[The following is the third and final part 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. Part One appeared on 7/10/17, and Part Two on 7/17/17. All of the remarks in italics are my father’s comments, as related to me in interviews for the book.]

In the wake of the 1962 Amendments, the FDA restructured its Division of New Drugs into five branches. [Frances] Kelsey became director of the Investigational Drug Branch, which evaluated all proposed clinical trials for compliance with the new IND regulations. When Larrick’s rules took effect Feb. 7, 1963, they immediately threatened Sjoerdsma and his enterprise.

According to John Oates [one of Sjoerdsma’s outstanding clinical associates who became a senior investigator in his operation and eventually, after Oates left the NIH, Chief of Medicine at Vanderbilt University; pictured above in recent photo], the FDA was prepared to “set in motion a common process for every single clinical study that was done, and we were very concerned about that. . . . They were about to implement one common mechanism that would apply equally to a study on 1,000 patients as well as a study on the first patient.”

The Wild Bunch [Sjoerdsma’s group in the Experimental Therapeutics branch of the National Heart Institute] exhaustively discussed the new regulatory burdens and drafted Oates, as he recalled, to write a letter to the FDA, “suggesting that they divide their studies up into phases and use different regulations for the introductory or first phase. Whether that influenced them or not, I don’t know, but they used our language.”

In order to earn the FDA’s approval of its IND, a sponsor would have to show through animal pharmacology and toxicology data that its drug had a reasonable chance of being effective in humans and would cause no undue harm. Once a sponsor met this standard, the FDA required it to put the drug through three phases of clinical studies.

In Phase I, clinical pharmacologists assess human tolerance, which is a matter of safety and toxicology, and evaluate the new drug’s fate, in terms of biologic activity and metabolism. Phase I subjects are usually normal, healthy volunteers. In Phase II, researchers study a dozen or so selected patients to determine drug efficacy and dosage range and form. Phase III encompasses broader clinical trials, with placebo control groups. Placebos are harmless, inert substances substituted for the drug under scrutiny.

Normal Phase I does not have anything to do with efficacy of a drug. Phase I is just safety and tolerance dosage.

Sjoerdsma never cared for testing normal volunteers: I think it depends on the drug. If you’ve got something that you think is going to be 100 percent safe, you can play around in normal volunteers. But the idea is to push the drug up to tolerated dose, and I don’t like that. . . . I never did like that. That’s why I always used my hypertensive patients as volunteers at NIH, which was pushing it a little bit.

What you want to get out of Phase II is, do you think this drug works or not? And what’s the dosage to use in Phase III? You need at least two large-patient groups against placebo in Phase III.

At the inception of this scheme, regulators had no idea how long each phase would take. Today, each phase takes years, especially Phase III. It takes forever.²⁰

In public comments, Kelsey explicitly recognized Phases I and II as the “clinical pharmacology” phases of investigational drug testing and sought to alleviate the fear of “pure” researchers like Sjoerdsma and Oates that the new rules would erect insurmountable barriers in their clinical explorations. 

“We didn’t want to be regulated with the rigidity of a large clinical trial,” Oates explained. “We didn’t want these Draconian restrictions imposed on Phase I of clinical research, or on the use of experimental tools. . . . for example, on something like the tyramine test.” But that’s exactly what happened.

In June 1963, Kelsey advised that a “well-qualified investigator with adequate research facilities [who] wishes to perform an experiment” need submit only “a simple statement of what he wants to do, with information showing that the experiment is safe in his hands.” She compared this “notice” to the data that a researcher, who wants to use a drug as an investigational tool, presents to an institutional research review committee to gain approval. While Kelsey promised leeway in the rigors of reporting requirements for Phase I and Phase II research, her pledge eroded with time.²¹

Before the 1962 amendments, we didn’t report to the FDA at all. The NIH had its own license to study drugs in people and its own internal clinical research committees. It was none of the FDA’s business. The biologicals division [vaccines] stayed independent longer than we did, and then Jim Shannon caved in, in my book. He let the FDA start to regulate us. What do they know about drugs? And then Frances Kelsey came into the act. First, she said, “Well, we’d just like to know what you’re doing.” . . . What does that mean? You have to send them reports, right? [Cornell clinical pharmacologist] Walter Modell was fit to be tied when the FDA started sticking its nose into early phase work. We wanted to keep the FDA out of the early phase—give us a chance to see what we think, not do our thinking for us, which is what the FDA does now.

