About Bio-Link
  Ed, Org & Companies
  
  National/Regional Centers
    - Newsletters
  Biotech News
  Curriculum Clearinghouse
  Online Courses
  Technician's Home
  Virtual Laboratory
    - Equipment
    - Supplies
    - Manufacturers
  Virtual Library
  Biotech Calendar
  Site Feedback
  Email Us

STUDENTS/TECHNICIANS
  Jobs
    - Submit Resume
    - View Jobs
    - Employment Links
    - Career Scenarios

EDUCATORS
  Join List Serve
  Curriculum Clearinghouse
    - FAQs
    - View Materials
    - Be A Subscriber
    - Be A Contributor
  Jobs
    - View Jobs
    - View Resumes
    - Career Scenarios
    - Submit Scenarios

BIOTECH PROGRAMS
    - Faculty Survey Log-In
    - National Directory

INDUSTRY
  Jobs
    Submit A Job
    View Resumes
    View Jobs
    Employment Links


logo

PHARMACEUTICAL REGULATION IN THE UNITED STATES:
HISTORY AND A CASE STUDY Lisa A. Seidman and Noreen Warren
lseidman@madison.tec.wi.us
Madison Area Technical College, Madison, WI
June, 2001

NOTES TO THE INSTRUCTOR

            The regulation of pharmaceutical/medical products raises a number of societal questions. Should AIDS patients be able to obtain drugs that have not been fully tested for safety or efficacy? How does society balance the potential benefit of new pharmaceuticals against their potential risk? What are the responsibilities of companies to ensure the safety of drugs? This article explores some of these topical issues, first with an introduction to the history of drug regulation and then through a dramatic case study.

            In the early 1960s, Dr. Frances Kelsey and her colleagues at the Food and Drug Administration refused to approve the sedative, thalidomide, for use in the U.S.  Thalidomide was later found to cause severe birth defects when taken by pregnant women. This case captures students’ interest and provides an effective springboard for discussion of many scientific, societal, and ethical issues. Moreover, we have found that our students, who are preparing to enter biotechnology careers, are receptive to learning about regulatory affairs (a sometimes “dry” topic), once they have explored this case study.

            Students can read the introductory historical information in class or at home.  We have found it effective to have the students read the case study about thalidomide in class so that we can stop them when they get to Questions 1 and 2. Then, without knowing what actually happened, the class discusses these first two questions. After discussion, the class votes on whether they would have approved the marketing of thalidomide, based on its use in Germany and its supposed safety record there. The students also list on the blackboard what scientific studies they think might adequately demonstrate the safety of a drug. This has been an effective way to get the students engaged in the story and discussions of later questions have been spirited. We use a two-hour block of time and do not get to all the questions, but some are assigned as homework.

PART I: HISTORICAL INTRODUCTION TO DRUG REGULATION IN THE UNITED STATES(1)

            When you reach into your medicine cabinet for a bottle of aspirin, you probably assume that the bottle indeed contains aspirin and that taking a couple of tablets will not lead to your untimely death. We take for granted that pharmaceuticals are properly manufactured, labeled, and tested for safety. We have confidence in pharmaceuticals because the production of medical products is stringently regulated and controlled by the federal government. However, this was not always the case; the quality of drugs and foods was virtually unregulated until the early 1900s. Around that time, a major industry emerged to process foods for urban consumers. This burgeoning food industry was filthy and badly managed. There were various efforts to regulate food processing, however, no legislation was passed until 1906. At that time, Upton Sinclair published the novel, “The Jungle,” intended as a study of the lives of immigrant workers in the Chicago stockyards. In his book, Sinclair graphically described alarming practices in the food industry. People were so outraged by Sinclair’s descriptions that Congress passed a law to help regulate the production of food and, at the same time, drugs. This law was the original Food Drug and Cosmetic Act (FDCA). In 1927 a separate law enforcement agency, eventually named the Food and Drug Administration (FDA), was formed to enforce food and drug laws.

