I. INTRODUCTIONThis guidance provides information on end-of-phase 2A (EOP2A) meetings for sponsors of investigational new drug applications (INDs). The purpose of an EOP2A meeting is to facilitate interaction between FDA and sponsors who seek guidance related to clinical trial design employing clinical trial simulation and quantitative modeling of prior knowledge (e.g., drug, disease, placebo), designing trials for better dose response estimation and dose selection, and other appropriate issues. This guidance is intended to further FDA initiatives directed at identifying opportunities to facilitate the development of innovative medical products and improve the quality of drug applications through early meetings with sponsors. An EOP2A meeting would occur after the completion of clinical studies that provide data on the relationship of dosing and response for the particular intended use (including studies on the impact of dose ranging on safety, biomarkers, and proof of concept). For the purposes of this guidance, end of phase 2A occurs after the completion of phase 1 studies and the first set of exposure-response studies in patients, and before beginning phase 2B (i.e., patient dose-ranging trial) and phase 3 clinical efficacy-safety studies. In the context of drug development programs, discussions at an EOP2A meeting could include exploration of dose estimation and dose selection to use in late stage efficacy trials. Where novel trial designs are a possibility, their utility and applicability could be discussed at an EOP2A meeting. This guidance focuses on the following specific topics:
This document does not discuss the general procedures for requesting, scheduling, conducting, and documenting formal meetings. For general information on those topics, see the guidance for industry on Formal Meetings with Sponsors and Applicants for PDUFA Products (the Formal Meetings guidance). 2. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
II. BACKGROUNDThe FDA has a long-standing interest in defining dose-response relationships and pharmacokinetic/pharmacodynamic (PK/PD) relationships (i.e., exposure-response) for the desired and undesired effects of new drugs. 3. Accurate dose-response information is important for understanding how patients should take drugs to maximize desirable effects and minimize undesirable effects. Dose selection for phase 2 and phase 3 studies is a challenge in many drug development programs and may lead to trial failure. Improving early dose selection may increase the likelihood of future trial success. FDA recognizes trial planning may be improved by clinical trial simulations that employ quantitative models of drug dose-response, placebo effect, and disease progression. FDA would like to encourage the best use of this science to facilitate the exploration of trial design alternatives to increase the likelihood for successful trials.
Currently, FDA and sponsors participate in meetings where drug development strategy is discussed, such as pre-IND, end-of-phase 2, pre-NDA or pre-BLA, and general guidance meetings. Often, these meetings do not allow for the in-depth discussion of quantification and analytical tools and approaches that could be helpful in dose estimation and selection. Our experience suggests that it may be important for sponsors and FDA to discuss the use of quantitative drug development methods (e.g., trial simulation using disease, drug, placebo, and dropout models) before conducting phase 2B and phase 3 clinical trials. An EOP2A meeting does not replace other meetings, but rather provides an additional opportunity for in-depth, exploratory discussion with FDA focused on optimizing next steps in drug development. The goal of earlier discussions is avoiding pitfalls in dose selection and clinical trial design that could result in subsequent safety issues due to selecting doses that are too high, in efficacy issues due to selecting doses that are too low, or in unnecessary clinical trial failure from not accounting for disease natural history, inappropriate patient selection, placebo effect, or dropouts. The Agency specifically encourages sponsors to use all prior knowledge (including data and analyses, quantification of disease variability, subgroup heterogeneity, and dose (concentration)-response models in the development of computer simulations) to make more informed drug development decisions on trial design and dosage regimen selection.
