Feedback: Quality of a herbal medicinal product is essential. Both the safety profile and the efficacy of a multi-component herbal medicinal product are irrevocably linked to quality. Quality should be assessed according to the monographs reported in the European Pharmacopoeia or in other Pharmacopoeias or pharmaceutical reference books [1
]. These record the methods to define the quality of multi-component herbal drugs and also of defined selected extracts, according to classification of active constituents, pharmacologically active markers and quality markers [3
]. Additionally, pharmacopoeial methods are fully validated to perform correctly under the given analytical proceedings irrespectively of the environment where they are performed [ICH guideline Q2(R1); www.ich.org
Quality of a defined multi-component herbal extract is strictly related to the quality of the botanical source (herbal drug) defined by the botanical name of the plant according to the binomial system (genus, species, variety and author) and the part used (e.g. leaf, root or fruit). In addition other factors should be considered such as the method of preparation (extraction process, solvents used; solubility and stability of the plant constituents), the drug extract ratio (DER), time and temperature operations, which could be crucial not only for safety but also for the efficacy of the product [5
]. Ideally, in analogy with the analytical procedures for testing, also the production-process should be fully validated, in order to guarantee consistency of the final product, as far as possible.
For these reasons the final mix of constituents in a multi-component extract may exert different activities and in some circumstances, may even have a different safety profile from another type of extract, that is derived from the identical herb. These facts are taken into consideration and documented for well-defined herbal extracts in a new series of published European Community Monographs, authorised by the EMEA [9
]. It is noteworthy that, among the various types of plant products, e.g. food and botanical products, on the world market, only Herbal Medicinal Products are produced under rigid quality systems, such as Good Sourcing Practices (GSP), Good Agricultural Practices (GAP), Good Field Collection Practices (GFCP), Good Processing Practices (GPP), as well as Good Manufacturing Practices (GMP). As a consequence the quality can be assessed and the final product can be considered reproducible. According to the above arguments, it is crucial to realise, that the identical botanical source cannot guarantee the bioequivalence of its various multi-component extracts and of the resulting different Herbal Medicinal Products. The situation in the Cochrane review on Serenoa repens [10
] leaves no doubt, that various different Serenoa extracts (not always defined) and their subsequently varying final medicinal products, have been summarised, then analysed, in order to obtain the final conclusions of the review. This left the reader to assume, that both comparable (bioequivalent) and non-comparable products were included and compared in this study, in spite of the fact, that they might have exerted different, e.g. non-comparable safety and/or efficacy profiles.
Considering statements and definitions mentioned above, the Cochrane Review on Serenoa repens [10
] has been evaluated by the contributors to the present ’Letter to the editor.’ Four in part-related problems were encountered. In the following four comments, these problems have been addressed.
Comment 1. Problem, missing conclusion regarding studies with a positive control Serenoa alone, was compared in 4 of the 30 investigated clinical trials with known BPH drugs, such as Finasteride, Tamsulosin and Gestonorone caproate as positive controls. Reported in the review were a few minor differences and many comparable results for the various evaluated symptoms and no difference for the overall urinary symptom scores, between treatments with either Serenoa extract or these BPH drugs in different studies with up to 1098 patients. This apparently demonstrated, that the efficacy of these drugs was not different from that of the Serenoa products. Selected results are shown here, to exemplify the commentary: 1 study compared Serenoa to Finasterid (MD, mean difference, −0,40 Points, 95% CI −0.57 to 1.37, p > 0.05); 2 studies compared Serenoa to Tamsulosin (WMD, weighted mean difference, −0.52 Punkte, 95% CI −1.91 to 0.88, p > 0.05).
The reader of the review, even without being in the position to repeat the full statistical analysis, could conclude, that efficacy of Serenoa should be similar or comparable to these BPH drugs. The final statement of the authors, that ?Sereoa is not different from placebo?, is in clear contradiction to these reports. This contradiction has not been addressed, nor discussed, by the authors of the review.
Conclusion to comment 1
Contradictions described here, unless resolved, prohibit a final conclusion about the efficacy of Serenoa repens products.
