[U.S. Food and Drug Administration]

Thalidomide Meeting Picture

Thalidomide: Potential Benefits and Risks
An Open Public Scientific Workshop
September 9-10, 1997

EXECUTIVE SUMMARY

On September 9 and 10, 1997, the National Institutes of Health (NIH), the Food and Drug Administration (FDA), and the Centers for Disease Control and Prevention (CDC) convened an open public workshop to examine the potential benefits and risks associated with the use of thalidomide. Initially, the NIH, the CDC, and the FDA had intended to develop a protocol to guide clinical research of thalidomide. It became obvious, however, that a single protocol would be insufficient to investigate the drug's wide array of potential applications. It was decided to convene an open workshop to examine the many complex issues associated with thalidomide research, use of the drug in the clinical setting, and risk communication and management.

Workshop participants included research scientists in the fields of pharmacology, immunology, neurology, oncology, dermatology, hematology, and infectious diseases, clinicians and pharmacists, legal and health communications experts, representatives from government public health and regulatory agencies, and consumer and patient advocates. The workshop itself was comprised of plenary panel sessions, concurrent "breakout" sessions to examine specific issues, and numerous opportunities for questions and comments from members of the audience.

This executive summary presents issues addressed during the formal presentations and in the workshop discussions.

SESSION I: OPENING REMARKS AND OVERVIEW

After welcoming remarks by William Harlan, M.D. (Associate Director for Disease Prevention, NIH), Stephen Groft, Pharm.D. (Director, Office of Rare Diseases, NIH) gave participants an overview of the workshop agenda. He noted that the workshop was intended to be neither a consensus development nor or a technology transfer conference. Instead, it was intended to be a forum for sharing information about the benefits and risks of thalidomide use, exchanging ideas about future research needs and new clinical applications, and discussing strategies to promote safe and ethical use of the drug.

Frances Kelsey, M.D. (Deputy for Scientific Affairs, Office of Compliance, Center for Drug Evaluation and Research, FDA) offered an historical perspective as the FDA official who, in 1960, had reviewed the original new drug application (NDA) for thalidomide use in the United States. She discussed the circumstances that led to FDA disapproval of the NDA and the role that the drug played in the development of more stringent regulations for drug approval in the United States and other countries.

Next, Janet Woodcock, M.D. (Director, Center for Drug Evaluation and Research, FDA) discussed the reasons behind the current interest in thalidomide and the challenges posed by its expanded use. She explained that a rapid resolution of symptoms of erythema nodosum leprosum (ENL) has been reported in patients administered thalidomide, and it is being evaluated for treating life-threatening diseases such as graft vs. host disease, AIDS wasting, and malignancies. Thalidomide also may be useful in treating immunologic disorders such as systemic and discoid lupus, Behcet's disease, Sjogren's syndrome, Crohn's disease, and rheumatoid arthritis. Additional conditions for which thalidomide is being considered for study include a range of dermatological conditions, macular degeneration, tuberculosis, and aphthous ulcers.

Dr. Woodcock also reviewed the challenges inherent in regulating the use of thalidomide. These challenges center around ensuring that (1) consistent supplies of high-quality drug are available to support investigational and clinical use, (2) the drug is distributed only through controlled medical channels, (3) the drug is properly studied, and (4) the public fully understands the risks associated with thalidomide use. Dr. Woodcock commented that the increased demand for thalidomide presents a regulatory dilemma; severe restrictions on the drug's availability may, in fact, lead to its wider distribution and use under uncontrolled conditions (e.g., buyers' clubs, pill-sharing).

To address these challenges, the FDA has formed a thalidomide working group to coordinate regulation of the drug and access programs so that seriously ill patients have the safest possible access to the drug. The agency also has taken legal action against distribution of thalidomide through buyers' clubs and other illegal venues. In addition, the FDA has held discussions with companies that are interested in conducting clinical studies with thalidomide to ensure that the drug used in these trials is of a consistently high quality.

