FDA Draft Guidance on End-of-Phase 2A (EOP2A) Meetings

Re: Docket No. FDA-2008-D-0514: End-of-Phase 2A Meetings

Dear Sir/Madam:

The Biotechnology Industry Organization (BIO) thanks the Food and Drug Administration (FDA) for the opportunity to submit comments on FDA’s draft guidance for industry on End-of-Phase 2A (EOP2A) meetings. BIO welcomes this guidance and believes that the EOP2A meeting is a valuable opportunity for sponsors to meet with the Agency to discuss quantitative modeling and simulation to determine the optimal dose-response relationship and pharmacokinetic / pharmacodynamic (PK/PD) relationship for new drugs entering Phase 2B and Phase 3 testing. BIO respectfully requests additional clarification to the guidance to further demonstrate the value of an EOP2A meeting as part of a drug development program.

BIO represents more than 1,200 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products, thereby expanding the boundaries of science to benefit humanity by providing better healthcare, enhanced agriculture, and a cleaner and safer environment.

DRUG SPONSORS VALUE THE OPPORTUNITY FOR EOP2A MEETINGS:

As evidenced by the level of industry participation in the EOP2A meeting pilot program, many BIO members find that EOP2A meetings provide a great deal of value for sponsors. We are particularly pleased to see that the EOP2A draft guidance encourages the use of quantitative clinical pharmacology in decision making during drug development. Clinical trial simulation and quantitative modeling of prior knowledge enables the design of trials for better dose response estimation and dose selection. BIO believes that FDA-sponsor interaction to facilitate these approaches is an important aspect of improving the efficiency of clinical development plans and minimizing the risk to patients of selecting the wrong doses for further study. We also appreciate the direct line of communication between scientists at the FDA and the sponsor to expeditiously resolve issues related to the exposure-response analyses. Although there exists a potential for delay in a product development program while the EOP2A meeting is being planned and the models and simulations are analyzed, it is our expectations that this delay via FDA-sponsor interaction would be kept to a minimal amount of time. However, for those companies that choose to have an EOP2A meeting with FDA, this potential for delay may be offset by the increased confidence in the dosing and potential for success in Phase 2B/3 studies. We suggest that the EOP2A meeting process would benefit from additional discussion of the value of the EOP2A meeting for sponsors, or presentation of case-studies of successful EOP2A meetings. For example, it would be helpful for the Agency to note explicitly how an additional four months might contribute to a successful development program that may have failed without such a meeting. This type of feedback could also be delivered via future public meetings, presentations, or other types of publications.

MEDICAL REVIEWERS SHOULD BE INVOLVED IN EOP2A MEETINGS:

While BIO member companies particularly welcome the chance to discuss quantitative clinical pharmacology approaches with quantitative groups within the agency, it is important that there is adequate representation, collaboration, and coordination with the review division. The guidance currently states that “FDA pharmacometricians and biostatisticians will generally perform most of the review work for these meetings. Reviewers from other review disciplines will participate in the preparation and conduct of these meetings.” (lines 111-113). BIO is pleased that the guidance explicitly mentions that the reviewing division must be closely involved in the meeting and believes that any FDA advice that comes as a result of the meeting should be developed in collaboration with the review division. To increase the ultimate value of an EOP2A meeting to a drug development program, it is important that there be close alignment between the medical reviewers and the pharmacometricians / biostatisticians in order to facilitate and inform later discussions with the review division. The EOP2A meeting would lose much of its value if there is a perception that the review division does not contribute to the final outcome.

THE GUIDANCE SHOULD ESTABLISH A FORMAL PROCESS FOR VALIDATING SIMULATIONS PRIOR TO THE EOP2A MEETING:

The draft guidance states, “Ideally, industry and FDA scientific staff will have agreed upon the modeling and simulation approaches before the EOP2A meeting so the meeting time can be used to interpret the results and discuss dose and/or trial design issues.” (lines 134-136) However, the draft guidance provides no mechanism and timing for how and when an agreement can be reached beforehand. We request that the guidance describe the timing and the mechanism by which industry and FDA scientific staff should interact in order to reach agreement prior to the meeting on the modeling and simulation approaches. The formal EOP2A meeting could be the culmination of 1 or 2 pre-meeting discussions, including provision of preliminary data and modeling, aimed at an EOP2A meeting where data and conclusions can be discussed and a point of view decided. BIO recommends stating in the guidance that sponsors should contact the Office of Clinical Pharmacology and the respective FDA review division to discuss planned modeling and simulation approaches early in the development program (Phase 1, Phase 2A).

Additionally, a teleconference between FDA and the sponsor should generally occur within fourteen days of the initial request for agreement and the agency should communicate any recommendations and comments to the sponsor in writing. Also, during the initial teleconference, the agency and sponsor will discuss follow-up procedures and expectations for an EOP2A meeting. If such a formal approach to reaching agreement on the modeling and simulation approaches is established, the actual EOP2A meeting may focus on more productive discussions around the outcomes of the modeling/simulations.

MEETING PROCEDURES SHOULD BE HARMONIZED WITH THE PDUFA FORMAL MEETINGS GUIDANCE:

BIO encourages FDA to take steps to harmonize the meeting request timing and submission of the background information with the formal PDUFA Meetings Guidance to improve the consistency and predictability of the meetings process.