            The 1906 FDCA authorized regulations to ensure that pharmaceutical manufacturers did not adulterate or mislabel their products but failed to deal with the safety or effectiveness of drugs. In 1933, FDA recommended a complete revision of the inadequate 1906 Food and Drug Act. A bill was introduced into the Senate, launching a five‑year legislative battle between those who wanted drug law reform and the industry that vigorously combated its passage. During these years, an exhibition of dangerous food, medicines, medical devices and cosmetics was prepared to illustrate the shortcomings of the 1906 law. The exhibit showed,  (http://www.fda.gov/oc/history/slideshow/Slide_134.html), for example, an eyelash dye that had blinded women, lotions and creams that caused mercury poisoning, hair dyes that caused lead poisoning, and a weight loss drug that increased metabolic rate to such an extent that many users died. Since the 1906 FDCA did not mandate drug safety, the FDA was powerless to seize these dangerous products. First Lady Eleanor Roosevelt borrowed the exhibit and invited congressional wives to the White House to view it. She and the congressional wives were among the most loyal supporters of drug reform throughout the five-year effort.(2)

            Eventually a dramatic tragedy facilitated the passage of stronger laws. The antibiotic, sulfanilamide, was introduced in the 1930s. The drug was a major medical advance in the treatment of infectious diseases. However, sulfanilamide is relatively insoluble and therefore was only available in a pill form that was difficult to administer to small children. In 1937, a chemist at the S.E. Massengill Company, in an effort to obtain a soluble form of the drug, dissolved a batch of sulfanilamide in the toxic industrial solvent, diethylene glycol. The company marketed the resulting “elixir” resulting in at least 358 poisonings and 107 deaths, mostly of children.

            In response to mounting reports of deaths due to the sulfanilamide preparation, FDA launched the first major recall of a drug product. The agency had the authority to seize the product, not because it caused deaths, but because it was inaccurately labeled an “elixir” when it did not contain alcohol. Most of the FDA’s staff of inspectors and chemists, along with many local law enforcement officials, traveled throughout the country looking for the toxic sulfanilamide preparation. James Harvey Young tells the following story about the sulfanilamide recall:

 

“In Atlanta, an elderly FDA inspector, who was also ill, drove through the rain into the north Georgia mountains to a drugstore that could not be reached by phone... A pint bottle of the 'elixir' had been sent to the druggist, and the inspector was charged with bringing it back. The druggist had the bottle but four ounces of its red contents were missing, all prescribed by a doctor for one patient, name unknown. When the physician returned from his rounds, he said that he kept no records but believed he had prescribed the medicine for a woman named Lula Rakes. He did not know where she lived, and her surname was not uncommon in the region. The inspector, shouting an inquiry to the deaf druggist, attracted the attention of a bystander who volunteered the guess that Lula lived eight miles over the ridge in Happy Hollow. The inspector drove over the dark mountain road, only to find Lula’s home abandoned. A neighbor said that the Rake’s family had moved one valley farther on. Driving onward the inspector at last found the house, and Lula was there. Busy with the moving, she had taken only a few doses of her medicine, but she could not recall what she had done with the bottle. An hour of conversation and exploring finally led to the medicine, with many other articles in a paper sack under the bed, The inspector began his weary way home.” (3)

 

In other cases, less fortunate cases, inspectors were not able to find the drug before it was consumed. Also, there were instances of druggists and doctors who falsified their records or lied when asked about the drug.

            Under the 1906 drug laws a company had no obligation to prove that their drug was safe, so Massengill was not held responsible for the deaths. (The company was, however, fined a small amount for labeling the drug an “elixir”.) In response to the sulfanilamide tragedy, drug reform became popular and industry resistance to regulation was overcome. A revised Food, Drug and Cosmetic Act was passed in 1938 that contained the critical provision requiring that a manufacturer prove the safety of new drugs with animal and clinical studies.

THE DRUG APPROVAL PROCESS

            Since the passage of the revised FDCA in 1938, a process for safety-testing new drugs has evolved along with a requirement that new drugs be effective. This process is complex and lengthy involving extensive development and testing, an approval process, and marketing and post-marketing surveillance. Only about 1 in 10 potential drugs performs successfully during testing and is actually marketed.

            The idea for a product is researched in the laboratory during the early stages of research and development (R&D). Until recently, FDA was not involved in the early R&D phases of a product. However, FDA is beginning to inquire about the rationale, documentation, experiments, and results from R&D, because the ultimate quality of a product depends on the foundation built in early development.

