by Suzanne M. Sensabaugh*

The Center for Biologics Evaluation and Research (CBER) has embarked on an initiative to facilitate the review and approval of biologic products and their availability to the consumer. This new initiative is the enhancement and expansion of CBER's Managed Review Process (MRP). The current process is a system that was put into place to meet the performance measures and backlog goals mandated in the Prescription Drug User Fee Act of 1992 (PDUFA).1 CBER's success in meeting these goals impressed upon senior management the need to expand the principles of managed review - a process that is efficient, consistent, seamless and streamlined - to CBER's entire regulatory process. To this end, the goal of "a managed and integrated regulatory process, which is continuous from discovery through postmarketing," was incorporated into CBER's strategic vision for the year 2004.2 The center's MRP was designed by a committee composed of individuals involved in CBER's day-to-day regulatory review activities. This committee was empowered to design the ultimate regulatory review process in an atmosphere of unlimited resources and without internal constraints. CBER's regulatory process comprises a large number of activities and, therefore, was divided into five phases: presubmission, investigational, applications/supplements, postmarketing and crosscutting.		The crosscutting phase includes activities that cut across CBER's regulatory process such as enforcement, research and product shortages and, thus, can occur at any time during the life of the product (see Figure 1). Subcommittees composed of subject-matter experts were formed for each of these subprocesses. Taking into account the results of a self-assessment conducted with internal and external stakeholders, these subcommittees designed CBER's new MRP through brainstorming and visualization of the ideal regulatory review process. This new process: spans drug development from discovery to postmarketing, includes all regulatory submission types handled by the center, expands milestones into additional phases of the biological products review process, introduces review target dates into the investigational submission phase, strengthens the role of project management and proposes a new, review-team leadership structure Elements of the New Process CBER's current MRP covers only the licensure phase of drug development, beginning with a request for a pre-pivotal trial
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meeting and ending with the licensure of the biological product. CBER's new process will begin with the period of discovery and continue through postmarketing. It also includes all of the regulatory mechanisms-investigational new drug applications (INDs), investigational device exemptions, new drug applications, abbreviated new drug applications, premarket approval applications and 510(k)s-used for the review and approval of the various products regulated by CBER, in addition to product license applications, establishment license applications and biologics license applications covered by the current process. Milestones are included in CBER's current MRP to move the review process forward. The new process includes not only these same milestones, but also additional ones for administrative processing of regulatory submissions and administrative actions. These milestones are present in all phases of the regulatory review process, not only during license application review. In addition, performance goals that resemble milestones have been introduced into the investigational phase of development. These target dates are review goals; however, they are different from milestones in that the goal dates will be decided upon by the review team.		They are found in the first 30 days of the review cycle of an IND, and include the dates by which: a written review by each team member is completed, the team meeting/conference call is held, an information request or clinical hold letter is in draft, management approves the decision to either allow the clinical trial to continue or issue a clinical hold, the draft letter is revised, team concurrence is gained on the final letter and the letter is signed by management A strong project management infrastructure supports the new process. Project management will be bolstered through the reassignment of responsibilities. In the current MRP, two individuals-the chairperson and the regulatory coordinator-share responsibility for facilitating and coordinating the licensing submission. The new process proposes that a single individual on the review team-the regulatory project manager (RPM)-be assigned these responsibilities. RPMs will have product and regulatory experience, manage the review process and
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participate in the review of the submission. By detecting potential problems before they become major review bottlenecks, the RPM will drive the review process forward. The managers will also serve as contact points for CBER staff and industry for all issues regarding the product during its life cycle. Shared leadership among review team members is a facet of the new process. Review teams will not be under the leadership of a single individual-all team members will be equals. Members on CBER's review teams are specialists who are highly educated, self-motivated and self-directed. In teams where members are this experienced and knowledgeable, the need for formal leadership decreases. Shared leadership will lead to shared decision making, shared power and shared vision that will drive the review process forward. Team leadership will be exercised by different members taking the lead role in the resolution of issues arising in their area of expertise. The electronic management of regulatory information and resources is critical to the success of this new process. An integrated tracking and database system to support the new MRP has been proposed. This database will be designed to link all regulatory components within the center. As planned, each center component would have the ability to access enforcement, review, product-testing and		surveillance information and decisions on a specific product. This database will increase access to crucial information and lead to enhanced decision making, acceleration in the performance of regulatory responsibilities and reduced redundancies in regulatory activities. Implementing the New Process An implementation plan, which describes the transition in three phases from the present process to the new MRP, has been completed. Phase I will consist of the presubmission, investigation and coordination of public health-based research subprocesses. Phase II will consist of the application/supplement subprocess. Phase III will consist of the postmarketing subprocess and any crosscutting activities not implemented in the first two phases (see Figure 1). Activities within each phase will be implemented as resources are available. The implementation plan describes not only the transition to this new process, but also additional projects that will facilitate the review and approval of biological products, such as training personnel and establishing CBER standard operating procedures and policies (SOPP). CBER is gearing up for implementation of Phase I. An electronic manual describing the regulatory review activities
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performed during this phase has been designed. This manual can be navigated both horizontally and vertically, allowing the viewer to obtain detailed information on CBER's regulatory review process or to "look forward" in the review process to plan for upcoming review events. An electronic manual has additional advantages over the current paper manual including a reduction in the paper load, the ability to examine review processes performed by components outside of the reviewer's immediate environment (which lends transparency to CBER's regulatory process), the facilitation of information-sharing throughout the center, better communication between review components and an enhanced ability to train new reviewers by having CBER's entire regulatory review process available in one place. The electronic manual will be available to center staff on CBER's Intranet in the near future. Other activities include drafting SOPPs, which describe procedures for various activities in Phase I, and revising SOPPs presently in use to accommodate the new process. Training courses are in development that will educate reviewers on the new process. Other core courses are being developed on topics such as project management, negotiation, conflict resolution,		team building and crisis management. The courses are being designed to facilitate the review and approval of biological submissions. A pilot now in progress will determine if the RPM and shared leadership team model will enhance the efficiency of the review process. In addition, electronic project-planning tools are being evaluated to assist reviewers in planning their review schedule. Conclusion CBER's mission is "to protect and enhance the public health through regulation of biological and related products…The regulation of these products is founded on science and law to ensure their purity, potency, safety, efficacy and availability."2 To fulfill its mission in an environment of decreasing resources and new mandated performance goals, CBER must have a regulatory review process that is seamless, efficient, thoroughly managed and streamlined. CBER's new MRP was designed with the strengths, weaknesses and bottlenecks of the present review process in mind. This new process expands and enhances the concepts of managed review to CBER's entire regulatory process. This in turn will facilitate the review and approval of biological products and their availability to the consumer.
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Figure 1

