• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services


  • Print
  • Share
  • E-mail

Appendix G

Table of Contents: Managing the Risks From Medical Product Use: Creating a Risk Management Framework

Previous Section : Appendix F

Risk Intervention Examples

A. Restrictions on Product Use

1. Thalidomide (See description in Appendix F.)

2. The Center for Devices Postmarketing Study Requirements

Issue: Premarket testing does not address all device-related concerns about a product.

FDA Action: FDA can require a manufacturer to conduct postmarketing surveillance as a condition of approval for a product brought through the premarketing approval (PMA) process or as part of FDA's authority to require postmarketing studies for high risk products under section 522 of the FD&C Act. The Modernization Act changed the scope of section 522. To implement these new provisions, the Center for Devices issued a guidance that outlines criteria the Agency intends to use routinely to implement postmarketing surveillance (Guidance on Criteria and Approaches for Postmarket Surveillance, issued November 2, 1998).

Outcome: The guidance provides general principles that will guide FDA's decisions concerning postmarketing surveillance. It identifies products in categories and describes how the needs for postmarketing surveillance will be assessed. These products may have been approved through either the PMA process or section 510(k) of the FD&C Act. The products may have been on the market for some time or may be new to the market.

In addition, the Center for Devices provides written notice of the general and specific postmarketing requirements to each holder of a PMA at the time of approval. The Center for Devices provides descriptive information about the product, the training required for professionals prior to the use of some products, and manuals that give detailed instructions for the setup, use, and maintenance of the equipment. For many medical devices, additional labeling intended for the patient, usually an information booklet, is also required at the time of market entry.

3. Proleukin (Aldeskleukin)

Issue: Proleukin is an example of a product where FDA identified a risk associated with the product and restricted its use through information in the product labeling.

FDA Action: FDA identified that there were risks of heart attack and sudden death associated with Proleukin early in IND development by reviewing the development plans of multiple IL-2 products submitted by sponsors. FDA was able to attribute the small number of heart attacks and sudden deaths to the product and not to other factors.

Outcome: FDA instituted procedures in the clinical trials to ensure that patients were given the product in a controlled environment (i.e., hospital setting). On approval, the Center for Biologics included boxed-warning information in the labeling, specifying product administration conditions and restricting the product use to patients with normal cardiac and pulmonary function.

4. Measles, Mumps, and Rubella Vaccine (MMR)

Issue: As a part of the monthly review of reports from the Vaccine Adverse Events Reporting System (VAERS), FDA noted that thrombocytopenia following immunization with measles- containing vaccines was more severe than was previously perceived. Approximately 40 percent of reports of postimmunization thrombocytopenia described cases with platelet counts # 20,000, a level that has been associated with spontaneous life-threatening hemorrhage. In reviewing all reported cases of post-MMR thrombocytopenia in VAERS, FDA found one case of thrombocytopenia that resulted from positive rechallenge with MMR vaccine. FDA also found two deaths that occurred in children with postimmunization thrombocytopenia; however, these two children had complicated medical histories, so a direct causal relationship with vaccination could not be made.

FDA Action: FDA discussed these findings and searched the literature for similar reports. The search showed that investigators in Finland had reported that 30 percent of children with thrombocytopenia after MMR immunization had detectable anti-IIbIIIa platelet antibodies. Following these reports, FDA's Laboratory of Pediatric and Respiratory Diseases initiated a research study to identify the vaccine antigens that might be responsible for inducing antiplatelet antibodies. These studies showed that (1) vitronectin receptor proteins derived from the chick embryo fibroblast cells (CEFs) used as the substrate for production of measles and mumps vaccine cross-react with anti-IIbIIIa platelet antibodies; (2) in mice, immunization with measles vaccine or with CEFs induces anti-IIbIIIa antibodies; (3) antibodies to measles matrix protein also cross-react with platelet protein IIIa; and (4) following immunization with measles vaccine 0.5-1 percent of children develop antibodies that react with human IIbIIIa, indicating that they may be at risk for episodes of immune thrombocytopenia when reexposed to any vaccine that contains cross-reacting antigens.

