Multinational Trials

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 same  Duration of Treatment should be same

should be

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 Local

120

Multi

100 30

80

60 17 40 5

57 45

20

42

42

42

31

28

27

`99

`00

`01

18 0

67 38

3

1 `90

18

`91

`92

`93

`94

`95

`96

`97

`98

`02

`03. 9

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.