Exploring the Regulatory Decision-making Process for Medicines
(2013; 202 pages)

The research presented in this PhD thesis was conducted under the umbrella of the Utrecht-World Health Organization (WHO) Collaborating Centre for Pharmaceutical Policy and Regulation, which is based at the Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.


The basis of regulatory decisions is the benefit-risk assessment, a complex process that requires the evaluation of quality, non-clinical and clinical data submitted by the pharmaceutical company. Unfortunately the scientific evidence supporting the use of a new product is always incomplete and therefore decisions have to be made under conditions of uncertainty. This thesis provides an insight into the regulatory decision-making process when it comes to dealing with situations of uncertainty and to evaluating the robustness and credibility of the evidence of medicines. We tried to describe the dynamics involved over the course of an application review and the factors guiding regulators in their decision-making process before the final outcome is presented to the world.

Regulatory decision-making follows a process that requires flexibility. Based on the case of proton pump inhibitors in children we demonstrated that under certain circumstances the evidence already available may be enough and conducting additional clinical trials may be unnecessary.In other cases, when data are based on trials prematurely stopped for apparent benefit, evidence should be viewed with caution. We discussed the issues related to the interpretation of results based on interim analyses, and assessed how often trials early stopped for benefit are used for registration purposes.

When evidence is considered insufficient this obviously leads to a non-approval, and it is especially due to lack of clinical relevance of the data submitted by the companies, as we highlighted in our research on applications withdrawn by companies prior to the conclusion of the evaluation process or refused at the end of it. However, even when a drug makes it to the market, an uncertain benefit/risk profile often leads regulators to what we call “precautionary approvals”, which tend to be tailored to restricted patient populations and are potentially distant from the actual clinical needs. We showed that the highest rate of regulatory restrictions is usually matched to shorter clinical developments in oncology.

Uncertainty may also be interpreted differently across regulatory authorities and this may significantly affect patients’ access to relevant therapeutic options. We identified cases where EMA and FDA made different decisions based on the same data package, and cases where differences in the outcome of the EMA and FDA approval process were clinically relevant. These divergences, which were explored in an interview study involving EMA and FDA regulators, are due to “formal factors”, such as a different interpretation of clinical endpoints, as well as to “informal factors”, such as a different perception of risk and differences in the core organisational structures of regulatory agencies.

The task of regulatory science is to evaluate and study regulatory systems in terms of their ability to ensure patient safety, enhance public health, and stimulate innovation.New and emerging sciences bring along new challenges for regulators and new potential avenues for regulatory science. Research in regulatory science in the next years will be facilitated by the increasing level of transparency and openness in the field of medicines regulation, fuelling better access to information on the decision-making process for the evaluation of medicinal products.

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