Under a pilot program started in 2004, FDA conducted a series of EOP2A meetings where data were modeled to simulate next trial design options. The main focus for the pilot was the use of the simulation results to inform the design parameters of subsequent trial and dosage regimen choice(s). Other topics included balancing efficacy and toxicity in terms of dose response, genotype, drug-drug interactions, and drug formulation. Modeling and simulation efforts utilized information from prior clinical trials, such as dose response, disease change over the likely duration of the trial, placebo effects including time-course, and patient baseline data. Clinical trial simulations were conducted to evaluate the adequacy of the proposed trial design and alternatives with respect to the predicted probability that the trial would successfully discriminate the treated groups from the control groups (e.g., placebo). Therapeutic areas in the pilot study included HIV infection, prostate cancer, bacterial infection, seizure disorders, pain, and obesity. Post-meeting utility evaluations indicated that sponsors found EOP2A meetings valuable. 4. III. The EOP2A MeetingThe overall purpose of an EOP2A meeting is to discuss options for trial designs, modeling strategies, and clinical trial simulation scenarios to improve the quantification of the exposure-response information during early drug development. The goal of these meetings is to optimize dose selection for subsequent trials to improve the efficiency of drug development. The exposure-response data discussed might be pertinent to evaluation of efficacy outcomes or adverse outcomes. In addition, the meetings would provide opportunities for discussions of critical data on drug interactions, studies in special populations defined by genetic characteristics or other biomarkers, and other PK or PK/PD relationships.
The main objectives of an EOP2A meeting are to help select the dosing regimens for the next phase of drug development and to design informative dose-response and dose-selection clinical trials that will inform later phase clinical trials by best incorporating prior quantitative knowledge. 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. The sponsor might also seek the advice of FDA on other issues, such as the design of exploratory studies that employ adaptive trial designs intended to be flexible in the choice of one of more doses for further evaluation and patient selection criteria.
The general procedure for requesting an EOP2A meeting should be that described in the Formal Meetings guidance. The EOP2A meeting is considered a Type C meeting. The sponsor’s written request (i.e., letter or fax), which should be directed to the appropriate Division Director within the Office of New Drugs (OND), should (1) specifically state that the request is for an EOP2A meeting and (2) ask that the request be forwarded immediately to the Director of the Office of Clinical Pharmacology (OCP) and the Director of the Office of Biostatistics (OB). All three directors will consult and determine whether to hold the meeting. 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. If FDA data modeling is requested, the sponsor should leave ample time before the date requested for the meeting. The following information should be included in the meeting request:
Considerations used to evaluate a meeting request might include:
To date, most requests for EOP2A meetings have been granted. On some occasions, the request did not fit the intended purpose of the meeting or there were insufficient resources to conduct the meeting in a timely manner and a meeting was not granted.
General instructions regarding timing and contents of the information package are found in theFormal Meetings guidance. Examples of useful background information specific to the EOP2A meeting package include:
Data sets should be submitted as SAS transport files with model codes and final model output submitted as ASCII files with ‘txt’ extension.
The procedures for conducting the meeting are described in the Formal Meetings guidance. The meeting topics determine which FDA office(s) will chair the meeting (e.g., OND, OB, OCP). Once the decision has been made to have the meeting, the appropriate FDA staff and sponsor staff can communicate, usually by telephone, to agree on the following:
FDA recognizes time is important if these meetings are to have value during drug development. The date set for the meeting will depend upon other priorities and the need for FDA staff to do analytical work. The exploratory nature of the analyses and discussions at an EOP2A meeting are intended to result in suggestions and options to assist the sponsor in optimizing the next steps of drug development. Clinical trial simulations and modeling should be shared between the sponsor and FDA staff before the meeting so that the actual meeting focuses on the interpretation and recommendations for next steps. In addition to the meeting minutes, any additional FDA-conducted modeling and simulation materials derived from sponsor-provided data should be given to the sponsor following the meeting. 1. This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 2. We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm. 3. For guidance related to exposure-response studies, see the guidances for industry on Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications and Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products available on the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm. 4. See Wang, Y., V.A. Bhattaram, P.R. Jadhav, L.J. Lesko, R. Madabushi, J.R. Powell, W. Qiu, H.Sun, D.S. Yim, J.J. Zheng, J.V.S. Gobburu, “Leveraging Prior Quantitative Knowledge to Guide Drug Development Decisions and Regulatory Science Recommendations: Impact of FDA Pharmacometrics During 2004-2006,” Journal of Clinical Pharmacology, 48(2):146-156, 2008.
Date created: September 25, 2008 
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