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

Local Multi
120

100

80 30

60

17
40
18 67
57 5
45 42 42 42
20 38
31 28 27
18
0 1 3
`90 `91 `92 `93 `94 `95 `96 `97 `98 `99 `00 `01 `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.