I started getting these enormous printouts of bullshit stuff that the FDA wanted from me before I could do anything. . . . You start to do a study in ten subjects, normal volunteers, or whatever, you end up with a stack of papers two feet high. You don’t even know what the hell you’ve got. I’m still angry about it.  

[Jim Shannon was NIH director.]

In 1964, Sjoerdsma testified before a congressional subcommittee investigating new drug safety and FDA oversight that he had administered more than 200 different compounds to hundreds of patients over a period of about ten years. And we considered what we had done to be pretty damn safe. Congressman L.H. Fountain, a conservative Democrat from North Carolina, chaired the subcommittee, which “was just curious about what was being done at the NIH with drugs,” Sjoerdsma said. “Yeah, right.”²²

Everybody was trying to get political mileage out of drugs. Congressmen were looking for publicity, but they didn’t know a damn thing about science or drug research. . . . The human body isn’t necessarily built the way Congress decides we should work on it.

In 1966, Merck President John T. Connor quantified the FDA’s burdensome new NDA as calling “for some thirty-five separate actions, reports and certifications, which include the monitoring of investigations, technical chemical information, and all the collected clinical and laboratory reports. [A recent Merck NDA had] contained 14,000 pages of reports and data in twenty-seven volumes [including its own] laboratory data and reports on preclinical tests in thousands of animals [and representing] the work of more than 100 independent clinical investigators with 4,500 patients over . . . three years.”

Connor knew of one manufacturer who had submitted an application that, stacked upright, stood nine feet high.²³The FDA’s new rules effectively shifted control in research to well-heeled drug companies who could bear the cost burden and, Sjoerdsma said, “compromised the ability of the individual to create research at the clinical level.” His ability.

After the phocomelia outbreak, research with thalidomide slowed, but never stopped. The FDA continued to permit physicians to use the drug, subject to restrictions, in individual patients, and, in 1998, formally approved Thalomid® for treatment of erythema nodosum leprosum, a debilitating inflammatory complication of leprosy. Only physicians and pharmacists who register to participate in a rigorous drug distribution program, designed to prevent birth defects, may prescribe and dispense it.²⁴

The notorious drug has since been FDA-approved for use in multiple myeloma and has shown promise against certain serious infections, autoimmune disorders, and other cancers.²⁵

***

[Elsewhere in my book, I explain that the FDA did not issue its “Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use” until 1966. Veterinary pathologist and toxicologist James W. Newberne, who would work under Sjoerdsma when he moved into the pharmaceutical industry, was a pioneer in veterinary pathology. The next two paragraphs are excerpted from page 330 of my book:

“Before the ‘60s,” [Newberne] explained, “there really wasn’t any serious teratologic work being done. No governments were evaluating the human birth-defect risks from drugs, environmental chemicals, or radiations. In fact, the prevailing medical opinion was that congenital abnormalities expressed a defective genome.

“[When] it was determined [with thalidomide] that the birth defects that occurred in people hadn’t been identified in the animal studies,” Newberne said, “that raised a real concern, and rightly so.”

The Teratology Society, co-founded by University of Cincinnati professors James G. Wilson and Josef Warkany, “started on a program to develop teratologic studies that became the order of the day . . . ,” Newberne said. “It was only then that animal SOPs [standard operating procedures] were set up. But it was an evolving process, and it took years.” [Wilson, Warkany, and other pioneering teratologists advised the FDA in formulating its guidelines.]

