TREATMENT IND DENIALS MOST OFTEN DUE TO LACK OF SAFETY & EFFICACY SUPPORT, FDA's TEMPLE TELLS AMA/FDA CONFERENCE; DRUG DIVISION CONSULTATION SUGGESTED

Executive Summary

FDA's most common reason for denying Treatment IND status to experimental drugs is lack of evidence of safety and efficacy, Office of Drug Evaluation I Director Robert Temple, MD, told a Feb. 16 conference on the Treatment IND, jointly sponsored by the American Medical Association and FDA. From the preliminary experience of 12 Treatment IND applications to date, Temple said FDA has learned that applicants understand the requirements that diseases for which Treatment IND status is requested must be serious or life-threatening and lack adequate alternative therapy. However, "the matter of evidence" has been the "most important" problem for applicants. "Evidence was considered insufficient in six" Treatment IND applications. On the other hand, lack of safety and efficacy information "was really the crucial matter in only two, ribavirin and [a] drug for respiratory distress syndrome. The others were lacking in other ways." Temple suggested that IND sponsors seeking treatment status consult with an agency reviewing division if they are confused by regulatory requirements. "It's probably worth the sponsors' while if they're in doubt about the state of things to consider discussing some of these with the appropriate division before they submit them," he said. The FDAer noted "the treatment protocol is not for drugs that are going nowhere; it's not a cheap or easy or deceptive way to market a drug. It's for drugs that are likely to be approved and are under serious and active study and look promising." He emphasized the importance of supporting evidence: "If there are no data at all, it really isn't worth trying." In a separate presentation, Commissioner Young reported that "FDA has made decisions on 12 applications for treatment protocols" since the regulations took effect last spring. "In the process," he added, the agency "has begun to establish procedents for approval and disapproval decisions under this regulation." Of the 12 applications, Young noted, "one was from an individual physician, four came from public health agencies -- three federal and one state, and seven requests were submitted by industry." The three approved Treatment INDs were sponsored by public health agencies: the Massachusetts Public Health Department (cytomegalovirus immune globin), the National Cancer Institute (ifosfamide and mesna), and NIAID (trimetrexate). Regarding the remaining nine submissions, the commissioner reported that "six are on clinical hold, which means that the investigational agents involved cannot be made available for treatment purposes. Two were returned to the sponsor because they did not meet the threshold criteria for FDA review, and the remaining one is being discussed with the firm." FDA placed clinical holds on six applications "because, as the regulation provides, the available scientific evidence, taken as a whole, failed to provide a reasonable basis for concluding that the drug may be effective for its intended use or would not expose the patients to an unreasonable and significant risk of illness or injury," Young explained. Another problem with Treatment IND applications has been the controlled trial requirement. "Controlled trials were completely lacking in only two cases, but in two more they were plainly going nowhere, which led us to conclude there was no active pursuit" toward full marketing approval, Temple said. Regarding the submissions denied by FDA, Temple noted that "one of the earliest" Treatment IND applications was for "a plant extract intended for treatment of stage three and four pressure ulcers, decubitus ulcers [and] stasis ulcers," Temple said. FDA would have granted Treatment IND status if other criteria had been satisfied "because these people weren't doing very well." The product "was under investigation in a controlled trial, but only six patients had been entered in the last year," he said. The application, being one of the first requests for Treatment IND status, reflected "some confusion about how rigorous the data needed to be," Temple said. A subsequent application presented "a more difficult decision," Temple continued. FDA reviewed "a proposed treatment of neonatal respiratory distress syndrome," which "clearly" represented "an immediately life-threatening condition that lacks alternative therapy." Temple said the product "was under investigation [in] a controlled study, but the results of that study and others were quite inconsistent." FDA "concluded that the evidence taken as a whole did not provide a reasonable basis for concluding that the drug may be effective." A third application was for "an animal extract for treatment of patients with malignant, solid tumors," Temple continued. The indication constituted a serious or life-threatening disease. However, although the sponsor was conducting a controlled trial, "there were only nine patients in it, and active pursuit didn't seem to be constituted by nine patients," he said. "There was no evidence of any kind submitted to us" regarding safety and efficacy; therefore, "it was a relatively easy conclusion" to deny Treatment IND status. Temple said "one of the more recent" applications proposed "to use an extract for treatment of AIDS and ARC" (AIDS-related complex). He noted the proposed treatment "is of interest in that as far as we can tell no person with AIDS or ARC had ever been given it." Temple said FDA could not grant the application because "it was not being studied under an IND, there was obviously no active pursuit, and the submission did not contain much of anything." Another application was for ribavirin, "and I wouldn't touch that with a 10-foot pole," he said, "but the major reason that was turned down, as you know, was the lack of sufficient evidence of safety and effectiveness." An additional submission involved a vitamin to treat asthma; however, Temple said, "there were no data at all submitted." A final denial was also due to lack of complete data, Temple said, and a pending application "remains under discussion with the manufacturer." Several applications "have been for biological products," the FDAer continued. Cytomegalovirus immune globin, or CMV-IG, was the first approved Treatment IND ("The Pink Sheet" Oct. 26, p. 6). The Commonwealth of Massachusetts sponsored the product, which is used in kidney transplant patients at risk of severe infection. The state is authorized to recover development costs through a charge for use of the product. Turning to ifosfamide, which was granted Treatment IND status on Dec. 28 ("The Pink Sheet" Jan. 4, p. 10), Temple called the drug "an exciting treatment for a difficult disease," germ cell carcinoma. The treatment actually combines two experimental drugs -- ifosfamide and mesna with two approved agents, cisplatin along with vinblastine or etoposide. "The disease is clearly immediately life-threatening, there was no acceptable alternative, there were investigations ongoing and a trial had been completed . . . this is progressing toward an NDA, and the evidence clearly suggested effectiveness in the patient population," Temple said. "So that was an easy yes." Earlier in the conference HHS Secretary Bowen noted that an estimated 500 patients per year "may be eligible" for the regimen. "Already a study in progress at Indiana University involving more than 50 patients treated with this regimen shows complete responses in about one-third of the patients treated," Bowen reported. "Another 15-20% of these patients were in complete remission of their cancers for more than a year." Bowen also announced that day's approval of trimetrexate as a Treatment IND.