If a potential product shows promise in the laboratory, tests are performed in animals to determine how the drug is handled in the body and whether the substance is safe for human testing. Before the mid-1970s, the conduct of animal testing was not scrutinized by the FDA. However, in 1975, FDA inspections of several pharmaceutical testing laboratories revealed poorly conceived and carelessly executed experiments, inaccurate record-keeping, poorly maintained animal facilities, and a variety of other problems. These deficiencies led the FDA to institute the Good Laboratory Practice regulations (GLP) (4). GLPs require that those who test pharmaceutical products in animals follow written protocols and standard operating procedures (SOPs), have adequate facilities and equipment, provide proper animal care, properly record data, are well-trained and competent, and conduct high quality, valid toxicity tests.

            If a drug appears to be safe and efficacious in animal studies then investigators prepare a plan to investigate the product in human volunteers. They submit their plan to the FDA for review, in the form of an Investigational New Drug Application (IND). The FDA decides whether or not the IND is acceptable and whether the company can test the product in humans.

            Good Clinical Practices (GCP) govern clinical trials of drug safety and efficacy in human subjects. GCPs protect the rights and safety of human subjects and ensure the scientific quality of the studies. Clinical trials are conducted in stages, each of which must be successful before continuing to the next phase. Phase I clinical trials are the first introduction of the proposed drug into humans where the safety of the drug is evaluated and its metabolic and pharmacologic properties are determined in healthy humans. If a drug meets the safety requirements and appears to have the desired properties, then it enters Phase II clinical trials. Phase II trials are performed on a small number of diseased patients to determine the drug’s efficacy. If the drug continues to meet safety requirements and demonstrates efficacy at Phase II, it progresses to a broader Phase III trial involving many patients. At this point, the safety and efficacy of the drug continue to be evaluated, dosages are determined, drug interactions are explored, and other data are collected.

            If a drug passes all three phases of testing, the company may submit a New Drug Application (NDA) to the FDA documenting their evidence that the new drug is safe, reliable, and effective. If the FDA reviewers decide the evidence is sufficient, the new product is approved by FDA and can be manufactured for commercial sale. As a therapeutic agent progresses through these various phases, the requirements for its manufacture become increasingly stringent. Once in commercial production, the manufacture, labeling, packaging, shipping, storing, quality control, and marketing of the product must meet extensive regulatory requirements. The regulations that govern the commercial production of pharmaceuticals are called Good Manufacturing Practices (GMP).(5)  Even after a drug is approved, its safety continues to be monitored. Note that FDA expert reviewers examine information submitted by the company to determine whether a product is acceptable, but do not themselves actually test each drug product. 

PART II: CASE STUDY -- FRANCES KELSEY AND THALIDOMIDE

 

THE BEGINNING OF THE THALIDOMIDE STORY(6)

            Thalidomide was first synthesized in 1953 by a West German Company. Early tests in animals and humans indicated that the drug had little toxicity and that in humans it promoted sleep, although it did not have any sedative effect on animals. By 1957 the drug was introduced to the West German market and soon became a popular sleeping pill in West Germany. Thalidomide could be ingested in large quantities without fatal results and was thought to be so safe that it did not require a prescription. Moreover, the drug was found to combat nausea due to pregnancy and was frequently used for this purpose.

            Eventually the German manufacturer began to license the distribution of thalidomide in other countries. The American pharmaceutical firm, William S. Merrell Company, wanted to license the drug to sell in the lucrative U.S. market. On September 12, 1960 the FDA received a New Drug Application from Merrell that requested approval for thalidomide. The NDA provided by Merrell contained glowing claims for the drug and reports of their previous animal and human tests indicating the therapeutic dosage and its presumed safety. Since thalidomide was already widely used, the NDA was thought to be relatively routine and was assigned to the agency’s newest medical officer, Dr. Frances Oldham Kelsey, who had joined the staff earlier that year. Kelsey later explained that "They gave it [the NDA for thalidomide] to me because they thought it would be an easy one to start on. As it turned out, it wasn't all that easy."(7)

