Answers to Stakeholders' Questions

BIOLOGICS

Q. The annual meeting held in New Orleans with the FDA and blood manufacturers is very informative and beneficial. Would it be possible to conduct a similar meeting on a local level?

A. The meeting held in New Orleans is not an FDA-sponsored meeting; it is sponsored and organized by the University of Rhode Island (URI), and has been held twice (1998 and 1999). The Agency participates on the planning committee for the meeting, and speakers from FDA are invited to participate. FDA welcomes the opportunity to participate in meetings such as the URI-sponsored meeting on the regulation of blood establishments, and would consider invitations to participate in meetings around the country contingent upon Agency resources.

Q. What is the plan to expand FDA inspections into transfusion service (facilities)?

A. FDA does not currently perform routine inspections of transfusion service facilities. The Health Care Financing Administration (HCFA), through a memorandum of understanding (MOU) with FDA, is responsible for inspecting these establishments. There are no current plans for FDA to take over this responsibility.

Q. In a risk/benefit analysis, the risks and benefits are generally well understood. Sometimes, however, a risk is not known, for example as in xenotransplantation. What is the FDA position on unknown risks in the risk/benefit analysis?

A. When evaluating any clinical protocol using an experimental biologic, FDA will weigh the risks from the product to the patient in terms of the potential benefit to the patients. Where the risks are known, appropriate safeguards are put into place to enhance patient safety. Where the risks are unknown, FDA may use its own expertise to devise preclinical studies that may reveal unexpected or theoretical hazards. FDA will also use its own or other government advisory committees to draw in pertinent expertise and discuss the potential hazards in public. FDA, for example, has used this process to discuss and devise appropriate safeguards for xenotransplantation and for gene therapy trials. FDA will integrate the advice and results of preclinical testing to formulate as safe a trial as can be done with current knowledge.

FDA also will not hesitate to modify or halt a trial should new information be discovered that bears on patient safety. One example was the FDA response to an unexpected adverse reaction to a gene therapy product in a cystic fibrosis patient. This particular adverse event was discussed in public at the National Institutes of Health Recombinant DNA Advisory Committee, and FDA required all sponsors using that gene therapy product to modify the dosing schedules to prevent another adverse event. It was later found that the adverse event was likely due to an unpredicted activation of interleukin-6 activity. Another recent example was the cessation of all clinical trials using pig cells, tissues and organs because of findings by three groups, including scientists from FDA, that discovered that a pig retrovirus that is normally silent in pigs could infect human cells in the laboratory. Because of the potential risks to humans undergoing pig xenotransplantation, FDA halted all trials until appropriate screening methods could be devised to screen both the pig xenograft, as well as all treated and future patients. A formal review of current xenotransplantation trials to evaluate data on pig virus screening will be presented in public on June 3 and 4, 1999.

In summary, FDA helps to design clinical trials to first assure patient safety, and then to evaluate potency and effectiveness based on current knowledge. Discussion with internal and external experts will be used when the risks are unknown and/or theoretical, and appropriate preclinical experiments will be done by the sponsor based on these discussions. Should new information develop during the course of a clinical investigation, FDA will not hesitate to modify or stop clinical trials until appropriate safeguards are met.

Q. Section 406(b) requires the agency to establish mechanisms by July 1, 1999 for eliminating backlogs and for meeting statutory time frames for submissions. What is the status of FDA's implementation of this section?

A. The Center for Biologics Evaluation and Research (CBER) is implementing FDAMA initiatives that are similar to CDRH's FDAMA initiatives. On April 26, 1999 FDA published a list of documents issued by FDA that apply to Medical Devices Regulated by CBER (64 FR 20312) that included concurrence with the policies and procedures published by CDRH relating to implementation of FDAMA initiatives. During recent 406(b) Stakeholders' public meetings, certain concerns were stated by industry representatives regarding CBER's commitment to implement the FDAMA law and to consistently apply CDRH policy and procedures to the regulation of medical devices at CBER. Stakeholders also expressed an interest in CBER's improving its medical device review performance and its communication with industry.

CBER has developed a Device Action Plan in order to facilitate the implementation of the device provisions of FDAMA and to assure consistency of policy and procedures between CBER and CDRH. It will assess any differences that may exist and determine if those differences are justified in the interest of public health. This plan addresses areas of cooperation, coordination and communication between CBER and CDRH to assure harmonized activities. It focuses on CBER review practices and performance goals under a new managed review process. The plan also includes ongoing outreach activities to maintain input and feedback from industry and the public. The Device Action Plan was posted on CBER's Website on April 27, 1999 (www.fda.gov/cber/dap/dap.htm). CBER included device review in the new managed review process that has been implemented to address review of the new Biologics License Applications, the CBER Strategic Plan and the Vice President's Reinventing Government initiatives. Performance goals exist for all applications for approval as required by the GPRA. The review backlogs for non-PDUFA products have been steadily reduced since implementation of the previous Managed Review Process in CBER, and it is expected that this trend will continue for devices.

CDRH continues to maintain a zero backlog of submissions, and has reengineered its premarket review processes to provide product sponsors more regulatory alternatives for premarket submissions. The Center has made available information about the process for review of applications on the FDA web site, including 14 guidance documents and 5 rules, and is implementing FDAMA requirements that call for earlier and more frequent meetings with sponsors. A new PMA initiative, the "modular PMA", allows sponsors to submit an application in parts rather than all at once, and utilizes early meetings with industry to identify data needs and resolve issues. In addition, many device types have been exempted entirely from premarket review. There are currently 13 accredited third parties and 157 different types of devices eligible for third party review. FDA has recognized over 400 consensus standards that can be used in declarations of conformity to shorten and simplify some applications.

These initiatives, along with the implementation of FDAMA, have shifted resources from lower-risk to higher-risk areas, increased interactions with sponsors, and streamlined review processes such that the Center has improved premarket review times in every category. FDA intends to continue applying its reengineered processes and the provision of FDAMA; however, additional improvements toward meeting statutory requirements are unlikely without additional resources.

horizontal rule