Masterarbeit

The re-evaluation regulatory assessment procedure for old herbal medicinal products in Germany, focussing on clinical aspects ***

Dr. Sabine Drechsler (2006)

a re-evaluation according to the new criteria was to be completed after a period of15 years.
Originally, the expert reports on pharmaco-toxicological and clinical trials which were demanded for all new applications, were waived for these products. Only the quality of the medicinal products should be appraisedin an individual regulatory assessment procedure while proof of safety and efficacy should be providedby reference to monographs which were to be compilatedby independent committees.

However, there was a considerable delay in finalization of the re-evaluation procedure, and with the 4th, the 5th and the 10th amendment to the German Drug Law relevant modifications of regulatory procedures were introduced which had heavy impact on the re-evaluation of old products.

The role of the commissions was cut down, the maximum time limit to clear up dossier deficiencies after the 1st phase assessment was stepwise reduced from 3 years to 12 months, justifications for drug combinations had to be provided, and finally, with the 10th amendment for all old medicinal products clinical and pharmacotoxicological expert reports had to be submitted. Meanwhile, the criteria for assessment of scientific documents had changed significantly. Besides the Drug Law and the German ‚Arzneimittelpruefrichtlinie also EU guidelines, drafts and position papers and statements of scientific societies had to be considered which had been published during the last 15 years. The BfArM assessors as well as the applicants had to find ways to handle these new demands for old products in a pragmatic manner which did not ignore the specific history of the preparations. Especially for herbal products and their peculiar characteristics the transfer of the new criteria, which were mainly tailored for chemical substances, caused significant problems:

• Pharmacokinetic data, which are an essentialmeans to identify the optimal dosing schedules for chemical substances, are hardlyavailable for herbals, and their significanceis very limited.
• Onset of efficacy is often gradually, and the effect increases over several weeks of administration; human pharmacological trials on acute effects are hampered by this typical property.
• In most cases, herbal products are used in disease stages of mild or moderate severity, and for symptom alleviation in self-limited diseases. The chance to distinguish effects, e.g. for different doses or for combinations vs. monotherapy, is thus strongly limited due to ceiling effects.
• Due to a good tolerability even in high doses, for many herbals the traditionally recommended dose ranges are located in the flat parts of the dose-effect curves, which means an extra handicap for dose comparisons.
• Blinding is hampered due to the pronounced organoleptic properties of herbal preparations.
• For many drugs used in herbal combinations no clinical data for single use are available.
• Many monographs on herbal drugs exhibit deficiencies from todays point of view, which limited their value as the main reference for bibliographic applications.

In the thesis the clinical assessment procedure in re-evaluation of old herbal medicinal products is described, particular problems in this field are outlined, and possible consequences for the German drug market are pointed out.

Pages: 49