DR. FRANCES KELSEY

            Dr. Frances Kelsey was born in Canada and later became a naturalized American citizen. She received a B.S. and M.S. degree in Canada and then came to the U.S. where she completed a Ph.D. in pharmacology at the University of Chicago. As a graduate student in Chicago, Kelsey witnessed the sulfanilamide tragedy. Recall that in the late 1930s, a sulfanilamide “elixir” caused a number of deaths. The cause of the deaths, however, was not immediately understood. The American Medical Association and the FDA therefore began intensive investigations. The AMA asked Dr. E.M.K. Geiling and his colleagues at the University of Chicago to perform pharmacologic and pathologic studies of animals treated with the commercial product, with the separate ingredients, and with a synthetic elixir compounded with pure substances in about the same proportions as in the commercial elixir. It was these animal studies that established that the diethylene glycol was the drug’s toxic component. At that time Frances Kelsey was a graduate student in pharmacology at the University of Chicago. As she later reported, “All graduate students were required to watch the progress of all these studies and to lend their assistance, wherever possible...”(8)  In a speech prepared for the Medical Alumni Association of the University of Chicago in 1963, Dr. Kelsey said: “The urgency of the situation, the intensive round-the-clock toxicologic studies and the subsequent changes in the law relative to the control of drugs could not and did not fail to make a deep impression on a graduate student such as myself in the University’s Department of Pharmacology.”(9)

            In 1950 Kelsey completed a medical degree and after graduation she worked as an editorial associate for the American Medical Association (AMA) Journal. Her responsibility was to help select interesting papers and then work with the authors to improve their presentations. As she reported, “I soon learned ... that good scientists are almost invariably good writers and that poor writing is often a sign of poor science ... when I came to the Food and Drug Administration some eight years later, I found that many of the studies in support of safety of the new drugs were done by investigators whose work had not been accepted for publication in the Journal [of the AMA].”(8)

            In 1952 Kelsey and her family moved to South Dakota. Until 1960 she taught pharmacology at the University of South Dakota and also worked as a temporary doctor in various small communities. In 1960 Dr. Kelsey was hired by the FDA to help review applications for drug approval.

QUESTIONS

1. Discuss the steps that the Merrell Company needed to complete to have thalidomide approved in the U.S. If you were Dr. Kelsey, what sort of scientific studies would you be looking for in the thalidomide NDA?

 

2. Thalidomide had been tested previously in West Germany, was reported to be safe in those tests, and compared to other sedatives, was remarkably safe at high doses. Moreover, it was widely used in Europe with apparently few if any problems. The drug was very popular in Europe and the William S. Merrell company was anxious to have the drug marketed as soon as possible. Based on all this, if you were Dr. Kelsey, would you approve the drug for distribution in the U.S.?

THE STORY CONTINUES

            Dr. Kelsey reviewed the NDA from Merrell Company in collaboration with an FDA chemist and a pharmacologist. As Dr. Kelsey later reported, the pharmacologist found that the animal data were not reported in full detail and that data from a study of how the drug was absorbed in rats did not correspond to information provided in the NDA. Furthermore, the chronic toxicity data were incomplete, meaning that no evaluation could be made of the safety of the drug when used for prolonged periods of time. The chemist found numerous deficiencies relating to details of the manufacturing processes and the methods used to determine the identity, strength, and purity of the new drug substance. There was no information as to whether the dextro or levo rotary form of the drug was used, or the racemic mixture. The clinical studies were not reported in sufficient detail and many of the cited cases were in foreign literature reports that were not deemed acceptable to FDA.(8) The reviewers were all concerned that thalidomide did not put animals to sleep because this might suggest that there are differences in the way humans and animals absorb, metabolize, or distribute the drug in their bodies.(9)  Such differences made all the safety studies performed in animals suspect.

            Under the laws in place at that time, Merrell would have been able to market thalidomide if it had not heard back from the FDA within 60 days of submitting its application. Therefore, if Dr. Kelsey had done nothing, the drug would have been marketed. Indeed, Merrell was poised to begin distribution in the U.S. having brought in at least 5 tons of the drug to its warehouses.(6)  Instead, on November 10, 1960, Dr. Kelsey sent a letter to Merrell outlining the deficiencies in the NDA and asking for more information.

            The Merrell company was anxious to get the drug approved and began a campaign to push the application through the FDA approval process. Dr. Joseph Murray of the Merrell Company repeatedly called and visited. However, Dr. Kelsey resisted approving the drug because of her concerns.

            Five months after the NDA was submitted, in February 1961, Dr. Kelsey read a letter published in the British Medical Journal that reported the possible occurrence of peripheral neuritis (deterioration of the nerves in the hands and feet) in patients who had used thalidomide over a long term. Investigators from the Merrell Company traveled to Europe immediately and reported back that the incidence of peripheral neuritis was low and the condition was rapidly reversible. They suggested that a caution about this side effect be put onto the label for the drug and that it be approved with the cautionary label. However, by this time Kelsey and other reviewers were even more concerned about the drug and continued to request more information.

