Ethnic Factors in Drug Development

Jurij Petrin, M.D.

Characteristics of Drug Metabolism Influencing Global Drug Development

• All drugs exhibit intersubject PK and PD variability

• Different populations around the world may handle drugs differently

• Influencing factors can be:– Intrinsic– Extrinsic

Some Typical Examples of Possible Ethnical Differences

• Chinese are more sensitive to the cardiovascular pharmacologic effects of beta-adrenoceptor antagonists than Caucasians

• Chinese have lower daily warfarin dose requirements than Caucasians

• Caucasians were more sensitive to the cardiovascular and respiratory effects of morphine than Chinese, although the former were less sensitive to its gastrointestinal side effects

• Etc

Intrinsic Factors• Age• Gender• Body weight• Genetic factors (polymorphism)• Presence of diseases influencing:

– Absorption (gastrointestinal disorders…)– Distribution (cardiovascular, GI…)– Metabolism (hepatic, genetic, ….)– Elimination ( hepatic, renal…)

• Ethnicity/race

Extrinsic Factors

• Diet• Medical practice• Life style• Tobacco use• Alcohol use• Concomitant medication• Environment• Etc

Definition of a Race

“Term once commonly used in physical anthropology to denote a division of humankind possessing traits that are transmissible by descent

and sufficient to characterize it as a distinct human type (e.g., Caucasoid, Mongoloid, Negroid)”

Encyclopedia Britannica 2002

Definition of Ethnic

”relating to large groups of people classed according to common racial, national, tribal, religious, linguistic, or cultural origin or background”

Merriam Webster Dictionary 2001

Difficulties With Assessment of Ethnical Differences in Drug Development

• Which ethnical groups?• Interethnical versus intraethnical differences • Is every drug ethnically sensitive?• Are small differences (if present) clinically

important?• Should studies on predominantly one ethnic

population really always be repeated on another group? (ethics, timing, cost)

ICH E-5:Ethnic Factors in the Acceptability of Foreign Clinical Data

• Status of Implementation (Step 5)

• EU: Adopted by CPMP, March 1998, issued as CPMP/ICH/289/95

• Japan: Adopted August 98, PMSB/ELD Notification No. 672, PMSB Notification No739

• USA: Published in the Federal Register, Vol. 63, No. 111, June 10, 1998, page 31790 in force September 98

Main Points of the E-5

• Most drugs are not ethnically sensitive• Ethnic populations classified as

– Asian– Black– Caucasian

• Assessment of ethnic sensitivity made from bridging data in full clinical data package

• Bridging study may be carried out in a new ethnic population if initial data assessment indicates ethnic sensitivity (Appendix D)

Appendix DProperties of a Compound That Make It More

Likely to be Sensitive to Ethnic Factors

• Nonlinear pharmacokinetics• A steep pharmacodynamic curve for both efficacy and

safety (a small change in dose results in a large change in effect) in the range of the recommended dosage and dose regimen

• A narrow therapeutic dose range• Highly metabolized, especially through a single pathway,

thereby increasing the potential for drug-drug interaction• Metabolism by enzymes known to show genetic

polymorphism

Polymorphism of Hepatic Metabolism

• Significant ethnic differences seem to exist in theenzymatic activity of several drug metabolizingenzymes (cytochrome P450):– CYP2C9 (S-warfarin)

– CYP2C19 (diazepam, omeprazole, trycyclic antidepressants)– CYP2D6 (codeine, quinidine, haloperidol)

– CYP1A2 (theophylline, imipramine, clozapine and olanzapine) – N–acetyltransferase (NAT-2 – isoniazid, hydralazid

NAT-1 - p-aminosalicylic acid )

Polymorphism of Hepatic Metabolism

• Whites are more likely than persons of Asian and African heritage to have abnormally low levels of CYP2D6 that metabolizes drugs such as antidepressants, antipsychotics, and beta blockers

• Slower enzyme metabolism (CYP2C19) has been observed in persons in the United States of Asian descent as compared to Whites and Blacks (diazepam, omeprazole, tricyclic antidepressants)

• Blacks respond poorly to several classes of antihypertensive agents (beta blockers and angiotensin converting enzyme (ACE) inhibitors)

• Racial differences in skin structure and physiology have been noted that can affect response to dermatologic and topically applied products

• Clinical trials have demonstrated lower responses to interferon-alpha used in the treatment of hepatitis C among Blacks when compared to other racial subgroups

Polymorphism of Hepatic Metabolism

• These differences can affect the PK and response profiles of drugs in different populations

• They need to be considered during the drug development process

• Compounds in development should and will be carefully screened, particularly for CYP mediated metabolic patterns

Appendix D Properties of a Compound That Make It More

Likely to be Sensitive to Ethnic Factors

• Administration as a prodrug, with the potential for ethnically variable enzymatic conversion

• High inter-subject variation in bioavailability• Low bioavailability, thus more susceptible to dietary

absorption effects• High likelihood of use in a setting of multiple co-

medications• High potential for abuse

E-5 Concepts

• Clinical Data Package (CDP) consists of foreign data

• Bridging Study (BS)“A bridging study is defined as a study performed in the new region to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen that will allow an extrapolation of the foreign clinical data to the population of the new region”

The Spirit and Intent of E5

• Not intended to request bridging studies every time• Intended to permit the requesting of one ‘confirmatory’

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

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

E5 Allows for a New Study in the New Region - Why is That Needed ?

