Ethnic Differences, Regulatory Policies, and COVID-19

Toshiyoshi Tominaga
Japan Self-Medication Industry

he ICH E5 guideline “Ethnic factors in the acceptability of foreign clinical data” and E17 guideline “General principles for planning and design of multi-regional clinical trials” present harmonized methodologies to efficiently develop drugs in multiple regions while considering ethnic differences in drug responses.

While the regulatory authority of a country is expected to judge if its jurisdictional population reacts uniquely to the tested drug to warrant inclusion in a Multiregional Clinical Trial (MRCT), the science often does not inform the judgement, for want of necessary evidence—especially in the earlier phases of development. Instead, the judgement often reflects a country’s policies on drug development in general. Recent development of anti-COVID-19 agents affords some relevant insights.

Regulators’ Responsibilities In Relation to Ethnic Differences

International harmonization of pharmaceutical regulations generally assumes that a good drug retains its virtue everywhere in the world, and its usefulness can be proven with a single crosscutting data set. The E5 and E17 guidelines uniquely allow, however, that a drug beneficial to one population may not offer the same benefits to others, and they justify country/ethnicity-specific data in the form of a bridging study or inclusion in a MRCT. It is ultimately each country’s regulatory authority that responsibly passes judgement on its population’s uniqueness in reaction to drugs, requests the clinical data, and reviews the market authorization application (MAA).

The regulator’s responsibility typically starts when a sponsor, having finished phase 2 studies in other countries, comes to a new country’s regulatory authority and asks for advice on a draft protocol for phase 3 MRCT, in which the country’s and some other countries’ populations are pooled based on the claimed similarity of their responses to the candidate drug. By agreeing, the authority risks having the country’s population replaced by the populations of other countries in the trial and ends up having a few or no in-country clinical data on which to base its decision on the drug’s approvability. Alternatively, the authority can deny the similarity and request an adequate number of patients to be enrolled in its own country.

The regulatory authority naturally estimates the population’s uniqueness based on the data provided by the sponsor and by utilizing its past experience with similar drugs and reference materials, such as the general characteristics of compounds that are sensitive to the ethnic factors that are cited in the E5 guidelines. There should be cases where such scientific approaches lead to a prediction of the uniqueness of the population with regard to its response to the drug.

However, during the earlier stages of drug development, which is precisely when the authority must take its stance, there are simply not enough data even to show if there is any ethnic difference in drug response, let alone the mechanistic basis of this difference. The situation is even worse for a newly participating country. The regulators thus face the impossible task of having to deliver binding advice on what cannot be known unless (and until) it is tried. In the author’s observation, when there is scientific uncertainty about ethnic difference, the decision on poolability is driven more by the authority’s general policies on drug development in the country and how to deliver them to the public.

Policy Considerations

Because a regulatory authority’s primary responsibility is to protect and promote the health of the country’s public, each authority should naturally wish to see data obtained from its own jurisdictional population before determining if a drug should be approved. One can thus expect that regulators will tend to be conservative with regard to other populations being able to represent their own population. When the country intends to enhance its own domestic clinical research as a matter of national strategy, this conservative tendency may be even stronger.

There are, however, at least two situations that can motivate regulators to be less conservative:

  1. Insisting on domestic clinical data may cause significant delays in the introduction of (typically quite promising or urgently needed) new drugs to the country. In such situations, the authority might choose to summarily approve the drug (without requesting a bridging study, for example) and supplement the evidentiary basis for such approval in the post-marketing phase.
  2. The authority wishes to prioritize regulatory cooperation. When a regulatory authority claims that its jurisdictional population reacts differently to the drug compared to other populations, other authorities’ assessments on their respective population are hardly relevant or usable. Furthermore, an authority belonging to a group of countries with an agreement to cooperate on regulatory reviews may hesitate to claim ethnic differences within the group. This also applies to an authority planning a unilateral reliance on other authorities for regulatory review results. In this situation, a regulatory authority may be more receptive to clinical data collected outside its territory.

As the country’s situation changes, so does the nature of its judgement. When a country gains importance in the world’s drug ecosystem in terms of drug market size, research capacity, and the authority’s capability, its regulators might become more conscious of ethnic differences and request more domestic data, even if the population itself has not changed. Countries’ general preference for (or indifference to) domestic clinical data that results from each country’s unique situation and strategy relative to drugs, cannot be harmonized across countries (at least not based on science).

Development of COVID-19 Therapies

A case in point is provided by urgently needed treatments for COVID-19. With the huge health impact and current lack of any proven therapy, almost every country is willing to accept available and promising clinical data, however preliminary and regardless of where they were collected, to justify use of the drug in their own territory. In fact, reliance on the decision of an advanced regulatory authority is already occurring.

Some of the policy considerations on drug development discussed above apply to this case. When a country urgently needs a remedy that is proven effective in other countries, and is willing to leverage the reviews and decisions of other authorities, its regulators cannot be too particular about possible ethnic differences; they are somehow “compelled” to allow the drug’s use with minimal or no local evidence. Of course, the available foreign evidence then needs to be supplemented in terms of ethnic differences and other aspects (such as undetected side effects) in the post-market phase.


Pooling populations expedites multi-regional drug development. Though it is tempting to think that poolability can be scientifically (and even quantitatively) assessed, scientific evidence is often not sufficient to give decisive direction when a confirmatory MRCT is being designed. Especially when the proposed pooling makes little or no domestic clinical evidence available for MAA review, the regulatory authority’s decision on whether or not to allow pooling is often driven more by policy considerations on drug development in general. The COVID-19 case confirms that some of the policy considerations are actually applied in practice.