“A bridging study is defined as a study performed in the new area to provide pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the population in the new region.
A bridging efficacy analysis may offer additional pharmacokinetic knowledge to the new region’s community.
Pharmacokinetic research in the new area can be assessed as bridging research where no bridging analysis is needed to include clinical evidence for efficacy.
These studies are designed to “bridge” the gap between diverse efficacies and outcomes of drugs among different populations.
The International Conference on Harmonization (ICH) has published a guideline entitled “Ethnic Factors in the Acceptability of the Foreign Clinical Data,” which is known as ICH E5 guideline.
The ICH E5 guideline provides a wide-ranging framework for evaluation of the impact of ethnic factors on the efficacy, safety, dosage, and dose regimen.
The most common type involves the need by industries to bridge or extrapolate the results of foreign, phase III, clinical studies by conducting the dose-response studies nationally in the form of bridging studies.
Purpose of bridging study:
As per the National Center for Biotechnology Information (NCBI), “the bridging study concept has mainly been brought up to overcome the difficulties inherent to the extrinsic factors caused by different ethnicity.”
When a particular medication is sensitive to the ethnic factors, a bridging study is necessary for approval in a foreign country.
Advantages of a bridging study
- To avoid replication of the large, expensive trials.
- To avoid replication of the whole development programmes.
- To fill in the gaps.
- To show significance (i.e., link or build a bridge) between completed studies and local (regional) factors.
- A bridging study shortens the period for the clinical development of the drug, as clinical evaluation from the beginning stages can be avoided.
- The study uses the complete clinical data package and additional tests.
When Are Bridging Studies Needed? : An Overview
|Study medication||Insensitive to ethnic factors||Sensitive to ethnic factors|
|Medical practice||Similar||Different: need controlled trials|
|Drug class||Familiar: need only pharmacodynamics||Unfamiliar: need controlled trials|
|Clinical experience||Sufficient||Insufficient: need controlled trials|
The studies are important for both pharmacodynamic and pharmacokinetic reasons.
Geographically separate populations have often evolved minor differences in receptor and enzyme makeup, this can lead to a drug having a significantly different binding affinity in one population to another.
There may also be more receptors in their body or those receptors may be more active once bound.
Generally it is differences in enzymes that lead to our bodies metabolising a drug at a different rate or in a different way that can cause problems though this is often solved as most of our drugs have a extensive gap between efficacy and toxicity.
Variations in the enzyme CYP2D6 is the conventional example of this and is an enzyme important for hepatic metabolism of tricyclic antidepressants as well as some more recent ADs.
Depending on the number of copies and any mutations in the CYP2D6 gene you can either be an fast, normal, intermediate or poor metaboliser of these drug types.
Fast metabolisers remove the drug too rapidly for it to exert its effect while intermediate and poor metabolisers are more likely to undergo side effects from the drugs remaining in circulation too long and accumulating if re-dosed.
Studies found that approx 40% of people of Asian descent are intermediate metabolisers and only about 1% are poor metabolisers, which is a very much different profile to that of Caucasians.
Equally it was found that the polymorphisms responsible for the differences were unique in many cases to the Asian population.
For example, the intermediate group was due to a CYPD2D6*10 mutation while the CYPD2D6*4 mutation is more predominant in Caucasians.
Later studies also revealed unique differences among African populations.
Overall these differences are important due to the side effect association among poor to intermediate metabolisers and as a result, you should be more careful in prescribing certain antidepressants and anti-psychotics to Asian people than Caucasians.
The bridging studies actually highlight what used to be and still is in many ways a big problem in drug development.
A lot of pharmaceutical companies are situated in the US/EU and as such their clinical trials are usually located there.
There is therefore a disproportionate representation of largely white populations during some trials so problems of using drugs within a different group can often be masked.
Since it is generally a Caucasian population who will purchasing the drugs too there was generally an unwillingness to worry about other ethnicities as the market in somewhere like Africa is likely to be significantly smaller and less profitable.
Bridging studies hopefully lend to dampen this problem although it is certainly not as prevalent as it used to be.”