Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Status, challenges and regulatory strategies to develop a malaria vaccine ***

Dr. Sarah Burrack (Abschlußjahr: 2013)

Summary

Today, malaria is judged to be a preventable and curable disease, although yearly around 1 million deaths and 219 million clinical malaria cases occur. To cover unmet needs, malaria vaccines are in development since decades, but the most advanced compound is just about to conclude in a phase III trial. In this thesis the status, the scientific grounds and the regulatory environment of developing a malaria vaccine meeting quality, safety and efficacy standards as well as strategies of a market implementation are evaluated. 

Plasmodium, the parasite causing malaria, passes a complex life cycle involving mechanisms to evade a natural occurring immunity. Recently global strategies target malaria eradication additionally to reducing mortality and morbidity, resulting in diversifying vaccine types rather than having a single one. The current data show that subunit vaccines composed of single or multiple Plasmodium antigens are mostly safe, and several candidates warrant further development due to proven immunogenicity or signs of efficacy. In early development different vector targets and adjuvants are evaluated to improve the vaccine prior late stage clinical trials. Especially viral based vectors show that most recent technology is applied. Whole cell vaccines are long known to elicit a high rate of efficacy. An Evolved manufacturing technology allowed testing of attenuated Plasmodium in a phase I clinical trial showing it is safe, immunogenic and able to elicit a complete protection against malaria. It implies new paths of development to be explored, like an intravenous vaccine dosing or storage requirements at -70 °C.

By targeting mainly developing countries, malaria vaccines are subject for a WHO vaccine prequalification followed by a marketing authorisation in the respective local countries. Laid down in Regulation (EC) No. 726/2004, article 58, EMA is facilitating a scientific advice for such a vaccine that is not targeting a EU marketing authorisation, furthermore the FDA is promoting development of medicines for developed countries. Currently the national competent authorities show a diverse pattern of marketing authorisation capabilities ranging from being fully functional up to relying strong on marketing authorisations granted in other countries. It can be seen that malaria vaccine development efforts resulted in streamlined local regulatory processes for clinical trials. In a similar manner the input of local regulatory authorities in future marketing authorisation processes is seen to be essential to better reflect the local requirements. The integration of regulatory expertise on a global level involving regulatory authorities of developed as well as less developed countries is thought to further increase support malaria vaccine development. However, as a clinical correlate of natural immunity has not yet been identified, also surrogate parameter and clinical endpoints for clinical trials are not firmly established yet and still require validation in the target population. Key biological assays are currently exploratory only or have just undergone validation to meet regulatory standards. Clinical development plans, clinical trial characteristics and target product profiles are discussed in the scientific community. Preferred product characteristics meant to be guidance to vaccine developers are planned to be established. Regulatory support has already been strengthened with a new malaria vaccine specific WHO guideline that integrated recent expertise of the most advanced products. Thus, malaria vaccine development relies strongly on the need to integrate most recent scientific results and a strong and early interaction with regulatory authorities.

Pages: 78