            As time went on, it became apparent that peripheral neuritis was more widespread than previously believed (affecting anywhere from one in a hundred to one in five hundred patients), that it could be severe, and that it might not always be reversible. Some medical reviewers consulted by the FDA thought that this side effect was sufficiently troublesome that thalidomide should not be marketed, since there were already other sleeping pills available.(8)

            While concern about the peripheral neuritis was simmering, FDA reviewers voiced another theoretical concern. Thalidomide was widely used by pregnant women and FDA reviewers considered the possibility that a fetus might be particularly sensitive to the drug. Kelsey had been involved in studies of the antimalarial drug, quinine, performed at the University of Chicago. She knew that a rabbit fetus lacked the ability to metabolize quinine; the required enzyme appeared only after birth. Subsequent studies showed that many drug-metabolizing enzymes are absent in the fetus. As Kelsey (1993) later explained "... at this time there was growing concern regarding the exposure of the fetus to drugs and other substances to which the mother was exposed during pregnancy.”(9) Dr. Kelsey brought up her concerns to Dr. Murray during one of his frequent phone calls. Merrell had limited studies that indicated the drug was safe in the third trimester of pregnancy, but FDA asked for evidence that it was safe throughout gestation. Merrell suggested releasing the drug with a warning on the label that the safety of the drug during pregnancy was not established, but Kelsey did not accept this suggestion.(8)

            The pressure on Dr. Kelsey and the FDA intensified during the spring and summer of 1961. “They came to Washington, it seemed, in droves. They wrote letters and they telephoned - as often as three times a week. They telephoned my superiors and they came to see them too... Most of the things they called me, you wouldn’t print”, recalled Dr. Kelsey in 1962.(10) Despite the intense pressure, Dr. Kelsey and other FDA officials continued to ask for proof of thalidomide’s safety.

QUESTIONS

3.  What would you have done if you were in Dr. Kelsey's place at this point?

4.  Dr. Kelsey was under tremendous pressure to approve thalidomide. Why do you suppose she resisted the pressure?

THE STORY CONTINUES

            In November 1961, more than a year after the NDA was submitted to FDA, Dr. Murray called Dr. Kelsey and told her that thalidomide was withdrawn from the German market because of reports of congenital abnormalities in children born to mothers who had used it. By 1962 it was clear that the drug caused crippling and disfiguring malformations of the arms and legs. Children had been born with hands and feet that protruded directly from the trunk, something like flippers. Others had limbless trunks with toes extending from their hips; others were born with just a head and a torso; and still others had cardiac problems. No one knows how many children were affected by thalidomide, but estimates range from 8,000 to 80,000 deformed babies were born in Europe. Because of the stubborn skepticism of Dr. Kelsey and others in the FDA, this tragedy was largely averted in the U.S.

            A few cases of deformities due to thalidomide were reported in the U.S. because Merrell had distributed thalidomide to more than 1000 physicians, supposedly for “investigational use”. (This distribution of such a drug for research purposes was not illegal at that time, although FDA had thought 35-60 physicians were “investigating” the drug, not 1,000.)

QUESTION

5.  A physician, Dr. Helen Taussig, visited Europe. When she returned to the U.S. she wrote several articles and gave several talks reporting on the tragic effects of thalidomide in Europe and the narrowly averted tragedy in the U.S. Despite her efforts to bring this story to the attention of physicians and the public in the U.S., the story received little press. Why do you suppose this incident did not interest the news media?

POLITICS

            At the time of the thalidomide tragedy, Senator Estes Kefauver of Tennessee had been involved for several years in an in-depth investigation of the drug industry. He was primarily interested in reducing drug prices, but he had also unsuccessfully tried to introduce a bill that would tighten drug safety regulations. In the summer of 1962, one of Kefauver’s staff read a report of a speech by Dr. Taussig in which she revealed the magnitude of the tragedy in Europe, and mentioned that the drug would have been released in the U.S. had it not been for the unusual diligence of Dr. Kelsey. The popular press did not pick up on the story but Senator Kefauver’s staff decided to promote the story in an attempt to help the passage of his proposed legislation. They were successful in getting a reporter from the prestigious Washington Post newspaper to interview Dr. Kelsey. The Washington Post printed the story on page one and it was followed by a media blitz with numerous follow-up stories around the country relating to drug safety.