CBER's New Managed Review Process Presubmission   - Manage initial contact - Prepare for pre-submission information exchange - Exchange pre-submission information Investigational   - Process IND/IDE application - Review IND/IDE application - Process IND/IDE amendment - Review IND/IDE amendment - Prepare for pre-pivotal trial/pre-application meeting - Conduct prepivotal trial/preapplication meeting - Prepare for application submission Applications/ Supplements - Perform administrative processing - Perform initial review - Continue license application review - Finalize license application Postmarketing   - Manage reporting of incidents/problems - Manage biennial inspections - Review promotional materials - Manage postmarketing commitments - Manage adverse experience reports - Manage lot release/exemption from lot release - Evaluate physical samples - Evaluate surveillance samples/protocols Crosscutting   - Coordinate public health-based research - Perform enforcement action - Manage exports - Manage product shortages - Manage CBER policy - Process master files - Manage emergency operations

 

Footnotes

Prescription Drug User Fee Act of 1992. PL 102-571; 21 USC 379; 106 Stat 4491; Oct. 29, 1992. FDA. CBER Vision: 2004, Center for Biologics Evaluation and Research Strategic Plan for 2004, Rockville, MD; Aug. 14, 1995. * Suzanne M. Sensabaugh is a special assistant in the Office of the Center Director, CBER, FDA. Her primary project is the assessment and redesign of CBER's Managed Review Process.

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