Originally Published March 2001
Karen J. Harder and Virginia Perry
Once a company files a premarket approval application (PMA) for its new device—and the same goes for companies filing a new drug application or a biologics license application—many people think regulatory affairs' work is over. For regulatory professionals, however, the work is just beginning.
Preparation for this critical event is a process that should parallel product development. Three key elements will enhance the likelihood of a successful panel meeting: a collaborative relationship with FDA, careful planning, and comprehensive rehearsal.
DURING THE PRODUCT DEVELOPMENT CYCLE
For medical product manufacturers, preparation for any significant FDA interaction should involve a simple, two-part process: define the issues and objectives, then take action to achieve those objectives. This cycle repeats itself many times during product development, with each cycle providing greater insight into the product. Collaboration with FDA is essential and must be continuous. This relationship begins with the first interaction with the agency and should be based on sound science and an in-depth knowledge of regulations and guidelines.
Successful interaction with FDA is best achieved by fostering a nonadversarial relationship with the agency from the start, and this requires a commitment of appropriate time and resources. Every regulatory professional faces the same challenge, large company or small: too much to do and far too little time. The regulatory challenge is to influence all levels of the company so that each FDA interaction is of optimal benefit to the product's successful development.
Early in the development process, the product characteristics begin to be understood (Table I). Safety concerns need to be identified and researched. It is also important for manufacturers to be realistic about the efficacy benefits of a device and their ability to measure them. This is when unique aspects of the product, both from a safety and an efficacy viewpoint, are explored.
|Product Development Stage||Key Activities|
|Early (Phase I)||Explore safety issues
Explore patient population
Explore efficacy measurements
|Middle (Phase II)||Identify efficacy end points
Identify relevant current FDA issues
|Late (Phase III)||Compile adequate safety data
Resolve remaining FDA issues
|After application filing||Address FDA reviewer questions
Assemble an advisory committee meeting team
Identify key messages
Identify and prepare issues
Prepare briefing book
Perform a mock panel meeting
Table I: Key product development activities.
At the earliest stages of development, FDA is already considering the potential impact of the product on the public, and its concerns need to be understood and addressed. It is critical to listen carefully to the advice of the FDA review team, and to determine its underlying concerns, not just the questions being asked. By working closely with FDA and anticipating its concerns, the sponsor (the company that is manufacturing the product) and FDA will stay harmonized on the various issues that invariably arise during product development.
Of course, not all products require an advisory committee meeting. By the middle of the development program, however, a manufacturer should know if a given product is likely to be selected. FDA chooses products for various reasons, generally related to safety or issues of public importance. Innovative products often raise new medical issues. Some products generate considerable scientific or public controversy, which FDA feels is best addressed by a panel of independent experts.
For regulatory professionals, one tool that can be helpful in understanding a device is to maintain an ongoing list of related issues. In many cases, this list serves as a reminder of outstanding commitments or unresolved questions related to the product.
Maintaining an issues list during the development cycle can help the product development team focus on weaknesses in the product and allow them to be addressed. This is a valuable tool when preparing for FDA meetings in which the manufacturer must reach agreement with the agency on the information required for a successful marketing application.
Furthermore, when the marketing application is being prepared, this list identifies unresolved areas of weakness. Clearly, an ongoing list of issues assists the company in recognizing the concerns that the advisory committee may eventually consider.
In addition to understanding potential committee concerns involving the device, manufacturers need to fully understand the function of the advisory committee panel. Although all committees operate within the guidance provided by FDA, each committee has its own style. All FDA panel meetings are open to the public; attending other sponsors' advisory committee meetings is an excellent source of information. It provides firsthand insight into the questions that arise and the procedures used.
Clearly, attending advisory committee meetings where products with similar medical indications or issues are discussed is of greatest benefit, but every meeting provides valuable information. If a particularly important meeting cannot be attended, videotapes are available from FDA through F-D-C Reports Inc. (see below). Videotapes reveal the dynamics of the meeting and the subtle interactions among the public speakers, the sponsor, panel members, and FDA.