            As had previously occurred response to the sulfanilamide tragedy, the thalidomide incident mobilized public opinion regarding drug regulation. As a result, Senator Kefauver’s previously unsuccessful bill was resurrected and passed in 1962 as the Kefauver-Harris Drug Amendments to the FDCA. These amendments greatly strengthened the regulation of drugs in various ways. Pharmaceutical manufacturers were required to test the safety of drugs in animals before administering them to humans for the first time. The laws made investigators responsible for supervising drugs under study; required manufacturers to inform patients if a drug was being used for investigational purposes and obtain their consent; required that drugs be shown to be effective before marketing; required manufacturers to report unexpected harm (adverse events); and gave FDA authority to regulate advertising of prescription drugs.

            Dr. Frances Kelsey was awarded the highest honor given to a civilian in the U.S. She received the Gold Medal for Distinguished Civilian Service from President John F. Kennedy. She was also made head of a newly created division to oversee the new regulations governing the clinical testing of experimental drugs.

QUESTION

6.  How did politics influence this thalidomide story? How does public opinion influence drug regulation today?

THE INVESTIGATION

            On July 20, 1962 the executive vice president of Merrell met with the FDA commissioner and told him that a recall of the thalidomide distributed to doctors in the U.S. had been completed. However, several days later an FDA inspector visited the William S. Merrell offices in Cincinnati. The inspector found that Merrell was still in the process of contacting the more than 1000 physicians who had received the drug. The FDA then tried to determine how much drug had been returned and destroyed. They found that company inventories showed that more than 5 tons of thalidomide had been received by Merrell and over 2 tons could not be accounted for. A similar inspection tour of another Merrell division, Vick Chemical Company, revealed a similar problem of accountability. The inspector reported “I cannot help but have doubts about the adequacy and effectiveness of the [recall] procedures followed since no formal letter was used [by Vick], no material was returned and Vick has no record or information as to how much material was destroyed or who destroyed it, if any”.(6) The FDA continued its own efforts to find the drug and in a press conference in August of 1962 President John F. Kennedy urged all women of the country to check their medicine cabinet for strange drugs and to destroy them or turn them over to the FDA.

            Meanwhile, the FDA discovered that many of the doctors who had received the drug had made no effort to contact patients to whom they had given it. Often they had no records of who had been given the drug. An FDA survey showed that more than 2,500,000 tablets had been distributed to over 20,000 patients of whom 624 were reported to have been pregnant. Eventually 10 well-documented cases were found where women who had received thalidomide in the U.S. during pregnancy delivered seriously deformed babies.(6)

            There was ample evidence that the Merrell company’s distribution of the drug supposedly for research purposes was, in fact, part of a sales campaign. Moreover, serious problems with the clinical studies of the drug were later discovered. Dr. Ray Nulsen working for the Merrell Company supposedly had studied more than 175 patients who had received the drug in late pregnancy and reported no ill effects. Yet, an FDA investigation revealed three abnormal babies in this group. Subsequently there was a lawsuit brought against William S. Merrell by a couple with a child allegedly deformed by thalidomide. Under questioning, Dr. Nulsen admitted that he did not keep records of the use of the drug.

            FDA continued its investigation and eventually decided that although there was substantial evidence that Merrell had distributed the drug for commercial purposes under the guise of investigation, there was not sufficient evidence to prove that they had withheld knowledge of the drug’s adverse effects. The justice department declined to consider criminal charges against Merrell. However, there were at least ten civil lawsuits against Merrell resulting in settlements to families with disabled children.

            During the time that the Merrell Company was seeking approval for the drug, they stated that the drug had been so widely used in Europe that any adverse effects on a fetus would have been reported. It turned out, however, that a group at Bonn University in Germany had noticed an increased incidence of babies born in their hospital with badly deformed extremities, as early as 1959. They learned that a similar increase in such deformities was reported in England and in Sweden. The Bonn investigators suspected thalidomide might be associated with the deformities but gave up the idea after finding out that similar increases in birth defects had not been noted in the U.S. or Canada. The Bonn researchers had assumed that thalidomide was available in the U.S. based on statements in the promotional literature of the German firm, and so did not realize that thalidomide was indeed the culprit.(8)

QUESTIONS

7.  What records would a company need to maintain in order to be able to effectively recall a drug that had been widely distributed? What would be involved in keeping such records?

