Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

HTA of orphan oncological medicinal products - A current critical assessment and discussion from authority, KOL and industry point of view

Dr. Martin M. Hartge (Abschlußjahr: 2012)

Summary

Since patients suffering from rare diseases have the same right to profit from medicinal product of high quality, safety and efficacy the European Community started according attempts to increase the research, development and marketing of orphan drugs, among other by adopting the Regulation 141/2000 on orphan medicinal products and related guidance documents. The stimulus to invest in such a development for a pharmaceutical company is set by several incentives, e.g. market exclusivity for 10 years, to enable the company to generate sufficient revenues. Otherwise orphan medicinal products stand in the focus of the reimbursement system due to their relative high costs, referring to costs per patient and year. And since the AMNOG came into force in Germany in 2011, especially the health technology assessment (HTA) of orphan medicinal products for oncological diseases is intensively discussed, not only as they form roughly half of the centrally authorised orphan drugs. But although the added medicinal benefit of orphan medicinal products is legally specified as given, the evidence of data on which the marketing authorisation in founded is intensively discussed and often doubted to be sufficient in terms of showing also an added medicinal benefit. Basis of this discussion is the data which often doesn´t get on the level of evidence demanded by the general methods of the German HTA authority. This is due to the situation that accordingly high numbers of patients for distinct oncological rare diseases could not be recruited, endpoints like overall survival (OS) or quality of life (QoL) don´t fit into the treatment scenario due to the investigated disease stage or not validated QoL surveys, and further aspects. As the field of rare oncological diseases is as large as manifold, and because of the fact, that many studied orphan drugs are the first in class for the investigated cancer, alternative endpoints like disease free survival or progression free survival have to be used as primary endpoints instead of OS or QoL. But since the number of available patients is limited a lot of times, the validation of the alternative surrogate endpoints is often hardly to achieve or sometimes not feasible. Post-marketing authorisation studies may form an option to gather the needed data for a reliable validation to be filed for a kind of follow-up HTA. But also the trial design is criticised in many cases as cross-over, randomisation etc. are considered as essential elements for a high quality of clinical studies to meet the requirements demanded by the health technology assessment. But since in special treatment scenarios e.g. cross-over is ethical not feasible, or randomisation not possible due to limited available patients, alternative study designs should also be acknowledged as in distinct cases the best available possibilities to source the best available data for the HTA. In fact, the evidence of data should be gathered at the highest possible level and should be accompanied by all other available evidence. Databases on the distinct rare cancers early established by the investigating pharmaceutical companies should become standard in the development process for this purpose. Furthermore, the cooperation with patient organisations should be increased to design the clinical trials as close as possible to the real life conditions of the patients. In this context also QoL surveys should be prepared easier to fit the distinct treatment scenarios.

The argument, that an assessment of an orphan drug with such a limited basis of evidence is not possible and hence an additional medical benefit is not give, should nevertheless be countered by the fact, that often the approved orphan drug is the only available treatment for many patients with rare cancers. But if the added medical benefit of such an orphan medicinal product wouldn´t be legally specified as given, a reimbursement on the current level may be questionable since an added medical benefit may often not be acknowledged due to the evidence of data. In consequence, a “withhold” of orphan drugs by the statutory health insurances (SHI) due to relative low, but explainable level of evidence and hence not existing added medicinal benefit from SHI´s perspective couldn´t be an ethical reliable solution. And one may go one further step and conclude that such a negative HTA would contradict the European attempts to stimulate the development of orphan drugs. Moreover, the pharmaceutical companies should be enabled to subsequently file additional data, if the initial health technology assessment hasn´t come to a satisfying conclusion from both perspectives.

In sum, one could conclude that after more than 1 ½ years with HTA of orphan oncological medicinal products in Germany the interaction between the HTA authority and the pharmaceutical companies has still to be improved. One can see first attempts to learn from each other, but this should indeed be strengthened. Due to the rarity of the orphan cancers on the one side and their manifoldness on the other side, a valid basis for the development of the orphan drugs and for the subsequent assessment of the gained data is only possible if the exchange of points of view, discussion of the most promising trial design and mutual recognition of endpoints including surrogates is intensified between the stakeholders. This communication has of course to include also the regulatory authorities, key opinion leaders and medical as well as patient organisations to comprise all perspectives.

To put it in a nutshell, this early stage of the new situation of HTA in Germany should be used for an intensive exchange between all involved parties to come as soon as possible into a living system that may be modified depending on treatment scenario of the distinct rare cancers and studied orphan drugs, at the end to serve the patients suffering from rare cancers.

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