FDA REQUIREMENTS FOR START-UP OF PHASE III HIV VACCINE TRIAL

FDA REQUIREMENTS FOR START-UP OF PHASE III HIV VACCINE TRIAL include the presentation of immunogenicity data from Phase I/II trials "that characterizes the immune response to HIV vaccine... dose and schedule" and "the relevance of various types of neutralizing antibodies to circulating T-lymphocytes to protection," FDA Division of Vaccine Applications Acting Director Karen Goldenthal, NM, said Nov. 4 at a conference on advances in AIDS vaccine development held in Alexandria, Va. The meeting was the sixth annual conference of the National Institute for Allergy and Infectious Diseases' National Cooperative Vaccine Development Groups for AIDS. Regarding safety data, Goldenthal noted that FDA would want to see specific "Phase I/II data from the country where the efficacy trial is to be conducted." She maintained that any animal data needed to "justify the initiation of a pivotal efficacy study in high-risk volunteers" should include animal protection studies. "A nonhuman primate challenge study would be viewed as a very desirable element that would substantially contribute to our overall assessment of the situation," the FDAer emphasized, adding "obviously, protection obtained under optimal experimental challenge conditions may not be applicable to field studies." Prior to trial initiation, it would be necessary to know whether the vaccine has a "a lot-to-lot consistency" and can be "consistently produced," Goldenthal said. FDA would also want to know if the manufacture of the product intended for licensure differs in any way from the product used in efficacy trials. "This is a critical issue for biological products," Goldenthal stated. "Ideally, the product used in pivotal efficacy studies should be manufactured in a facility by methods that would be suitable for licensure in the U.S. if that is the sponsor's goal." Efficacy studies conducted in foreign countries will face the problem of geographic HIV strain differences, the FDAer pointed out. If "a successful efficacy trial is performed in a developing country with a vaccine based on a local strain," Goldenthal noted, how would one "know that the results would be applicable to MN strain...vaccine in the U.S.?" In that case, she emphasized that "identification of an immunological surrogate of protection in a preventive HIV vaccine trial would be very helpful." There could be a "a variety of approaches...to address this," such as using "sera from various vaccines to neutralize the relevant strain." Another critical issue to consider for foreign trials would be "epidemiological differences in factors such as route of transmission, pattern of transmission, and frequency of transmission," Goldenthal said. "For example, a vaccine with a 50% efficacy in a country with a high incidence of certain [sexually transmitted diseases], might be expected to have a higher efficacy to prevent transmission in the U.S." Regarding study design, Goldenthal noted that all aspects of the investigational plan, such as study hypothesis, study population, inclusion and exclusion criteria, dose schedule, control group randomization scheme, endpoints, estimated treatment effect and justification for sample size in the statistical plan, "should be defined prospectively." Primary endpoints of the study should be blocking initial infection, or permitting the initial infection but preventing the establishment of permanent infection, Goldenthal said, while the secondary endpoint should be modification of disease course. FDA would consider it important to "prospectively define the plan for interim analysis, including the timing, statistical methods, the personnel...the conditions required to hold the interim analysis, criteria for early termination of the study, especially for efficacy, and a list of the data safety monitoring board members with their respective affiliations and expertise, and [a list] of who will have access to the interim results." FDA is also "very interested in the date of each protocol modification," Goldenthal noted. "We're interested in enrollment at the the time of [each] modification, and was that modification made by individuals with access to the interim results." In terms of licensure, Goldenthal emphasized that "total safety data would be a factor for licensure, as would the bridging of clinical data to demonstrate the equivalence of immune responses in different populations for different schedules in individual situations." Additionally, if a drug sponsor is conducting a foreign efficacy trial, "it would be highly advisable to conduct the pivotal study under a U.S. IND if the sponsor is planning to obtain licensure in the U.S.," she stated. In a separate presentation at the HIV vaccine meeting, representatives of several vaccine manufacturers, including Biocine, Cambridge Biotech, Genentech, MicroGeneSys and Pasteur- Merieux, addressed the question of possible incentives and disincentives involved in the development of HIV vaccines for international evaluations. Two primary incentives mentioned by most of the discussants include reduction of potential liability risks, establishment of agreements for governments or international organizations to purchase supplies of vaccine and the commitment of international governments to participate in the costs of vaccine development. Disincentives discussed included the need for a local trial in the U.S. prior to approval when the efficacy trial is primarily conducted overseas, inordinate delays in start-up of trials when a vaccine is ready, the possibility of pricing controls and low profit margins.