8.  If you were a member of Congress and heard about the thalidomide incident, what (if any) legislation would you introduce to best protect the American public?

9.  Comment on the actions of various characters in this real story. What impact did their various choices have on other people? 

10.        a. What is the role of Congress in ensuring drug safety?

            b. What is the role of the FDA in ensuring drug safety?

            c. What is the role of a pharmaceutical company in ensuring drug safety?

            d. What is the role of the consumer in ensuring drug safety?

11.  Suppose you were hired to prepare a position paper for the pharmaceutical industry on regulation. What principles would you promote? What would be your position on government regulation of your industry? Prepare arguments to support your position.

12.  AIDS raises some interesting issues relating to the regulation of drugs. One of the complaints of AIDS patients is that drug companies are very slow to get out new drugs to treat their illness. Drug companies attribute the delays to the stringent regulatory requirements for testing. Patients argue that while elaborate drug safety studies are conducted, they are dying. Therefore, FDA has provided avenues by which AIDS patients are often able to obtain drugs that have not been fully tested. What do you think about this “fast-tracking” of AIDS drugs? What do you think of allowing patients with other conditions access to drugs that are not well-tested, assuming the patients know the drugs have not been through a complete approval process?

A POSTSCRIPT TO THE THALIDOMIDE STORY

            At the time of the thalidomide tragedy, no one knew why thalidomide causes malformations. It was later discovered that thalidomide has multiple effects on the body. One of these is that it inhibits new blood vessel growth (angiogenesis). This inhibition is detrimental to a developing fetus because angiogenesis provides a "road map" for the normal growth of limbs and organs. However, in an interesting twist, it has been found that thalidomide may be useful in treating a number of diseases. In the 1960s, an Israeli physician gave thalidomide to patients with leprosy in order to help them sleep in spite of painful, debilitating lesions caused by that disease. Surprisingly, thalidomide not only sedated the patients, it also helped to heal the lesions. More recent work showed that thalidomide can help reduce tumor necrosis factor alpha, a molecule that has a broad role in the immune system. This effect might make it useful in treating diseases such as rheumatoid arthritis.(11)  Thalidomide is being investigated to treat adults with breast, prostate and brain cancer by inhibiting angiogenesis. It is also being investigated for treating the extreme weight loss that occurs in AIDS and similar diseases.

            On July 16, 1998, FDA approved the use of thalidomide for the treatment of the lesions associated with leprosy. Because of thalidomide’s potential for causing birth defects, FDA invoked unprecedented regulatory authority to tightly control the marketing of thalidomide in the United States. FDA instituted a program that limits the distribution of thalidomide to only authorized physicians and pharmacies, requires extensive patient education about the risks associated with thalidomide, and requires that a registry of all patients taking thalidomide be maintained. The intention of these regulations is to ensure that thalidomide is never taken during pregnancy.

QUESTIONS:

13.  Check out the following websites and articles with varying perspectives on thalidomide. What do you think about the use of thalidomide today as a drug for treating varied disorders? 

Check out the extensive FDA website on thalidomide: Thalidomide Information.
http://www.fda.gov/cder/news/thalinfo

For a very different perspective, check out the website: Thalidomide Victims Associaltions of Canada an organization of thalidomide-affected individuals and their supporters.  http://www.thalidomide.ca/

Another interesting perspective is found in “FDA’s Drug Approval Process Under a Microscope Again”, by Allan Freedman and Susan Benklman, in CQ Weekly, 56(29):1214, 7/18/98.

