by Janis G. Hammer
Small Animal Science and Conservation
Delaware Valley College, Doylestown, PA
This cased is based on the actual development, FDA approval, and market withdrawal of dexfenfluramine, a drug used in the late nineties in combination with phentermine for weight loss (commonly referred to as fen-phen). It is used as an example of the prescription drug approval process and how it works in the United States. Most people think that if they are taking a prescription drug, it must work and it must be safe. Very few understand what is involved in developing a new prescription drug. With the recent explosion in mergers between pharmaceutical companies, and the recent withdrawal of a number of drugs from the marketplace, drug development and approval has come under increased scrutiny.
In the United States, prescription drugs are approved for market by the Federal Drug Administration (FDA). The drug approval process is a long, tedious, and expensive process. However, once (and if) a drug is approved, the potential financial gain for the company can be enormous. This case study allows the student to evaluate the process and develop an understanding of what is involved. They can then decide for themselves if the process is adequate.
This case will be used in a senior, small animal science class with about 45 students. It is planned for four to five 50-minute periods. It is applicable to any science major, and particularly those students who may go on to graduate school or work in research. It is expected to be particularly useful for our students, since many of them go on to work in the pharmaceutical industry. The objectives are broad, but the study could be modified to enhance just one or two of the objectives.
This case study allows the student to incorporate critical thinking with research. It incorporates information about a disease process, treatment, and the possible ramifications of treatment. It also requires the student to make an informed decision.
Class one - Students are divided into groups of about 6 people. The group decides who will be the expert in each area. As a class discuss what they currently understand about the process and how to go about finding the information needed.
(I have a number of classes scheduled in-between class one and two to allow adequate research time) Class two and three (four?) - Pretrial hearing, dissemination of information to the class, as explained in the case study. See additional information below. May possibly extend into another class session. The instructor acts as moderator, allowing questions throughout.
Class four - Actual "trial," jury deliberation. In a large class, there may need to be multiple trials going on simultaneously. The instructor acts as judge and moderator. Questions are limited to the cross-examination.
Class five - Jury decision and justification. This should take approximately 10 minutes. Additional time may be spent on a final discussion of the information covered and the trial itself.
Two classes later - Summary assignment due.
I ran the case for the first time in March 2000. The students really had fun with it and did a very good job of retrieving the information. One thing that I will change in the future: the jury vote will be by anonymous ballot. A number of students indicated that they were uncomfortable giving their opinion when it was not the same as the majority. I was surprised, but I will change that portion of the case.
Note: The information requested is not difficult to find. Information on the majority of topics can be found in various places on the FDA home page: http://www.fda.gov. The most difficult part for the students will be sifting through the vast amount of scientific and nonscientific literature on fen-phen.
History
Since approximately 2 million prescriptions are filled in the U.S. every year, safety and efficacy is a major concern. The Food and Drug Administration (FDA) is responsible for ensuring the safety and efficacy of all drugs in the United States. The first law in this area was the Food and Drugs Act of 1906, which only provided standards for strength and purity, not safety. In 1938 the Food, Drug and Cosmetic Act was passed. It revamped the Act of 1906. At this time the producer had to show that the drug was safe. The Kefauver-Harris amendment in 1962 was in direct response to the thalidomide tragedy. Drug companies now had to prove that the drug was not only safe but efficacious also. Adverse reactions now had to be reported to the FDA and the risks as well as the benefits of the drug had to be provided.
The FD&C Act is a law that is being updated and clarified on a regular basis. It is important for the students to understand that it is an evolving process. Problems will and have occurred, initiating many of the changes. However, no drug can ever be proven completely safe - there is always a risk of an allergic or adverse reaction.
