he recent reform of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) with regard to membership and structure has drawn a great deal of interest. The expansion of participants and the creation of a new decision-making organ (the ICH Assembly) have been closely followed and discussed. But since the principal mission of ICH is to develop harmonized guidelines, which are the essential products of the organization, the nature as well as the impact of these “products” (especially the most recent guidelines) should deserve no less attention than the organization itself.

Impact Outside ICH

One of the triggers for the revision of the ICH E6 Guideline (ICH GCP) was a rather harsh criticism from the academic community to the effect that the guideline is too strict for academic clinical research. It is a fact that ICH guidelines are meant for clinical trials for commercial drug development purposes by the industry, and they are adopted by the representatives of the industry and drug regulatory authorities. ICH GCP is no exception. Though clinical research for commercial purposes and clinical research for academic purposes should both be conducted with the same high ethical and quality standards, ICH GCP presupposes certain types of clinical trials often employed in drug development, such as double-blind trials. Some types of academic medical research, the argument goes, are simpler (and larger, too) and if conducted according to the rigorous ICH guideline, become unreasonably resource-consuming.

Technically, this criticism is barking up the wrong tree.

The visibility and role of ICH, particularly when it published its GCP Guideline in 1996, were such that academia did not pay much attention. But now its visibility is greater, and its GCP Guideline has been treated as if it were a gold standard for conducting clinical research in general, regardless of ICH’s intention. ICH now needs to formulate this “product” considering possible effects outside its natural constituents, as it increasingly interacts with and affects those who are not represented within the ICH community, including academia and patients. The long-term plan for renovation (Reflection Paper on “GCP Renovation”, see below) incorporates opportunities for such “outside stakeholders” to provide input as the sources of evidence on drug efficacy and safety diversify to include academic research and real world medical records.

Training for Guideline Implementation

Soon after it finishes drafting a guideline, ICH often starts preparing Q&A documents and other training materials for the new guideline. This is partly because ICH is now increasing its efforts to help new members implement its guidelines. But the main reason is that some new ICH guidelines are so difficult and conceptual that even ICH’s founding members and national regulatory authorities need to confirm their understanding and discuss the guidelines’ application to practical situations before publishing them as their own domestic guidelines.

A typical example is the “Q trio (Q 8, 9, 10)” Guidelines, inspired by the Quality by Design (QbD) concept. Upon completion of the three guidelines (2010), a round of training courses was organized in Europe, US, and Japan so that the experts in the industry and the authorities could fully understand the concept in order to promote uniform and practical implementation throughout the regions and countries. The materials used in the Course and the associated discussions formed the basis for the Points to Consider document for ICH Q8/Q9/Q10 implementation, published in 2011.

More recently, the Working Groups for E 17 and E9 started preparing training materials and Q&A documents soon after the completion of the guideline or even during its drafting. This is to cope with situations, for example, where regulators need further details and a deeper understanding on how E17’s newly-introduced concept of “pooled population” can guide sample size allocation in practical settings among the countries participating in a multi-regional clinical trial (MRCT), before they incorporate the guideline into their domestic regulations.

Strategic Themes

ICH guidelines used to be formulated on a one-off basis. Recently, however, ICH started publishing strategic themes along which multiple guidelines will be formulated or revised. The first and currently the only example is GCP Renovation, published in 2017. According to this strategy, the E8 Guideline General Considerations for Clinical Trials is being modernized, followed by a planned renovation of ICH GCP. The author understands that there are several similar initiatives in other fields, such as quality and safety, which are being discussed at ICH.

This approach is reasonable, because ICH guidelines constitute a network in which multiple guidelines are interconnected and meaningful when implemented together.

Guidelines for Regulators

As indicated by its name, ICH has been producing guidelines that define primarily what data the applicants should submit to the regulatory authorities (technical requirements) for regulatory purposes (registration and post-market measures). Although regulators are indirectly obliged to accept, evaluate, and take measures based on the data submitted, the guidelines themselves have so far not directly defined any actions expected by regulators.

The Q 12 Guideline Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, whose draft is currently published for public comment, has “regulatory” in its title and directly encourages regulatory authorities to utilize a system that incorporates risk-based regulatory processes, beyond giving technical guidance to manufacturers. This constitutes a noteworthy new feature of ICH guidelines. The author believes that this comes from a realization among ICH participants that, in order to attain real value in regulatory harmonization, there needs to be a higher-level harmonization that goes beyond the required technical data.

Guidelines and Science Developed Simultaneously

The consensus used to be that a certain maturation in the underlying science is needed to find the common ground necessary to prepare harmonized guidelines. Although this still holds true to some extent, the time interval between the generation of scientific evidence and the issuance of ICH guidelines seems to have decreased significantly.

For example, under the project to revise the ICH S1 Guideline Rodent Carcinogenicity Studies for Human Pharmaceuticals, a Regulatory Notice was issued in 2014 by the regulatory authorities participating in ICH, requesting prospective data collection in order to know if enough data existed to justify revision. Thus the scientific insight was being created and gathered as part of the effort to revise the guideline. The author understands that the discussion regarding the necessity of performing the revision is still underway.

In this case, the notion of “carcinogenicity” needed no clarification; what was lacking were data or evidence indicating the ability of rodent tests to predict carcinogenicity in humans.

But there is an example when, while formulating a guideline, ICH needed to define a core concept that was not mature enough: When the Expert Working Group started drafting an addendum to the ICH E9 Guideline Statistical Principles for Clinical Trials, the concept of “estimand” was not fully established in academia or elsewhere. The Working Group had to work on defining it in collaboration with the academic community. In clinical development, statisticians urgently needed guidance to address drop-outs, no matter whether the basic science afforded a solution. Hence the effort by ICH. With more and more advanced guidelines being formulated at ICH, similar cases are expected to occur more frequently.

Conclusions

The author has been watching the growth of ICH from the inside as well as the outside for the past 25 years. ICH expanded both geographically in terms of its constituents and scientifically with regard to its work products. Its effects are now far-reaching and its existence visible and inescapable. In the author’s view, ICH’s success is attributable to its focus on harmonizing regulatory requirements but not the regulations themselves in the respective participating countries and regions. How this global enterprise will further evolve is of great interest.