Guillermo Bierzwinsky, M.D. (Director, Drug Control Directorate of Mexico) reported on experience with thalidomide in Mexico. Since 1988 thalidomide has been licensed in Mexico for treatment of ENL. Recently, the drug was approved by Mexico's Ministry of Health to treat AIDS wasting syndrome. Dr. Bierzwinsky presented data from one of the studies of thalidomide for this indication that served as the basis for this approval. Dr. Bierzwinsky discussed the precautions being taken to control the distribution of thalidomide in Mexico. The drug is manufactured at a single plant and directly distributed to infectious disease physicians and dermatologists. Thalidomide is not sold in drugstores.

Carol Braun Trapnell, M.D. (Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research, FDA) discussed the clinical pharmacology of thalidomide, including its mechanism of action and metabolism, its interactions with other drugs, and its potential toxicities. Dr. Trapnell believed there to be adequate pharmacokinetic data on thalidomide to support the design of large trials and to carry out bioequivalence studies for more than one manufacturer of the drug. Additional research is needed, however, to:

Norman Fost, M.D., M.P.H. (Director, Program in Medical Ethics, University of Wisconsin at Madison) discussed the ethical issues related to use of thalidomide by women of childbearing potential, specifically, the benefits of thalidomide treatment for the mother versus the risk of severe deformity for the unborn child. Dr. Fost emphasized the need to balance the interests of mother and child and suggested that this could be done by weighing the following variables: seriousness of the disorder being treated, likelihood of benefit, availability of alternative therapies, probability and severity of risk to the future child, and importance of the particular pregnancy.

Jonathan Wilkin, M.D. (Director, Division of Dermatologic and Dental Drug Products, Center for Drug Evaluation and Research, FDA) reported on the recent (September 4-5, 1997) meeting of FDA's Advisory Committee on Dermatologic and Ophthalmic Drugs, at which Celgene's NDA for thalidomide in treatment of ENL was reviewed. The committee found that the sponsor had demonstrated efficacy, and that the benefits of thalidomide outweigh its risks in the treatment of cutaneous ENL. Dr. Wilkin emphasized that this is a recommendation only; the FDA will make the final decision regarding this NDA.

 

SESSION II: PERSPECTIVES FROM THE PUBLIC--A CONSULTATION WITH...

Moderator Theresa Toigo, R.Ph., M.B.A. (Associate Commissioner for Special Health Issues, FDA)

This session featured presentations by individuals and representatives from groups directly affected by various issues associated with thalidomide use. Leo Yoder, M.D. (American Leprosy Mission) spoke from more than 20 years of experience prescribing thalidomide for patients with ENL at the Hansen's Disease Center, which is located in Carville, Louisiana, and is the Nation's referral center for ENL. Dr. Yoder reported that in most patients, thalidomide controls ENL completely, either without the use of prednisone or at much reduced doses. Dr. Yoder believed that the two major side effects of thalidomide--severe birth defects and neuritis, could be avoided if sufficient precautions are taken. He noted that under the current thalidomide IND protocol, the sponsor requires that women of childbearing potential must either be sterilized or admitted to the hospital in Carville to receive thalidomide. He stated that there have been no known cases of birth defects in the United States from the use of thalidomide for ENL, although some have occurred in other countries where controls and monitoring plans have been less stringent.

Randolph Warren (Chief Executive Officer, Thalidomide Victims' Association of Canada) provided the perspective of a thalidomide survivor (i.e., "thalidomider"). He noted that approximately 5,000 people have been born disabled as a result of thalidomide worldwide, 125 of whom are now living in Canada. He stated that the Thalidomide Victims' Association of Canada fears unregulated access to thalidomide (e.g., through buyers' clubs and smuggling) even more than it fears regulated availability. He stated that the goal must be the temporary use of thalidomide, while thalidomide analogues are developed that lack the drug's devastating side effects. The association's position is that thalidomide should only be licensed for the medical condition for which it is approved; for each new intended use, the drug should be required to undergo a new application.

He called for the following stipulations to guide the distribution and use of thalidomide. First, there must be a guarantee that when the drug is prescribed or distributed the word "thalidomide" will be shown beside any brand name or trade name. Second, patients agreeing to take thalidomide must be given clear warnings regarding the drug's side effects. Third, physicians who prescribe thalidomide and pharmacists who dispense thalidomide must be certified, and thalidomiders must be involved in developing the certification curricula. Fourth, research must continue into alternatives for thalidomide. Fifth, "someone must be accountable for dealing with any new victims" of thalidomide.