Sources:
The Evolution of U.S. Drug Law - http://www.fda.gov/fdac/special/newdrug/benlaw.html/
A Brief History of the Center for Drug Evaluation and Research, Donna Hamilton - http://www.fda.gov/cder/about/history/histext.htm
Thalidomide
Thalidomide is an excellent example of how the drug approval process works to our benefit. Thalidomide was a sedative utilized to treat nausea in pregnant woman in Europe and other countries in the 1950’s. A marked increase in babies with severe limb deformities such as "flipper" arms and/or legs was observed in these countries and this increase was directly linked to the use of thalidomide during pregnancy. It is reported that somewhere between 10,000–20,000 children were affected in 46 countries. Thalidomide was never approved for use in the United States, although some children with deformities were seen because of the drug being obtained outside of the U.S. or because the company gave samples to physicians to distribute before market approval, which was allowed at that time. The FDA was pressured to approve thalidomide but had concerns about the safety of the drug, although testing in pregnant women was not required at that time. The link between limb deformities and thalidomide was then observed and the company that produced thalidomide withdrew the request for FDA approval. Because of the thalidomide tragedy, drug safety and approval came under the scrutiny of the public, initiating the Kefauver-Harris Drug Amendment of 1962. Thalidomide brought attention to the fact that taking certain drugs during critical times in pregnancy related to fetal development have the potential to have profound effects on the unborn baby.
Thalidomide caused the birth defects by inhibiting the formation of new blood vessels, a critical component of limb development in the growing fetus. It has several modes of action in the body and continues to be studied. It was approved by the FDA in 1999 for use in treating certain side effects of leprosy and is being considered for treatment of diseases such as macular degeneration and diabetic retinopathy. However, even though approved, its use must be strictly controlled, particularly if it is to be used in women of child bearing age.
Sources:
Giving Thalidomide a Second Chance, Herbert Burkholtz - http://www.fda.gov/fdac/features/1997/697_thal.html
The Right Lesson to Learn from Thalidomide, Steven Harris - http://w3.ag.uiuc.edu:8001/liberty/Tales/Thalidomide.Html
"Thalidomide as Hope," Huntly Collins, Philadelphia Inquirer, March 29, 1999.
The Drug Development Process
A drug doesn't just show up at the pharmacy – it takes a great deal of basic research, screening, and animal testing before it is allowed to go into human clinical trials. Then the clinical trials must be completed and the results approved by the FDA before the drug can be put on the market. This takes a great deal of time, effort, and money, often taking 8 to 15 years and approximately 360 million dollars. Before a drug is started through the maize of the drug approval process, there must first be data indicating that the drug looks promising. The purpose of this section is to show the students how a drug is developed, screened, and tested in animals to collect preliminary data.
There is no one set way a drug is discovered. The research process is complex and takes cooperation between chemists, physiologist, pharmacologists, toxicologists, statisticians, and many others. There may be a search for specific drugs to treat a specific problem, where thousands of compounds are produced by the chemists and screened for specific activity (high through-put screening), or a drug may be found by serendipity whereby in screening a compound for one activity another activity is discovered (e.g., Rogaine, used to stimulate hair growth, was originally under review as a cardiac drug). All methods require basic research to understand how the body works and how we can manipulate that knowledge for our benefit. Once a promising compound is identified, it must then go through a battery of screening processes to understand how it works, how to get it to where it is needed, and to see if there are any potential negative side effects. The screening process may include computer modeling, tissue culture, and studies with micro-organisms. If the compound continues to look promising and without negative side effects, animal testing will begin. Animal testing is performed to understand what happens to the drug (how is absorbed, distributed, metabolized, and excreted) and to ensure safety. Animal testing requires compliance with the Animal Welfare Act (AWA). The AWA provides basic information on how research animals are to be taken care of, including veterinary care, basic husbandry and sanitation, and environmental requirements. However, the AWA only covers specific species; it does not cover rats and mice bred for research and rats and mice are the majority of animals used in research. The AWA also requires each institution to form an Institutional Animal Care and Use Committee (IACUC) which is responsible for overseeing all animal research. The purpose is to ensure humane treatment of all research animals. The USDA has the responsibility to enforce the AWA and they inspect each registered facility. The inspections are unannounced. If an institution receives government funding for research involving animals, it must also abide by the Public Health Service Policy and the Guide for the Care and Use of Animals.
Many compounds do not make it through animal testing. It is estimated that only 5 out of 5000 compounds go on to human clinical trials because they may not work as expected or have unexpected toxic effects. If a compound makes it through the process, the company then organizes the data and submits an Investigational New Drug Application (IND) to the FDA for review. The research studies must have been performed following government mandated Good Laboratory Practices (GLP's). GLP's require the writing and following of standard operating procedures and quality assurance reviews of all procedures and work performed. If the FDA feels the data indicates efficacy and safety, human clinical trials may begin. Testing prior to human clinical trials is referred to as preclinical testing.