***

20. In 2000, a contributor to a prominent clinical pharmacology textbook estimated that Phase I takes from three to six months; Phase II, from six to twelve months; and Phase III, a year to more than four years. See Richard D. Mamelok, “Drug Discovery and Development,” pp. 1291-96, in Melmon and Morrelli’s Clinical Pharmacology, 4^th ed., ed. S. George Carruthers, Brian B. Hoffman, Kenneth L. Melmon, and David W. Nierenberg (New York: McGraw-Hill, 2000).

Today, the Pharmaceutical Research and Manufacturers of America (PhRMA) estimates that three to six years of  “preclinical studies” occur before drugs are tested in clinical trials, with Phases I and II each taking from six months to a year to complete, and Phase III consuming one to four years. The FDA now has the option to require companies to engage in Phase IV “post-marketing” studies to evaluate long-term safety or to generate additional data. These can continue indefinitely.

 See PhRMA, “Research and Development,” at http://www.phrma.org/index.php?option=com_content&task=view&id=382&Itemid=118.

 21. Frances O. Kelsey, “The Investigational Drug Branch: A Review of Objectives and Function” (1963), Appendix B, pp. 281-89, in Clinical Testing of New Drugs (note 15, supra). The new regulations appear in Clinical Testing of New Drugs, Appendix G, pp. 338-55.

 22. Fountain chaired the House Subcommittee on Intergovernmental Relations.

 23. John T. Connor and I. Louis Wolk, “Basic Philosophy of American Patent System: Part 3—Pharmaceutical” (1966), pp. 30-31, in The Law of Chemical, Metallurgical and Pharmaceutical Patents, ed. Howard I. Forman (New York: Central Book Co., 1967).

After drug approval, a company now entered the newly mandated record-keeping and reporting phase, during which it was required to report “unexpected side effects, injury, toxicity, or sensitivity” that occurred in actual use, Connor said. “Failure to maintain such a reporting system [could] result in withdrawal of the FDA approval to market. Still further governmental requirements contain the submission of samples, labeling of the product, information to physicians, restrictions on advertising, and the like.” Ibid.

24. For press accounts about thalidomide’s return see: Justin Gillis, “Victims and Drugmaker, Unlikely Collaborators,” The Washington Post, July 17, 1998, p. A1; Sheryl Gay Stolberg, “Thalidomide Approved to Treat Leprosy, With Other Uses Seen,” The New York Times, July 17, 1998, p. A1; and Peter Huber, “FDA Caution Can Be Deadly, Too,” The Wall Street Journal, July 24, 1998.

For FDA approval details, see “Thalidomide Safety Information,” and links therein, at http://www.fda.gov/cder/consumerinfo/druginfo/thalomid.htm.

25. See “MedlinePlus Drug Information: Thalidomide,” a service of the U.S. National Library of Medicine and the National Institutes of Health, at http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a699032.html; and Herbert Burkholz, “Giving Thalidomide a Second Chance,” U.S. Food and Drug Administration, at http://www.fda.gov/fdac/features/1997/697_thal.html.

Researchers have studied thalidomide, and received encouraging results, in patients with advanced melanoma and renal cell, ovarian, and breast cancers. Ganesh C. Kudva, Brian T. Collins, and Frank R. Dunphy II, “Thalidomide for Malignant Melanoma,” Correspondence, NEJM 345 (2001): 1214-15; and T. Eisen, C. Boshoff, I. Mak, F. Sapnuar, M.M. Vaughan, L. Pyle, S.R.D. Johnston, R. Ahern, I.E. Smith, and M.E. Gore, “Continuous Low Dose Thalidomide: A Phase II Study in Advanced Melanoma, Renal Cell, Ovarian and Breast Cancer,” British Journal of Cancer 82 (2000): 812-17.