William Zellmer, M.P.H. (Vice President, American Society of Health-System Pharmacists) discussed the role of the pharmacist in protecting patients from the risks of thalidomide use. He observed that the pharmacist's responsibilities will be broader for thalidomide than for other drugs, in that pharmacists can reinforce information delivered by physicians and answer any additional questions patients might have at the time the prescription is filled. To this end, pharmacists could verify that (1) patients understand the potential risks related to taking thalidomide, (2) women of childbearing age are practicing effective birth control, (3) patients are aware of the drug's adverse effects and the measures to be taken if an adverse event occurs, and (4) patients know what to do with unused dosage units. Mr. Zellmer believed pharmacists should be reimbursed for this additional patient counseling function by the drug manufacturer, and that the compensation should be "built in" to the cost of the drug.

James Allen, M.D. (Vice President for Science and Technology, American Medical Association) offered his personal perspective as a practicing physician. (The AMA currently does not have a position on thalidomide.) He did not believe the use of thalidomide in clinical trials presented a problem as long as the investigators are well informed and dedicated to reducing risks to patients. The major risks, he believed, lay in the wider clinical use of the drug. He noted that physicians will be concerned about a system that is too restrictive or onerous in terms of paperwork and time required. Dr. Allen feared that such a system would likely be circumvented instead of used.

In addition, most physicians feel strongly about having the flexibility to prescribe a drug "off-label" if they believe it to be the treatment of choice for their patient. Another potential problem lies in developing a system for selecting and accrediting physicians to prescribe thalidomide. He believed that the issue of accreditation needs careful discussion. Also problematic for physicians would be a requirement to write a specific diagnosis on a prescription, which physicians would likely view as a breech of doctor/patient confidentiality.

Cynthia Pearson (Executive Director, National Women's Health Network) offered the perspective of a women's health advocate. She cautioned that FDA approval of thalidomide brings with it the potential for unwise and careless use. To reduce the risk for women, physicians need to be educated about how to prescribe thalidomide and how to counsel patients. Physicians should prescribe the drug only for the most serious of conditions where there is substantial evidence of benefit. In addition, physicians must obtain written informed consent from patients. To prevent administration of thalidomide during pregnancy, women must take a pregnancy test before taking thalidomide. Ms. Pearson cautioned, however, about repeated pregnancy tests, noting that they are not a substitute for pregnancy prevention methods. A related issue concerned access to and use of contraception. This is a problem because many health insurance companies do not cover contraception.

Ms. Pearson also remarked on the need to challenge stereotypes. Not all women who ovulate are at risk--they may be lesbian or celibate. Another stereotype is that women cannot be trusted to manage their lives. Under the current ENL treatment protocol, for example, the sponsor requires that women of childbearing potential must be hospitalized or sterilized in order to be treated with thalidomide, which she found unacceptable.

Nancy Paller offered her personal perspective as the mother of an HIV-positive patient who had benefited from thalidomide treatment. Specifically, thalidomide was effective in treating her son's aphthous ulcers and wasting syndrome. She discussed how he had originally obtained the drug, which had been smuggled into the United States from Brazil, and how he eventually was able to access it through the single-patient IND mechanism. Finally, she stated that because of thalidomide, her son was able to live his last year with a quality of life that other AIDS drugs could not provide.

 

SESSION III: MONITORING FOR SAFETY AND MANAGING ADVERSE EVENTS

Moderator: Debra Birnkrant, M.D. (Acting Director, Division of Antiviral Drug Products, Center for Drug Evaluation and Research, FDA)

Melody Lin, Ph.D. (Office for Protection from Research Risks, NIH) discussed Institutional Review Boards (IRBs) and their role in protecting patients enrolled in clinical trials of thalidomide. She explained the criteria used by IRBs to evaluate protocols and the type of information included in the "informed consent document" subjects must review before they can enter a clinical trial.

