EMEA's Protocol Guidelines: Towards harmonisation of clinical trials in Europe (I)
The draft was opened for discussion and some EATG members made comments and sent them to the EMEA. The text below brings together their input on the general aspects of study design.
On the ”background“ and ”introduction“
Our reviewers point out that although, and as stated in the background of the document, some issues remain under debate such as ”the optimal timing of initiation of anti-retroviral therapy, the benefits and risks of structured treatment interruptions, and treatment strategies that further improve long-term outcomes“, guidelines from different European countries are in agreement on various points. Most of European guidelines for instance consider that the CD4 count should ideally be between 200 and 350 cells/ml at treatment initiation. It would therefore be very useful that the text be more precise on its expectations, should it mean to revise regularly these guidelines.
Within the introductory part it is acknowledged that these guidelines ”provide guidance on the clinical development of new medicinal products for the treatment of the HIV infection“ and that “Primary HIV infection or postexposure prophylaxis is not covered.“ On this aspect, clarification should be included on whether pre-exposure prophylaxis is covered or not, and the text should remind that no unethical trial will be taken into account for registration.
Looking at the general aspects of study design
The section starts with a reminder that monotherapy studies with novel agents ”must be limited to proof-of-concept/ dose finding studies of the shortest possible duration“. Along with this should be mentioned that it be done with the smallest amount of patients.
As for the ”blinding of information that is used in the routine management of patients such as viral load, CD4+ T-cell count, or drug resistance pattern “, it is suggested that other relevant information for medical management be included such as CCR5/CXCR4 receptor distribution patterns, or the possible co-receptor shifts during studies with CCR5-inhibitors.
On ”patients to be studied“
In this section, it is emphasised that for compounds with a promising activity profile, studies in heavily pre-treated and ”treatment refractory patients“ should be ”conducted early in the clinical development programme“.
Here our reviewers recommend that a stronger wording be used such as ”as early as possible in the clinical development“.
As for the populations to be included in clinical trials, a point is made that ”safety and efficacy should be evaluated in patients who are treatment naïve and in those who are treatment- experienced, including heavily pretreated patients”, and ”the numbers of women and individuals from ethnic minorities should be sufficient to allow generalised conclusions on safety and efficacy“. Topics such as sex and ethnicity have been pushed by the EATG's XX Study Group on women issues to be included in the EMEA guidelines, and it was satisfying to see that they had been added in this new version. However it was surprising and disappointing that IVDUs be totally neglected, considering also that these guidelines would shape AIDS treatment research for several years. Given the characteristics of the HIV/AIDS epidemic in Europe, our reviewers urge the EMEA to include considerations on persons who are actively injecting recreational drugs.
On ”clinical events“
The guidelines stipulate that ”the occurrence of HIV-related clinical events should always be reported in the efficacy analysis of clinical studies”.
The advise here is that EMEA give precise criteria on the definition of HIV-related events, in order to avoid partial analysis as well as to have some homogeneity on this topic among the different trials.
On ”Viral Load“ and ”Immune Function“ The recommendation is that the text be clearer by indicating that the limit of detection of the viral load assay, ”the appropriate measure of efficacy“, is currently of 50 copies/mol.
Concerning the immune function, it should not only be stipulated that the consequences of a possible shift in viral tropism studies with HIV entry inhibitors such as CCR5-blockers be ”considered“, but also that they should be studied and documented, and the results made available for the person providing medical care to the patient.
On ”pharmacogenetics and immunogenetics“
Here the wording should strongly advise to take into account the reasons for inter-individual differences in trials.
On ”safety“
In regards to safety, our reviewers stress that in the study design, along with emphasizing the importance of long-term safety, it is very important to focus on short-term safety, which should also appear in these guidelines.
It is also advised that instead of one year, the minimum duration be two years for the documentation of the effects of lipodystrophy. In addition, and given the well-known importance of Quality of Life for day-to-day life itself but also for treatment success, the group strongly supports that an incisive wording be used on the importance of instruments to measure QoL. Finally, this section should mention the need to do safety studies on HIV-negative volunteers.
The second part of their comments will be published in the next issue.
EATN - European AIDS Treatment News, Volume 14, II – Autumn 2005
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