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, MD6-9 (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.) More than a decade passed before concerned marketing authorization holders were
able to contest BfArM’s kava decision in court. The reason is of an administrative
nature: German law allows the contest of regulatory decisions only when there
is a finalized decision. As a matter of fact, the decision was not finalized
until 2012, and even then only under the pressure of a lawsuit triggered by the
marketing authorization holders of kava licenses, based on BfArM’s inactivity.
This final decision opened the way for the presentation of the mutual arguments
to the administrative court of Cologne, the judicial seat responsible for BfArM
decisions.
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.
Full Disclosure:
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.
References
- 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.
- Anonymous 2014. Court ruling 7 K 6972/11 of 10. June
2014, Cologne, Germany, Administrative Court.
- Sales data. IMS Health website. Available here. Accessed July 3,
2014.
- 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).
- 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.
- Teschke R. Kava hepatotoxicity - a
clinical review. Ann Hepatol. 2010;9:251-265.
- 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.
- 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.
- Teschke R,Wolff A.
Kava hepatotoxicity: regulatory data selection and causality assessment. Dig Liver Dis. 2009;41:891-901.
- 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.
- 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.
|