Monitoring relevant precedents is also important during product development. There is a vast amount of information that can impact the product a company is investigating. In addition to the regulations and guidelines, the regulatory team should be actively seeking information that may influence the product, such as decisions made on similar products or related to an issue currently under discussion by the agency. Attending a meeting where FDA is speaking—or one where FDA and industry collaborate to exchange information—gives manufacturers a broader sense of the agency's current concerns.
As the final stages of a development program are planned, in-depth knowledge of the relevant issues and requirements is crucial for reaching concurrence with FDA on the specific studies and end points that will ultimately be required for product approval.
|PANEL MEETING VIDEOTAPES
Videotapes of advisory committee meetings are available from FDA through F-D-C Reports Inc., 5550 Friendship Blvd., Ste. One, Chevy Chase, MD 20815-7278; phone: 800/332-2181; fax: 301/656-3094.
Toward the end of the development program, it is wise to learn as much as possible about the members who serve on the relevant advisory committee panel. Members are appointed for a set term, which can be up to four years. Their area of expertise can be explored by generating a list of their scientific publications, which provides insight into the reasons they were selected for the advisory committee.
Industry Representatives. Although the position of industry representative has been filled on all new advisory committees, FDA has recently decided to add such a position to all existing committees.1,2 This member does not vote, but he or she can have considerable impact on the outcome of an advisory committee meeting.
Unlike other committee members, the sponsor is permitted to discuss issues with the industry representative. In turn, the industry representative assists the academic members of the committee in understanding the sponsor's viewpoint. Consequently, the importance of this member of the committee cannot be underestimated.
Patient Advocacy Groups. Unique or groundbreaking products often generate considerable public discussion or controversy. As a result, patient advocacy groups form to promote cures or disease management for the medical condition of interest to them (for example, the Juvenile Diabetes Foundation).
If there is a patient advocacy group concerned with a product, it is wise for the manufacturer of that product to learn and understand the group's position. If the product is important to the treatment of the medical problem the group is representing, it may choose to participate in the public portion of the advisory committee meeting. Sponsors often provide ongoing information to these groups, keeping them informed of the product's progress.
If there is controversy involving their product, manufacturers must be aware of all the forums in which the product may be discussed. The device can be affected by discussions held by healthcare groups, industry groups, and even non-FDA government groups, such as Congress.
PREPARING FOR THE ADVISORY COMMITTEE MEETING
As soon as the design and development of the product is concluded and a PMA has been prepared, energy should be redirected into preparation for the advisory committee meeting. This task may seem overwhelming, but depending on the type of application and whether FDA has granted an expedited review, the advisory committee meeting will usually be scheduled for a date 6 to 12 months away. During those months, preparation should follow a four-step process (Table II): designing a blueprint for success, building a framework for the meeting, constructing the presentation, and performing a mock panel and other finishing touches.
|Design a Blueprint
* Small dedicated team
* Defined decision maker
* Support of senior management
* Identify key messages
* Identify key issues
Build a Framework
* Research the data for each issue
* Identify speakers
* Match each issue with a speaker
* Identify the team moderator
* Prepare the briefing book
Construct the Presentation
* Prepare slides for presentation and issues
* Exchange constructive criticism
* Practice handling questions
* Practice calling up slides for questions
Perform Finishing Touches
* Mock panel
* Provide FDA with the sponsor's presentation slides
* Review questions for the panel
* Schedule time to rest prior to the meeting
Table II. Stages of panel preparation.
Designing a Blueprint for Success. As with any complex project, planning is critical. The key is to create a small, dedicated team with a clearly defined decision maker. First and foremost, the team should design a blueprint for success—a step-by-step plan for the preparation leading up to the meeting. This plan should be complete, including a timeline and any required resources. Meetings and rehear-sals should be scheduled; two or three times a week is not excessive.
As the team formulates the plan, members must enlist the support of senior management. This is essential to the effective functioning of the team. Throughout preparation and up to the day of the meeting, senior management should receive regular status updates from the team leader.
