[The following is Part Two of a chapter excerpt from “Starting With Serotonin: How a High-Rolling Father of Drug Discovery Repeatedly Beat the Odds” (Improbable Books, 2008), the biography of Dr. Albert Sjoerdsma. The first part appeared on 7/10/17. All of the remarks in italics are my father’s comments, as related to me in interviews for the book.]
Ironically, that same summer , [U.S. Surgeon General] Luther Terry [pictured above] dropped by Sjoerdsma’s office and confided his worries about a homegrown public-health crisis-in-the-making.
The Surgeon General had received reports from Oregon of paralytic poliomyelitis, apparently caused by ingestion of Dr. Albert B. Sabin’s new oral polio vaccine. Dr. Jonas Salk’s vaccine, introduced in 1955, contained “killed” poliovirus and had to be injected; Sabin’s vaccine, a sugar cube that needle-fearing children could easily swallow, contained the live virus. Because evidence suggested that the Salk vaccine failed to completely immunize patients, health officials favored the inherently more dangerous, but more effective Sabin vaccine, of which there were three types.
The USPHS [United States Public Health Service] approved the Sabin vaccine in 1960, but did not clear it for a mass immunization program until 1962. Reports of vaccine-associated paralytic polio emphatically threatened its future.
Luther came in one Saturday morning—he used to get his hair cut at the NIH, and sometimes he’d drop by. And he sat there in my office, and I said, “How’s it going?” And he said, “Well, OK, except we have a little problem maybe in the Pacific Northwest where there have been some cases of polio that seem possibly related to the oral vaccine, the Sabin vaccine. But my statisticians studying the whole thing say it’s not statistically significant.” I looked at Luther and said, “Oh, yeah.” . . . Statistics don’t mean a damn thing, and Luther was kind of agreeing because he knew he had a problem.
On Aug. 22, 1962, Terry announced that he and his polio advisory committee had met to study twelve cases of poliomyelitis that had occurred outside of natural epidemic areas and within thirty days of oral vaccinations. About three weeks later, Canada suspended use of the Type III oral polio vaccine, in response to four new cases of vaccine-induced paralytic polio within its borders. This cautionary action forced Terry’s hand.
On Sept. 15, the Surgeon General officially recommended that physicians stop giving the Type III oral vaccine to adults, while assuring them that no children had been involved in any of the Canadian or U.S. polio cases. But Terry had been misinformed: One victim was sixteen, another eighteen. Three months later, he approved the use of all three types of the live-virus oral vaccine by all patients, especially children, with the caveat that adults over thirty run “a very small risk” of contracting polio.
Terry had sided with the statisticians, who estimated that older adults had a one-in-a-million chance of contracting vaccine-induced polio. Despite the favorable odds, Sjoerdsma would never let his children receive the live-virus vaccine.13
Statistics are little consolation for the one person who gets polio.
In time, the United States would cease routine production of the oral poliovirus vaccine, yet still maintain an emergency stockpile to use in the event of a poliomyelitis outbreak. Polio has not existed in the Americas since 1994, but it still circulates in Asia and Africa. In 2000, the U.S. Centers for Disease Control and Prevention recommended an all-inactivated (dead) poliovirus vaccine schedule for children, to eliminate any risk of vaccine-associated polio. It took national eradication of the virus before the government would reject Luther Terry’s long-shot odds. 14
While The Post covered the polio scare, thalidomide dominated its medical headlines. After it broke the Kelsey story, the lackadaisical FDA stirred into action.
Previously, Merrell had assured the FDA that it had undertaken a thorough recall of all thalidomide stock. Now, however, the agency launched its own probe to determine how much drug was still in circulation among the more than 1,000 U.S. investigators who had received it. Seventy-nine doctors, it learned, still had over 25,000 tablets on hand, and hundreds of others had not bothered to track down patients for whom they had prescribed thalidomide.15
Ultimately, thalidomide use by women in early pregnancy resulted in the births of more than 10,000 severely deformed babies worldwide, including in Europe, South America, and Canada. Because of the drug’s ready availability, seventeen American children with associated defects were born—ten in the United States and seven abroad.16
On Aug. 10, 1962, in response to Merrell’s haphazard handling of early thalidomide clinical studies, FDA Commissioner George P. Larrick proposed new, tighter regulations for the investigational drug process. This proposed rulemaking would mark the first step in what Sjoerdsma eventually considered an intolerable regulatory infringement on his scientific freedom.