Dr. Birnkrant discussed the regulatory and safety considerations in the clinical development of thalidomide. She explained that because of its unapproved status, thalidomide is considered an "investigational" drug. She reported that five divisions within the FDA currently are reviewing clinical trials where thalidomide is under study. All these studies seek to take advantage of the drug's immunomodulating and/or antiangiogenesis properties.

To ensure consistency among the reviewing divisions regarding the safe use of thalidomide, the FDA established a Thalidomide Working Group. To date, the working group has developed two documents: a model informed consent form and a patient education brochure to assist patients, study investigators, physicians, and pharmaceutical companies with safety issues related to thalidomide. She reviewed the pregnancy testing schedule developed by the FDA for women of childbearing potential who take thalidomide.

She also noted that the FDA has developed a database of 500 patients who have received thalidomide in HIV clinical trials, including 72 women. The database is used to track safety trends according to a range of variables, including age, gender and birth control methods. The database also has yielded information regarding potential side effects of thalidomide. For example, there have been 15 reports of neutropenia and increased viral load has also been reported among patients being treated for aphthous ulcers. Although the increase (.43 log) is statistically significant, it is not yet known if it is clinically significant.

Herbert Schaumburg, M.D. (Professor and Chairman, Department of Neurology, Albert Einstein College of Medicine) presented a general overview of toxic neuropathy caused by drugs like thalidomide. He stated that for most toxic neuropathies, sensory symptoms precede neurophysical and physical degeneration. The neuropathy progresses gradually, over a period of weeks and months. If one can stop the drug in the early stages of neuropathy, the patient will usually recover. Because patients react differently to neurotoxic drugs, the onset of neuropathy cannot be predicted. Therefore, physicians must take a thorough medical history before prescribing and carefully monitor patients while under treatment with neurotoxic drugs.

Colin Crawford, M.R.C.P., D.P.M.& H. (Imperial College of Science, Technology and Medicine, London) discussed the difficulty of detecting thalidomide-induced neuropathy in ENL patients, given that similar clinical symptoms and changes in electrophysiological measurements can result from the underlying ENL disease. He reviewed methods for detecting neuropathy and recommended that ENL patients undergo a neurological exam before thalidomide is started. Because of the slow onset of ENL-related neuropathy relative to thalidomide-related neuropathy, any subsequent new signs of neuropathy over weeks or months are likely to be drug-related.

Tucker Patterson, Ph.D. (National Center for Toxicological Research, FDA) presented preliminary results from a study being conducted in primates to assess thalidomide toxicity including peripheral neuropathy. It is hoped that results from this study will clarify (1) if there is a relationship between dose/duration of therapy and the development of neurotoxicity and (2) if thalidomide-induced neuropathy is reversible.

Mary Floeter, M.D., Ph.D. (Chief, EMG Section, National Institute of Neurological Disorders and Stroke, NIH) discussed strategies for monitoring for neuropathy. She believed irreversible neuropathy from thalidomide could be avoided by using the following approach: (1) self-monitoring by patients for typical symptoms (e.g., sensory loss in the feet, muscle cramps, (2) serial neurological exams performed by physicians to assess strength, sensation, and reflexes, and (3) electrophysiologic tests, such as nerve conduction studies (e.g., SNAPs), evoked potentials, and quantitative sensory testing.

After reviewing the advantages and disadvantages of each type of measurement, she cautioned that variability in SNAP amplitudes restricts their usefulness for monitoring thalidomide neuropathy, and she discussed the causes for this variability. To limit variability, she advised that the same examiner perform the baseline and follow-up tests, and several SNAPs should be measured on each occasion.

SESSION IV: PREGNANCY/EMBRYOPATHY

Moderator: James Mills, M.D. (Chief, Pediatric Epidemiology Section, National Institute of Child Health and Human Development)

Characterization of Embryopathy Risks

Barbara Hill, Ph.D. (Division of Dermatological and Dental Drug Products, Center for Drug Evaluation and Research, FDA) discussed the types of thalidomide-induced embryopathy and the hypotheses that have been proposed to explain their etiology. She reported that exposure of the fetus to even a single dose (100 mg) of thalidomide during the sensitive period (34-50 days post-menstruation), has been associated with a characteristic profile of birth defects (e.g., phocomelia, defects in organ systems).

