HerbalEGram: Volume 11, Issue 7, July 2014

By Mathias Schmidt, Guest Contributor

Almost 12 years after the German drug regulatory authority, the Federal Institute for Drugs and Medical Devices (Bundesinsitut für Arzneimittel und Medizinprodukte, BfArM), issued an immediate withdrawal of marketing authorizations for products containing extracts of kava (Piper methysticum) root and/or rhizome,¹ the case has been reviewed by a German Administrative Court in Cologne. According to the court’s ruling on June 11, 2014, there was no justification for the German government’s ban of kava medicinal products. The court ruled that based on the available data, the benefit-risk (also referred to as risk-benefit) ratio of kava medicinal products was confirmed as positive and must be considered positive.² As a consequence, German kava products have been formally restored to their market status of June 2002.

The background of the kava case is admittedly difficult to understand for interested parties not directly involved in the German regulatory process. According to this author’s experience, the “ban” of kava frequently was misunderstood as a safety measure to protect the population from kava. In reality, the ban was a result of a complex regulatory issue. It was not a ban in the strict sense of the word; it was technically a withdrawal of marketing authorizations of medicinal products containing kava extracts. However, the mechanisms leading to the decision of a ban were more or less unrelated to kava as a constituent of the products; the applied mechanism of determining a negative benefit-risk assessment described below can be applied in regulatory decisions on any other herbal preparation. The risk issue plays only a minor role.

Kava is endemic to the islands of the South Pacific. Major kava producing and exporting countries include the Melanesian states of Vanuatu, Fiji, Tonga, and Samoa. More recently, Hawaii has rediscovered kava cultivation. With an ever-growing demand, kava is exported to international markets such as the United States, Australia, South America, and Asia. The exports to the United States are the highest they have been since 2001, after having been stifled by increased liability insurance costs (M. Schmidt personal communications to kava traders in the South Pacific and the United States).

The roots of kava are made into a recreational relaxing drink. It has no addiction potential or significant intoxicating effects, despite its genus name “methysticum” (Greek for “intoxicating”). Overdosing would make the users sleepy, and the skeletal muscle-relaxing effects would at some point make coordinated motor movements difficult, but these effects do not last for more than a few hours. The relative safety of kava products is one of the reasons for its popularity in Europe, where kava extracts have benefitted from official marketing authorizations as medicinal products for the treatment of stress-related anxiety.

By 2001, the overall retail sales of medicinal products containing kava had reached approximately 10% of that of benzodiazepines (conventional pharmaceutical anti-anxiety drugs), with a total of 450 million daily doses sold between 1991 and 2000, and no significant risks were observed.³ It therefore came as a surprise when, in 1999 and 2000, there were case reports of potential liver toxicity associated with ingestion of kava products, which then led to a so-called graduated plan procedure with the aim of examining risks and benefits of kava-containing preparations.⁴

Graduated plan procedures propose the re-evaluation of the benefit-risk ratio of medicinal products and measures to be taken for the improvement of consumer safety. Typically, graduated plan procedures result in the addition of safety-related information to the medicinal product information texts (e.g., labeling and/or package inserts). The withdrawal of marketing authorizations is the ultima ratio (last resort), to be taken only when no other appropriate, less restrictive measure is available to control or reduce the risk.

Benefit-risk assessments address not only the risk but also the efficacy of a pharmaceutical agent: when a benefit to the patient’s health is demonstrated, a risk may be deemed acceptable. This part of the equation led to misunderstandings on the international level with respect to kava. The German regulatory authority did not look at the plant per se, or the general picture of international kava use, but narrowed its focus to the specific medicinal products with German marketing authorizations. In other words, the question was not whether or not kava had a therapeutic effect (which few properly informed people doubt), but rather if the specific kava extract preparations with marketing authorizations in Germany could be shown efficacious in the indication they claimed on their labels.

When Germany issued its decision to withdraw marketing authorizations, the European Medicines Agency (EMA) also examined the situation in the United Kingdom, where kava preparations were available as medicinal products for the indication of bladder disorders. The EMA’s Pharmacovigilance Working Party used the very same approach by first examining kava’s efficacy for bladder disorders, which they were not able to confirm due to the lack of clinical studies for this indication.⁵ No proven efficacy meant no proven benefit, and therefore a negative benefit-risk ratio.

In Germany, things were much more complex, as there are in fact clinical trial reports on the specific type of kava extract preparations used for the treatment of stress-related anxiety, as labeled on the products. For the first time, the BfArM created new rules for the assessment of risks and benefits in the case of kava.

