New Rules for European Investigational Medicines

Gaps in the good manufacturing practice controls on medicines for clinical trials are targeted in new rules from the European Union.   A new regulation setting out GMP for investigational medicinal products (http://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R1569&from=EN) will enter into force on October 9, but national authorities in the EU member states will have until April 2018 to modify their national legislation accordingly.    "Good manufacturing practice for investigational medicinal products for human use ensures that there is consistency between batches of the same investigational medicinal product used in the same or different clinical trials, and that changes during the development of an investigational medicinal product are adequately documented and justified," it says.   It has been issued in parallel to an update of GMP rules for authorized products, but goes further in many respects, because, as the introduction to the regulation says, in this area "there are no fixed routines, there is a variety of clinical trial designs and consequently packaging designs. The toxicity, potency and sensitizing potential of investigational medicinal products for human use may not be fully understood at the time of the trial. Because of this complexity, the manufacturing operations should be subject to a highly effective pharmaceutical quality system," according to the new measure.   Manufacturers will be obliged to meet similar requirements as manufacturers of authorized products on GMP requirements such as personnel, premises, documentation, and procedures. But there is an emphasis on the need for close cooperation between manufacturer and sponsor, particularly in sharing inspection reports and information on quality issues. The importance of documentation is also stressed, to allowing tracing of the history of the manufacture of each batch and any changes introduced during development.   There are additional requirements for retention of samples. Samples of each batch of bulk formulated product, key packaging components, and each finished batch will have to be retained for "at least two years after the completion or discontinuation of the last clinical trial in which the batch was used." And for advanced therapy investigational medicinal products, GMP provisions should be adapted "in accordance with a risk-based approach."   Detailed requirements for inspections also feature prominently. "Provisions on inspections by the competent authorities of the member states should be established," says the new rule. For third country manufacturers of investigational medicinal products, inspection frequency should follow a risk-based approach. Common standards and procedures for GMP inspections for investigational medicinal products "should be developed," and inspectors should be given adequate powers to conduct inspections. National authorities are to cooperate with each other and with the European Medicines Agency, sharing information on inspections planned and conducted. And the conclusions reached in an inspection report in any member state or non-EU country-whether positive or negative-will be valid throughout the EU.   To avert the risk of accusations of favouritism or bias, national authorities will have to set up systems to "ensure that inspectors are free of any undue influence that could affect their impartiality and judgment." In particular, they must be independent of the trial sponsor, the management and personnel of the clinical trial site, the investigators in the trials where the products manufactured by the inspected manufacturer are used, of the financial backers of the trial, and of the manufacturer. Inspectors will have to make an annual declaration of their financial interests.    The changes amount to a follow-up of the EU's 2014 Clinical Trials Regulation, which is gradually coming into force over the next two years. The European Commission said in an accompanying statement that the principles and guidelines "take into account recent updates to the well-established EU rules on the safety of medicines." Its updates also reflect international developments in GMP and in the approaches of inspectors and manufacturers.   Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.