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Appendix F

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

Previous Section : Appendix E

Examples of Risk Confrontation

Collaboration/Partnerships with Stakeholders

1. Thalidomide

Issue: Although beneficial in the treatment of erythema nodosum leprosum (ENL), FDA had serious concerns about the risks related to thalidomide's use in women of childbearing age or pregnant women.

FDA Action: FDA invoked unprecedented regulatory controls over the marketing of thalidomide in the U.S. During the approval process, FDA'>s Dermatologic and Ophthalmic Drugs Advisory Committee listened to presentations from FDA, the product sponsor, and interested members of the public regarding the risk and benefits of thalidomide use. Public participants included representatives from the Canadian Thalidomide Victims Association. Following the presentations, the Committee voted that thalidomide was effective for the treatment of cutaneous ENL lesions.

Subsequently, on September 9-10, 1997, FDA, NIH, and CDC cosponsored an open public scientific workshop to further discuss the potential benefits and risks of thalidomide, including the medical, scientific, legal, ethical, and other policy issues related to research and treatment. There was extensive discussion of the proposal of Celgene Corporation (the product sponsor) for a fetal exposure prevention program.

FDA approved thalidomide for the treatment of ENL on July 16, 1998, along with regulatory controls over marketing the product in the U.S. To ensure safe use of the drug, Celgene developed a comprehensive program for patients, physicians, and pharmacists, in cooperation with experts in public health and women's health. The System for Thalidomide Education and Prescribing Safety (STEPS) oversight program includes limiting authorized prescribers and pharmacies, providing extensive patient education about the risks associated with thalidomide, and providing a 100 percent patient registry. This program is designed to help ensure a zero tolerance policy for thalidomide exposure during pregnancy.

FDA's efforts to inform the public about the approval of thalidomide included telephone conferences with members of the consumer, patient, and healthcare communities, extensive press interviews, and background briefings. The Center for Drugs created a thalidomide Internet page (www.fda.gov/cder/news/thalidomide.htm) to present consumer and patient information, thalidomide advisory committee and workshop transcripts, the approved labeling text, and the medical review on which the decision to approve this drug was based. This thalidomide page includes selected links to other websites containing thalidomide information.

Outcome: Thalidomide was approved by FDA with a risk management program that limits authorized prescribers and pharmacies, provides extensive patient education about the risks associated with thalidomide, and provides a 100 percent patient registry. This program is designed to help ensure a zero tolerance policy for thalidomide exposure during pregnancy. As of April 1999, FDA has received no reports of thalidomide exposure during pregnancy.

2. Tamoxifen

Issue: In 1998, FDA received the first application (supplemental new drug application) to market a drug for a cancer prevention indication. Interim results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial had shown that tamoxifen reduced breast cancer incidence by almost one half. However, two other studies reported no significant difference in the number of breast cancer cases between women taking tamoxifen and women given placebo. In addition, questions were raised about tamoxifen's treatment benefits versus its risks of serious side effects, including endometrial cancer, deep vein thrombosis, stroke, cataract formation, and pulmonary embolism. Some of the events reported were fatal. Furthermore, the study did not demonstrate a reduction in overall or breast cancer specific mortality with tamoxifen treatment.

Action: FDA convened the September 1998 Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the results of the National Cancer Institute (NCI) sponsored NSABP Breast Cancer Prevention Trial (BCPT) and two articles published in The Lancet in July 1998, following Zeneca's supplemental new drug application. The BCPT included over 13,000 patients and was halted 14 months early when interim results showed that tamoxifen reduced breast cancer incidence by almost one half. However, the articles in The Lancet reported that European scientists found no significant difference in the number of breast cancer cases between women taking tamoxifen and women given a placebo.

Data from the studies were presented at the ODAC meeting and discussed in great detail. FDA invited Trevor Powles, the author of one of the European trials, to present his trial and comment on the difference in results. The meeting was well covered by the media and the public comment session provided a forum for comments from consumer, women's health, and breast cancer patient advocates. Many committee members and public speakers raised concerns about Zeneca's proposed tamoxifen indication for prevention of breast cancer in women at high risk, in that treatment with tamoxifen did not completely eliminate breast cancer risk and that its longer-term effects were not known. Also, ODAC recommended that NSABP perform additional studies on banked specimens that might identify women at particularly high risk of certain adverse events.

Outcome: On October 29, 1998, FDA approved tamoxifen for reducing the incidence of breast cancer in women at high risk for developing the disease. Zeneca was asked to provide an educational program for physicians and patients, including information about the drug's potential benefits and risks. The approval included a professional and patient information brochure and a breast cancer risk assessment tool developed by NCI.