Under the 1938 law, the FDA had no authority over the clinical testing of investigational new drugs. The then-current regulations only required a drug “sponsor” (usually a pharmaceutical company) to obtain a written commitment from investigators that they would use new, unapproved drugs only for investigational purposes and in adequate facilities. The FDA could inspect records of drug shipments and investigator statements, but not otherwise intervene. Larrick’s proposed rules, which charged sponsors with extensive reporting and record-keeping responsibilities, and the agency with broad oversight, radically altered the division of power.
Before a sponsor could begin clinical investigation with a drug—no matter how few the number of subjects—the new rules required submission to the FDA of a “Notice of Claimed Investigational Exemption for a New Drug” (an “IND”), consisting of:
- a detailed description of the drug, its components, and its manufacture;
- detailed reports of preclinical tests, such as animal studies, that attested to the drug’s safety; and
- a detailed outline of the sponsor’s plan of investigation, including specifics about the individual investigators, the stages of investigation and their duration, and the selection of patients.
Signed statements from all investigators attesting to their education and experience and to the safety of their facilities also had to accompany this notice. Although the sponsor was not obligated to wait for the FDA’s permission before proceeding with its study—silence signified implicit approval—the agency could terminate experimentation once it was under way.17
The U.S. Congress also responded to the thalidomide expose and the public alarm it aroused. A compromise bill came out of a House-Senate conference committee that was tougher than either Kefauver’s eviscerated S.B. 1552 or the toothless H.R. 11581. On Oct. 10, 1962, President Kennedy signed the Drug Amendments of 1962, known more commonly as the Kefauver-Harris Amendments. Less than a year later, Kefauver died suddenly of a ruptured aorta. He was sixty years old.18
Although it amended the 1938 drug act in many significant respects, the 1962 law is best known for its efficacy mandate. Henceforth, in order to obtain FDA approval to market a new drug, a sponsor would have to submit “substantial evidence from controlled studies” of drug efficacy, as well as safety. Exactly what constituted “substantial evidence” would be left to the agency to decide. The law also removed the sixty-day deadline and automatic approval, giving the FDA an indefinite amount of time in which to complete its NDA evaluation—an open-endedness that quickly proved problematic.19
Ironically, clinical efficacy tests would not have kept thalidomide off the market. Kevadon worked as intended: It put people to sleep. No governmental agency anywhere in the world had guidelines for using animal embryo- and feto-toxicity studies to evaluate the human teratological risk from an investigational drug, and the FDA did not require them after the crisis.
The amendments further directed pharmaceutical companies to prove the efficacy of drugs already on the market and the FDA to review and either re-approve or reject all previously approved drugs within two years of legislative enactment. Despite Kefauver’s tireless efforts, the new law was silent on drug prices, which skyrocketed, as companies exacted compensation for increased research expenditures.
It was ironic because Kefauver was going after the pharmaceutical companies because of the price of antibiotics. But after thalidomide, it had nothing to do with the efficacy, just safety. . . . You can waste a lot of money trying to prove efficacy to the FDA’s satisfaction. At the NIH, freedom to do our own thing soon evolved into FDA oversight and control.
10. McFadyen, “Thalidomide in America,” pp. 83-84; and Harris, The Real Voice, pp. 154-55.
11. For a detailed account of Senator Kefauver’s crusade to reform the drug industry, see Richard Harris’s The Real Voice, supra, note 7. See also chapter six, “Reforming the FDA,” in Stephens and Brynner, Dark Remedy, pp. 101-10; McFadyen, “Thalidomide in America,” p. 84; and Temin, Taking Your Medicine, pp. 122-25. The author used all of these sources to construct her account.
