The ICH E5 Guidance:The ICH E5 Guidance:

An Update on Experiences An Update on Experiences with its Implementationwith its Implementation

Robert T. O’Neill, Ph.D.Robert T. O’Neill, Ph.D.

Director, Office of BiostatisticsDirector, Office of Biostatistics

CDER, FDACDER, FDA

To be presented at the 3rd Kitasato University - Harvard School of Public Health Symposium, October 2-3, 2002

Outline of talkOutline of talk

Recent ICH meetings and their purposeRecent ICH meetings and their purpose

Summary of FDA report on experiencesSummary of FDA report on experiences

Some draft Question and Answers to Some draft Question and Answers to clarify E5clarify E5

Plans for E5 as a result of Washington Plans for E5 as a result of Washington meetingmeeting

Some thoughts on bridging and Some thoughts on bridging and prospective planningprospective planning

Why ?Why ?

Four years of experiencesFour years of experiences

Agreement that some clarification Agreement that some clarification is neededis needed

The need for more data - how The need for more data - how muchmuch

Bridging StudiesBridging Studies

WhenWhen

WhyWhy

What typeWhat type

E5 is purposely vague on how to do this or what their design should be

The Spirit and Intent of E5The Spirit and Intent of E5

Not intended to request bridging studies every Not intended to request bridging studies every timetime

Intended to permit the requesting of one Intended to permit the requesting of one ‘confirmatory’ phase 3 clinical trial (bridge study) ‘confirmatory’ phase 3 clinical trial (bridge study) in the region (not specifically defined, nor meant as in the region (not specifically defined, nor meant as ‘country’) if needed or necessary to extrapolate.‘country’) if needed or necessary to extrapolate.

Recognized that there would be a period of time Recognized that there would be a period of time where experience with foreign clinical studies where experience with foreign clinical studies would be accumulated and evaluated - not to be would be accumulated and evaluated - not to be confused with always asking for a new confirmatory confused with always asking for a new confirmatory trial in local region.trial in local region.

ICH meetings on E5 ICH meetings on E5 ImplementationImplementation

Brussels: February 6-7, 2002Brussels: February 6-7, 2002

Washington, D.C: September 10-Washington, D.C: September 10-11, 200211, 2002

E5 Informal Discussion E5 Informal Discussion GroupGroup

Brussels discussionsBrussels discussions

Acknowledgement that E5 has made a major Acknowledgement that E5 has made a major contribution towards acceptance of foreign contribution towards acceptance of foreign data.data.

Each of 6 parties summarized experienceEach of 6 parties summarized experience

MHLW has most experience of regulatory MHLW has most experience of regulatory authorities to date with E5 implementation, authorities to date with E5 implementation, described their experiencedescribed their experience

Determine strategies for clarification of E5 in Determine strategies for clarification of E5 in view of experiencesview of experiences

FDA’s experiences based FDA’s experiences based upon:upon:

An informal survey of medical review divisions An informal survey of medical review divisions regarding their experiences in asking for bridging regarding their experiences in asking for bridging studies and relying on foreign clinical trial data for studies and relying on foreign clinical trial data for regulatory decisions.regulatory decisions.

A review of approved applications in calendar year A review of approved applications in calendar year 2001 with respect to number of clinical trials all of 2001 with respect to number of clinical trials all of whose data was foreign, and/or multi-national in whose data was foreign, and/or multi-national in naturenature

A summary of the number of domestic and foreign A summary of the number of domestic and foreign clinical trials documented in 18 of 30 New clinical trials documented in 18 of 30 New Molecular entities approved in 1998Molecular entities approved in 1998

Summary of FDA Summary of FDA experienceexperience

Majority of NDA’s contain foreign Majority of NDA’s contain foreign clinical trial data, often used as primary clinical trial data, often used as primary evidence of efficacy and safety - rarely, evidence of efficacy and safety - rarely, does the entire data base on efficacy does the entire data base on efficacy consist of foreign clinical dataconsist of foreign clinical data

Until recently, discussion have rarely Until recently, discussion have rarely been held with sponsors during been held with sponsors during IND/NDA development stages that IND/NDA development stages that specifically consider bridging strategies specifically consider bridging strategies when relying on foreign clinical datawhen relying on foreign clinical data

Summary of FDA Summary of FDA experienceexperience

Some, but not all review divisions, during the Some, but not all review divisions, during the process of evaluation of the clinical efficacy data process of evaluation of the clinical efficacy data examine regional differences in efficacy and examine regional differences in efficacy and safety. Part of the reason for this is that safety. Part of the reason for this is that sponsors have not, a priori, designed the clinical sponsors have not, a priori, designed the clinical trials with this objective in mind -this may be trials with this objective in mind -this may be chaningchaning

Most multi-national trials have included patients Most multi-national trials have included patients from Western Europe, U.S., Canada, New from Western Europe, U.S., Canada, New Zealand and Australia. Minimal but increasing Zealand and Australia. Minimal but increasing experience with Latin America Eastern Europe.experience with Latin America Eastern Europe.

Summary of FDA Summary of FDA experienceexperience

Few examples of formal bridging studies done in the U.S. Few examples of formal bridging studies done in the U.S. that were performed subsequent to development of a that were performed subsequent to development of a complete clinical data package, and that were carried out complete clinical data package, and that were carried out in response to an FDA requestin response to an FDA request

Generally, when FDA asks for more data/studies, it is Generally, when FDA asks for more data/studies, it is because the clinical trial evidence in the NDA is not because the clinical trial evidence in the NDA is not convincing and other formal phase 3 studies conducted in convincing and other formal phase 3 studies conducted in the U.S. are needed.the U.S. are needed.

Despite the inclusion of foreign clinical data in an NDA, Despite the inclusion of foreign clinical data in an NDA, sponsors have anticipated an FDA request by carrying out sponsors have anticipated an FDA request by carrying out U.S. trials without being asked. Sometime these trials are U.S. trials without being asked. Sometime these trials are ongoing at the time of NDA submissionongoing at the time of NDA submission

Summary of FDA Summary of FDA experienceexperience

As trials come from new regions , it As trials come from new regions , it may become critical to agree in may become critical to agree in advance on the sources of dataadvance on the sources of data

There has not often been a There has not often been a prospective evaluation during the IND prospective evaluation during the IND of differential pk, pd or clinical of differential pk, pd or clinical endpoints to treatment responseendpoints to treatment response

About 7 examples illustrating the About 7 examples illustrating the types of issues faced.types of issues faced.

Plans from the Brussels Plans from the Brussels meetingmeeting

MHLW to provide more detailed and MHLW to provide more detailed and comprehensive description of its experience comprehensive description of its experience with E5 implementation, since MHLW has with E5 implementation, since MHLW has most experience with bridging strategiesmost experience with bridging strategies

Industry to provide more specifics about Industry to provide more specifics about case studiescase studies

All six parties to specify questions for All six parties to specify questions for consideration for possible Q & A doc.consideration for possible Q & A doc.

Washington, D.CWashington, D.C

September 10-11, September 10-11, 20022002

ICH Meeting ICH Meeting

Summary of Summary of Discussions at the Discussions at the

Washington meetingWashington meeting

Evaluation of all written Q and A from 6 partiesEvaluation of all written Q and A from 6 parties

Evaluation of the case studies from MHLW and Evaluation of the case studies from MHLW and EFPIA which illustrate bridging issues and EFPIA which illustrate bridging issues and examplesexamples

Categorization of Q and A in selected topic Categorization of Q and A in selected topic areas to reduce redundancy and build areas to reduce redundancy and build consensusconsensus

Discussions on selected Q and A that all parties Discussions on selected Q and A that all parties agreed to be importantagreed to be important

Examples of the type ofExamples of the type of Q and A’s that will be Q and A’s that will be

developeddeveloped

Questions and Answers Questions and Answers (Q&A’s) to clarify intent of (Q&A’s) to clarify intent of

E5E5

Q1. I am planning to develop my new drug globally. Does E5 provide guidance for this approach?

Q2. I have developed my drug in one region, addressing safety, efficacy, dosing, etc., as well as use in special populations such as patients with renal/hepatic impairment, the elderly, children, and pregnant and lactating women. If I can successfully demonstrate (e.g., through a bridging study), that my safety, efficacy, and dosing information in the general population are relevant to the new region, will I also need to further address the extrapolatability of the special populations data?

Questions and Answers Questions and Answers (Q&A’s) to clarify intent of (Q&A’s) to clarify intent of

E5E5Q3. My drug is sensitive to ethnic factors and the medical settings in

which it is used may vary between regions. Does that mean that my efficacy study in one region is of no value in support of my application in another?