3. Latex Allergy

Issue: Cases of sudden death associated with the use of barium enema kits were reported to the FDA in 1989 and 1990. In some instances, the reported incidents occurred prior to the introduction of the barium solution.

FDA Action: Based on these reports, FDA postmarketing clinical area experts initiated an investigation and follow-up that directed firm inspections and a comprehensive review of the scientific and clinical literature. This review revealed the potential for serious allergic or anaphylactic reactions to devices containing natural rubber latex.

As a result of FDA's initial postmarketing investigation of these reports, one manufacturer of natural rubber latex cuffed enema tips voluntarily agreed to send a Medical Alert to approximately 10,000 practicing radiologists, alerting them to the possibility of allergic reactions to latex-containing enema tips. The Alert advised healthcare professionals to minimize the use of tips with retention cuffs and recommended the use of noncuffed tips whenever possible. Physicians were also urged, for the first time, to screen patients for latex allergy history prior to procedures. Based on additional health hazard evaluations of inspection findings, FDA determined that the problems associated with the firm's latex cuffed enema tips presented a high risk of serious adverse health consequences. Thus, FDA recommended that the firm's Medical Alert be expanded to include more health professionals and organizations. As a result, the firm expanded their clinical alert and initiated a nationwide recall of all their latex cuffed enema tip products.

FDA's postmarketing activities have continued to be a catalyst for both national and international clinical education efforts, scientific and clinical research, and voluntary standards activities on natural rubber latex allergy. Notable postmarketing activities are listed below.

  • FDA issued a 1991 medical alert entitled "Allergic Reactions to Latex-Containing Medical Devices." This indicated that FDA considered the problem to be generic and not limited to barium enema tips. The alert suggested ways to identify and protect allergic individuals in clinical settings. This alert was provided to approximately 1,000 radiological and medical organizations and was published in the July 1991 FDA Medical Bulletin.
  • The Center for Devices sent a letter to all manufacturers of latex-containing devices that discussed how to manufacture latex products to minimize the possibility that latex contaminants are either a source of, or a contributing factor to, adverse reactions.
  • In 1992, the Center for Devices sponsored the first international forum for addressing natural rubber latex allergy. The conference was entitled International Latex Conference: Sensitivity to Latex in Medical Devices, and was cosponsored by CDC and the National Institute of Allergy and Infectious Diseases (NIAID).
  • The Center for Devices sponsored a March 1994 workshop entitled Contact Sensitivity to Latex. Recommendations from expert participants were used as a basis for developing a Center for Devices guidance document entitled Testing for Skin Sensitization to Chemicals in Natural Rubber Products.
  • FDA devoted the Spring 1997 edition of FDA's User Facility Reporting Bulletin entirely to natural rubber latex allergy issues. This bulletin was sent to over 70,000 healthcare professionals in hospitals, nursing homes, other user facilities, and healthcare professional organizations.
  • FDA proposed regulations to help healthcare professionals and consumers identify medical devices that contained natural rubber latex to facilitate the ability of clinicians to provide latex-free products for individuals with diagnosed latex sensitivity. "Natural Rubber-Containing Medical Devices; User Labeling," was published as a final rule in the Federal Register (62 FR 51021, September 30, 1997).
  • The Center for Devices Medical Glove Working Group released the Medical Glove Powder Report in September 1997. This document is available as a resource to regulated industry and consumers.
  • The Center for Devices and its Office of Surveillance and Biometrics (OSB), worked with the Office of Health Affairs (OHA) and the Food and Drug Law Institute, initiating and leading a precedent-setting postmarketing initiative to develop and fund a live educational teleconference in recognition of the need for Federal agencies to provide their constituencies with current, consistent scientific and regulatory information on natural rubber latex allergy. The collaboration involved seven Federal agencies, seven major U.S. health professional and industry organizations, the Canadian Royal College of Physicians and Surgeons, and Health Canada. The goal of this consortium was to create an educational resource that would provide important baseline information to healthcare professionals and others concerned with latex allergy, and that could serve as a resource for similar collaborations in the future.

Outcome: This benchmark collaboration resulted in the broadcast of a live educational teleconference entitled Natural Rubber Latex Allergy: Recognition, Treatment, and Prevention, May 5, 1998. Due to the power of the combined marketing efforts of the cosponsoring groups and medical device manufacturers, the satellite teleconference reached the largest live audience of multidisciplinary healthcare professionals and others ever assembled. FDA alone mailed out over 130,000 teleconference brochures to various healthcare professionals.

