"CHMP has demonstrated that it is highly efficient even under the most difficult conditions."

When the European Medicines Agency recommended a marketing authorisation of the first Corona vaccine in December 2020, the focus shifted to a body that until then had been known mainly to the specialist public: the Committee for Medicinal Products for Human Use (CHMP), in which experts from all Member States decide on approval recommendations for new medicines in the EU. Since then, the CHMP has been in the public eye in a special manner - and so has its chairman: Dr. Harald Enzmann, who has been a member of the CHMP for more than 15 years and was just unanimously confirmed as its Chair for another four years.

Enzmann, who holds a doctorate in medicine, has been working at the BfArM since 2002 when he came to the regulatory authority from the pharmaceutical industry, having held management positions in toxicology and research at Bayer. At the BfArM, Dr. Harald Enzmann headed, among other things, the Licensing Division for medicinal products before taking over the executive department "EU and International Affairs" five years ago; an ideal combination with his work at the EMA, where he became vice-chairman of the multinationally staffed CHMP in the same year and finally its chairman in 2018.

Nearly 50 experts deliberate on new medicines in this committee, which is one of the EMA's highest bodies. In order to do so, the CHMP convenes monthly in meetings that last several days. In the period between meetings, Member States work in different constellations to prepare decisions. For this purpose, a huge amount of data and numerous documents from applicants are reviewed and carefully evaluated, recommendations for or against the authorisation of a medicinal product are prepared and finally presented to the members for discussion. In the end, this results in the official recommendation of the CHMP while formal approval is granted by the EU Commission.

Decision-making is not always an easy process. Some deliberations last several days, requiring special tact and sensitivity on the part of the moderator. Rarely, however, have decisions by the CHMP had a greater impact on the population of Europe than the market approvals of the Corona vaccines.

Dr. Enzmann, the CHMP’s decisions have been the focus of attention throughout the EU in recent months, especially with regard to the Corona vaccines. Do you feel any particular pressure as chairman? How did you deal with the situation?

The evaluation procedures on the vaccines were certainly of exceptional public interest. The members of the committee and I are naturally aware of the expectations of the public or politicians. However, it was much more crucial, and also more stressful, for us to know about a year ago that more than a thousand infected people were dying of COVID-19 every day in Europe - and that the vaccines were our best chance to contain this disease. Thus, it was clear to everyone, that in this case it would really make a difference whether we came to a decision a few days earlier or a few days later - but that above all the decision had to be correct, sound, scientifically irreproachable as well as based on a solid assessment of the efficacy and safety data of the vaccines. It really was quite spectacular how, in December of 2020, the CHMP was able to shorten the already tight timeline for European approval of the first vaccine even more; how we all could agree that now, during our evaluation, scientific content and speed would have to take precedence over regulatory formalities and purely procedural standards (in our internal email correspondence within the CHMP at that time, we called this "procedural niceties and formalities" which do not matter now). At the same time, there was a clear consensus that our high standards for the scientific assessment would remain the same ("we should not, and we will not, diminish the scientific quality of our assessment").

Controversial opinions are also exchanged regularly in the CHMP. What is your role as chairman in such cases?

Scientific discussion in the committee is one of the strengths of the European system. Decisions are not based on a decision-making hierarchy or a secluded small group, but rather we consider input from all over Europe, and thus a wide range of different positions where appropriate. The end result should be a consistent and balanced European decision that is scientifically well-founded and, if possible, supported by all. As chairman, I therefore try to steer the discussion toward consensus; and with more than 50 participants in a plenary session, I have to structure the discussion in terms of content in order to work through individual issues or controversies one after the other. In such a large group, it is very important to actively involve as many committee members as possible in the discussion, if necessary to encourage the more reserved members and sometimes to slow down the more extroverted members, in order to fully bring out this broad spectrum of views which is the strength of the European system.