Sources:
The Beginning: Laboratory and Animal Studies, Jeffrey Cohn - http://www.fda.gov/fdac/special/newdrug/begin.html
The Animal Welfare Act, The Guide for the Care and Use of Animals - http://www.nal.usda.gov/awic/legislat/awicregs.htm
Good Laboraory Practices (GLP's) - http://www.fda.gov/ora/compliance_ref/bimo/7348_808/default.html
Drug Approval Process
Once a company submits an IND to the FDA, the FDA has 30 days to reject it. If the IND is not rejected, human clinical trials can begin. All clinical trials must be reviewed and approved by the Institutional Review Board (IRB). The IRB is responsible for ensuring appropriate disclosure and treatment of everyone enrolled in clinical trials. There are three phases of clinical testing which must be performed. Phase I involves testing the drug in a small number (20-80) of normal, healthy people. The purpose is to ensure safety; to see how it is absorbed, metabolized, and excreted; and to determine the frequency of dosing. Phase II clinical trials are designed to test for effectiveness. Approximately 100-200 people with the disease are tested. Phase III requires a large number of people with the disease (1000-3000) to continue to look at efficacy and also to look for side effects/toxic reactions. Clinical trials may take 2-5 years to complete. If a drug makes it through clinical trials (1 of 5 drugs entering clinical trials is found useful enough to complete all phases), the company organizes the data showing safety and efficacy and submits a New Drug Application (NDA) to the FDA. The FDA has 6 months to review the data, although it often takes longer. If the FDA agrees the drug is safe and efficacious, the drug is approved and is given an NDA number. It can now be marketed to physicians. Clinical trials must follow Good Clinical Practices (GCP's) and manufacturing of the drug must follow Good Manufacturer Practices (GMP's). Post market approval, the FDA may require additional or long term testing. This is referred to as Phase IV testing. If problems or toxicity are found after a drug is marketed, manufacturers are require to inform the FDA. The FDA can require market withdrawal if indicated.The use of drugs, in ways or for reasons other than that which they were approved, is referred to as off-label use.
Sources:
Benefit Vs. Risk: How FDA Approves New Drugs, Dixie Farley - http://www.fda.gov/fdac/special/newdrug/benefits.html
The Drug Development and Approval Process, Bertram Spilker - http://www.newlifebp.org.cn/pharmol/approval.html
Testing Drugs in People, Ken Flieger - http://www.fda.gov/fdac/special/newdrug/testing.html
Fen-phen (dexfenfluramine or fenfluramine and phetermine)
Fen-phen refers to the combination of two drugs; fenfluramine or its isomer, dexfenfluramine, and phetermine. All are/were prescription medications, approved by the FDA for the treatment of obesity. Phetermine was approved in 1959, fenfluaramine in 1973, and dexfenfluramine in 1996 (on the market in Europe since 1990). The use of fen-phen is an example of off-label use. The use of the combination was not tested and was not reviewed by the FDA.
Dexfenfluramine was approved for short-term use in people that were at least 30% overweight to assist in weight loss. It was to be given only under the supervision of physicians specializing in weight loss, and used only in conjunction with diet and exercise programs. Studies indicate that it was effective, helping 60% of patients loose up to 10% of their body weight. Dexfenfluramine was found to be more effective than its relative and earlier version fenfluramine. Both work by inhibiting the re-upake of serotonin at the synaptic junction and also causes the increase release of serotonin. Serotonin is a neurotransmitter that is felt to inhibit the feeling of hunger. One year after the approval of dexfenfluramine, it was estimated that 85,000 prescriptions were being written each week.
Phentermine is an amphetamine that increases the release of the neurotransmitter, dopamine, which is also important in the formation of epinephrine. Thus it has a stimulatory affect on the CNS.