The teleconference continues to serve as a consumer and industry resource due to its continued availability on videotape, CD-ROM, and as an Internet webcast. Each year Teleconference Magazine and TeleCon honor the most outstanding achievements in teleconferencing, business television, and distance learning. Award recipients are judged on their immediate or potential future impact on interactive multimedia communications, and the product must provide a new or unique solution to ensure seamless high quality transport and use of video, voice and/or data. These awards are often referred to as the Academy Awards of Teleconferencing. In recognition of the innovative use of multimedia formats for presenting the clinical educational material, the latex allergy teleconference was awarded second place for Best User Application in the Interactive Multimedia Communications category.

4. Regulation for the Waiver of Informed Consent in Clinical Trials

Issue: FDA wanted information and input from Federal, private, and public sectors regarding the development of the regulation for the Waiver of Informed Consent in Clinical Trials involving emergency research.

FDA Action: The Office of Health Affairs, in collaboration with the Office for Protection from Research Risks at NIH, held open public conferences and workshops during the development of the rule and after the rule's implementation. These conferences provided an opportunity for interested parties to raise concerns about the rule's potential impact and for FDA to learn about details to assist in implementation following the rule's publication.

Outcome: The information gained from meetings with the relevant parties affected was used to publish the regulation.

5. The Center for Devices STAMP Program with Cerebrospinal Fluid (CSF) Shunt

Issue: Procedures are needed to engage the healthcare community to discuss the risks associated with medical products and motivate the manufacturing community to improve the risk-benefit profile of the highlighted products.

FDA Action: An example of FDA engaging the healthcare community in the goal of minimizing risk and improving technology in our regulated products is the Center for Devices' new Systematic Technology Assessment of Medical Products (STAMP) program. In this program, the Center identifies products with potentially significant problems that also offer significant clinical benefit. STAMP provides a forum to discuss products in the anticipation that this will motivate the healthcare and manufacturing community to improve the products' risk-benefit profiles. Information for this forum is provided by journal articles, public workshops, conferences, and FDA advisory panels. A recent example is CSF shunts.

Neurological CSF shunts have served a purpose in the overall armamentarium for treating hydrocephalus for over 40 years, but literature and adverse event reporting indicated continuing problems. Standards provide some guidance for mechanical testing but this alone has not been effective in predicting the clinical performance of these devices. The Center for Devices believed that holding a conference on the subject of shunt technology would provide an opportunity to examine the current state of the technology and explore different approaches to improve patient outcomes. Since there were a variety of stakeholders interested in this subject and the current research seemed fragmented, a conference format was selected that allowed the Center for Devices to use a multidisciplinary approach to tackle the issues. The conference was held on Friday, January 8, 1999, at the National Naval Medical Center (NNMC). NNMC was chosen in an effort to expand Agency contact with the military medical community and establish further collaboration.

The Center for Devices contacted all of the known stakeholders for input and decided on four session topics:

1. Shunt Technology Perspectives. Stakeholder representatives (from the Hydrocephalus Association, the American Association of Neuroscience Nurses, industry, and a neurosurgeon) spoke about their perspectives on the issues.



2. Hydrocephalus and Assessment of Shunt Function. Scientific talks on the pathophysiology and methods of evaluating shunt performance were presented.



3. Challenges of Infection and New Perspectives. Issues of shunt-centered infections and the emergence of antimicrobial resistance were discussed.



4. Clinical Outcomes and Methods of Surveillance. Strategies to improve clinical outcomes and the performance of CSF shunts were presented.


Following the four sessions, a panel discussion was held to establish priorities. The panel consisted of FDA and NIH representatives, several notable neurosurgeons, and a representative of a patient group.

Outcome: The Center for Devices is now in the process of reviewing the material presented during the conference and plans to submit a summary article for publication in several journals so that what was shared on January 8, 1999, can reach a larger audience. The Center for Devices will propose some recommendations that will include further involvement of stakeholders and perhaps publishing an update of action items completed or in progress. Some proposed recommendations include developing better patient labeling that would include information on a patient's specific implant, continued work on standards development with new contacts and players to be involved, and a collaborative effort to collect data on CSF shunts using the on-line outcomes database of the American Association of Neurological Surgeons and Congress of Neurological Surgeons (AANS/CNS).

6. Blood Products and CJD

Issue: While there are no recorded cases of Creutzfeldt-Jakob Disease (CJD) transmission in humans through blood, there is a theoretical possibility for transmission from donors with or at risk for CJD. Ensuring the safety of America's blood supply is a high priority for FDA. Thus, FDA needed to take aggressive actions to mitigate the potential risk of CJD transmission and decide how best to protect the public health, having only incomplete or emerging scientific knowledge.

