MULTINATIONAL TRIALS

- Ajay Kumar P

Why?

Rapid patient enrollment

Expediting the development of new medicine

conducting a trial that otherwise might be impossible

To compare patients

Patients with a rare disease are to be studied

In which therapeutic areas?

Those have similar diagnosis, incidence, classification & treatment in the participating countries are considered for the enrollment.

Many bacterial & viral infections leads to multinational trials.

In which phases of development?

Phase 1: single country.

Phase 2: few countries(pilot trials)

Phase 3: acceptable to conduct multinational trials by keeping similar groups

Phase 4: safety surveillance studies.

Safety versus efficacy

Are multinational trials necessary if a disease has a low incidence or prevalence?

Other factors affecting M Ts

Existence or prevalence of disease ex: topical diseases, hypotention etc

Genetic background of patients ex: g6pd deficiency

Differences in culture :- 1. Language 2. Ethics 3. Diet 4. Customs 5. Religion

Ethics Committes/ Institutional Review Boards:

According to section 3.1.1 of ICH GCP guidelines:“An IRB/IEC should safeguard the rights, safety & well being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects”.

EC in UK, ~250 LRECs 10 MRECs COREC in London Trust’s R&D department

EC in France, CCPPRB( comite consultatif de protection des personnes dons la recherche)

EC in Canada, REB, Canadian claimant to a multinational clinical trial (CCMC)

Flexibility of Protocol Design (1)

Primary Objective

should be same

Secondary Objective

should be same

additional item is possible

Flexibility of Protocol Design (2)

Study Population　　 patients diagnosed with similar assessment

Inclusion Criteria

main criteria should be same

Exclusion Criteria main criteria should be same

Flexibility of Protocol Design (3)

Washout Period

should be similar

Dose and Mode of Administration should be same

Duration of Treatment should be same

Flexibility of Protocol Design （ 4 ）

Excluded medication

should be similar pharmacological class

Dose and Mode of Active control

should be same

Flexibility of Protocol Design （ 5 ）

Primary Endpoint

should be same

Secondary Endpoint should be same

additional item is possible

Flexibility of Protocol Design （ 6 ）

Vital signs main items should be same

Clinical Laboratory tests

central laboratory should be utilized or main items should be same

Flexibility of Protocol Design （ 7 ）

Record adverse events definition, severity, causality

should be assessed using same categories

Dropouts and/or End of Study

should be assessed using same categories

Increased Number of Clinical Trials

1 3

18

4557

42 42 4231 28 27

38

675

18

17

30

0

20

40

60

80

100

120

9̀0 9̀1 9̀2 9̀3 9̀4 9̀5 9̀6 9̀7 9̀8 9̀9 0̀0 0̀1 0̀2 0̀3.9

Local Multi

Common problems with Foreign Trials Concomitant medications may be unknown in host country. Devices may be called by different names in host country Diseases may be diagnosed or classified differently in host

country Concomitant therapies may be common, unreported, or

unconventional. Inclusion/exclusion requirements may be difficult in local

medical practice Language idioms may not have equivalent translations English is not the same everywhere . Smaller US banks may not be familiar with wire transfers. Numbers & dates may be written differently.

Tips & suggestions for conducting Foreign Trials Keep trial design simple. Use only one or two endpoints. Use objective not subjective end points. Have investigator critically review protocol for practical

implications. Use two-part case report forms, one part on home

language, one part in host language. Use a locally-based CRO Use monitors accustomed to device trials. Don’t pool data from different countries. Double translate all trial documents. Monitor heavily. Conduct a limited feasibility study first to test the protocol.