Real World Data (RWD) represents an enormous potential for drug regulation. Regulatory decisions can be underpinned with evidence from medical practice. How does this development impact the work of the CHMP?

RWD are a valuable and highly welcome addition to our gold standard in regulatory affairs, randomised controlled trials. In the context of digital health, the quantity and quality of RWD will increase considerably. RWD can contribute quite significantly to the advancement of marketing authorisations on at least two levels.

First, RWD will increasingly show us whether what we have seen in terms of efficacy and safety under the optimised conditions of clinical trials will fully benefit patients when the drug is administered under everyday conditions. Should it then become apparent that the efficacy outside the trial is not at all as good as had been anticipated, or that the unavoidable side effects in routine use of the medicinal product cannot be controlled nearly as well as was the case in the clinical trials, the question of a positive benefit-risk ratio may well come up again. In this case, the CHMP will have to deal with the drug again and, if necessary, will initiate regulatory measures.

Another, increasingly important function of RWD is to answer questions or provide results for which randomised controlled trials are unsuitable from the outset. One example for this is medicine for very rare diseases, where not enough patients are available even for small randomised trials; or take emergency situations that are unpredictable with regard to place and time - it is not possible to design an appropriate randomised trial for these either.

At the same time, however, we must not forget the weaknesses of RWD. There is often a danger of over-interpreting the results, a danger of erroneously inferring causal relationships from associations - the classic anecdotal example for this being that the decline in storks and the decline in birth rates appear to run in parallel.

It will remain to be seen in more detail for which questions RWD can provide meaningful answers, where they may even be superior to randomised controlled trials, and which questions cannot be reasonably addressed with RWD. The challenge for the CHMP now, is to balance how good the quality of RWD needs to be in order to base regulatory decisions on it and at what point the uncertainty in RWD is too great for us to use for decision-making. Of course, this will not be an isolated opinion formation within the CHMP, it will be essential to develop a common understanding here together with non-European regulators, as well.

Which of the CHMP’s achievements are you particularly proud of?

During the pandemic, the CHMP showed that it is highly efficient even under the most difficult of circumstances. After all, it wasn't just that massive expectations and demands were placed on the committee's performance by the pandemic. At the same time, lockdown, contact restrictions, and working from home offices made it impossible for us to meet in Amsterdam to work in the tried and true way that we are familiar with. It has been a tremendous achievement by the CHMP to meet the high demands and expectations caused by the pandemic, while at the same time having to find completely new ways of collaborating and communicating.

The BfArM provides monthly information on its website at www.bfarm.de/chmp about CHMP meeting highlights as well as marketing authorisation recommendations for new medicinal products, new indications for already approved medicines, and the initiation of procedures for select medicinal products in the European Union.

Dr. Harald Enzmann

Harald Enzmann has experience in academic, corporate and regulatory settings. A physician by training (graduation 1985), he received his MD “summa cum laude” from the Karl Ruprechts University, Heidelberg, Germany. Subsequently, he held positions at the German Cancer Research Center, at the Institute of Pharmacology and Toxicology at the University of Erlangen, at R&D at Bayer AG, Wuppertal and at the American Health Foundation in Valhalla, NY, USA. In 2002, he joined the German Federal Institute for Drugs and Medical Devices (BfArM).

Harald Enzmann received the Award of the German Cancer Research Center for Outstanding Research in 1987 and the Animal Welfare Research Award of the German Ministry of Health in 1995. He received the Master of Science Degree for Experimental Pathology from the New York Medical College 1996, the title “Privatdozent” and the venia legendi in Experimental Pathology from the University of Heidelberg in 1999.

Harald Enzmann is a fellow of the International Academy of Toxicologic Pathology, member of the European Society of Toxicological Pathology, of the Society of Toxicology and of the European Association for Cancer Research.

Member of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) since 2005, Harald was elected vice chair of CHMP in October 2016, chair of CHMP in September 2018 and unanimously elected for a second term in September 2021.