• When all the clinical data is derived from a foreign region and extrapolation is an issue

• When the experience with clinical trials in that region is minimal

• When there is concern with ability to confirm a finding from a study(ies)

• A confirmatory clinical trial is the bridging study

Individuality vs Population Response

• Medicines are prescribed as a treatment for an individual patient, not a population

• The variability of response to a drug is likely to vary as much, or more, within a given population as between different populations

• It is unusual for a population defined simply by ethnicity to share consistently enough characteristics to predict a different dose-response relationship to a drug

• Bridging justification may be needed

Current Issues With Bridging Studies

• Asia only • Some authorities more frequently demanding data

on ethnical differences than others– Japan– Korea– Taiwan

• Some others “observers”

Bridging in Japan

• Sponsor prepares a bridging package to be discussed with KIKO

• Consultation results in instructions and suggestions

• The company has to decide whether to use bridging or go into full development

• Few examples of successful bridging approach so far

Bridging - Korea• With the new law the Koreans have indicated that

local registrational trials were no longer needed. • However, the KFDA had stated that “since the

application of foreign clinical data directly toKorean population may raise problems due to ethnical differences”, the need for a bridging study would always have to be assessed.

• They require studies on Koreans living in Korea, and no data generated on Asians of other nationalities may be accepted.

Bridging - Korea• However, there may be instances where bridging study

requirement could be waived. These are as follows:

• Orphan drug • Drugs for treating AIDS, cancers or life-threatening diseases for

which a standard remedy is either unavailable or, even if it is available, not working:

• New drugs under development inside or outside of Korea for which clinical trials will be conducted in Korea

• Diagnostic reagents (including radiopharmaceuticals)• Drug that do not effect systemically but locally• Drugs that have demonstrated no differences by ethnic factors

Taiwan – Bridging

• Organized 2 APEC meetings on bridging• Center for Drug Evaluiation (CDE)

evaluates each product for the need for bridging of data. Consultations encouraged

C o n s i d e r a t i o n s f o r A s s e s s i n g t h e N e c e s s i t y o f a B r i d g i n g S t u d y

I s t h e r e a c o m p l e t e c l i n i c a l d a t a p a c k a g e t h a t n a t u r e a n d d a t a q u a l i t y ( G C P ) m e e t s T a i w a n l o c a l r e g u l a t o r y r e q u i r e m e n t s ( I C H E 5 a n d D O H g u i d a n c e s o n c l i n i c a l t r i a l s ) ?

D o e s i t m e e t D O H a n n o u n c e m e n t o n e x e m p t i o n o f b r i d g i n g s t u d y ? A n d d o e s n o t n e e d t o s u b m i t E t h n i c s e n s i t i v i t y d o c u m e n t ?

N o b r i d g i n g s t u d y r e q u i r e d

D o e s i t i n c l u d e d a t a o b t a i n e d i n A s i a n p o p u l a t i o n * ?

N o b r i d g i n g s t u d y r e q u i r e d

D o e s i t i n c l u d e t h e d a t a f r o m t h e t r i a l ( e a r l y p h a s e t r i a l s ) o r g l o b a l c l i n i c a l t r i a l s c o n d u c t e d i n T a i w a n a n d a p p r o v e d b y D O H a n d f u l f i l l t h e D O H b r i d g i n g s t u d y r e q u i r e m e n t ?

A p r o t o c o l o f a n a d e q u a t e b r i d g i n g s t u d y s h o u l d b e d e s i g n e d a n d s u b m i t t e d t o D O H f o r a p p r o v a l . T h i s a d e q u a t e b r i d g i n g s t u d y c a n b e a P K a n d / o r P D s t u d y o r a n y c l i n i c a l s t u d y e v a l u a t i n g e f f i c a c y a n d s a f e t y o f t h e m e d i c i n e .

W h e t h e r t h e d r u g w i t h n o i n t r i n s i c s e n s i t i v i t i e s f a c t o r s a n d t h e e x t r i n s i c f a c t o r s b e t w e e n f o r e i g n a n d o u r c o u n t r y p o p u l a t i o n i s s i m i l a r ; o r b a s e o n s a f e t y a n d e f f i c a c y , t h e c l i n i c a l d i f f e r e n c e i s a c c e p t a b l e ? P s . A c c o r d i n g t o E 5

U s i n g c u r r e n t d a t a f o r d o s e a d j u s t d e t e r m i n a t i o n

I s i t r e a s o n a b l e t o a s s u m e s i m i l a r c o n c e n t r a t i o n ( d o s e ) - r e s p o n s e ( C - R ) r e l a t i o n s h i p i n A s i a n s * w h e n e x t r a p o l a t e d f r o m f o r e i g n c l i n i c a l d a t a ?