In 1997, at the Mayo Clinic, a cluster of cases of cardiac valvular disease was observed in people taking fen-phen. Studies were then begun to see if there was a true relationship between fen-phen and the disease. Incidences of valvular problems were then reported with the use of fenfluramine and dexfenfluarmine alone. Initial reports indicated that 30% of people taking the drugs had an abnormal echocardiogram. In the summer of 1997 the FDA published a health advisory. Later that year the FDA called for a voluntary removal of dexfenfluramine from the market. The company voluntarily withdrew both dexfenfluramine and fenfluramine from the marketplace in the fall of 1997. A withdrawal of phentermine was not requested.
The cause and effect relationship between the use of the drugs and cardiac valvular disease has not been proven. There are conflicting studies in the literature, with some supporting the cause and effect relationship and others finding none.
Sources:
Questions and Answers about Withdrawal of Fenfluramine and Dexfenfluramine - http://www.fda.gov/cder/news/phen/fenphenqa2.htm
Weight Loss Drug Update - http://www.ahp.com/releases/walabs_082296.htm
Wee, Christana C., "Risk for Valvular Heart Disease Among Users of Fenfluramine and Dexfenfluramine Who Underwent Echocardiography Before Use of Medication." JAMA vol281 i4 p308, Jan 27,1999. Fricker, Janet. "Balancing the risk of anti-obesity pills." The Lancet vol349 n9062 p1374, May 10, 1997.
Pulmonary Hypertension/Cardiac Valvular Disease
Pulmonary hypertension (PH) is a serious, life threatening disease process involving the cardiopulmonary system. It can be secondary, where it is associated with another condition, or it can be primary, when no cause for its occurrence is found. Diagnosis is based on a mean pulmonary arterial blood pressure of 25 mm Hg at rest or 30 mm Hg during exercise. PH is rare. It is estimated that 1-2 people out of a million adults in the general population will develop PH. It usually occurs in young adults and is twice as likely to be seen women as compared to men. Clinical signs include fatigue, shortness of breath, dizziness, leg swelling, and chest pain/pressure. It often progresses to right heart failure with continued deterioration and death. Treatment at this time may alleviate symptoms to some extent but does not cure the disease. It was known that there was an increased risk of PH when taking dexfenfluramine. The company estimated the risk at 23-46 cases per million people. The company, as well as the FDA, was aware of this potential risk. It was felt that the health risk due to obesity was greater than the potential risk of developing PH.
Cardiac Valvular Disease (CDV) is a cardiovascular disease involving one or more of the four valves of the heart. The problem is caused by one or more of the valves not closing properly, due to being too stiff or tight (stenosis) or leaking (regurgitation). The result is a heart that has to work harder to pump the blood effectively. With severe valvular problems, right or left heart failure may occur. Many people with CDV do not have any clinical signs. However, a heart murmur may be found on oscultation or abnormalities may be seen on an echocardiogram. If the disease is severe, the person may have shortness of breath, fatique, chest pain, or swelling of the ankles or legs. Symptoms can usually be controlled by medication. However, if severe, valve replacement surgery may be required.
Valvular regurgitation is the most common type observed in relation to fenfluramine.
Sources:
Mayo Pulmonary Hypertension Clinic - http://www.mayo.edu/cv/wwwpg_cv/pul_cln/pulclnhp.htm
Valvular Heart Disease - http://www.heartpoint.com/valvularheartdx.html
This case conjures up many questions. Why were physicians prescribing off-label use of these drugs? Why were sales representatives discussing dexfenfluramine with all physicians, not just obesity specialists? With 85,000 prescriptions being written a week, isn’t it obvious to the company and the FDA that dexfenfluramine was being used inappropriately? Why was the drug on the market so long in Europe without seeing the cardiac valvular problems? Was the company aware of the potential risk prior to the general public?
Ditzen, L. Stuart. "Mass-litigation lawyers: A wolf pack or Robin Hoods?" Philadelphia Inquirer, Sunday November 21, 1999.
Ditzen, L. Stuart. "In mass litigation, the serious cases can get lost." Philadelphia Inquirer, Monday November 22, 1999.
Rheingold, Paul D. "Fen-phen and Redux: a tale of three drugs." Trial vol34 n1 p78, Jan 1998.
Acknowledgements: This case was developed as part of a National Science Foundation-sponsored Case Studies in Science Workshop (NSF Award #9752799) held at the State University of New York at Buffalo on June 7-11, 1999.