The type of defect depends on the point in time within the sensitive period when the fetus is exposed to thalidomide. Dr. Hill presented a table illustrating this point (e.g., exposure during days 34-38 post-menstruation results in aplasia of the ear, exposure during days 41-43 post-menstruation results in malformation of the respiratory tract). Effects of exposure after day 50 have not yet been well characterized.

Dr. Hill presented the three leading hypotheses to explain thalidomide's teratogenicity: neural crest hypothesis, inhibitor of angiogenesis hypothesis, and downregulation of adhesion receptors on early limb bud cells and on cells of the heart in embryos.

Christine Mauck, M.D., M.P.H. (Division of Reproductive and Urologic Drug Products, Center for Drug Evaluation and Research, FDA) reported on the issue of pregnancy prevention in patients who take thalidomide. She remarked that although only hysterectomy, total abstinence, and menopause are 100 percent effective in preventing pregnancy, contraception can reduce the chance of pregnancy by up to 99.9 percent.

However, pregnancy rates vary according to contraceptive method and the degree of compliance, particularly in regard to use of birth control pills and barrier methods. She stated that two birth control methods, used concurrently, can improve effectiveness, especially if two highly effective methods are selected. She also stated that women should be instructed in the use of emergency contraception if they suspect a loss of contraceptive effectiveness. Male thalidomide users should use condoms, even if vasectomized.

If pregnancy is not prevented, it can be diagnosed about 10 days after conception, before the menstrual period is late and quickly enough so that the patient can stop using thalidomide before the "sensitive period" of potential damage to the fetus begins. If fetal exposure occurs during the sensitive period, and the patient decides to continue the pregnancy, there is a high probability of fetal abnormality.

Dr. Mauck concluded that inadvertent fetal exposure cannot be completely avoided. Therefore, education of potential thalidomide users will be key to minimizing the number of affected infants.

Robert Miller, M.D., Dr.P.H. (National Cancer Institute, NIH) spoke about how environmental effects on child health are recognized. He remarked that almost all environmental teratogens and carcinogens have been identified by an astute observer, usually a physician. For example, thalidomide, rubella, and therapeutic radiation all were identified as teratogenic by clinical observation.

He noted that epidemiologic investigations are still required to confirm such observations. Confirmation can be achieved by demonstrating a dose-response effect, replication of the finding by other investigators, determining the biologic plausibility of the association between putative cause and effect, obtaining similar effects in experiments with animals, excluding alternative explanations, and finding that the effect disappears after removal of the putative causal factor.

Allen Mitchell, M.D. (Associate Director, Slone Epidemiology Unit, Boston University) reviewed the Pregnancy Prevention Program (PPP) for Accutane, a treatment for severe cystic acne. Because the drug has proven teratogenic effects, the drug's manufacturer, Roche, introduced the PPP in 1988. This aggressive patient and physician education program has the following components: a blister package with prominent warnings, detailed guidelines for use (for patients and physicians), contraceptive information, a free contraception referral program, and a patient qualification checklist. The guidelines for physicians instructed them to warn patients of the risks, obtain negative pregnancy tests, and delay therapy until the second or third day of the next menstrual period.

Since 1989, a voluntary followup survey has been conducted to assess physician and patient compliance with the PPP and to identify the rate of pregnancy during therapy and in the month following treatment. Among the 210,009 women who completed followup, 623 pregnancies occurred while they were on therapy (a pregnancy rate of 7.7 per 1,000 woman-years). This is 7 percent of the expected rate for women of childbearing age. It is difficult to predict if a similar program would be effective for thalidomide. Only one manufacturer was involved in the formulation and marketing of the PPP. In addition, prescribing of the drug occurred largely in a single specialty and the patient population was well educated (the mean educational level was 2 years of college).

