval of a new drug application. The Patient Protection and Affordable Care Act of 2010 provides for 12 years of patent protection for new drugs. After expiration of the patent, any company may produce the drug, file an abbreviated new drug application (ANDA), demonstrate required equivalence, and, with FDA approval, market the drug as a generic product without paying license fees to the original patent owner. Currently, more than half of prescriptions in the USA are for generic drugs. Even biotechnology-based drugs such as antibodies and other proteins are now qualifying for generic (“biosimilar”) designation, and this has fueled regulatory concerns. More information on drug patents is available at the FDA website at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ ucm079031.htm.
A trademark is a drug’s proprietary trade name and is usually registered; this registered name may be legally protected as long as it is used. A generically equivalent product, unless specially licensed, cannot be sold under the trademark name and is often designated by the official generic name. Generic prescribing is described in Chapter 65.
Conflicts of Interest
Several factors in the development and marketing of drugs result in conflicts of interest. Use of pharmaceutical industry funding to support FDA approval processes raises the possibility of conflicts of interest within the FDA. Supporters of this policy point out that chronic FDA underfunding by the government allows for few alternatives. Another important source of conflicts of interest is the dependence of the FDA on outside panels of experts who are recruited from the scientific and clinical community to advise the government agency on questions regarding drug approval or withdrawal. Such experts are often recipients of grants from the companies producing the drugs in question. The need for favorable data in the new drug application leads to phase 2 and 3 trials in which the new agent is compared only to placebo, not to older, effective drugs. As a result, data regarding the efficacy and toxicity of the new drug relative to a known effective agent may not be available when the new drug is first marketed.