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The Long Road to Perfect Harmony

We have discussed how globalization has led to increasing regulatory harmonization – with global bodies such as the ICH playing an important role in that process. However, in certain areas, there is significant disharmony across the ICH regions. Hisashi Urushihara, Professor in the Division of Drug Development and Regulatory Science at Keio University, Tokyo, Japan, looked specifically at the differences in ethical standards for pharmacovigilance studies between Japan, the US and the EU, and found disharmony and inefficiency caused by a lack of international standards (1).

What were your main results?

We found that the requirements for obtaining informed consent in phase IV observational studies differed across the three regions, or were not well defined – especially in Japan and the US. Having to satisfy the different and/or arbitrary requirements for informed consent must have wasted an enormous amount of limited time, resources and money. For example, we found that studies with the same purpose were often replicated among different regions without considering data integration due to high hurdles involved in meeting multiple national standards covering data integration and transfer, in order to derive a single result. There were also complex logistics involved in carrying out multi-regional studies, and study data wasn’t being transferred.

What role does the ICH play in the regulation of post-marketing observational studies?

So far, the ICH has played a relatively small role in standardizing the planning and implementation of post-marketing observational studies when compared with pre-marketing – where we have seen how data sharing across regions is based upon compliance to the same ethical standards. ICH E2 pharmacovigilance (clinical safety) guidelines, including E2A to E2F, mainly focus on the regulatory reporting of drug safety (except for the E2E guideline on pharmacovigilance planning). The 2004 E2E guideline is the sole guideline that describes the standards and policies in planning pharmacovigilance activities, but it only provides high‐level policy regarding research ethics and compliance to applicable national ethical standards.

Is there a problem with international standards not being incorporated into legislative structures?

As we said in our paper, “without effective development and use of regulatory guidance for data quality and data sharing for regulatory‐driven post-marketing observational studies, we may find that important collaborative research that could address rare safety events, and drug safety and effectiveness of subgroups, will be at best inefficient and at worst left undone.”

We see that pharmaceutical companies, and sometimes regulatory agencies, do not always comply with or respect the ICH guidelines. This prevents opportunities to reduce duplication of activities related to drug development and safety.

How do we “bridge the gap” between the different ICH regions?

The ICH’s Good Clinical Practice (GCP) renovation concept paper was issued in January this year, and offers a new perspective on observational studies, such as registries for regulatory decision making. The new GCP stipulates the standard policies and procedures for both interventional clinical trials and observational studies. We propose this revised GCP guideline be used to standardize the ethical and quality conduct of observational studies for the purpose of regulatory decision making.


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  1. H Urushihara et al., “Bridge the gap: The need for harmonized regulatory and ethical standards for postmarketing observational studies”, Pharmacoepidemiol Drug Saf. [Epub ahead of print] (2017). PMID: 28815982
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