Outcome: Based on the review of the VAERS data and the literature, labeling for measles-containing vaccines was revised to provide adequate information to warn and inform healthcare providers about the use of measles vaccine in children with thrombocytopenia or with a history of thrombocytopenia following previous doses of MMR. The Center for Biologics research suggested a mechanism as to why there might be an association with thrombocytopenia and MMR vaccines in some individuals.

B. Center for Biologics and Center for Drugs Phase-4 Commitments

1. Herceptin (Trastuzmab)

Issue: Herceptin is a monoclonal antibody approved for the treatment of patients with metastatic breast cancer whose tumors express the HER2 protein and who have received one or more chemotherapy regimens. Clinical adverse event reports showed symptomology of cardiac toxicity.

FDA Action: FDA requested that the Data Safety Monitoring Board (DSMB) look at cardiac toxicity during an interim data analysis. Based on the interim analysis, FDA worked with the manufacturer to revise consent forms and reinstitute cardiac monitoring. Further data analysis showed that patients who were treated with Herceptin in combination with anathracyclines and cyclophosphamides had a particularly high incidence of cardiac dysfunction.

Outcome: When approved for market, the Center for Biologics required boxed-warning information in the product labeling for physicians using the product to treat patients who also have cardiomyopathy. The Center for Biologics also required that patients with early signs of Herceptin-induced cardiotoxicity be evaluated to weigh the risks and benefits of continuing therapy with Herceptin. The manufacturer committed to a postmarketing study in patients using the product.

2. Celebrex (celecoxib capsules)

Issue: Celebrex, a new COX-2 selective nonsteriodal anti-inflammatory drug (NSAID), was approved for use in the treatment of osteoarthritis and rheumatoid arthritis. Studies used for the basis of approval showed that patients taking Celebrex had a substantially lower risk of ulcers detected by endoscopy over the study period of 12 to 24 weeks, as compared to patients who took other NSAIDS. However, FDA believed that the limited data available on gastrointestinal outcomes were not sufficient to support a product claim that Celebrex was safer than other NSAIDs regarding serious GI effects. Such a claim would need additional studies in many thousands of patients to demonstrate that Celebrex causes fewer clinically important GI complications.

FDA Action: On approval, FDA included a slightly modified standard warning in Celebrex's approved product labeling for doctors and patients about the risk associated with NSAIDS, including risks of GI ulceration, bleeding, and perforation, and requested further study of the GI and renal effects.

Outcome: The product sponsor committed to studying the GI effects further using protocols agreed to by FDA. If additional information relating to the safety or effectiveness of the drug product becomes available, substantial revision of the product labeling may be required.

 C. Market Withdrawals/Recalls

1. Blood products (See previous blood product CJD example.)

2. Drug Withdrawals

a. Posicor (mibefradil)

Issue: On approval of the product in August 1997, FDA described enzyme-inhibiting properties in Posicor's approved labeling and listed three drugs that could accumulate to dangerous levels if coadministered with Posicor (a calcium-channel blocker). FDA strengthened the labeling in December 1997 after learning of several cases in which patients suffered serious adverse reactions after taking Posicor with one or more of other drugs. FDA included more drugs in the labeling that should not be administered with the product and issued a public warning about the problem. The company also issued a Dear Healthcare Professional letter alerting healthcare professionals of the drug interaction problems.

FDA and the company continued to learn of adverse reactions related to coadministration of Posicor with other drugs. More than 25 drugs were known to be potentially dangerous if used with Posicor -- a number and diversity of drugs that cannot be practically addressed by standard labeling warnings.

FDA Action: Due to the complexity of the prescribing information needed for Posicor and the seriousness of the side effects, FDA and the company agreed that it would be difficult to administer Posicor safely. In addition, Posicor had not been shown to offer special benefits, and its problems were viewed as unreasonable risks to consumers.