For example, although the EOP2A meeting is described as a Type C meeting, the timing suggested in the draft guidance is not in synchronization with either the PDUFA IV goals1 or the current Formal Meetings Guidance.2 While the PDUFA IV goals and the meetings guidance provide for a type C meeting to occur within 75 days of Agency receipt of the meeting request, the draft EOP2A guidance (line 249) states that the meeting date is usually 6 – 10 weeks after FDA’s receipt of the meeting package. PDUFA IV goals, on the other hand, indicate that the meeting package should be submitted at least 4 weeks before the date scheduled for the meeting. The apparent discrepancy in process and timing for requesting and scheduling the EOP2A meeting compared to the PDUFA IV goals and the formal meeting guidance should be resolved. If these meetings are to be handled differently, the final guidance should specifically state that the normal procedures and timing for type C meetings do not apply. With respect to background materials, the draft guidance states that, "Sponsors are strongly encouraged to submit all relevant information with the meeting request, including data, any models or simulations of trial design, or disease or outcome models that have been explored that provide insight into the issues for discussion.” (lines 179-181.)

However, the guidance later states, “General instructions regarding timing and contents of the information package are found in the Formal Meetings guidance.” (lines 209-210.) These two sentences appear to conflict with one another. The former implies that the information package should be submitted approximately 10 weeks before the formal meeting, while the latter implies that the information package should be submitted 2-4 weeks prior to the formal meeting. If the meeting request and the information package are to be submitted approximately 10 weeks before the formal meeting, the initial information package should include the preliminary data analyses, and the final data analyses may be submitted 4 weeks prior to the formal meeting. A four week time frame is consistent with Type B and C meetings as recommended in the FDA Formal Meetings Guidance. This “phased” approach would allow sponsors to submit a meeting request shortly after the completion of phase 2A trials, while providing the agency with sufficient time for review prior to the formal meeting.

THE EXACT POINT IN DRUG DEVELOPMENT FOR THE EOP2A MEETING SHOULD REMAIN FLEXIBLE:

The guidance tends to treat drug and biological development as a process where the phases are separate and distinct, but drug development is often a continuum. In many development programs, particularly in the biotechnology industry, there is not a clear separation or transition of phase 2A vs. phase 2B in the development timeline. This fusion of the discrete of the steps of the drug development process is becoming more common, particularly as adaptive “Phase 2/Phase 3 “learn and confirm” trial designs and non-standard development plans become more accepted. Therefore, there should be flexibility regarding the point in development when the EOP2A meeting occurs. We suggest that the overall time frame for such a meeting be widened and that a modeling/simulation meeting should be considered as soon as appropriate data are available that would allow modeling to inform and optimize the clinical development plan. FDA may also consider amending the title of the EOP2A meeting to acknowledge that not all drug development programs have a discrete separation between phase 2A and phase 2B. Rather the meeting name could focus on the modeling/simulation aspects of the FDA-sponsor interaction.

CLARIFICATION IS NEEDED ON THE GROUNDS FOR REJECTING EOP2A MEETINGS BASED ON RESOURCE CONSTRAINTS:

BIO recognizes that the FDA and the drug review divisions currently face challenging circumstances due to increasing responsibilities and corresponding lack of funding. However, we are hopeful that recent increases in FDA appropriations, industry user fees, and staffing will begin to address this significant problem and provide medical reviewers, statisticians, and pharmacometricians with the time to commit to important drug development activities, such as EOP2A meetings. The guidance notes that one of the considerations used to evaluate EOP2A meeting requests will be “appropriate FDA resources available for the project.”

We recognize that EOP2A meetings can be resource intensive for all parties involved, but we note that unlike the EOP2A pilot program, industry will be performing the modeling and analysis rather than FDA staff. Additionally, earlier interaction between sponsors and FDA can facilitate drug development and help minimize the potential for other resource-intensive problems arising late in drug development or during FDA review. If FDA anticipates that staff may have to reject EOP2A meetings due to limited resources rather than valid scientific rationale, we request that the guidance provide additional clarity on the criteria used for rejecting a meeting based on resource constraints.

LESSONS LEARNED AND FUTURE ACTIVITIES:

Over time the agency will have seen and reviewed modeling and simulation results across a significant number of compounds and across a wide variety of indications based on submissions from a range of sponsors across the industry. As FDA and sponsors gain this experience, there may be an opportunity to disseminate some of the lessons learned through future guidances, presentations at public meetings, or other types of publications. For example, FDA may wish to further articulate certain “best practices” for modeling and simulation. This would be particularly helpful for small and mid-size biopharmaceutical companies that may have less experience in this area. Additionally, based on the experience gained through EOP2A meetings, FDA could detail which diseases or indications would most benefit from quantitative modeling and simulation. These future activities would continue to enhance the value of the EOP2A meeting.

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CONCLUSION:

BIO appreciates this opportunity to comment on the draft guidance for industry on End-of-Phase 2A Meetings. We would be pleased to provide further input or clarification of our comments, as needed.

Sincerely,

/S/

Andrew J. Emmett

Director for Science and Regulatory Affairs

Biotechnology Industry Organization