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FDA DRUG REVIEW Postapproval Risks 1976-85

United States General Accounting Office (GAO) GAO/PEMD-90-15 Apr1990

[ source:  7nov02 ]

Report to the Chairman, Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government Operations, House of Representatives

Executive Summary


Assessing the efficacy and safety of a drug to obtain Food and Drug Administration (FDA) approval is a lengthy and complex process. But even after approval, many additional risks may surface when the general population is exposed to a drug. These risks, which range from relatively minor (such as nausea and headache) to serious (such as hospitalization and death) arise from the fact that preapproval drug testing is inherently limited. The extent of postapproval risks and the reasons they go undetected during preapproval testing, however, have not been analyzed.

The Chairman of the Subcommittee on Human Resources and Intergovernmental Relations of the House Committee on Government Operations asked GAO to study the frequency and seriousness of drug risks identified after FDA approval for marketing and to examine some of the characteristics of these drugs as a first step in understanding why these additional risks occur.


The drug approval process begins with the submission of an “investigational” application, when a drug company applies to FDA for permission to test the drug in humans. Then, when the clinical studies involving humans provide evidence of a particular drug’s beneficial effect at an acceptable level of safety, the company submits a new drug application (120 were submitted in 1986) to FDA for approval of the drug for wide- spread use. The agency subsequently reviews all evidence pertaining to the drug’s efficacy and safety. If it finds the cumulative evidence acceptable, FDA approves the drug for marketing (after, on the average, 29 months of review).

The preapproval human clinical trials for a drug involve testing with a relatively small sample of the potential user population under controlled conditions that limit the extent of risk assessments. However, when therapeutic benefits appear to outweigh the estimated potential risks, the new drug is approved as soon as possible for the benefit of those who can use it. After FDA approves the drug for marketing, it is then used by patients under conditions much less controlled than those that prevailed during testing.

When a company markets an approved drug, it is required by law to include directions for its use-as well as warnings, precautions, and adverse reactions-on the drug’s label. Postmarketing surveillance then identifies potential adverse reactions not included on the original label that are discovered after marketing is begun. If an adverse reaction is found to be linked to the use of a drug, its label is changed to include the additional risk. GAO reviewed the label changes for all 209 new drugs FDA approved between 1976 and 1985 in order to determine the frequency and seriousness of the additional risks linked to these drugs after their initial approval. GAO plans to continue its examination of the factors underlying the occurrence of serious postapproval risks in FDA-approved drugs.

Results in Brief

In studying the frequency and seriousness of risks identified after approval, GAO found that of the 198 drugs approved by FDA between 1976 and 1985 for which data were available, 102 (or 51.5 percent) had serious postapproval risks, as evidenced by labeling changes or withdrawal from the market. All but six of these drugs were currently marketed as of September 1989 and are deemed by FDA to have benefits that outweigh their risks. The serious postapproval risks are adverse reactions that could lead to hospitalization, increases in the length of hospitalization, severe or permanent disability, or death. These adverse reactions resulted in a substantial change in the labeling of the drugs, typically either limiting the population for which they are intended or adding major warnings or precautions for their use.

The number of serious postapproval risks is small when compared to the number of adverse reactions that had been identified at the time of approval. GAO did not attempt to determine the reasons why the risks emerged (or whether they could have been identified during preap- proval testing), the extent to which patients were exposed to them before they were identified, or the number of patients affected. How- ever, these findings make clear that further understanding is needed of the characteristics associated with these additional risks and why they arose.

Principal Findings

The serious postapproval risks identified in studying their frequency and seriousness involved a wide variety of adverse reactions, including heart failure, myocardiai infarction, anaphylaxis, respiratory depression and arrest, convulsions, seizures, kidney and liver failure, severe blood disorders, birth defects and fetal toxicity, and blindness. These adverse reactions occurred over many drug classes. GAO found that in 12 of 22 classes more than 50 percent of the drugs approved had serious postapproval risks. The 12 classes are cardiac drugs, psychopharmacologic drugs, drugs to combat drug abuse, antibiotics, fertility and antifertility drugs, metabolic and endocrine drugs, ophthalmic drugs, antiparasitic drugs, oncology drugs, anti-inflammatory drugs, anesthesia drugs, and surgical drugs. The degree of additional risk varied: It was more serious and occurred more often for some drugs than for others, with approximately one quarter having serious postapproval risks affecting three to five body systems (including cardiovascular, respira- tory, central nervous system, renal, and gastrointestinal). Additional risks in a body system fall along a spectrum that includes other less severe adverse reactions. (See pages 24-41.)

In examining some characteristics of drugs approved by FDA, GAO found several that are associated with the presence of serious postapproval risks. Drugs that appeared on FDA'S postmarketing surveillance list because of adverse reactions not present on the current label were over 10 times as likely to have serious postapproval risks as those that did not. Drugs that were reviewed for use in children were more than twice as likely to have serious postapproval risks. Drugs approved between 1976 and 1980 were almost three times as likely to have serious postap- proval risks as those approved between 1981 and 1985, although some evidence suggests that GAO'S assessment for the latter period may be low (see pages 51-53). GAO also found that among drugs approved in fewer than 4 years, those that turned out to have serious postapproval risks had generally been approved by FDA in a shorter time than those with- out such risks. The class of a drug may also be related to the emergence of serious postapproval risks. (See pages 42-56.)


GAO recommends that the Commissioner of FDA establish formal procedures to evaluate postapproval risks for new drugs and use this information in premarketing review and postmarketing surveillance. GAO believes that such procedures would contribute to better and more timely drug labeling. GAO believes that FDA, in implementing this recommendation, should build upon the steps followed in this report: (1) identifying serious and nonserious postapproval risks, (2) enumerating the risks by drug class, (3) identifying the body systems affected by the risks, and (4) comparing the additional risks with those identified at the time of approval. The Commissioner should also try to estimate the population exposed to the additional risks and assess their significance in terms of expected fatalities and morbidity.

Agency Comments

While agreeing that it is important to know whether the current drug review process may overlook serious risks, HHS objected to GAO'S methodology. The department was also concerned that this report will unnecessarily alarm consumers, causing some to reject the use of lifesaving drugs out of fear of adverse events that might occur only in extremely rare instances, and that it could create a misleading impression of the drug review process, by identifying drugs as having serious postapproval risks that could not have been so identified in the drug review process, Also, HHS did not concur with GAO'S recommendation, indicating that it was vague and that it assumed FDA could somehow anticipate the unknown.

GAO believes the study methodology was sound and, consequently, no substantial changes have been made in the findings, conclusions, or recommendation. However, GAO has modified the presentation in certain parts of the report to clarify the language and to avoid misunderstandings about the research performed (that is, the questions posed and the methodology for answering them).

With respect to HIIS'S view that consumers will be unnecessarily alarmed by this report, GAO has noted that 96 of the 102 drugs identified as hav- ing serious postapproval risks were currently marketed as of September 1989 and thus are deemed by FDA to have benefits that outweigh their risks, despite the additional risks that have been identified. GAO does not dispute FDA'S assessment of benefits and risks. What is in question here is the degree to which careful analysis can help in reducing predictable risk to the consumer.

HIIS'S comments are reproduced as appendix V to this report. GAO'S response to each point is contained in appendix V and presented at other appropriate places in the body of the report.

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