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Oral presentation

For decades the quality of clinical research depended on individual scientific and ethical approaches, allowing the coexistence of excellent research with cases of completely irrelevant or unreliable data. In order to establish consistency in the interest of protection of public health, standards had to be defined. As a first step, health authorities all over the world developed various guidelines, often independently. In several further steps these guidelines became more and more congruent, for example, within the European Union, culminating in the successful ICH guidelines.

Due to remarkable efforts during the past decade(s), clinical research is able to provide evidence for efficacy and important requirements for clinical research have been specified in various guidelines. Moreover, it has been realised that clinical research has become a global endeavour, and the challenge of international harmonisation has been addressed with enthusiasm and remarkable success.

Guidelines for clinical research today cover a wide range of fundamental issues and address various parts of a clinical development programme. Also, numerous guidance documents for certain therapeutic indications and substance classes as well as for clinical trial design planning (e.g. choice of comparator, biometrical issues) are available in the various regions; harmonisation in this area has just begun.

Major advances have been achieved in establishing global requirements, facilitating the design of clinical development plans and of large international multi-center clinical trials. Moreover, a large step towards a truly global drug marketing application has been achieved by introduction of the common technical document (CTD).

However, even after establishment of a first set of guidelines we should take care to retain flexibility in the regulatory framework in order to allow for future progress in biomedical research. Instruments, like the Committee on Proprietary Medicinal Products (CPMP) "concept papers" or "points to consider" may be more appropriate for fast evolving topics than formal "guidelines" or "notes for guidance", since they allow for a more rapid updating.

Guidelines for drug approval show a complex interrelation with the underlying scientific disciplines. A guidance document reflects consensus on a certain scientific field. More recent developments, for which relevance and general applicability are not yet known or not yet generally accepted, will in most cases be missing. In a historical context, consensus is always lagging behind cutting-edge science. Guidance documents unfortunately are no exemption to this rule: They cannot but reflect science of the current status and the past. On the other hand, problems listed in a guidance with a request for proper attention may trigger new scientific efforts in addressing the underlying questions. Thus such a guidance may as well be the basis/kernel for science yet to come.

It is hard to foresee how many guidelines will exist in the future. When it becomes apparent that certain symptoms, previously considered more or less synonymous with a disease, actually result from different underlying diseases, which respond differently to available therapies, it is obvious that more knowledge will lead to more differentiation (e.g. current developments in genomics). On the other hand, it may become apparent that a growing set of specific guidelines actually can be combined by a common denominator. These opposing trends towards both more differentiation and more generalisation will become more or less important according to the needs of all those involved in development and evaluation of medicinal products

Key issues in the development of new guidelines as well as in the update process of existing guidelines will be discussed in more detail in the presentation. Topics of particular importance for a Regulatory Agency include e.g.:

· the definition of clinical relevance of study results, definition and amount of responders,

· the definition (and restriction) of non-inferiority criteria,

· mortality as a (secondary) endpoint,

· definition and specification of endpoints,

· the surrogate value and the validity of endpoints,

· the control of the quality of a study by analysis of drop-outs.

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