Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Clinical trial standard protocols, approaches for more regulatory efficiency? ***

Ulrich Härtel (Abschlußjahr: 2012)

Clinical research is an area which is poorly standardised on an international basis. Clinical trials are most often unique projects developed from scratch for a specific purpose using company-specific procedures and definitions. Protocol standards determining clinical design characteristics for trials intended for a specific purpose can contribute to higher quality and efficiency of research. The regulatory bodies as well as sponsors may benefit from increased regulatory acceptance and faster study approval.

Only little experience for standard protocols is available. Examples include two templates issued by CTEP providing a high level of details and guidance for two Phase I study designs in oncology. In the EU, standard paediatric investigational plans (PIPs) were recently released for pandemic influenza vaccines and allergen products for specific immunotherapy (SIT), the latter ones being the focus of this thesis.

The circumstances under which the standard PIPs for allergen SIT products were issued are unique; paediatric clinical trial obligations were defined for a large number of products, most of them being established in medical practice since a long time. Being previously on the German market with a named patient basis, this product group was recently subjected to the EU medicinal product legislation. Applying the EU paediatric legislation and making a standardised 5-year paediatric trial design for many of these products obligatory led to a difficult situation for manufacturers of these products. Factors such as the non-standardisation of product tests, high itemisation of the products, and the non-harmonisation of legal status in the EU contribute to the fact that the hurdles imposed to the industry of this product group are disproportionally high.

The obligatory use of placebo control raises ethical concerns. Although the products are not identical and allergen types are different, the high number of trials conducted in accordance to the standards (according to currently approved PIPs, about 70 long-term trials) is considered a duplication of studies. The fact that obligations of the paediatric regulations were imposed for established products without patent protection or market exclusivity is considered to be not in line with the spirit and purpose of the paediatric regulation. The rationale to request long-term trials rather than short-term trials can be challenged.

As standard protocols narrow down the options for clinical development, they potentially impact the timelines of development, impact the claims that can be achieved and economic aspects of drug development. For this reason, standard protocols that are made obligatory require careful evaluation of ethical aspects, compliance with current legislation and alignment with all involved stakeholders. A four-step formal decision process is proposed to validate the scientific and regulatory rationale for the request the conduct of a trial, to decide on the standardisation versus non-standardised regulatory approaches, to decide on the clinical trial design and individual elements thereof and, finally, to evaluate risks associated with the approach.

Despite the controversial aspects as discussed above, the concept of standard protocols may become a success in the regulatory context, which could be applicable to many situations. A key success factor of such standard protocols is alignment with all stakeholders. Where applicable, the industry is asked to discuss alternatives and to clarify any outstanding issues. The ultimate goal must be to provide medications with proven efficacy and safety to patients, in which standard protocols can help but are probably not the only route, especially in a regulatory context with many challenges.

Pages: 40, No Annexes.