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RIBAVIRIN TREATMENT IND FOR ADVANCED LAS PATIENTS WOULD HAVE BEEN REJECTED UNDER PROPOSED TREATMENT IND RULE, FDA COM. YOUNG TESTIFIES BEFORE WEISS SUBCMTE.

Executive Summary

The expanded use of ICN's ribavirin for advanced lymphadenopathy syndrome (LAS) patients would have been rejected under FDA's proposed treatment IND regulation as well as under existing treatment IND criteria, FDA Commissioner Young assured Chairman Weiss (D-N.Y.) at a House Government Operations Subcommittee hearing on April 29. Young called the ribavirin treatment IND review a prototype for disapproval under the proposed treatment IND rule. Noting that ICN's proposal for expanding the use of ribavirin with a treatment IND was evaluated under both criteria established in the proposed rule and current criteria, Young said that ribavirin "was a candidate for disapproval, show[ing] that the Commissioner would have the capability [to deny a treatment IND] even under the [proposed] rule." Deputy Commissioner Norris identified Burroughs Wellcome's AZT (Retrovir) and ribavirin as examples of approvable and unapprovable treatment INDs under the proposed rule. "We use AZT and ribavirin as two of the models [for the proposed rule] -- the upside and downside of practicing this [proposed] regulation," Norris said. Young emphasized that the treatment IND proposal was kept in mind during the evaluation of ICN's request to expand ribavirin trials to a larger number of LAS patients and asymptomatic AIDS patients. FDA denied the request for a treatment IND in mid-April because of concerns that the drug was "ineffective and possibly harmful" in patients with more advanced stages of AIDS-related complex ("The Pink Sheet" April 20, p.3). "I was intimately involved [in the ribavirin review]," Young said, "and actually felt that under this [proposed] rule we would have had the same way of interpreting [the approvability of a treatment IND]." Weiss asked the commissioner if ribavirin would have been approved for a treatment IND under the proposed rule if the proposed patient population was viewed as having an immediately life-threatening disease. Setting up the hypothetical situation, Weiss said: "Let's suppose that the manufacturer of ribavirin had instead of applying as it did, applied for a treatment IND for terminally ill, advanced AIDS-related complex . . . patients, who would qualify as having an immediately life-threatening condition. Had the proposed regulations been in effect at that time, wouldn't FDA have been inclined" to approve the treatment IND? Young responded: "Absolutely not -- we would have taken the same action if the regulations had been in place as if they were not." Young noted that the proposed rule states that FDA can deny a treatment IND for an immediately life-threatening illness if "the drug clearly does not provide a therapeutic benefit." With ribavirin, he said, "there were some concerns that we had on safety, but we were also concerned that clearly it provided no therapeutic benefit." AZT was cited numerous times as a model for the treatment IND proposal, because unlike ribavirin, AZT satisfied the threshold effectiveness standard. National Institute for Allergy and Infectious Diseases' AIDS Treatment Branch Chief Maureen Myers, MD, testified that "what happened with AZT and the award of that treatment IND . . . was appropriate." Burroughs Wellcome's controlled clinical trial of AZT "demonstrated efficacy and was terminated early because of . . . the anticipated degree of efficacy -- and the system responded appropriately," she said. Myers suggested, however, that the standard of efficacy as proposed for qualification for a treatment IND may be inadequate. She commented that the proposed rule establishes a treatment IND system that is more comparable to compassionate use IND than it is to existing treatment IND procedures. "My understanding of a treatment IND is . . . that efficacy is part of the information that must be available before a treatment IND is awarded." Under the proposed rule, Myers said, "I see my understanding of a treatment IND to have been now possibly redefined to what my understanding of a compassionate use IND is." Under a compassionate use IND, Myers explained, "an agent may be made available for life-threatening disease without substantial information on efficacy." Noting that the existing treatment IND approval criteria allowed the widespread use of AZT, Myers maintained that the current approach "is a perfectly adequate and appropriate way to go . . . and should be continued." Martin Hirsch, MD, Harvard Medical School, suggested that the approval of AZT might have been slowed down had the proposed rule been in effect when the drug was being studied. Hirsch said that under the proposal, AZT would have been eligible for a treatment IND following Phase I testing. Widespread, uncontrolled use at that time would have prevented the placebo-controlled AZT trial, that ultimately led to approval of the drug, from occurring, Hirsch testified. Hirsch also maintained that if the proposal had been in effect two years ago, a drug "such as suramin could have been given to thousands of patients, with disasterous consequences." He noted that "we now know [that suramin] is neither safe nor effective because of a careful trial that was done." If the treatment IND proposal "had been in place" then, Hirsch said "no one would have volunteered for a placebo controlled trial [and] we would still today . . . be in the same position . . . where we wouldn't know what the situation with the drug was." Young told Weiss that suramin would not meet the criteria for