According to these new rules, the benefit had to be addressed according to the most recent guidelines on medicinal product efficacy. Since the clinical studies on the extract preparations marketed in Germany were published between 1990 and 2000, BfArM discarded all studies from the assessment, leaving not a single clinical trial to demonstrate the efficacy of the specific kava extract-containing preparations. According to BfArM, a lack of acceptable studies meant no proven efficacy; therefore, any reported adverse effect would automatically result in a negative benefit-risk ratio.

The case reports of adverse events (n=26) that led to the first decision of BfArM in June 2002 to withdraw marketing authorizations were not discussed in much detail. To date there has been no in-depth causality assessment by regulatory authorities, just an ad hoc assessment using more-or-less arbitrary parameters. Assessments using the Council for International Organizations of Medical Sciences (CIOMS) scale for drug-induced liver toxicity were published by the working group of Professor Rolf Teschke, MD^6-9 (Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University Frankfurt/Main, Frankfurt Main, Germany), but these results — suggesting a positive benefit-risk ratio of kava medicinal products — were never adopted by BfArM.

Around the time of the benefit-risk assessment, BfArM — in an unprecedented move — declared kava as a new and unknown drug entity, and referred to the corresponding guidelines for marketing authorizations according to International Convention on Harmonisation (ICH) rules.¹⁰ For new and unknown drug entities, these rules call for a complete set of preclinical data as a precondition to human exposure, including pharmacokinetics, toxicokinetics, toxicity studies, and more. In other words, the manufacturers were implicitly expected to deliver a complete new drug approval dossier, and even that would serve only as the precondition for permission to perform new clinical trials. There was, however, never an explicit call for data beyond the question of toxicity, which is why the marketing authorization holders were left in the dark with respect to the type and amount of data to be presented.

Additionally, all of the supporting evidence would have to be delivered as GLP (Good Laboratory Practices)-certified data¹⁰ — a standard not met by many basic studies. At this point, the debate became completely independent of the kava issue. As such, kava was just a generic case; the same mechanism for denying marketing authorization could have been (and partly was) applied to any other herbal or conventional medicinal product. Moreover, such a mechanism could be applied to merely hypothetical risks. An example is the European discussion of plant materials containing potentially toxic furocoumarins, for which the hypothesis of a risk¹¹ led to restrictions of marketing authorizations of various products. Once this potential risk was proposed, efficacy in the claimed indications could no longer be substantiated by existing studies. (The phytomedicine companies* contesting BfArM’s kava decision wanted to correct this general approach for benefit-risk assessments, with kava being a prominent example.)

German administrative legislation allows companies to go to court only if they reject a BfArM decision by filing an appeal in the time frame defined by BfArM. If such an appeal was not made or if the marketing authorization holders explicitly declared their acceptance of BfArM’s decision, companies lose their right to contest that decision.

After 12 years of debating with BfArM, only seven companies^* covering 14 individual marketing authorizations remained that were still actively pursuing the case. BfArM’s decision to withdraw the marketing authorizations was not a general decision, but was issued individually for every single product with a marketing authorization or a corresponding application. Consequently, all complaints to the court had to be filed individually. However, the individual legal actions were bundled and filed as a group of identical cases, and all were represented by the same lawyer (Professor Burkhard Straeter of Bonn, Germany).

The major arguments of the marketing authorization holders for the justification of contesting the BfArM’s decision were as follows:

• Kava is efficacious against stress-related anxiety and scientifically accepted in this indication.
  
  
• The number of hepatotoxicity case reports showing a certain degree of causality by kava is very small (n=3), and absolutely insignificant when compared to the exposure figures (i.e., number of estimated daily doses taken across Germany). The observed risk does not justify the extreme measure of a ban.
  
  
• The therapeutic alternatives proposed by BfArM in every decision and expert statement, namely the benzodiazepines^†, cannot be regarded as safer remedies. With all proposed conventional pharmaceutical drug alternatives (e.g., benzodiazepines) the risk for the patient will be increased by renouncing kava use.

The court fully endorsed the arguments of the kava marketing authorization holders in its decision on June 10, 2014. They stressed that mere doubts regarding the efficacy of a medicinal product cannot justify a withdrawal of marketing authorizations or the conclusion of a negative benefit-risk ratio. The court pointed out that the most recent rules of efficacy assessment cannot be retrospectively applied to older products — in addition to the fact that this question could have been solved in a much less restrictive way than by withdrawing the marketing authorizations.

The court ruled that risks would have to be assessed in the context of therapeutic alternatives. If these risks are higher than the risk of continuing kava use, this advantage of kava should have been considered. The court did not even accept the alleged risk of kava as proposed; it considered the presentation of the risk of kava as a mere collection of assumptions and hypotheses that should have been substantiated by the presentation of scientifically sound data. The risk of liver toxicity was even considered minor, rated as “rare” or “very rare,” and a pattern of toxicity could not be established from the available data.