Comment 2. Problem, chemical complexity of a multi-component plant-extract; ?non-equivalence? of analysed products The authors of the review appear to have treated the various Serenoa fruit preparations, derived from different extracts, used in the 30 clinical trials, which they analysed, as if these extracts were identical single chemical entities. i.e. the authors appear not to have considered in their analysis, that components of different multi-component preparations vary, according to their extraction procedure, the solvent used, the drug-extract-ratio, the total constituents probably vary, the co-active constituents probably vary and the standardization can vary. Thus the doses can vary.
The authors have stated in the review, that “of the 15 trials (in true only 14 appeared to have been actually analysed in the review), that were placebo-controlled and compared to Serenoa repens monotherapy, 7 utilized the commercialized Permixon, which assured that our comparators were equivalent” [page 13]. Thus the reader may conclude, that 7 out of 14 placebo-controlled trials were included in this analysis, that were ’non-equivalent’ (i.e. 50% of the comparators). This causes concern about the validity of the authors’ statement as well as the authors’ conclusions.
Comment 3. Problem, variation of dose
The dosage relates directly to the composition of a multi-component extract (see comment 2 as well). Thus, the dosage between studies can vary, even if identical amounts are given. Naturally, the dosage must also vary, if the administered amount differs. The ’daily dose’ of an extract administered, varied from study to study, in the 30 studies analysed: from 20 drops, 100 mg, 160 mg, 212 mg, 286 mg, 320 mg (a number of studies), 480 mg up to 640 mg, mostly applied in two portions. There was no statistical evaluation in the review, taking these different dosages, that were used in the 30 clinical trials, into account.
The BPH treatments using non-identical Serenoa preparations at strongly varying dosages, were summarized and investigated in the review, as if identical treatments with defined dosages, had been used. This is, as if one would assume, that apples, pears and even lemons will taste the same, merely because they are round.
Conclusion to comments 2 and 3
The statistical comparative analysis by the authors of the review, focuses on clinical symptom-scores of BPH in 30 trials, but they have omitted to fully address the consequences of analysing heterogenous Serenoa preparations administered in heterogenous dosage schemes, in those trials. For example the 7 ’non-equivalent’ placebo-controlled trials should not have been considered as a valid part of a comparative clinical analysis of the placebo-controlled studies.
Comment 4. Problem, studies conducted with Serenoa-containing combination products.
Nine (9) of 30 analysed studies, were conducted with combination products containing Serenoa repens extracts, besides one or more other potentially active phytotherapeutic agent (there was no consideration of the dosage, the various extracts were not defined, in the Cochrane review).
Conclusion to comment 4
These studies do not give evidence concerning the efficacy of Serenoa. Any efficacy or lack of efficacy cannot be attributed to Serenoa, such as would be the case in mono-therapy, but could be influenced by the other plant components in each product. The reader may conclude, that these studies do not qualify for a comparative analysis and cannot support a conclusive statement concerning the activity of Serenoa repens.
Summarising conclusions from comments 1–4
- Of 30 analysed studies, 7 placebo-controlled studies with “non-comparable” Serenoa products and 9 studies with combination products, could be deleted for good reasons, possibly leaving 14 studies for a revision of the comparative analysis.
- The authors final conclusion in this review “Sereoa is not different from placebo,” does not appear to have been corroborated by rigorous scientific reasoning. Even without repeating the full statistical evaluation (which appears to be necessary as well), the authors final conclusion regarding the efficacy of Serenoa repens, needs to be reconsidered.
Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.
1. Saw Palmetto Fruit. Sabalis serrulatae fructus. European Pharmacopoeia. Council of Europe.
2. Saw palmetto. USP, United States Pharmacopeia.
3. Guideline on declaration of herbal substances and herbal preparations in herbal medicinal products/traditional herbal medicinal products in the SPC (Summary of product characteristics). EMEA adopted guideline. London, 26 July 2007 Doc. Ref: EMEA/HMPC/CHMP/CVMP/287539/2005
4. Reflection papers on markers used for quantitative and qualitative analyses of herbal medicinal products and traditional herbal medicinal products. EMEA adopted guideline. London, 15 July 2008. Doc. Ref. EMEA/HMPC/253629/2007
5. Gaedcke F, Steinhoff B. Herbal medicinal products. Scientific and regulatory basis for development, quality assurance and marketing authorisation. CRC Press; Boca Raton: 2003.
6. Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products. EMEA adopted guideline. London 30 March 2006. CPMP/QWP/2819/00 Rev 1. EMEA/CVMP/814/00 Rev 1
7. Guideline on quality of herbal medicinal products/traditional herbal medicinal products. London, 30 March 2006. EMEA adopted guideline. CPMP/QWP/2819/00 Rev 1. EMEA/CVMP/814/00 Rev 1.
8. Vlietinck A, Pieters L, Apers S. Legal requirements for the quality of herbal substances and herbal preparations for the manufacturing of herbal medicinal products in the European Union. Planta Med. 2009;75:683–8. [PubMed]
10. Tacklind J, MacDonald R, Rutks I, Wilts TJ. The Cochrane Collaboration, The Cochrane Library. 2. Publishers John Wiley & Sons, Ltd; 2009. Serenoa repens for benign prostatic hyperplasia (Review) pp. 1–56.
Thank you for your comments.
The reviewer remarks that we are acting non-scientifically by lumping, for example, Permixon and generic Serenoa repens, is mistaken. Others have made claims that Serenoa repens (whether generic or as Permixon) alleviates symptoms associated with BPH. We have merely tested their hypothesis.
The reviewer makes two excellent points on bioequivalency and dosages, and in a forthcoming update we will address both. However, we disagree with the reviewers’ suggestion that we should have utilized only the Permixon trials. We conducted a systematic review of the evidence related to these products.
The Permixon trials, which the reviewer urges us to use exclusively, are of almost uniformly poor quality. For example, the 7 RCTs that compared Permixon to placebo had study populations of 22, 30, 60, 80, 110, 168, and 215. These trials were egregiously underpowered, with the possible exception of the last two. Follow up for the 7 Permixon-versus-placebo trials, measured in weeks, was 4, 4, 4, 4, 8.5, 10 and 12. Only one of the six Permixon trials that were compared to an active control (or combination therapy with either Permixon or the active control) utilized a placebo arm.
The reviewer states: “The reader of the review, even without being in the position to repeat the full statistical analysis, could conclude that efficacy of Serenoa
should be similar or comparable to these BPH drugs. The final statement of the authors that ‘Serenoa
is not different from placebo,’ is in clear contradiction to these reports.” We are not contradictory, but the evidence is ambiguous, as we put it in the review. For example, Carraro [1
] (Permixon versus finasteride) reported a decrease in IPSS symptom scores for both arms (−37% versus −39%, respectively); unfortunately, he did not include a placebo arm. Carraro’s trial was certainly well powered (N = 1098), but follow up was only 26 weeks.
The consequence of the reviewers’ recommendation to use only the Permixon trials would eliminate the highest quality trial of the thirty, and Bent’s NEJM trial [2
] (Serenoa repens
versus placebo) is methodologically superior to all of the other twenty-nine. Bent writes “these studies [previous RCTs] are limited by the small numbers of subjects enrolled, their short duration, their failure to use standard outcome measures, and the lack of information from participants concerning how effectively the placebo was blinded.” After 12-month follow up Bent reported “[b]oth groups also had a small decrease in the AUASI score …: the score decreased by 0.68 in the saw palmetto group (95 percent confidence interval, −1.37 to 0.01) and by 0.72 in the placebo group (95 percent confidence interval, −1.40 to −0.04) (). There was, however, no significant difference between groups in the mean change in AUASI scores over time (difference in mean change, 0.04 point; 95 percent confidence interval, −0.93 to 1.01).”
Can these results be extrapolated to European populations using Permixon? We think so. Nevertheless, we welcome an equivalent European trial utilizing Permixon when it becomes available.
References 1. Carraro J-C, Raynaud J-P, Koch G, Chisholm GD, Di Silverio F, Teillac P, Da Silva FC, Cauquil J, Chopin DK, Hamdy FC, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. The Prostate. 1996;29:231–40. [PubMed] 2. Bent S, Kane C, Shinohara K, Neuhaus J, Hudes ES, Goldberg H, Avins AL. Saw palmetto for benign prostatic hyperplasia. The New England Journal of Medicine. 2006;354(6):557–66. [PubMed]