Guidance for Industry 

 
End-of-Phase 2A Meetings 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
September 2009 

Procedural
 
   
Guidance for Industry 

 
End-of-Phase 2A Meetings
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  

 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
September 2009 

Procedural
 
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
 
 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
A.   Strategies for Early Dose Selection...............................................................................................2
  
B.   EOP2A Pilot Program ...................................................................................................................3
  
III.   THE EOP2A MEETING.................................................................................................. 4 
 
A.   Objectives of an EOP2A Meeting.................................................................................................4
  
B.   EOP2A Meeting Requests .............................................................................................................5
  
C.   Useful Information for an EOP 2A Meeting Package ................................................................6
  
D.   EOP2A Meeting Arrangements....................................................................................................6 
 
  Contains Nonbinding Recommendations 
 
1
 
Guidance for Industry  
 
End-of-Phase 2A Meetings 

 
 
This guidance represents the Food and Drug Administration's (FDA's) 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, 
placebo group responses, disease), designing trials for better dose response estimation and dose 
selection, and other related 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 trials that provide data on the 
relationship of dosing and response for the particular intended use (including trials 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 trials and the first set of exposure-
response trials in patients, and before beginning phase 2B (i.e., patient dose-ranging trial) and 
phase 3 clinical efficacy-safety trials. 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 
 
                                                 
1 This  guidance has been  prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug 
Administration. 
  
  1
 
  Contains Nonbinding Recommendations 
 
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.  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 (effectiveness) and undesired (toxicity) 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 trials is a 
challenge in many drug development programs, and poor choice 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 exposure-response, effects in placebo group, 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 strategies are 
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 modeling and 
simulation 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.    
 
 
                                                 
2   We  update  guidances periodically.  To make sure you  have the most recent version of a guidance, check the FDA  
Drugs guidance page at  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
3  For guidance related to exposure-response trials, see the guidances for industry on  Exposure-Response 
Relationships  Study Design, Data Analysis and Regulatory Applications; Dose-Response Information to  Support 
Drug  Registration (International Conference on  Harmonisation (ICH) E4);  and Providing Clinical  Evidence of  
Effectiveness for Human  Drug and Biological  Products available on the Internet at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
  2
 
  Contains Nonbinding Recommendations 
 
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 to avoid 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, effects in 
the placebo group, 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 clinical trial 
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, effects in the placebo group 
including time-course, and patient baseline data. Typical sources of information included 
literature, previous trials within the organization, and publicly available databases. 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 program  
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 sponsors model.  It is expected that FDA pharmacometrics, biostatistics, and medical 
reviewers will generally perform most of the review work for these meetings.  Reviewers from  
other review disciplines will participate, as needed, in the preparation and conduct of these 
meetings, and FDA intends to provide consolidated FDA comments to the sponsor. 
 
                                                 
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. 
 
  3
 
  Contains Nonbinding Recommendations 
 
 
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 from 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 
complex issues pertaining to drug interactions, trials 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 (typically phases 2 and 3) of drug development and to design informative dose-response 
trials that will inform later phase clinical trials by best incorporating prior quantitative 
knowledge. 
 
Preferably, industry and FDA scientific staff will agree on 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 trials that employ adaptive trial designs intended 
to be flexible in the choice of one or 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 for both 
effectiveness and safety  
 
 	  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: 
 	 Effects in the placebo group 
 	 Disease severity (baseline) effect 
 	 Disease endpoint variability and time course  
 
 	  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, cross-over, adaptive, 
randomized withdrawal) and analyses (e.g., Bayesian) 
 
 	  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 
  4
 
  Contains Nonbinding Recommendations 
 
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 trials 

   
 	  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 sponsors 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 
Pharmacometrics in 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 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.  Sponsors can elect to submit the 
electronic data and model files only if the meeting is granted. If the sponsor requests that the 
FDA develop model(s) for the submitted data, the sponsor should request a meeting date at least 
10 weeks after FDAs receipt of the meeting package. While FDA modeling is feasible, FDA 
resources are limited; therefore, decisions to do this work, including timelines, are made on a 
case-by-case basis. 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 sponsors organization and consultants who 
will attend the proposed meeting. Sponsors should provide names of scientific experts 
(and the preferred channel of communication) who can provide clarification on the data 
sets and/or the quantitative analyses to facilitate communication between FDA scientific 
staff and the sponsors counterparts, especially when analyses are to be conducted in the 
limited time between the EOP2A meeting request and the meeting date.  
	   A list of completed trials describing key design features. 
	   Summary reports of the modeling and simulation to support the proposed trial design and 
dose range selection. 
	   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.  
	   Current Investigators Brochure and relevant literature and/or public information.  
  5
 
  Contains Nonbinding Recommendations 
 
 
Considerations used by FDA to evaluate a meeting request might include:  
 
	   Are the appropriate FDA resources available for the project? 
	   Has the sponsor conducted necessary modeling and simulation to support the discussion 
of questions related to the development of the drug?  
	   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 unique experience that would be of particular value to the project?   
	   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 EOP 2A Meeting Package 
 
General instructions regarding timing and contents of the information package are found in the  
Formal Meetings guidance.     
 
Examples of useful background information specific to the EOP2A meeting package include: 
 
	   Electronic data sets and modeling files. 
 
	   Detailed modeling and simulation reports and interpretation that support the proposed 
designs or analysis methods, including relevant tables and figures. 
 
	   Appropriate nonclinical and phase 1 data and any modeling performed pertaining to 
pharmacokinetic variability due to intrinsic and extrinsic factors. 
 
Data sets should be submitted as SAS transport files with model codes and final model output 
submitted as ASCII files with txt extension.  FDA accepts results of pharmacometric analyses 
conducted using a variety of software.  Sponsors should use their scientific judgment in selecting 
appropriate software. 
 
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). 
The final minutes and recommendations will be issued through the OND division. 
 
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: 
  6
 
  Contains Nonbinding Recommendations 
 
	   meeting objectives and attendees  
	   information that will be supplied for the meeting 
	   model and data submission formats 
	   modeling approaches and additional simulation conditions, if appropriate 
	   collaboration on additional modeling and simulation work to shorten the wait time before 
the meeting, as appropriate  
	   the meeting date (usually 6 to 10 weeks after FDAs receipt of the meeting package, data, 
and models)  
	   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 
perform additional modeling and simulation work. Should the meeting be granted, FDA will 
make every effort to hold the meeting in a timely manner. 
 
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 will be given 
to the sponsor following the meeting.  Any further follow-up can be decided at the meeting.  
  7