Cynthia Moore, M.D., Ph.D. (Acting Deputy Chief, Birth Defects and Genetic Diseases Branch, Centers for Disease Control and Prevention) presented recommendations from the CDC-sponsored meeting, "Preventing Birth Defects Due to Thalidomide Exposure," which was held on March 26, 1997. The draft recommendations are noted below.

SESSION V: RISK MANAGEMENT

Moderator: Louis Morris, Ph.D. (Chief, Marketing Practices and Communications Branch, Division of Drug Marketing, Advertising, and Communications, Center for Drug Evaluation and Research, FDA)

Dr. Morris began his presentation with a general theoretical overview of risk communication. He then discussed specific issues related to communicating the risks associated with thalidomide use. He added that when people process information they only retain a small amount, which they then integrate with their current situation. People also behave differently, depending on their familiarity with the product. In terms of risk communication for thalidomide, a major concern is how a patient will behave when faced with a potential sexual encounter. Dr. Morris stated that the behavior will depend greatly on what the patient retrieves in memory at that point. He also presented data from a recent survey to determine people's familiarity with thalidomide. Most people under age 45 did not correctly define "thalidomide," while most people over age 45 had very vivid memories of pictures of thalidomide-affected infants.

Effective risk communication for thalidomide will require the following: warning messages, vivid, memorable images, and a persuasive argument to counter misconceptions about one's ability to control risk. He stressed the importance of creating vivid images for users of thalidomide to aid in risk communication.

Martin Fishbein, Ph.D. (Public Policy Center, University of Pennsylvania) discussed the role of communication in influencing behavior. Simply educating potential thalidomide users about the potential dangers of taking the drug during pregnancy is unlikely to lead to behavioral change.

He presented some of the lessons from behavioral science research that could be applied to thalidomide risk communication. First, there is abundant evidence, particularly from work in AIDS prevention, that behavior can be changed by theoretically-based risk communication and intervention. Second, information in and of itself can produce behavior change; however, the type of information is important. Third, the most effective interventions are directed at changing specific behaviors, not at behavioral goals.

Dr. Fishbein added that only a limited number of variables need to be considered to influence or maintain behavior. These variables include: intention to perform a specific behavior, skills, environmental constraints, attitudes toward performing the behavior, norms, and self-efficacy. He noted that the importance of specific variables may vary among population groups. Regardless, the kind of interventions and messages necessary to produce behavior change are going to be very different, depending on "where people are in terms of their commitment to engage in some course of action."

Gail Povar, M.D., M.P.H., F.A.C.P. (Clinical Professor of Medicine and Health Care Sciences, George Washington University School of Medicine) spoke from a practitioner's perspective about using thalidomide in the clinical setting. She stated that despite the drug's risks, it is an attractive treatment choice because of its effectiveness in treating a wide variety of immune-mediated disorders and because of its relatively few side effects. She believed that strong ethical justification existed for use of the drug. For the most part, thalidomide poses no more--and no less--of a challenge to the physician than any other promising drug that has potential serious side effects. With all such drugs, the physician must adhere to the core tenants of medical ethics: "to do good, to avoid unreasonable harm, and to respect the patient's values and wishes." The physician should consider each thalidomide patient as an "n=1" experiment and carefully monitor the patient.

Mark Senak, J.D. (Director of Public Policy, AIDS Project, Los Angeles) spoke about patients' rights and physicians' responsibilities. First, he discussed the new environment of patient activism in which the debate on thalidomide use is occurring. Patients are becoming more assertive in pursuit of their own treatment options, and may even seek thalidomide from non-regulated sources. Another aspect of the new environment is the changing doctor/patient relationship and the emergence of managed care. In this environment a patient's access to thalidomide may be limited because of (1) the limited amount of time physicians may spend with a patient, (2) restrictions on the patient's ability to obtain a second opinion, and (3) managed care organizations' drug formularies and restrictions on off-label use.

Another issue is that the administration of thalidomide will, particularly for AIDS patients, take place concurrently with other potent medications. For many AIDS patients, particularly women of color, thalidomide will add to the challenges in their often already chaotic lives. These circumstances require physicians and the health care delivery system to "go outside the medical box." If, for example, a patient is unable to comply with treatment guidelines, the patient must be supported in ways that reduce the impediment to compliance.