I s A s i a n * P K a n d / o r P D d a t a a v a i l a b l e t o b e u s e d t o c o r r e l a t e w i t h d o s e o r p r e d i c t e f f i c a c y ?

* w h e n e v i d e n c e i n d i c a t i n g p o t e n t i a l i n t r i n s i c a n d

e x t r i n s i c f a c t o r s d i f f e r e n c e s b e t w e e n

O u r c o u n t r y a n d o t h e r A s i a n p o p u l a t i o n s , A B r i d g i n g

s t u d y s h a l l b e c o n d u c t e d .i n o u r c o u n t r y .

Y e s N o

N o

Y e s N o

Y e s N o

Y e sN o

Y e s N o

C o n s i d e r a t i o n :k e y p o i n t o n w h e t h e r p r o d u c t t o b e t h e t r i a l w a i v e r c a t e g o r y a s t h a t n o n e e d t o s u b m i t d a t a t o s h o w n o n -e t h n i c s e n s i t i v i t i e s

C a n t h e d a t a p a c k a g e r e a s o n a b l e s h o w b o t h n o i n t r i n s i c a n d e x t r i n s i c f a c t o r s s e n s i t i v i t i e s i n A s i a n w h e n e x t r a p o l a t e d f r o m f o r e i g n c l i n i c a l d a t a ; o r b a s e o n s a f e t y a n d e f f i c a c y , t h e c l i n i c a l d i f f e r e n c e s i s a c c e p t a b l e ? P s . a c c o r d i n g t o E 5

Y e s N o

* * G e n e r a l l y n o b r i d g i n g s t u d y r e q u i r e d

Y e sN o

Y e s

R e q u e s t s u b m i t s u f f i c i e n t d a t a b e f o r e r e v i e w

N o b r i d g i n g s t u d y r e q u i r e d

* * I f h a s s a f e t y c o n c e r n , t h e n b r i d g i n g s t u d y i s r e q u i r e d .

* * G e n e r a l l y n o b r i d g i n g s t u d y r e q u i r e d

Recent developments

• Literature review • FDA Draft Guideline (January 2003)• Questions and answers – ICH Steering

Committee (February 2003)

US FDA• January 2003 – Draft “Guidance for Industry Collection

of Race and Ethnicity Data in Clinical Trials”

– A standardized approach for collecting race and ethnicity information in clinical trials conducted in the United States and abroad for certain FDA regulated products.

– Developed by the Race and Ethnicity Working Group from the Office of the Commissioner, the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) of the Food and Drug Administration (FDA).

US FDA

• FDA regulations require sponsors to present in certain marketing applications an analysis of data according to demographic subgroups (age, gender, race), as well as an analysis of modifications of dose or dosage intervals for specific subgroups (21 CFR 314.50 (d)(5)(vi)(a)).

US FDA

• Draft Guideline Recommendations:– consistency in data collection required– use of a two-question format– have trial participants self-report their racial and

ethnic category to enhance consistency – individuals should be permitted to designate a

multiracial identity.

–

US FDA• Draft Guideline Recommendations:

– For ethnicity, the FDA recommends the following minimum choices be offered:

• Hispanic or Latino• Not Hispanic or Latino

– For race: • American Indian or Alaska Native• Asian• Black or African American• Native Hawaiian or Other Pacific Islander• White

US FDA• Draft Guideline Recommendations:

– In certain situations more detailed race and ethnicity information may be desired

• e.g., White can reflect origins in Europe, the Middle East, or North Africa;

• Asian can reflect origins from areas ranging from India to Japan.

– If more detailed characterizations of race or ethnicity are collected to enhance data consistency, FDA recommends these characterizations be traceable to the five minimum designations for race and two designations for ethnicity listed before.

Studies Performed Outside of the USA

– FDA recognizes that the categories for race and ethnicity were developed in the United States and that these categories may not adequately describe racial and ethnic groups in foreign countries.

– For ethnicity:• Hispanic or Latino • Not Hispanic or Latino

– For race:• American Indian or Alaska Native • Asian • Black, of African heritage • Native Hawaiian or Other Pacific Islander • White

Summary

• Influence of ethnical differences on drug development more often anecdotal (although documented) than based on hard scientific evidence

• ICH E-5 was prepared to facilitate global drug development and simplify registrations around the world

• The guideline is intentionally vague• This may be used by some to always demand local clinical

trials • In 2003, the ICH Steering Committee prepared Q&A to

facilitate global drug development and understanding of the E-5 Guideline

Summary

• Also in 2003, the US FDA issued a draft guidance with more detail concerning the ethnicity and race collection requirements than the ICH E-5

• Europe (for now) lacks a guideline concerning race and ethnicity

• The topic continues to evolve, especially given the expanding role of global drug development

Conclusions

• US, EU will continue to be the main locations for NCE clinical trials

• International, including emerging markets have an important role in global drug development

• Need to continue aligning their local regulatory requirements with developed countries

• Need to increase local clinical research expertise• Need to accept and enforce strong patent

protection