Finally, the court rejected the proposal of benzodiazepines and other chemically defined pharmaceutical medications as therapeutic alternatives to kava; with respect to these conventional drug alternatives, the court acknowledged an increase of the individual risk for the patient.

As a consequence, the administrative court did not find a sufficiently strong foundation for BfArM’s withdrawal of marketing authorizations for kava medicinal products, which, in practice, reset the clock to the regulatory situation in 2002 prior to the ban (i.e., the introduction of warning labels, the regular measuring of liver function tests, and kava being considered a prescription medication).

Update:

On June 30, 2014, BfArM appealed the court’s ruling. The kava debate may therefore be around for many more years. However, the ruling is still a major breakthrough, as it strengthens the legal certainty and predictability of authoritative decisions for herbal medicinal product manufacturers in general.

* The seven companies that independently filed lawsuits against BfArM over the withdrawn market authorizations for kava medicinal products are as follows: (1) AME Arzneimittel-Entwicklungsgesellschaft mbH & Co. KG (Kava-Regulanz-Drops N); (2) Ardeypharm GmbH (Ardeydystin forte); (3) Harras Pharma Curarina Arzneimittel GmbH (Kavasedon Capsules and Kavasedon Drops); (4) Krewel Meuselbach GmbH (Antares 120 mg Tablets, Kava-Mara Tablets, Kava Mono Capsules, Semaren Tablets, and Wati Tablets); (5) MIT Gesundheit GmbH (Ka-Sabona Capules and Ka-Sabona Drops); (6) Steigerwald Arzneimittelwerk GmbH (Fri Capsules); and (7) Agnon Pharma (Limbao 60 Capsules and Kav-activ Capsules).

^† With respect to the risk of benzodiazepines, BfArM singled out the question of liver toxicity, which seems to be a minor issue with this class of drugs. Other risks such as addiction were not discussed, which the marketing authorization holders for kava medicinal products deemed unacceptable.

Mathias Schmidt, PhD, studied pharmacy at the University of Tuebingen in Germany. He works as a freelance specialist for herbal medicines, with emphasis on quality issues of medicinal plants, including kava.

Dr. Schmidt started working on the question of kava cultivar quality and its relation to efficacy and safety in 1997, and was therefore sought as an expert in the kava phytomedicine graduated plan procedure in Germany. From 2000 to the present he has been involved with expert statements in all steps of the German graduated plan procedure and the recent kava court case. He also was selected as a scientist in several EU-ACP (African-Caribbean-Pacific states)-financed projects on the issue of kava quality and safety in the South Pacific kava-producing states. He has performed botanical, pharmacognostic, and toxicological research on kava.

The author received financial support from the group of pharmaceutical companies mentioned above for the expert statements and the contributions to the kava court case. He declares that the companies did not interfere with his expert statements.

1. Anonymous 2002b. Averting drug risks, stage II. As related to: Kava-Kava (piper methysticum) - and kavain-containing drugs including homeopathic preparations with a final concentration up to and including D4. Bonn, BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte - Federal Institute for Drugs and Medical Devices). Translation available here.
   
   
2. Anonymous 2014. Court ruling 7 K 6972/11 of 10. June 2014, Cologne, Germany, Administrative Court.
   
   
3. Sales data. IMS Health website. Available here. Accessed July 3, 2014.
   
   
4. Anonymous 2001. Measures against drug-related risks: Hearing letter, Stage II. November 8, 2001. Bonn, Germany, Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM).
   
   
5. Anonymous 2002a. Agenda Item: C. Title: Kava rhizoma - Piper methysticum: Hepatotoxicity - Update following withdrawal of marketing authorisations in Germany (DE). Assessment Report (UK) dated July 2002. Pharmacovigilance Working Party, 9.-10. July 2002, London (UK), European Medicines Evaluation Agency.
   
   
6. Teschke R. Kava hepatotoxicity - a clinical review. Ann Hepatol. 2010;9:251-265.
   
   
7. Teschke R, Fuchs J, Bahre R, Genthner A, Wolff A.. Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment. J Clin Pharm Ther. 2010;35:545-563.
   
   
8. Teschke R, Schwarzenboeck A, Hennermann KH. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol. 2008;20:1182-1193.
   
   
9. Teschke R,Wolff A. Kava hepatotoxicity: regulatory data selection and causality assessment. Dig Liver Dis. 2009;41:891-901.
   
   
10. ICH (M3)R2: Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. European Medicines Agency; July 2008. Available here. Accessed July 2, 2014.
    
    
11. EMA Committee on Herbal Medicinal Products. Reflection paper on the risks associated with furocoumarins contained in preparations of Angelica archangelica L., EMEA/HMPC/317913/2006. October 31, 2007. European Medicines Agency. Available here.