The team's initial plan should include the key messages that will be presented at the advisory committee meeting and identify the issues likely to arise. The team should not underestimate the amount of time it will take to fully understand the issues and the messages it must convey. Outside experts can often be very helpful in enabling the team to take a critical viewpoint. Colleagues from other disciplines can also be used, or, in a smaller company, appropriate consultants can be hired. The critical factor is having people who are objective about the product and knowledgeable about FDA and the process of advisory committee meetings.
When defining the strategy, the team should be fully aware of the strengths and weaknesses of the PMA. Ideally, the strategy is evaluated prior to submission; as questions arise during the review, however, further insight into perceived deficiencies may arise.
When this occurs, the team may need to consider bringing in additional speakers. A large part of gauging the potential strengths of the planned presentation lies in anticipating which speakers might be critical to the presentation. Often, committee members perceive independent speakers (people from outside the sponsor company) as less-biased sources of information. If an external participant is critical to success, the team must secure his or her availability far in advance. It is also a good idea to have a backup for each key participant.
Building a Framework. Once the overall strategy is defined, the next step is to build a basic framework outlining what the company wants to convey at the meeting. This requires clearly identifying the appropriate response to each potential issue. The key is to know the facts thoroughly and to be able to present and discuss the data clearly.
At this point, the speakers who will give oral presentations should be identified. Speakers are chosen for strategic effect. In most cases, they are scientific or medical experts, but good speakers must have more than knowledge. They must be able to communicate effectively, answering questions accurately and concisely. In addition, speakers need to control the natural tendency to speak at length about their topic of expertise. To maintain focus and clarity throughout the presentation, it is best to keep the number of speakers to three or four.
In the course of preparing the speakers, the team should identify the best person to address each issue (which may arise as a question during the meeting). Although it is best to use the primary speakers when possible, additional scientific or medical experts may be used if their responses provide the best information. These additional responses must still focus on data presented in the original application, unless FDA has agreed to accept new data. When questions from the committee arise, the team leader must be ready to direct them to the right person on the presenting team. Rehearsing this interaction can prevent the team from appearing confused or disorganized. A clear, high-quality presentation at the advisory committee meeting often removes FDA concerns and introduces the product favorably to the public.
In addition to presenting information orally, it is the sponsor's responsibility to prepare a briefing book, which contains all the essential information regarding the device. This is a critically strategic document. The advisory committee members will only know what the sponsor and FDA tell them about the product and the issues contained in this document. Their time to review the information is limited, so a concise, factual, and clearly laid out document is vital. In general, sponsors should allow a minimum of two months to prepare this document and have it reviewed.
The briefing book should be consistent with the PMA application and arranged so that it prepares the reader to fully understand the oral presentation. As a part of fostering a collaborative relationship with FDA, the sponsor should ask the agency to review the draft of this document. FDA's comments can be very helpful in fine-tuning the briefing book.
Constructing the Presentation. Rehearsals are crucial to preparation. The presenters need to be comfortable with the data, the issues, and the messages to be delivered. There may be resistance to the amount of time scheduled for meetings and rehearsals. People have conflicting priorities and can be very busy or become complacent. Such resistance needs to be overcome; having the support of the senior management is essential in this regard.
Practice sessions should be designed so that constructive criticism can be easily given and received. The objective of the rehearsals is to anticipate and prepare for all potential questions. Working one-on-one with speakers can help them overcome unconscious habits or body language. Videotaping a speaker can identify areas of weakness.
When working on such an intense project for an extended period of time, people have a tendency to get too close to their own work. To counter this, outside critics can identify inconsistencies and problems. These critics may be medical or statistical consultants, former advisory committee members, or medical opinion leaders.