Outcome: The company voluntarily withdrew Posicor from the market as a result of new information about potentially harmful interactions with other drugs.

b. Duract

Issue: FDA and the company received postmarketing reports of severe hepatic failure associated with the use of the nonsteroidal anti-inflammatory analgesic Duract, resulting in four deaths and eight liver transplants. All but one of the cases involved the use of Duract for longer than 10 days -- the maximum recommended duration of treatment.

FDA Action: In response to the reports, FDA and the company strengthened the warnings in Duract's labeling with a special black-box warning and the company issued a Dear Healthcare Professional letter. Despite these efforts, the Agency and the company continued to receive reports of severe injuries and death with long-term use of Duract.

Given the availability of other therapies, FDA and the company concluded that it would not be practical to implement the restrictions necessary to ensure the safe use (less than 10 days) of Duract and that the drug should be withdrawn from the market.

Outcome: Duract was withdrawn from the market.

c. Seldane

Issue: Seldane (terfenadine) and Seldane-D have been associated with rare but serious heart problems when taken with certain other drugs, including certain antibiotics and antifungals.

FDA Action: Due to the serious drug interaction, FDA proposed removing all terfenadine products from the marketplace because of the approval of a safer alternative drug, Allegra (fexofenadine), in January 1997. FDA also advised patients taking Seldane, Seldane-D, and generic terfenadine products to talk to their healthcare providers about switching to alternative medications.

Outcome: Following the approval of Allegra-D, the manufacturers of Seldane, Seldane D, and generic terfenadine discontinued U.S. distribution and marketing of the products. FDA has completed administrative procedures to finalize the permanent withdrawal of all terfenadine-containing products from the U.S. market.

3. Device Withdrawals

Issue: Medline Industries, Inc., marketed three basic versions of an enteral feeding pump. These pumps had a number of design defects apparently caused by an initial flawed design and/or lack of validation and the inability to comply with the GMPs.

FDA Action: The Center for Devices issued an order for recall and required Medline Industries, Inc., to stop distributing all Medline/Dynacor Dynafeed Enteral Feeding Pumps, to notify health professionals and device user facilities to stop using the device immediately, and to recall the products on the market.

Outcome: The defective devices were recalled from the market.

D. Interventions by Enforcement Activities

HIV Home Test Kits

Issue: In 1998 the Office of Special Health Issues was notified by constituents that HIV home test kits were being advertised and sold over the Internet. Results from these kits could be obtained immediately and in the privacy of the home. No such kits had ever been approved by FDA. The Office of Compliance and Biologics Quality at the Center for Biologics had also received complaints about the kits.

Home HIV test kits are medical devices within the definition of section 201(h) of the FD&C Act and are regulated by the Center for Biologics as Class III devices under the current Intercenter Agreement between the Center for Devices and the Center for Biologics.

Because the HIV home test kits being sold over the Internet were unapproved, there was no assurance that the test kits were manufactured under good manufacturing practices, that the kits had been tested properly, or that the results obtained by the persons testing themselves would be accurate. This could have presented a serious hazard to the public health, including possible HIV transmission to partners and delayed access to medical care due to false negative test results. The home HIV test kits sold over the Internet did not have capabilities for confirmatory testing. Furthermore, there was no provision for counseling and referral for confirmatory testing or medical and social support services in the area where the patient lived.

FDA Action: The Office of Special Health Issues (OSHI) and the Center for Biologics worked closely to find ways that the Internet promotions could be halted. A Question and Answer (Q&A) document was developed and posted on several of the Agency's web pages. A directed inspection of the firms took place and the Center for Biologics initiated several enforcement actions, including criminal prosecution and seizures of the products. The Federal Trade Commission (FTC) also joined with FDA to help stop the illegal sale of the HIV home test kits on the Internet.

Outcome: Websites of this type have been greatly reduced because of intra- and interagency cooperation. FTC continues to sponsor Internet surf days dedicated to looking for sale of fraudulent products on the Internet. With the Center for Biologics' cooperation, notices are sent to the websites notifying them of the violation and requesting that the site be removed.

Next Section : Appendix H