Officials in the Office of Compliance in the Center for Drug Evaluation and Research of FDA began an investigation of the FIAU and FIAC trials within a month of the deaths of the PPPC trial subjects. The investigation apparently continues to this day, although it has already resulted in the public censure of four scientists and two drug companies (Schwartz, 1993; Hilts, 1994).
Part of the mission of the Division of Scientific Investigations of the Office of Compliance is to perform on-site audits of sponsors and investigators performing research under INDs. The division carries out hundreds of such audits every year. Most of them are routine and performed as part of the ongoing activities of the Division in relation to its general mission of assuring compliance with federal guidelines for research performed under INDs. A small fraction of them are performed because of suspected problems, because of complaints from investigators or patients as to possible wrongdoing, or because of publicity surrounding a study. The audits in the case of the FIAU trials were prompted via the last of these and were initiated by the division after publicity in the media and the threat of hearings in Congress.
Most audits conclude with an oral briefing of the findings and the provision of a list of problems or violations to the investigator or sponsor being audited. On other occasions this is followed up with letters notifying investigators or sponsors of problems or violations noted in the audit. Letters conveying such information are broadly referred to as warning letters and in terms of action indicated are classified as no action indicated (NAI), voluntary action indicated (VAI), or official action indicated (OAI). Letters of the first type, as implied by the name, do not require a response from the recipient. VAI letters request a response within 30 days of receipt with a proposal for correcting or preventing the cited problems or deviations in the future. OAI letters are intended to warn of an impending action such as disqualification from future drug research or even criminal prosecution and require a response within 15 working days. The committee was unable to determine exactly how the decision on what type of letter to send is reached, but it would appear to be a subjective decision based on some combination of the number of violations and their perceived seriousness.
The division has issued a total of 3,731 such letters since beginning the practice in 1977 (20 percent NAI, 74 percent VAI, and 6 percent OAI). The number issued in fiscal year 94 was 187 (31 NAI, 91 VAI, and 8 OAI, with 57 remaining to be classified at the time of the testimony [July 25, 1994]).
Letters were sent by the division pursuant to FIAC and FIAU trials to four scientists and two sponsors: Stephen E. Straus, Douglas Richman, Lawrence Corey, Jay Hoofnagle, Oclassen Pharmaceuticals, Inc. (Terry L. Johnson addressee), and Eli Lilly & Company (Randall Tobias addressee). These letters were generated as a result of on-site audits carried. out in the latter half of 1993 (all were started in August or early September). All letters were dated May 11, 1994 and were sent out by fax and overnight mail on May 13. The letters to Richman, Corey, Hoofnagle, Oclassen, and Lilly were OAI letters. The letter to Straus was a VAI letter.
Technically, the letters are intended simply to note violations of protocol or procedure, devoid of judgment as to the relevance of the citations to patient care or treatment, as indicated below in testimony before the Committee: