International clinical trials_asent regulatory affairs

ASENTASENT11th Annual Meeting

March 5-7, 2009Arlington, VA

I t ti l Cli i l T i lInternational Clinical TrialsA Regulatory Perspective

James Ottinger, RPhVice President, Consulting and Compliance

P i R h GPremier Research Group

Agenda

• The case for international clinical trials • Items for consideration• Global country venuesy• Clinical trials in the European Union • Submission of foreign dataSubmission of foreign data • Regulatory acceptance of foreign data• ConclusionConclusion• Questions

International Clinical Trials

• The case for international clinical trials− Patient access, patient access, patient access!− Availability of patients not in the U.S.

− Trials in Multiple Sclerosis − Regulatory requirements include DB PC trials of two years

duration− Most patients in the U.S. will not enroll in a trial of this

design− Trials in Alzheimer’s Disease

− Most donepezil-naïve patients are outside the U.S. and Western Europe


• Patent Access (continued)− Speed to enrollment

− Lack of adequate medical care drives patients into clinical trialsE t C t l E− Eastern Central Europe

− Latin America− Parts of Asia

− Standard metric of number of patients per site per month higher than in the U.S. or Western Europe

Metrics from an International Clinical Metrics from an International Clinical TrialTrial

CountryCountry Number Number of Sitesof Sites

Patients Patients PlannedPlanned

Patients Patients EnrolledEnrolled

Time Active Time Active (months)(months)

Patients/Site/MonthPatients/Site/Month

Austria 5 40 31 16 0.39

TrialTrial

Belgium 17 136 120 12 0.59

France 13 104 118 12 0.76

Germany 27 324 255 14 0.67

Italy 13 104 28 12 0.18

Netherlands 9 72 180 12 1 67Netherlands 9 72 180 12 1.67

Portugal 3 24 8 13 0.21

Spain 14 112 92 15 0.44

United Kingdom 11 88 80 14 0.52

Czech Republic 25 500 343 14 0.98

Estonia 5 100 109 15 1.45

Hungary 10 80 299 14 2.14

Latvia 5 100 94 16 1.18

Poland 35 700 538 14 1.10

Slovakia 15 300 285 16 1 19Slovakia 15 300 285 16 1.19

Bulgaria 20 400 391 15 1.30

Romania 5 100 168 17 1.98

Russia 25 500 637 16 1.59

Ukraine 25 700 781 14 2.23

Switzerland 1 12 0 0 0

TOTALTOTAL 283283 44964496 45574557 -- --


• Regulatory reasons to conduct international clinical trials− Generates dialogue with international regulatory

th itiauthorities− Early regulatory strategy discussions− Issue identification and resolution

− Experience with key opinion leaders− Supports clinical development, regulatory and marketing efforts

F ilit t l− Facilitates approval− Trials are required in some countries

− China India Taiwan Japan and othersChina, India, Taiwan, Japan and others


• Cost per patient− In ECE, Latin America, and parts of Asia

− Trials can be cost effective relative to the U.S.

A t i I di ill h $1500 t 2000 ti t− A center in India will charge $1500 to 2000 per patient, 1/10 the comparable rate in the U.S.1

− NDAs will have thousands of patients,NDAs will have thousands of patients, − The cost advantage can add up

− An exception to this rule is Japan

1Garnier JP. Rebuilding the R&D engine in big pharma. Harv Bus Rev 2008;86:68-76


• Quality of clinical trials− Are we being “penny wise, pound foolish”− Sites from pivotal clinical trials (Phase 3) will be

i t d b th l t th iti i th U S dinspected by the regulatory authorities in the U.S. and Europe− FDA Bioresearch Monitoring Programg g− EU National Authority Inspections

− Will the data pass a regulatory inspection?

Quality Quality –– Analysis of FDA InspectionsAnalysis of FDA Inspections

FDA inspections:Geographical area Number of i i

Numberf fi di

Findings per i i

pGeographical area inspections of findings inspection

Central & EasternEurope (incl. Russia) 23 36 1.56

Latin America 21 53 2.52

W t E 263 547 2 07Western Europe 263 547 2.07

US and Canada 5302 9778 1.84

Total (1981-2001) 5,609 10,414 1.85

Considerations for International Cli i l T i lClinical Trials

International Clinical Trial - Considerations

• Placebo-Controlled Studies− Required for regulatory approval of most drugs− Declaration of Helsinki

− “The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists”

− Regulatory Authorities and IRBs in some countries may not approve a placebo-controlled trial− e.g. Major Depressive Disorder, Multiple Sclerosis

International Clinical Trials - Considerations

• Disease incidence and medical practice− Consider differences in disease incidence

− MS trials in Latin AmericaMDD i A i− MDD in Asia

− Local acceptance of disease− Fibromyalgia trials in some countriesy g

− Treatment differences− Other treatments

U f h th i E− Use of psychotherapy in Europe− Concomitant medications

− Approved dose of Aricept in Japan is half that in other countries


• Primary endpoints− Do the authorities agree on primary endpoints?− Rating scales

− Validated in the local language− ADAS-Cog

− Familiarity by investigatorsy y g− Montgomery-Asberg Scale vs. Hamilton Depression

• Statistical considerations− Do the statistical tests and imputation methods meet

regulatory scrutiny− LOCF not an acceptable imputation method for analgesic trialsLOCF not an acceptable imputation method for analgesic trials

in the US


• Other issues− Infrastructure

− Local representation needed for clinical trial monitoring− Interaction with the local regulatory authoritiesInteraction with the local regulatory authorities− Contract Research Organizations

− Drug Importation issues− Qualified Person in Europe to approve clinical trial importation− DEA Scheduled drugs pose additional challenges

− Multiple languagesMultiple languages− Informed consents, rating scales, etc

− Ethical issues− Ethical oversight in developing countries− Recent case of Pfizer and Nigeria

Clinical Trial Venues

International Clinical Trials - Venues

Open Phase 3 Trials Sponsored by the 20 Largest U.S. Corporations

Glickman et al, Ethical and Scientific Implications of the Globalization of Clinical Research. N Engl J Med 2009;360:816-849

Venue Selection

• Australia/New Zealand− Relatively cost effective, matches U.S. population− Regulatory pathway easier than most− General use

• Canada − Excellent sites and investigators− Use for specialty centers, rare diseases, global

programsprograms− Different IND application, possible pre-IND meeting,

French language requirements− Tax incentives for local offices

Venue Selection

• Japan− Not to be used for additional sites− Reserve for Japanese registration

• China− Huge patient population, but dissimilar to the U.S.− Long regulatory lead times− Mandatory for Chinese registration

Oth A i /P t i• Other Asia/Pac countries− Use for global programs, rare diseases, special

circumstancescircumstances− Cost effective, esp for Pan-Asian registration

Venue Selection

• IndiaIndia− Very cost effective− Huge population, good enrollmentg p p g− Longer regulatory lead times− General use

• Latin America− Cost effective− Good enrollment− Regulatory lead times vary by country

General use− General use

Venue Selection

• Other areas− Africa

− South AfricaQ lifi d i ti t− Qualified investigators

− General use− Other countries

− Special situations – HIV, malaria

− Middle East− Israel has good infrastructure− Israel has good infrastructure− Qualified sites− General use

Initiation of Clinical Trials in EuropeEurope

European Studies

• Why conduct studies in Europe− Qualified investigators and sites− Large pool of patients− Open a dialogue with the European Regulators in

advance of a marketing application− Among the world’s largest pharmaceutical market as a regionAmong the world s largest pharmaceutical market as a region

− Differing regulatory requirements and medical practice

Lost in Translation

• IND • CTA• IND Summaries• IND Number

• IMPD• EudraCT Number

• FDA• IRBs

• Competent Authority• Ethics CommitteesIRBs

• Country• ---------

Ethics Committees• Member States• EMEA/CHMP

• Federal RegulationsEMEA/CHMP

• EU Directives and National LegislationNational Legislation

Development of the EU

• 1957 European Economic Community

Germany, France, Italy, Netherlands, Belgium, Luxembourg

• 1973 European Community. United Kingdom, Denmark, Irelandp y g , ,

• 1981 Greece

• 1986 Spain, Portugal

• 1995 European Union. Austria, Finland, Sweden

• 2004 Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta,

Poland, Slovak Republic, Slovenia

• 2007 Bulgaria and Romania

27 M b St t27 Member States

3

European Regulatory Overview

• To conduct Investigational clinical research in the European Union, a sponsor must have− Offices in an EU Member State, or

− EU Legal Representative− EU Applicant

− Qualified PersonQualified Person− An approved Clinical Trial Application

− Unlike marketing applications, there is no option for European-id CTA lwide CTA approval

− Approval of the Ethics Committees (EC) in every member state in which the trial is being conductedg

European Union Regulatory Overview

• Clinical Trial Directive (2004)− Goal was to harmonize the requirements− The 27 member states have implemented the Clinical Trial Directive

in their national legislation differently− Each member state may have its own submission requirements− EC approval and Competent Authority approval

− In parallel orIn parallel or− In sequence

− 23 official languages E li h i t t d f ll t f th li ti− English is not accepted for all parts of the application

Clinical Trial Application Content

• EudraCT Number• Clinical Trial Application Form

− Web based, complicated• Investigational Medicinal Products Dossier

− The IMPD contains a summary ofQ li (Ch i M f i d C l )− Quality (Chemistry, Manufacturing and Controls)

− Pharmacology and Toxicology Data− Clinical Data− Overall Risk and Benefit Assessment

• Supporting Information• Fees

CTA Requirements

Obtain an EudraCT Number• Required to start the CTA process• Obtained at: http://eudract.emea.europa.eu

Generated automatically and consists of the year followed• Generated automatically and consists of the year followed by the trial number− The 42nd trial in 2009 would be

− 2009-0000042− This is a unique number used to refer to this study

EudraCT numbers issued since 2004

Total EudraCT numbers issued 2004 - 2008

7987

9334

9000

10000

d

6214

7124

7987

46135000

6000

7000

8000

num

bers

issu

ed

2000

3000

4000

5000

otal

Eud

raC

T n

0

1000

2004 2005 2006 2007 2008

Year

To

Year







Clinical Trial Application




− Quality (Chemistry, Manufacturing and Controls)Ph l d T i l D− Pharmacology and Toxicology Data

− Clinical Data− Overall Risk and Benefit Assessment








Same Guidelines – Different needs







Fees

• CTA fees are applied on a national basis in each member state− Fees are often charged by both Competent Authorites

d ECand ECs− Generally individually less than $5,000, but can add up

to a substantial sumto a substantial sum

• Regional difference – U S INDs are “free”Regional difference U.S. INDs are free

CTA Review

• The CTA is submitted to each Member State − Application is validated

− There is a 60-day initial review− Member States may have differing timelines, e.g.,shorter for

phase 1 studies

A d fi i l tt b i d− A deficiency letter may be issued

− Responses are submitted, an additional review is completedcompleted

− No trial can begin until the CTA is approved by the CA and the ECs

Submission and Acceptance of I t ti l Cli i l T i lInternational Clinical Trials

Submitting Data from International Trials

• International Conference of Harmonisation − E3 – Structure and Content of Clinical Study Reports

− Outlines the format and reporting requirements for any clinical trialtrial

− Now harmonized in all regions (U.S., EU, Japan)

− M4 – The Common Technical Document− Outlines the format for a Marketing Application (NDA,MAA)− Now harmonized in all regions− Additional requirements in the U.S. for an ISS and ISEAdditional requirements in the U.S. for an ISS and ISE


New FDA Requirements (April 2008)• 21 CFR 314.106 Foreign Data

A) Acceptance of foreign data is governed by 312.120− Foreign clinical studies not conducted under an IND. Must

submit in an NDA documentation on:− Qualification of investigatorsg− Description of research facilities− Protocol, Clinical Study Report, Case Report Forms as

requestedrequested− Chemistry, Manufacturing and Controls information− The study is adequate and well controlled

Th t d f ith thi l i i l− The study conforms with ethical principles


New FDA Requirements (April 2008)• 21 CFR 314.106 Foreign Data

B) Can be the sole basis for approval− Foreign data are applicable to the U.S. population− Studies have been performed by competent investigators− FDA can validate the data (inspection)FDA can validate the data (inspection)

C) Applicants are encouraged to meet with the agency


Regulatory acceptance of clinical data• International Conference of Harmonisation

− E5 (R1) Ethnic Factors in the acceptability of foreign clinical data− Developed to establish the framework for acceptance of foreign

clinical studies by the Japanese MHLWy p− ICH guidelines are adopted in three regions

− European Union, Japan and the U.S.− Widely recognized by other authorities− Widely recognized by other authorities


ICH E5• Acknowledges and balances

− Ethnic differences can affect safety, efficacy, dose or dose regimen

− Duplication of clinical trials is inefficient and wastefulC h i di i f f t t id• Comprehensive discussion of factors to consider− Intrinsic factors – genetic polymorphism, age, gender,

body weightbody weight − extrinsic factors – medical practice, diet, socioeconomic

status, exposure to pollution and sunshine


ICH E5− Data generated in a clinical program from one region will

be accepted if it resembles the population of the new regionregion− A program conducted in Western Europe, will most likely be

accepted by the FDA− A program conducted in Japan will require new studies for the

U.S.− A program conducted in the U.S. will require new studies for

China


• Conclusion− Conducting an international development program

results inAdd d l it− Added complexity

− But....can− Accelerate developmentp− Reduce costs− Facilitate global registration

Questions?

An International thank youAn International….thank you Merci, Danke, Domo Arigato

Education

International clinical trials_asent regulatory affairs