Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

A comparative study of the different approaches for approval of new HIV drugs according to guidelines of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) including possible implications on future drug development ***

Dr. Tim Rakemann (Abschlußjahr: 2015)

Summary
Language: English
The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) apply different approaches for development and approval of new HIV drugs. The objective of this thesis was to compare their respective guidelines and to discuss the impact of the current pathways on the future of drug development. Development of new drugs for HIV and other chronic diseases is for different reasons a complicated undertaking for pharmaceutical companies. On the one hand, viral strains with resistance to the active substances emerge and patients no longer respond to therapies based on the original drugs with the consequent urgent need for new regimes. On the other hand, it is not economically profitable for a company to develop drugs tailored for small subpopulations. Apart from this, the greatest challenge is the legislatory one: The lack of harmonization of drug approval procedures for these two important markets impedes commercialization and may result in a distortion of competition. 
A comparison of the different approaches revealed a significantly higher flexibility in the FDA guidelines than those of the EMA for both the development and the approval procedure. The FDA facilitates development of any kind of drug for any patient group (naive, general and heavily treatment experienced) in any combination. The corresponding clinical trials are adapted to patients’ needs and the characteristics of the population. An essential part of the FDA procedures is a continuous intensive communication between the FDA and the manufacturer during all stages of development (‘Fast Track Designation_’ since 2007, ‘Breakthrough Therapy Designation’ since 2012). In contrast, the EMA allows development of any new agent only on the basis of data for quality, safety and efficacy generated in randomized double-blind clinical trials with first-time patients to get a broad indication. Exceptions for late general and patients with heavy treatment experience are possible on a case-by-case basis. 
For the approval of new drugs tailored for subpopulations, the FDA enables a fast-track process by means such as the ‘Rolling and Priority Review’ and the ‘Accelerated Approval’ procedure which furthermore can be combined to allow a flexible step-by-step approval. Since 2005, the EMA has facilitated a ‘Conditional Marketing Authorization’ (CMA), but only in 2014 did it initiate a pilot project, the ‘Adaptive Licencing’ (recently renamed Adaptive Pathways) process, for testing measures for faster approval. The used tools for implementation of CMA and Accelerated Assessment were revised in July 2015. The updates now endorse ‘innovative medicine’ and, hence, allow development of drugs under the same conditions as the Breakthrough Therapy Designation in the USA. An intensive continuous communication between all stakeholders, including the Health Technology Assessment bodies is now also an essential part. As a consequence, for many applications the review time can be reduced from 210 to 150 days.
To assure the long-term safety for all patients, post approval studies are required according to the pharmacovigilance regulations in place since 2012.
The difference between the health care systems in the EU and the USA is the additional hurdle faced by companies wishing to enter the European market whereby the National Health Assessment bodies and the manufacturers must agree on the amount of reimbursement to be paid by health insurances. Reimbursement is only possible after manufacturers have proven the so-called additional benefit of a new drug in comparison to standard therapies. Proof of added benefit is a mandatory requirement for achieving market access (Efficacy-Effectiveness-Gap). To overcome this obstacle, the adaptive licensing procedure permits the integration of proving the added benefit already during the pre approval phase in adapted clinical trials. A soon to be introduced and efficient revision of the current EMA guideline should integrate the adaptive clinical trials and pathways, this would be a real incentive for companies to develop innovative new HIV pharmaceuticals. The adaptive approaches have already been used for approval of drugs for some types of cancer and HCV, but the matter of reimbursement is still un-solved for these drugs due the lack of data for Phase 3, i.g. no proof for added benefit, of the registration package.
The legal implementation of the adaptive pathways into the EMA guidelines is a precondition to develop new therapeutic interventions for the HIV disease which provide opportunity for functional healing. Taken together, it can be stated that, after the legalization of the adaptive pathways, the HIV drug development and approval approaches between the EU and USA will be widely harmonized. The unsolved problem is the patients' unfriendly reimbursement in the USA and the different financial power of the member states of the EU.
Pages: 48-49