At the time, many doctors prescribed only brand-name drugs, because, as congressional testimony showed, they chose their medicines based upon pharmaceutical companies’ advertisements, and they lacked faith in the smaller companies that made cheaper generics.
12. Morton Mintz, “‘Heroine’ of FDA Keeps Bad Drug Off Market,” The Washington Post, July 15, 1962, p. A1. Blair tipped off Washington Post economics reporter Bernard Nossiter, who had been covering the drug bill. Nossiter relayed the news to a city editor, who asked Morton Mintz to investigate. Harris, The Real Voice, pp. 183-84.
13. For a contemporaneous account about administration of the Sabin live-virus oral polio vaccine, Surgeon General Luther Terry’s response to vaccine-induced polio cases, and the initiation/postponement of a mass immunization drive, see coverage in The Washington Post: “The Polio Vaccines,” The Washington Post, Sept. 11, 1960, p. E4; Nate Haseltine, “Mass Use of Live Polio Virus Seen Within Year by Public Health Service,” The Washington Post, Aug. 25, 1960, p. A1; “Oral Type Polio Vaccine Delayed for Use in 1961,” The Washington Post, Dec. 1, 1960, p. D1; Associated Press, “Oral Polio Vaccine III Use Halted,” The Washington Post, Sept. 16, 1962, p. A1; Nate Haseltine, “Live Vaccine Polio Plan Collapses,” The Washington Post, Sept. 18, 1962; Nate Haseltine, “Polio Muddle Raises Many an Eyebrow,” The Washington Post, Sept. 23, 1962, p. E3; and John Maffre, “Oral Polio Vaccine Wins Approval Of PHS for Children, Young Adults,” The Washington Post, Dec. 20, 1962, p. A1.
For a biography of Albert B. Sabin, M.D. (1906-1993), see Hauck Center for the Albert B. Sabin Archives, University of Cincinnati Medical Heritage Center at http://sabin.uc.edu/biography.cfm.
14. See Centers for Disease Control, “Poliomyelitis Prevention in the United States: Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP),” at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr4905a1.htm.
15. McFadyen, “Thalidomide in America,” pp. 85-86. According to McFadyen, “By the third week of August, the FDA had contacted about 92 percent of the investigators involved, but the findings of the survey were disturbing. Some seventy-nine physicians still had over 25,000 tablets on hand. Another 410 doctors had made no effort to contact patients to whom they had given the drug or did not have records to indicate which of their patients had received it.” Ibid.
16. See Bren, “Frances Oldham Kelsey,” p. 27; and Janssen, “Outline of the History of U.S. Drug Regulation and Labeling,” supra, ch. 2, note 7, p. 437.
17. George Larrick, “New Drugs for Investigational Use: Proposed Exemptions,” Federal Register 27 (10 August 1962): 7990-92, microfiche. These rules were codified at 21 Code of Federal Regulations 130.3 (1963). See also Earl L. Meyers, “The Food and Drug Administration’s Role in the Testing of New Drugs” (1963), Appendix A, pp. 262-66, in Clinical Testing of New Drugs, ed. Arthur D. Herrick and McKeen Cattell (New York: Revere Publishing Co., 1965).
18. See John Goshko, “Sen. Kefauver Dies After Heart Seizure,” The Washington Post, Aug. 11, 1963, p. A1; and Jack Anderson, “The Tall Man From Tennessee,” The Washington Post, Aug. 14, 1963, p. B11.
19. The new law also required drug companies to register with the FDA and be inspected at least once every two years; to report all adverse drug effects promptly; and to obtain written informed patient consent before conducting trials with human subjects—a requirement tacked on at the eleventh hour by Senator Jacob Javits of New York.
Author’s Interviews With Dr. Frances O. Kelsey; Kelsey, “Four Federal Achievements”; Janssen, “History of U.S. Drug Regulation and Labeling,” pp. 437-41; McFadyen, “Thalidomide in America,” pp. 85-90; Temin, Taking Your Medicine, pp. 125-26. See generally The Real Voice, for an excellent chronological analysis of the legislative process, both on the record and behind-the-scenes.