FDA ANTI-INFLAMMATORY/ANALGESIC/ANESTHETIC DIVISION WILL BE SPLIT BY NDA AND PROTOCOL REVIEW FUNCTIONS; ADVISORY COMMITTEES' ROLE SHIFTING

Staff responsibilities for reviewing study protocols and study results will be separated in FDA's new pilot review division for anti-inflammatory, analgesic, and anesthetic drugs, the division's acting director John Harter, MD, told FDA's Arthritis Drugs Advisory Committee April 24. Harter, who previously served as anti-inflammatory drugs group leader in FDA's Oncology and Radiopharmaceutical Drug Products Division, will be in charge of medical reviewers involved with the evaluation of study protocols. Rudolph Widmark, MD, PhD, formerly a medical reviewer with the oncology/radiopharmaceutical division, will head the group of reviewers that evaluate NDA submissions. The pilot division officially began operations on April 23 but staffing decisions for the division have not yet been completed. The agency currently estimates that the division will have 26 staffers, including 12 medical reviewers and five consumer safety officers. The new division, which reports directly to Center for Drug Evaluation and Research Director Carl Peck, MD, was carved out of existing divisions in the Office of Drug Evaluation I, which is headed by Robert Temple, MD, ("The Pink Sheet" April 3, T&G-1). The division takes on the drug abuse unit and the analgesic drug review function that were previously under the Neuropharmacologic Drug Products Division. The new division also adds the anti-inflammatory drug review responsibilities from the former oncology/radiopharmaceutical division (now the Oncologic and Pulmonary Drug Products Division), and the anesthetic drug review duties from the Surgical Dental Drug Products Division. The staff for the new division, for the most part, will come from the old analgesic, anti-inflammatory and anesthetic groups in the other divisions. The pilot division was set up as a testing ground for new ideas to speed up the drug approval process. FDA views its involvement in the planning of clinical trials as central to this effort. "There is a growing [sentiment] among our staff," Peck told the advisory committee, "that if we could influence the design of clinical trials, and could influence the direction of drug development earlier, [then] we could simultaneously compress the drug development period and could greatly compress the drug evaluation time once the NDA reaches our door." One of the concerns of both the agency and the industry, Peck noted, "is that if we become too involved in decisions early in the development, that we will be compromised in our decisions later on." That concern is part of the rationale behind splitting the protocol and NDA study review functions among different staff in the anti-inflammatory/analgesic/anesthetic division. Harter noted that sponsors will be encouraged, but not required, to work with FDA in planning their NDA studies. In conjunction with the protocol review functions of the pilot division, FDA plans to get its advisory committees more involved in the development of trial designs by routinely bringing IND issues before them, Harter noted. The Arthritis Advisory Committee reviewed issues relating to a current IND drug during a closed session at its April 25 meeting. FDA also plans to have members of the advisory committees regularly participate in the agency's recently instituted "NDA Day" review forums. Harter noted that the division would be conducting an "NDA Day" in a few weeks to examine four NDAs and invited the committee to consider having a few members attend. The "NDA Day" review process, reportedly developed by Temple and Harter, is less than one year old. Under the procedure, FDA reviewers meet to consider issues related to a particular NDA while the drug's sponsor remains available in a nearby FDA office to answer questions ("The Pink Sheet" Dec. 5, p. 7). To date, three NDAs have been reviewed using the procedure: Upjohn's Ansaid (flurbiprofen), Ciba-Geigy's Voltaren (diclofenac sodium), and an undisclosed product that has not been approved. The three drugs were all under Harter's anti-inflammatory drug group. The Arthritis Advisory Committee expressed general support for the idea of participating in "NDA Days," but wanted assurance that members with appropriate expertise would be chosen to attend. The agency's current thinking is to ask only two or three advisory committee members to attend any given "NDA Day" -- due, in part, to public disclosure notice requirements for meetings with more than a few committee members. The advisory panel pointed out that preparation for such meetings could be time consuming, and suggested that committee members first participate on a trial basis. Advisory committee involvement in both "NDA Days" and the review of study protocols will at first be limited to the two committees associated with the anti-inflammatory/analgesic/anesthetic division -- the Arthritis Drugs Advisory Committee and the Anesthetic & Life Support Drugs Advisory Committee, according to FDA. The agency expects to be expand the roles of the other committees, if the pilot program is successful. In recent years, FDA has made efforts to broaden its role as the final judge of study results to also include active participation in the design of study protocols. For example, the agency's participation in the planning of Phase III studies at an end-of-Phase II conference was codified in the IND Rewrite, and even earlier involvement by FDA in trial designs was proposed in the recent regs for drugs to treat life-threatening diseases. Harter's anti-inflammatory drug group was apparently moving in that direction prior to establishment of the new division. Harter reported to the committee that "we've been doing this for some time in our group; we've been trying to have input earlier." Reportedly, the idea of FDA involvement in study design has not been enthusiastically embraced by all agency review staff. Harter identified three reasons why FDA reviewers have generally been "resistant to getting involved" in protocol review: (1) FDA regulations technically state that early FDA involvement in studies should be limited to safety issues; (2) early involvement could lead to a situation where "you look just as stupid as other people [if] at the end everybody says you should have done this or you should have done that"; and (3) the industry, with its "own agendas, [has] resisted like crazy [and] it's hard to deter a company that's made up its mind what it wants to do." However, Harter continued, "if we can get companies to cooperate and we can reach a compromise, I think when the NDA comes in, we will have detected the problems." He noted that the process will "require not only looking at the plans for studies, but also . . . doing an analysis once [a study] is completed." By doing an analysis, Harter explained, "you can decide whether you disagree or not [about] what the interpretation is, and if you disagree early and the company knows that, they then have the option of doing another study or trying to remedy it." Harter has a number of other ideas for changing the drug review process, including limiting the bureaucratic levels of review. The pilot division will not have supervisory chemists or pharmacologists and will grant more authority to its reviewers. "I expect the reviewers to sign the letters that have [the NDA's] deficiencies in it instead of having it all signed by three or four people at the top," Harter said. "You'll now get letters from chemists, pharmacologists and medical officers about your studies." The system, he said, will require that reviewers talk to each other to make sure that decisions they make are in line with previous agency policy. "I would like to develop a group of individuals who are able to institutionalize their performance and worry about the fact that they are speaking for the institution," Harter explained. The anti-inflammatory/analgesic/anesthetic division is also hoping to better coordinate efforts with the biopharmaceutics, statistics and postmarketing surveillance groups by having staff from each of the groups detailed to the pilot division. One of the things that has not "synchronized well is our biopharmaceutic reviews, our statistical reviews, and the support that the postmarketing surveillance and epidemiology [groups provide]," Harter explained.