Before the first human subject receives an investigational medicinal product, the clinical trial has to be approved according to applicable local laws and regulations. In order to get the right drugs to the right patients as quickly as possible, it is of critical importance to understand how these regulatory processes work. In Europe, clinical trials are regulated by the Clinical Trials Directive (Directive 2001/20/EC), which is translated into local law by each member state. In this overview, we will take a closer look into the regulatory landscape of the Netherlands.
The Scope of the Law
Since 01 December 1999, clinical research in the Netherlands is regulated by the Medical Research Involving Human Subjects Act (WMO: wet medisch-wetenschappelijk onderzoek met mensen). This law covers any research that meets both of the following criteria: 1) it is aimed at generating medical knowledge and 2) it subjects participants to procedures (such as administration of experimental drugs) or imposes behavioral rules. Retrospective research or experimental treatments aimed at providing optimal care to patients are not covered by this act. The law has special provisions for research on minors or incapacitated adults, as these cannot grant informed consent on their own. WMO stipulates that the risks and burdens for this group must be minimal, and research may only be carried out in this group if it cannot be performed in capable adults. Not covered by the WMO are other forms of clinical research, such as population screening (Dutch population screening act, WBO) and biobanks (no specific legislation). Additionally, non-interventional research that is sponsored by the pharmaceutical industry does not fall under the WMO. This type of research is reviewed by the non-WMO committee (nWMO) since January 2015.
The Dutch Reviewing Institutions
The WMO established a system that is decentralized, controlled and peer-reviewed. Prior to this law, each hospital had the opportunity to appoint its own ethical committee, and no standardized framework existed for how these committees operated. According to the WMO, any medical research that falls under its scope should be reviewed and approved by two parties: an ethics committee (EC) and a competent authority (CA). The Netherlands has 18 medical research ethics committees (MRECs). MRECs are required to be composed of different experts, including at least a physician, a clinical statistician, an ethicist, a legal expert, a lay member, a clinical pharmacologist, and a hospital pharmacist, and can contain other experts as appropriate. For example, a pediatrician has to be involved in review of trials for subjects younger than 16 years.
The composition and operating procedures of the MRECs are approved by the Central Committee on Research Involving Human Subjects (CCMO: centrale commissie mensgebonden onderzoek). The CCMO also functions as the CA and performs its review after that of the EC. However, depending on the clinical trial, exceptions to this process apply: for instance, in the case of non-therapeutic trials with a pediatric population or with incapacitated adults, or trials that require special expertise such as gene or somatic cell therapy, the CCMO acts as the reviewing EC. In this case, the Medicines Evaluation Board (MEB) acts as the CA. These exceptions can complicate the selection of reviewing institutions, but a tool exists to identify the appropriate committees for a clinical trial. In the Committee Finder of Paul Janssen Futurelab, Sponsors can find the right EC and CA for a clinical trial by entering the type of trial population, medicinal product, and type of research.
The CCMO provides a standard format for submission of research files. This includes the general assessment and registration form (ABR: algemeen beoordelings- en registratieformulier). This form serves as the national review form, and is also used for releasing information in the national registry on medical research in the Netherlands. The research file further contains additional relevant documents, such as the clinical trial protocol, correspondence with the reviewing committee, EudraCT forms, and others. Standardization of the format results in harmonization of review procedures and reduction of review time.
After submission, the reviewing EC performs a full review of all ethical, medical and scientific aspects of the clinical trial. The CA performs a so-called ‘marginal review’, which consists of screening the EudraVigilance database for adverse effects of the drug that were not reported in the regulatory documentation. The response of the CA is limited to declaring if there are grounds for ‘non-acceptance’ or not.
Final approval for the application is provided by the EC. If an investigator or sponsor does not agree with the final decision of an EC, an appeal can be submitted to the CCMO.
Each step of the Dutch review process is bound by time restrictions: review times for ECs consists of 60 days for studies with medicinal products. Exceptions include trials with gene therapy medicinal products, somatic cell therapy medicinal products and genetically modified organisms, in which case the review time is extended to 90 days. The marginal review performed by the CA is limited to 14 days. In case additional information is requested by the EC or CA, the clock is temporarily stopped until this information is supplied.
Do you need support navigating the Dutch regulatory system? Contact us to see how we can help you to advance your program from strategy to approval.