He hoped that managed care organizations would see the benefit of providing physicians with more time to support the patient in compliance, rather than take the chance of having to care for a child injured by thalidomide.

Bruce Williams (Vice President, Celgene Corporation) presented the company's Thalidomide Fetal Exposure Prevention Program. Key elements of the program are as follows: patient and physician education, pharmacy registration, counseling on effective contraception, regular pregnancy testing protocols, informed consent, prescribing guidelines, and a controlled distribution system. In addition, all patients will be listed in a registry and followed up with a confidential survey to track compliance and fetal exposures.

 

SESSION VI: PERSPECTIVES ON PRESENT AND FUTURE NEEDS

Moderator: Ann Ginsburg, M.D. (National Institute of Allergy and Infectious Diseases, NIH)

Research Perspective

Gilla Kaplan, Ph.D. (Associate Professor, The Rockefeller University) discussed the scientific rationale for research on the immunomodulating effects of thalidomide. Her presentation focused on studies of the immune response in leprosy patients and the use of thalidomide as a tool for discovering the causes of ENL. She also explained how the immune system of patients with leprosy and tuberculosis, for example, could be modulated to improve clinical outcomes. The central issue is determining the role that the cells and cytokines play in a specific disease. Dr. Kaplan believed that if the mechanisms of immune response in infectious and autoimmune disease are better understood, so will the potential role(s) of thalidomide, thus enhancing the likelihood of developing more active, safer drugs to treat these diseases.

Peter Andrulis, Ph.D. (President, Andrulis Pharmaceuticals Corporation) noted that in 1987, Andrulis became the first firm to manufacture thalidomide, the first to begin clinical trials, and the first to report its effectiveness in the treatment of aphthous ulcers. Peter Andrulis commented on his company's pharmaceutical support of an NIH trial of thalidomide for AIDS-related aphthous ulcers. Andrulis is now testing thalidomide for use in kaposi's sarcoma, prurigo nodularis, Crohn's disease, brain cancers, and multiple sclerosis. He stated that the responsibilities assumed by a company that develops and markets thalidomide are unprecedented.

He noted that the paradigm of medical care is shifting from "government as protector" to one of less regulation and more citizen decisionmaking. Dr. Andrulis stated that three key issues must be addressed: (1) determining how to safeguard against gaps in the thalidomide distribution and tracking system, (2) determining what the risks are to patients if the FDA has to have the drug removed from the market for any reason, and (3) ensuring that the rights of women of childbearing potential who are treated with thalidomide are protected.

Thomas Bleakley, J.D. (Bleakley and McKeen, Detroit, Michigan) provided the viewpoint of a plaintiff's lawyer. He reviewed the current legal climate that will be faced by the "certain future victims of thalidomide."

He believed that tort reform measures instituted over the past decade have sharply limited the ability of people harmed by the health care system to recover compensation. Recent court decisions also have seriously compromised victims rights. He feared that these developments would have a "trickle down" effect. The likelihood of noncompliance along the thalidomide distribution chain will grow, with the net effect of exposing people to serious risk of harm.

Frank Woodside, III, M.D., J.D. (Dinsmore & Schol, Cincinnati, Ohio) spoke from his perspective as a defense lawyer who represents manufacturers of medical devices and drugs in birth defects lawsuits. Dr. Woodside described two types of liability: negligence (fault-based) and strict liability (no-fault, based on whether the product is defective and therefore, unreasonably dangerous). He stated that most pharmaceutical products are considered "unavoidably unsafe." Thus, the marketing of thalidomide is justified, notwithstanding the risks, if its known or perceived benefits outweigh its known or perceived risks. Manufacturers, physicians, and pharmacists involved in a risk-reduction program as discussed in this meeting are in a good position to defend themselves against liability claims related to use of thalidomide.