For more information about thalidomide and its current use in medicine, read the following: Giving Thalidomide a Second Chance by Herbert Burkholtz FDA Consumer magazine (September-October 1997)
http://www.fda.gov/fdac/features/1997/697_thal.html

FOOTNOTES AND REFERENCES:

(1)  The FDA website site is an invaluable resource for information relating to pharmaceuticals, medical products, and food regulations. The FDA homepage is simply. Within this page, the following articles are helpful:
http://www.fda.gov/

Learn more about the organization of the Food and Drug Administration with the On-Line Tutorial A Tour of the FDA

About the history of the FDA:

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, Prepared by Donna Hamilton, Historian, FDA History Office, November 1997
http://www.fda.gov/cder/about/history/histext.htm 

About the Drug Approval Process

Jeffrey Cohn, The Beginning: Laboratory and Animal Studies, FDA Consumer special report, January 1995.
http://www.fda.gov/fdac/special/newdrug/begin.html

The Animal Welfare Act, The Guide for the Care and Use of Animals, Institute of Laboratory Animal Resources Commission on Life Sciences, National Research Council, National Academy Press Washington, D.C., 1996. ‑ http://stills.nap.edu/html/labrats/

Good Laboratory Practices (GLP's)
http://www.fda.gov/ora/compliance_ref/bimo/7348_808/default.html

Dixie Farley, Benefit Vs. Risk: How FDA Approves New Drugs, FDA Consumer special report, January 1995

http://www.fda.gov/fdac/special/newdrug/benefits.html

Bertram Spilker, The Drug Development and Approval Process, Phrma,
http://www.phrma.org/searchcures/newmeds/devapprovprocess.phtml

Ken Flieger, Testing Drugs in People, FDA Consumer special report, January 1995. ‑  http://www.fda.gov/fdac/special/newdrug/testing.html

(2)   "FDA Milestones in Women's Health:  Looking Back as We Move into the New Millennium", US Food and Drug Administration Office of Women's Health, found at:
http://www.fda.gov/womens/ 

Suzanne White Junod, Ph.D. Historian, U.S. Food and Drug Administration, “The Rise and Fall of Federal Food Standards in the United States: The Case of the Peanut Butter and Jelly Sandwich.  Society for the Social History of Medicine. Spring Conference 1999. Aberdeen, Scotland. "Science, Medicine and Food Policy in the Twentieth Century". http://www.fda.gov/oc/history/slideshow/default.htm

(3)  Young, J.H. (1983). Sulfanilamide and Diethylene Glycol. In J. Parascandola and J.C. Whorton (Eds.), Chemistry and Modern Society: Historical Essays in Honor of Aaron J. Ihde (pp. 105 -125).  Washington D.C.: American Chemical Society.

(4) “Good Laboratory Practices, GLP”, when used in reference to pharmaceuticals, is a narrow term that refers to practices involving animal testing. These GLPs are enforced by the FDA. The Environmental Protection Agency, EPA, also mandates “Good Laboratory Practices” that guide investigators who are studying the health and environmental effects of agrochemicals. The GLPs from FDA and EPA are not identical but they do serve the same overall purpose of ensuring trustworthy test results. The term “good laboratory practices”, glp, is often used much more broadly to refer to good practices and procedures in any type of laboratory.

(5)  For further introductory information about GMP, see “Basic Laboratory Methods for Biotechnology: Textbook and Laboratory Reference”, by Lisa A. Seidman and Cynthia J. Moore, Prentice Hall, (January, 2000) Paperback - 800 pages Spiral edition ISBN: 0137955359 Price: $48.00. http://vig.prenhall.com/catalog/academic/product/1,4096,0137955359,00.html

(6) For a thoroughly researched review article about Thalidomide, see “Thalidomide in America: A Brush With Tragedy” by Richard E. McFadyen, Clio Medica, Volume. 11, No. 2, pp. 79-93, 1976.

(7)  Quoted in “Giving Thalidomide a Second Chance”, by Herbert Burkholz, FDA Consumer magazine (September‑October 1997) on the FDA website at http://www.fda.gov/fdac/features/1997/697_thal.html

(8) From a speech “Denial of Approval for Thalidomide in the United States”, by Frances O. Kelsey, presented at the Medicine and Health Since World War II, National Library of Medicine, Bethesda, MD, Dec. 9, 1993.

(9)  From a speech “Chicago and New Drug Legislation” by Frances O. Kelsey, presented to the Medical Alumni Association, University of Chicago, June 6, 1963.

(10)  Quoted in “A Woman Doctor Who Would Not be Hurried”, Life Magazine, 53:  28-9, August 10, 1962.

(11)  “Redeeming Thalidomide”, by Jim Kling, Modern Drug Discovery (a publication of the American Chemical Society), pp. 35-39, June, 2000


TOP
black line rule NSF logo Bio-Link.org
Web: www.Bio-Link.org
Email: info@Bio-Link.org
NSF Award #9850325