Q4. My drug is insensitive to ethnic factors and there are no significant, relevant differences in extrinsic factors, including the practice of medicine, among the regions. The pharmacokinetics of the drug are insensitive to intrinsic and extrinsic factors. The diagnosis and therapy of the condition in the indication do not significantly vary among regions. Nonetheless, the regulatory authority of the new region is requiring an additional study of safety and efficacy for bridging. Is that requirement inconsistent with E5?

Questions and Answers Questions and Answers (Q&A’s) to clarify intent (Q&A’s) to clarify intent

of E5of E5Q5. My drug has been approved in 2 ICH regions and I am about to

meet with regulatory authorities in the third region to discuss an application for marketing. I believe that the present data should be accepted by the new regulatory authority and that little or no additional data should be required by that regulatory authority. What information should I submit to support my case that additional data are not needed?

Q6. My drug is insensitive to ethnic factors and drugs in its class have similar activity in all regions. However, the endpoints I studied (or control group I used) were acceptable to regions in which the studies were conducted but not to the new region. Does E5 indicate that the new region should accept those data as evidence of efficacy?

Q and A Summary Q and A Summary TopicsTopics

Need for Safety DataNeed for Safety Data

Considerations on Special PopulationsConsiderations on Special Populations

Multiple IndicationsMultiple Indications

Global Development Strategy/Global Study Global Development Strategy/Global Study (Study Design Issues)(Study Design Issues)

Medical PracticeMedical Practice

Requesting One More StudyRequesting One More Study

Responsibility to Justify Bridging Responsibility to Justify Bridging

Plans for the next yearPlans for the next year

An Implementation Working Group will An Implementation Working Group will be constituted under ICH auspices to be constituted under ICH auspices to complete the Q and A’s and to collect complete the Q and A’s and to collect new issues as experience accruesnew issues as experience accrues

Final Q and A’s need to be consistent Final Q and A’s need to be consistent with intent of E5 and with regulatory with intent of E5 and with regulatory policy in each regionpolicy in each region

Timeframe: Feb 2003, Tokyo or July Timeframe: Feb 2003, Tokyo or July 2003, Brussels 2003, Brussels

Some thoughts on Some thoughts on bridging studies and bridging studies and

strategies strategies Many different bridging strategies, depending upon Many different bridging strategies, depending upon

data, disease and individual circumstances of studiesdata, disease and individual circumstances of studies

There are clinical study design issues which need to There are clinical study design issues which need to be addressed at the planning stage to facilitate be addressed at the planning stage to facilitate extrapolation and interpretability for bothextrapolation and interpretability for both

Multi-regional studiesMulti-regional studies

Simultaneous global drug developmentSimultaneous global drug development

Similar designed studies in two different regions Similar designed studies in two different regions (1 year vs. 2 year endpoints)(1 year vs. 2 year endpoints)

Issues to consider at Issues to consider at the planning stagethe planning stage

Definition and diagnoses of disease and patientDefinition and diagnoses of disease and patient

Variation in frequency or rarity of clinical Variation in frequency or rarity of clinical endpoint -impacts benefit risk evaluation endpoint -impacts benefit risk evaluation (Number needed to treat)(Number needed to treat)

Medical practice, concomitant medicationsMedical practice, concomitant medications

Prospectively, planning to examine a regional Prospectively, planning to examine a regional subgroup in a manner that may be different than subgroup in a manner that may be different than overall treatment effect [e.g. more emphasis on overall treatment effect [e.g. more emphasis on one of the endpoints, certain entrance criteria]one of the endpoints, certain entrance criteria]

Issues to considerIssues to consider

Same or different endpoints in each regionSame or different endpoints in each region

Same or different comparator treatments in Same or different comparator treatments in different regionsdifferent regions

Difficult issue; implications for interpretation in Difficult issue; implications for interpretation in superiority and non-inferiority trialssuperiority and non-inferiority trials

Size of regional component of multi-regional study Size of regional component of multi-regional study to evaluate similarity of responseto evaluate similarity of response

Dose responseDose response

Benefit/risk (efficacy and safety data)Benefit/risk (efficacy and safety data)

Concluding RemarksConcluding Remarks

The intent of the updated Q and A’s is to The intent of the updated Q and A’s is to clarify some areas of perceived clarify some areas of perceived misunderstandingmisunderstanding

More dialogue with regulators on study More dialogue with regulators on study design strategies will continue and design strategies will continue and experiences with completed studies and experiences with completed studies and bridging approaches sharedbridging approaches shared

My talk is primarily intended to be an update My talk is primarily intended to be an update on the informal working group ICH meetingson the informal working group ICH meetings