a treatment IND under the proposed rule for either a serious or immediately life-threatening illness. Young indicated that a treatment IND for suramin could have been denied on grounds that prior to the controlled trial there would have been insufficient data to evaluate the application. FDA Office of Drug Research and Review Director Robert Temple, MD, has also expressed concern that the language of the proposed treatment IND rule, as written without the preamble, would allow widespread availability of inappropriate drugs. Temple's initial reservations about the plan were expressed in a memo to Center for Drugs and Biologics Acting Director Paul Parkman, MD, and made available at the hearings. The memo was written before Temple had seen the proposed rule's explanatory preamble. Temple wrote: "It is perfectly clear that the proposal will permit the use, paid for by the patient, of every hoax in the book, including laetrile, Wobe-Mugos therapy, megavitamins treatment (trisomy-21) and every other agent, not necessarily a hoax, in Phase I studies without any limitation." In notes made available to the subcommittee, Temple pointed out a number of situations in which treatment INDs have been used effectively. He cited antiarrythmics as a class of drugs that have been often used in open studies. Encainide (Mead Johnson's Enkaid) and flecainide (Riker's Tambocor) were both "given open protocols, but only to qualified, specified investigators, with proper facilities," the notes state. Young said that synthetic growth hormone can be viewed as another recent example of a product which would qualify for the wider pre-approval use. Unlike Retrovir, which qualifies as a product to treat a "life-threatening" disease, growth hormone would meet the definition of a drug intended to treat a "serious" disease. Young declared: "As a general rule, drugs for immediately life-threatening diseases [would] be made available, at the earliest, near the end of Phase II and more likely into Phase III [trials]. This was exactly the case with Retrovir. In contrast, we would expect, as a general rule, drugs for serious diseases to be made available well after Phase III trials are underway, more towards the middle of Phase III. The synthetic growth hormone was granted a treatment IND status at the end of Phase III. When done in this way, we would not anticipate any significant conflict between enrolling enough patients in clinical trials and providing additional patients access to drugs under treatment INDs." Temple's notes indicate that he prefers an "open trial" expansion of clinicals over the treatment IND as defined in the proposed rule. Both approaches allow use of the experimental drug without a control group; however, the open trial system requires evidence of efficacy and allows use only by medical experts, whereas the proposed treatment IND does not, the notes indicate. FDAer TEMPLE's EARLY RESERVATIONS ABOUT TREATMENT IND PLAN The following memo was written by FDA Office of Drug Research and Review Director Robert Temple, MD, and forwarded to Center for Drugs and Biologics Acting Director Paul Parkman. In the memo, Temple discusses his reservations about the proposed treatment IND and sale rule as it is presented by the language of the regulation. In the last paragraph, written after the other portions of the memo, Temple notes that the language of the reg-preamble could mitigate some of his reservations. Temple had not seen the preamble at the time he wrote the first sections of his memo to Parkman. It is perfectly clear that the proposal will permit the use, paid for by the patient, of every hoax in the book, including laetrile, Wobe-Mugos therapy, megavitamins treatment (trisomy-21) and every other agent not necessarily a hoax in Phase I studies without any limitation. The data needed to declare the drug unsafe or fraudulent (as required in the regulation) will never be available to the [commissioner] if the drug has not been extensively studied. The effect of this proposal is plainly to obliterate all protections of the FD&C Act for immediately life-threatening conditions, however these are defined. It is difficult to imagine what legitimate interest this serves. I doubt any responsible sponsor would even release an agent in these circumstances; it leaves only the fly-by-nights. What is incredible to me in all this is that OMB has not even felt they have the burden of identifying a problem, an example of FDA rigidity -- some aspect of the system that is broke. They have not obtained, so far as we know, AMA, PMA support or had discussions with anyone. And without any such record they are moving to a final reg that obliterates a section of law allowing marketing (sale anyway) of a new drug that has met no standard at all, except for obtaining an IND. A possible FDA response to all this, I should note, is to become significantly stricter [in] granting an IND at all. Apart from the waste of time in this, it is potentially anti-scientific, forcing us to try to pre-judge the sense of proposals when we should await evidence. (Added 4/23/87) There was no preamble written at the time; I realize the commissioner believes the preamble does provide authority to require data to support use, even in life-threatening situations and intends to implement the regulation that way if the final regulation is unchanged from the proposal. To the extent this can be done, and sustained if challenged, the concerns above are diminished. The basis for this interpretation in the preamble still seems weak to me and the words of the regulation itself pose all the problems described above.
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