FDA Action: As clinical and epidemiological knowledge of CJD has increased, FDA has responded aggressively by reviewing and modifying its policy and communicating revised recommendations to the healthcare community. Throughout this process, FDA has worked closely with CDC and NIH, among others, in determining the most appropriate regulatory course of action. FDA has also had extensive discussions with all segments of the community involved, including medical professionals, academicians, industry representatives, and recipients of blood components and products.

FDA's involvement in addressing the possible impact of CJD on the Nation's blood supply began with the early awareness of possible transmission. In 1987, FDA issued a memorandum to all blood establishments, recommending that all persons who received human growth hormone (HGH) defer donating blood or plasma. For the period of 1983-1992, there were only four reported blood donors who had a confirmed diagnosis of CJD reported postdonation. Blood and plasma manufacturers initiated a voluntary withdrawal of in-date products that had been prepared for donation from the individuals with a confirmed diagnosis of CJD.

In 1993, FDA expanded its position and issued recommendations for more complete reporting of safety-related information from blood and plasma donors postdonation. In 1994 and early 1995, FDA began receiving additional reports of CJD-affected individuals who had donated blood and plasma. At FDA's request, the manufacturers placed in-date, licensed, retrievable derivatives of blood and plasma, as well as products used in further processing, into quarantine. Market withdrawals for CJD were discussed at the Blood Products Advisory Committee (BPAC) in 1994 and 1995; however, the committee was unable to reach consensus on all of the issues related to product disposition and recipient notification.

In an effort to further develop policy on CJD, FDA formed a Special Advisory Committee on CJD, later rechartered the Transmissible Spongiform Encephalopathies Advisory Committee (TSEAC), to address outstanding issues and encourage additional public discussion and consideration. (The outcome of this meeting is presented below.) TSEAC also met to discuss recommendations for reentering deferred donors based on genetic testing and the disposition of plasma derivatives prepared from products collected from donors having a family member diagnosed with CJD. In 1996, FDA and the National Heart, Lung, and Blood Institute (NHLBI) sponsored a workshop on Design of Experimental Studies of Transmission of CJD, and FDA participated in a Canadian Consensus Conference (CJD - Decision Making in Times of Uncertainty) and a liaison meeting with the Pharmaceutical Research and Manufacturers of America (PhRMA) regarding transmissible spongiform encephalopathies (TSE). In addition, CJD policy was discussed at seven Public Health Service (PHS) conference calls attended by representatives of the Center for Biologics, CDC, NIH, and the Department of Defense.

Outcome: After considering recommendations from TSEAC and after extensive internal discussions, FDA issued an interim policy that broadened guidance on donor exclusion for CJD risk and called for withdrawal of implicated blood products. Provisions were made for release of affected products with special labeling, in case of a documented shortage. FDA and NIH also held a workshop on design of experimental studies on transmission of CJD.

FDA revised its recommendations for CJD in 1996 and again in 1998 to include retrieval, quarantine, destruction, and notification of consignees in the event that in-date products are manufactured from donors who developed new variant CJD. In its decision, FDA carefully considered the delicate balance of the need for the products and the risk of using the products. FDA made information concerning product recalls and market withdrawals widely available to interested and affected parties through voice information systems, fax-on-demand, automated e-mail, and the FDA Home Page. In addition, industry is implementing a registry that will allow for notification of individual product users. For the BPAC, the Center for Biologics routinely provides updates on CJD policy discussions and changes.

7. Abnormal Fat Redistribution

Issue: HIV/AIDS-related abnormal fat redistribution, or lipodystrophy, is a complex syndrome that occurs among patients receiving protease inhibitors and other antiretroviral agents. Further knowledge is needed to address this product risk.

FDA Action: To help coordinate efforts to define, track, and seek appropriate approaches to HIV/AIDS-related abnormal fat redistribution, FDA is working with the HIV/AIDS community and other government agencies to discuss the current situation and communicate about what steps need to be taken to address the problems. Because abnormal fat redistribution is a complex syndrome that crosses several medical subspecialties, extensive collaboration by government, and academic and pharmaceutical scientists will be required. FDA may be able to stimulate pharmaceutical sponsor interest in certain projects related to abnormal fat redistribution. FDA has requested additional information from sponsors regarding reports of abnormal fat redistribution among patients receiving protease inhibitors and proposed package insert revisions to include information on abnormal fat redistribution. All protease inhibitor package inserts have been or soon will be revised to include this information. FDA has also encouraged sponsors to investigate potential mechanisms for abnormal fat redistribution and to assess the frequency of this syndrome in ongoing and future trials. FDA has sent a follow-up letter to sponsors asking them to enumerate ongoing or planned research projects that may address issues relating to abnormal fat redistribution.

