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`Guidance for Industry
`End-of-Phase 2A Meetings
`
`(PDF version of this document)
`
`DRAFT GUIDANCE
`
`This guidance document is being distributed for comment purposes only.
`
`Comments and suggestions regarding this draft document should be submitted within 60 days
`of publication in the Federal Register of the notice announcing the availability of the draft
`guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and
`Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments
`should be identified with the docket number listed in the notice of availability that publishes
`in the Federal Register.
`
`For questions regarding this draft document contact (CDER) Robert Powell at
`301-796-1589.
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`September 2008
`Procedural
`
`Guidance for Industry
`End-of-Phase 2A Meetings
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`1 of 8
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`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2015
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`Guidance for Industry
`
`http://www.fda.gov/cder/guidance/8297dft.htm
`
`Additional copies are available from:
`
`Office of Training and Communication
`Division of Drug Information
`Center for Drug Evaluation and Research
`Food and Drug Administration
`10903 New Hampshire Ave., Bldg. 51, rm. 2201
`Silver Spring, MD 20993-0002
`(Tel) 301-796-3400
` http://www.fda.gov/cder/guidance/index.htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`September 2008
`Procedural
`
`TABLE OF CONTENTS
`
`I.
`II.
`
`III.
`
`INTRODUCTION
`BACKGROUND
`Strategies for Early Dose Selection
`A.
`EOP2A Pilot Program
`B.
`The EOP2A Meeting
`Objectives of an EOP2A Meeting
`A.
`EOP2A Meeting Requests
`B.
`C.
`Useful Information for an EOP2A Meeting Package
`EOP2A Meeting Arrangements
`D.
`
`Guidance for Industry 1.
`
`End-of-Phase 2A Meetings
`
`This draft guidance, when finalized, represents the Food and Drug Administration's (FDA's)
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`current thinking on this topic. It does not create or confer any rights for or on any person
`and does not operate to bind FDA or the public. You can use an alternative approach if
`the approach satisfies the requirements of the applicable statutes and regulations. If you
`want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the
`appropriate number listed on the title page of this guidance.
`
`I. INTRODUCTION
`
`This 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:
`
`Objectives of the EOP2A meeting
`Considerations for evaluating EOP2A meeting requests
`Useful information for an EOP2A meeting package
`EOP2A meeting arrangements
`
`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.
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`II. BACKGROUND
`
`The 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.
`
`A. Strategies for Early Dose Selection
`
`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.
`
`B. EOP2A Pilot Program
`
`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
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`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.
`
`FDA often performed the modeling analyses for the pilot program. However, in the future we
`expect that sponsors will perform these modeling analyses and include them in the meeting
`package so that FDA can review this information in planning subsequent work. In addition,
`FDA may perform in-house modeling to address particular problems or to independently
`assess the sponsor’s model. It is expected 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.
`
`III. The EOP2A Meeting
`
`The 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.
`
`A. Objectives of an EOP2A Meeting
`
`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.
`
`Topics for discussion at an EOP2A meeting might include:
`
`Use of quantitative information for dose selection using mechanistic or empirical
`relationships among biomarker, surrogate endpoints or clinical endpoints
`
`Use of quantitative knowledge of drug effects in animals and human subjects to aid in
`both dose-ranging trial design and safety assessment. Examples include:
`
`Placebo effect
`Disease severity (baseline) effect
`Disease endpoint variability and time course
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`Use of available preclinical and clinical exposure-response data and discussion of
`implications for dose-response trial design
`
`Contrasting alternative trial design strategies (e.g., parallel, adaptive, randomized
`withdrawal)
`
`Use of pharmacogenetic information from preclinical studies and clinical trials and
`discussion of the implications of genetic factors on PK, PD, or both. The discussion
`might include a quantitative evaluation of genetic effects on dose selection and the use
`of genetics to inform assessments of drug safety and effectiveness in future trials.
`
`Discussion of blood or DNA sampling strategies and other trial design features to
`optimize the usefulness of future studies
`
`Discussion of the utility of PK/PD data for dosing adjustments in special populations
`(e.g., pediatrics)
`
`B. EOP2A Meeting Requests
`
`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:
`
`A list of objectives, specific issues for discussion, and expected meeting outcomes.
`
`A list of all individuals (with titles) from the sponsor’s organization and consultants
`who will attend the proposed meeting. Sponsors should provide names of scientific
`experts (and the preferred channel of communication) that are able to provide
`clarification on the data sets and/or the quantitative analyses to facilitate
`communication between FDA scientific staff and the sponsor’s counterparts, especially
`when analyses are to be conducted in the limited time between the EOP2A meeting
`request and the meeting date.
`
`Considerations used to evaluate a meeting request might include:
`
`Are the appropriate FDA resources available for the project?
`Would the product fill an unmet therapeutic need?
`Does past experience suggest that there could be a high clinical trial failure rate in the
`therapeutic area?
`Does FDA have experience that would be of value to the project?
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`Would the project benefit from modeling and simulation?
`
`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.
`
`C. Useful Information for an EOP2A Meeting Package
`
`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:
`
`Questions about drug development issues including trial duration, dose
`individualization, pharmacogenomics, and data analyses.
`
`Proposed trial designs or analysis methods if they are to be discussed.
`
`Appropriate nonclinical data, phase 1 and phase 2A trial results, specific questions
`about dose response and/or PK-PD, strategies for selecting doses, and an overview of
`the clinical development plan (e.g., investigator’s brochure).
`
`Preliminary exposure response analysis and its interpretation that support the proposed
`designs or analysis methods, including relevant tables and figures.
`
`The conditions and methods used for modeling and simulation so that FDA can provide
`comment. Alternatively, the sponsor should indicate if they wish FDA to do this work.
`While this is feasible, FDA resources are limited; therefore, decisions to do this work
`are made on a case-by-case basis.
`
`Analysis and interpretation of available exposure-response data supporting the
`proposed trial designs (which ideally would include a list of completed studies
`describing key design features, trial data used for drug modeling, details and results of
`modeling and simulation methods, and copies of relevant literature).
`
`Data sets should be submitted as SAS transport files with model codes and final model output
`submitted as ASCII files with ‘txt’ extension.
`
`D. EOP2A Meeting Arrangements
`
`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:
`
`meeting objectives
`information that will be supplied for the meeting
`simulation conditions, if needed
`the meeting date (usually 6 to 10 weeks after FDA’s receipt of the meeting package)
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`whether the meeting will be in person or by telephone
`
`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.
`
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`Date created: September 25, 2008
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