BRISTOL-MYERS SQUIBB'S VIDEX APPROVAL FOR BROAD REFRACTORY INDICATION WILL PROVIDE "LATITUDE" FOR MD DECISIONS: CLINICAL TRIAL UPDATE PLANNED FOR SPRING 1992

The approved refractory indication for Bristol-Myers Squibb's Videx (ddI/didanosine) is designed to provide "latitude" for physicians considering use of the product. The approved indication is for adult and pediatric patients over six months of age with advanced HIV infection "who are intolerant of zidovudine [AZT] therapy or who have demonstrated significant clinical or immunologic deterioration during zidovudine therapy." The second-line status of Videx is also conveyed by direct references to the use of AZT (Burroughs Wellcome's Retrovir) in the ddI label. Because AZT has shown an effect in controlled studies on survival and opportunistic infections, labeling states: "zidovudine should be considered as initial therapy for the treatment of advanced HIV infection, unless contraindicated." The breadth of the Videx indication, however, is reflected in the phrase "significant clinical or immunologic deterioration," which leaves the specific criteria for determining AZT failure to the discretion of the prescribing physician. FDA Division of Anti-Viral Drug Products Supervisory Medical Officer Sandra Kweder, MD, discussed the discretion allowed by the label at an Oct. 9 press conference held by HHS to announce the approval. "The way the indication is defined in the label," Kweder said, "we think gives [physicians] guidance but without being overly restrictive, so that physicians feel that they have some latitude to use their clinical judgment in prescribing the drug." FDA approved the three Videx dosage formulations (NDA 20-154, 20-155, 20-156) following a six-month review and less than 12 weeks after they were recommended for approval by FDA's Antiviral Drugs Advisory Committee ("The Pink Sheet" July 22, p. 3). FDA and Bristol-Myers Squibb navigated the regulatory approval process within a two-year Treatment IND (expanded access) period of clinical testing. If the product had lingered longer as a Treatment IND, that would have added another major disincentive to future expanded access development programs. The difficulties of enrolling clinical trial patients with an on-going Treatment IND has already been cited as a barrier to expanded access programs. At the Oct. 9 press conference, FDA Commissioner Kessler pointed out that agency reviewers were actively analyzing the Videx data even before the NDA was submitted on April 2 and noted that "they found creative ways to supplement the data in the NDA." Kessler reported that FDA is making a similar effort to expedite the review of Hoffmann -La Roche's Hivid (ddC) for which the agency expects an application to be submitted soon. "We are seeking the data even before the application is submitted," Kessler said. At the end of September, Roche said that the submission for ddC would be completed in the next month or so ("The Pink Sheet" Sept. 23, p. 8). FDA's confirming approval letter to Bristol indicates the intensive communications between the company and the agency during the six-month review period and the rolling submission of data from the company throughout the review. The letter records 39 submissions of amendments, with the last on Friday, Oct. 4, just prior to approval. In the month of May alone, there were 10 amendments filed by the company. Fourteen FDA staffers, led by Center for Drug Evaluation and Research Director Carl Peck, MD, and Office of Drug Evaluation II Director James Bilstad, MD, signed the approval letter. The Canadian Department of Health and Welfare announced approval for ddI simultaneously with FDA. Kessler said that medical reviewers from both agencies had worked in close cooperation while analyzing the ddI database. CDER's Peck said the agency was "engaged in weekly meetings with the Canadians." Bristol-Myers Squibb began shipment of Videx on the day of approval and expected the drug to be in pharmacies by the end of the week (see following story on the cost and distribution of the product). A boxed warning at the top of the labeling notes that the approval of Videx is based "primarily on results of non-randomized Phase I trials in which an increase in CD4 cell counts was observed for many patients." The labeling continues that "at present there are no results from controlled studies regarding the effect of Videx therapy on the clinical progression of HIV infection such as incidence of opportunistic infections and survival." Although the FDA commissioner emphasized that the agency's clearance of Videx is a "full approval," as opposed to a conditional approval, the FDA approval letter poses some conditions for the continued marketing of Videx. Reading from the approval letter, Kessler said "FDA and the Antiviral Drugs Advisory Committee expect [Bristol-Myers Squibb] to analyze and submit data from the ongoing controlled clinical trials with the drug to the FDA and present the data to the committee in March or May of 1992. If those data from the clinical trials do not demonstrate the anticipated clinical benefit of ddI, FDA understands that [BMS] expect[s] to withdraw the drug from the market expeditiously." The activity of ddI, which was assessed by using the surrogate markers of CD4 cell counts and p24 antigenemia, must be confirmed by clinical evidence from the three ongoing Phase II/III trials (AIDS Clinical Trials Group protocols 116, 117 and 118), Kessler observed. Those studies involving over 2,300 patients are expected to be completed by early next year. Analyses of the data, as suggested in the approval letter, are expected to be presented to FDA's Antiviral Drugs Advisory Committee as early as March. ACTG 116 is a comparison of ddI and AZT. The trial is divided into two subparts: patients who have received AZT for less than 16 weeks; and patients who have received AZT for longer than that period before being switched to ddI. ACTG 117 looks at patients who have received at least one year of AZT before taking ddI. FDA obtained preliminary data from these two trials to supplement the efficacy information in the Videx NDA. The agency found that Videx caused a modest increase in CD4 count over baseline out to 24 weeks. ACTG 118 is testing three doses of ddI in AIDS patients who are intolerant to AZT. The labeling includes clinical data on 170 individuals from Phase I studies. Patients receiving Videx experienced a CD4 count increase of 29% at four weeks, 27% at eight weeks and 14% at 12 weeks into therapy. These results were compared to historical controls, which had progressive declines in CD4 counts, of 5% to 27% by 12 weeks. Preliminary results from the ongoing ACTG studies showed a mean percent increase in CD4 count of 11% from baseline after 12 weeks of Videx therapy. Meanwhile, the comparison group in those studies experienced a decrease in CD4 of 3.2% from baseline. Results were similar in 89 pediatric patients treated with Videx. At eight weeks, the HIV-infected children had a mean increase of 27% in CD4 count over baseline. In addition, 39% of the children experienced weight gains and 28% showed increases in neuropsychometric response. FDA's approval letter specifically notes that the agency is okaying the product for pediatric use without "adequate and well- controlled studies" in a pediatric population. The agency waived the standard criteria because of "evidence" of safe and efficacious use of the product in children and the qualitative similarities of the disease and ddI treatment between adults and children. The major toxicities of Videx therapy are noted in the label's box warning. "Pancreatitis, which can be fatal, occurred in 9% of the Phase I patients treated with Videx at or below the recommended dose," labeling notes. Peripheral neuropathy occurred in 34% of the Phase I patients. In addition, Videx buffered powder was associated with diarrhea in 34% of adult patients. Labeling notes, however, that safety data from the expanded access program, in over 20,000 patients enrolled since late 1989, show lower incidences of pancreatitis (5%) and neuropathy (16%). Fatal pancreatitis occurred in 0.35% of patients in the expanded access program (27 from a sample of 7,806 patients).