The Agency is working in a consultative capacity to the NIAID AIDS Clinical Trials Group and the Forum for Collaborative Research in HIV/AIDS to develop a case definition for this syndrome. Based on a workable case definition, FDA plans to ask pharmaceutical sponsors to monitor changes in body morphology in ongoing and future clinical trials of antiretroviral drugs. FDA is also working with the NIH working group on Metabolic Complications of Antiretroviral Therapies, which will include representatives from several NIH institutes and the Department of Veterans Affairs, to develop suggestions for research into potential mechanisms for this syndrome. FDA has a representative on this working group and will attempt to stimulate interest among pharmaceutical sponsors to collaborate with Government and academic scientists in suggested research projects.

Outcome: FDA has requested that protease inhibitor sponsors revise the product labeling to include risk information about abnormal fat redistribution and plan research to study the problem. FDA is continuing to work with the healthcare community and other agencies to gain further insight about how to manage this product risk.

8. Vaccine Safety

Issue: Nearly every child in the United States is immunized for vaccine preventable diseases, but unlike other pharmaceutical products, vaccines are given to mostly healthy children and infants. The irony of the success of the immunization programs, demonstrated by the near or record low levels of occurrence of most vaccine-preventable diseases, is that there is a loss of awareness about the severity of the diseases prevented by the vaccination program. This loss of disease awareness results in reduced tolerance for adverse reactions following vaccination and loss of parental confidence. Loss of parental confidence in the vaccination program may cause parents not to have their children vaccinated in accordance with recommendations, resulting in outbreaks of vaccine-preventable diseases with subsequent increases in morbidity and mortality.

FDA Actions: To limit the risks of vaccinations to healthy children, FDA collaborates with other Public Health Service (PHS) agencies and healthcare organizations to study or address issues of vaccine safety. For example, FDA participates in a variety of PHS cross-agency efforts on vaccine safety and has liaisons on other PHS advisory groups, such as the National Vaccine Advisory Committee, the Advisory Commission on Childhood Vaccines, and the Advisory Committee on Immunization Practices. FDA also has a liaison to the American Academy of Pediatrics' Committee on Infectious Diseases.

One cross-agency group in which FDA participates is the Interagency Vaccine Group (IAVG), coordinated by the PHS National Vaccine Program Office. IAVG analyzes extensive risk-benefit data in response to public concerns about safety and has played a major role in the development of the National Vaccine Plan, the Pandemic Influenza Plan, and the Vaccine Safety Action Plan.

In addition, FDA had representatives on the Task Force on Safer Childhood Vaccines that was established by the Secretary of HHS at the direction of Congress. This task force examined vaccine safety and made recommendations to the Secretary to ensure research and development of safer childhood vaccines and to improve such factors as licensing, manufacturing, labeling, and adverse reaction reporting for vaccines.


Outcome: Collaborative efforts have addressed and continue to address areas to ensure vaccine safety.

The Task Force on Safer Childhood Vaccines recently issued its final report with several recommendations for vaccine safety. One recommendation was to charge the IAVG with the ongoing responsibility of ensuring that appropriate vaccine safety activities are carried out. The group would monitor the vaccine safety activities of the various agencies and work to improve interagency communication.

The National Vaccine Program Office was charged by the Secretary with implementing the recommendations of the Task Force (i.e., to develop a vaccine safety action plan). The IAVG developed the Vaccine Safety Action Plan, which details a variety of actions that need to be initiated or continued to ensure vaccine safety.

9. The Center for Devices and Other Healthcare Organizations

Issue: Risks associated with the use of some medical device products may occur following market approval.

FDA Action: The Center for Devices interacts with other healthcare organizations to evaluate or perform specific investigations of device problems from existing databases and registries. Examples include the National Center for Health Statistics National Mortality Follow Up Survey, the Medicare Database from HCFA, Harvard Pilgrim Health Plan, and the NACI Registry for Coronary Implants. The Center for Devices also evaluates patterns of failures and injuries, using open workshops, focus groups, and questionnaires.

Outcome: These interactions have resulted in the publication of brochures, checklists (used by professionals in their everyday practice), guidance to industry for the development of safer products, guidance to users on injury avoidance practices, manuals to assist the industry in its risk communication about product labeling and interactions with its customers, and a series of video tapes that provide instruction for a variety of medical devices.

Next Section : Appendix G