 

SESSION VII: CONCURRENT SESSIONS ON SCIENTIFIC ADVANCES, PHARMACOLOGY, POTENTIAL CLINICAL APPLICATIONS, AND RESEARCH TRENDS FOR THALIDOMIDE

Section A: Pharmacology, Pharmacokinetics, and Teratology of Thalidomide and Analogues

This workshop was chaired by David Erickson, D.D.S., Ph.D. (Chief, Birth Defects and Development Disabilities Branch, Centers for Disease Control and Prevention) and included the following presentations:

The group concluded that while aspects of the clinical pharmacology of thalidomide have been well characterized, many basic questions remain unanswered. Research on issues such as mechanism of action and minimum effective dose will facilitate optimal use of this drug, and development of animal models will further this research. Celgene is conducting research on thalidomide analogues that may ultimately exert the beneficial effects of thalidomide without its embryopathic and neuropathic effects.

Section B: Dermatology

This workshop was chaired by Mervyn Elgart, M.D. (Clinical Professor, George Washington University School of Medicine) and included the following presentation:

Favorable patient outcomes and research findings with thalidomide were discussed with respect to the above dermatological indications. The need for more clinical trial data was discussed, as were adverse events and limitations in use of thalidomide resulting from the paucity of information about its mechanism of action and the pathophysiology of some of these diseases.

Section C: Immunology/Rheumatology

This workshop was chaired by Philip Fox, D.D.S. (Chief, Clinical Investigations Section, National Institute of Dental Research, NIH) and included the following presentations:

Theoretical considerations, research, and use of thalidomide were discussed for these autoimmune and inflammatory diseases, with evidence of efficacy presented from controlled trials of thalidomide in chronic cutaneous lupus erythematous. Clinical trials are planned or underway for the other uses discussed. It was also discussed that these diseases can be very severe or less severe, and it will be necessary to develop criteria for determining when disease severity is sufficient to warrant use of thalidomide. The lack of data about mechanism of action in specific diseases was again pointed out, as was the need to characterize the lowest effective dose, develop standards for neurological monitoring, and develop animal models. Tremor was reported in a small group of patients administered thalidomide for rheumatoid arthritis.

Section D: Hematology/Oncology

This workshop was chaired by James Pluda, M.D. (National Cancer Institute [NCI], NIH) and included the following presentations:

Mixed results were reported from use and studies in GVHD and the solid tumor types discussed, as well as the need for more data on efficacy, safety, dosing, anti-angiogenic effects, activity of metabolites, and thalidomide analogues. Also discussed were GI effects of thalidomide in cancer versus AIDS patients, and the absence of reports of peripheral neuropathy with thalidomide in oncologic use.

Section E: Infectious Diseases

This workshop was chaired by Lawrence Fox, M.D., Ph.D. (Medical Officer, HIV Research Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH) and included the following presentations:

This group discussed data from studies of thalidomide in these infectious diseases, with favorable outcomes attributed to immunomodulatory effects of thalidomide. Studies of thalidomide in AIDS wasting syndrome reported viral load to increase, and a possible mechanism was postulated. Also discussed was the need to characterize effects of thalidomide on TNF-a at the cellular level. Considerable variability in the incidence of thalidomide neuropathy was reported as related to the type of infectious disease treated. Pharmacokinetics and dosing data in women, as well as neuropathy data and testing methodologies, were pointed out as research needs.

OPEN PUBLIC SESSION

Iris Long (ACTUP-New York) advocated the following:

SUMMARY OF KEY ISSUES AND RESEARCH NEEDS

The following presents highlights of issues and research needs identified by the workshop presentations, discussions, and working group sessions.

Safety Monitoring and Management of Adverse Events

Clinical Pharmacology

Clinical Trials

Risk Communication

CLOSING REMARKS

Dr. Woodcock reviewed the many challenges that lie ahead with regard to understanding the benefits of thalidomide and minimizing the risks associated with its use. Meeting these challenges will require the cooperation of those groups involved in the workshop: public health, research and regulatory agencies, pharmaceutical companies, health professional organizations, health care providers, pharmacists, the legal profession, and patient advocacy groups.

ADJOURNMENT

Posted on the Web March 27, 1998
Office of Special Health Issues
Food and Drug Administration

Return to Patient Involvement Index Page     |  

Return to HIV/AIDS Meeting Page        |       Return to Cancer Index Page