Speakers should be trained to listen carefully to questions. As simple as it sounds, it is vital to address the specific question that is asked by a committee member. If a question is unclear, speakers should not hesitate to ask for clarification. Some questions posed by committee members may not be well thought out. If a question doesn't make sense to a speaker, it may be because that speaker has information or knowledge the questioner lacks. It is always best to ask for clarification until it is clear what additional information is needed, and then to be sure to provide that information. Advisory committee members are experts in their fields, but the sponsor is the expert on the product. Rehearsals force participants to practice this method of question clarification. Some committees hold questions until after the formal presentations, but others interrupt the speaker during the presentation. Team members must know the style of their committee and be able to address questions smoothly.
Any presentation aids that will be used at the advisory committee meeting should be developed parallel to the oral presentations. These visual tools, usually slides or Powerpoint material, need to be well managed. They should be clear, easy to read, and should highlight one point per slide. If the information is too complex, the message may be lost or misinterpreted.
In addition to slides supporting the primary presentation, backup slides for questions will be needed. Each anticipated question should have one or more slides at the ready. Many sponsors prepare three to five times the number of backup slides to address potential questions on every issue they can identify. Slides need to be indexed by topic and should be configured so that any slide can be electronically accessed instantly. Managing the slides skillfully is crucial to the success of the team. Obviously, this is another element that requires thorough rehearsal.
|PREPARING THE FDA BRIEFING BOOK
It is the sponsor's responsibility to prepare an FDA briefing book. This critical document is the company's opportunity to provide the agency with all essential facts about the product. The book should be approximately 20 to 30 pages long, and should be organized in a way that complements the sponsor's oral presentations. Essential information should include the following:
* An annotated synopsis of the briefing book.
A well-organized briefing book is essential. It must be easy to read, strategic, and persuasive. Finally—though it seems obvious—the book must be consistent with all data presented in the application.
Performing a Mock Panel Meeting. The mock panel serves as a simulation of the advisory committee meeting and is the final tool to polish the presentation. The mock panel is different from the other rehearsals. Participants should attempt to form a group of people that mirrors as closely as possible the composition of the actual advisory committee they will face. It is often helpful to include people from outside the sponsor's organization; the list should include scientists, medical experts, a biostatistician, an industry representative, and a patient representative.
No detail should be overlooked. Participants should dress and act exactly as they would at the meeting. The room and equipment should be arranged to simulate the meeting room, and mock panel members should be objective about the product. The panel should receive the briefing book no more than two weeks in advance of the meeting.
During the meeting, panelists should be as critical as possible, probing for deficiencies. Constructive criticism should be given afterwards—to all involved—as well as positive reinforcement. The result of the mock panel will be a team that is well prepared and confident for the actual presentation.
Undertaking Finishing Touches. FDA should be given a copy of the presentation slides in advance of the meeting. This permits the panel participants to fine-tune their own presentations, and the agency representatives will be very appreciative. The advisory committee executive secretary should be contacted at this point to verify the committee participants and invited consultants.
FDA must provide the sponsor with a copy of the questions that will be posed to the committee in advance of the meeting, but the "advance" warning may be only a few days. When these questions arrive, however, it is important to review the presentation with the questions in mind. Once again, being able to change slides up to the last minute is helpful.
Finally, being well rested is important. All participants should schedule time to relax immediately prior to the actual advisory committee meeting. The ability to think and act quickly may make a real difference at the meeting.
Preparing for an advisory committee panel meeting requires time, resources, critical thinking, and patience. Participants must be prepared for stress and pressure, both internally and externally. Being prepared for the worst allows manufacturers to do the best job possible—a successful advisory committee meeting is vital to the success of the product.
1.Federal Register: 65 FR:49991–49992, August 16, 2000: Advisory Committees; Industry Representation.
2."CDRH Guidance on Amended Procedures for Advisory Panel Meetings, Final" (Rockville, MD: FDA, July 22, 2000).
Karen J. Harder is the vice president of regulatory affairs for NeurogesX Inc. (San Carlos, CA) and Virginia Perry is a partner with Perry-D'Amico and Associates (Half Moon Bay, CA).
Illustration by Warren Gebert/Sis
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