Posted 21 November 2013
The CAMS Regulations were published on the 15th November and can be downloaded from here or from the Government website. They need to be read in context with the document, Complementary medicines – Quality, safety, and efficacy, which can be downloaded here.
Andy Gray (BPharm MSc(Pharm) FPS FFIP), a Senior Lecturer in the Division of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal (and Consultant Pharmacist, Centre for the AIDS Programme of Research in South Africa (CAPRISA)), has written a commentary on his view of the published regulations, and how they may be implemented.
His commentary, first published on an email discussion group, DrugInfo, is reproduced with his permission.
The amended General Regulations to the Medicines Act provide some detail of the proposed approach to regulating complementary medicines (CMs), but much will still depend on how the guidelines are implemented.
Here are some thoughtshr on the process as outlined to date:
1. The first key design feature is that the Act itself has not been amended – it has been decided to use the current provisions in sections 14 and 15, and the standard approach to assessing quality, safety and efficacy. That is not to say that every medicine requires the same approach – new chemical entities are assessed on all three criteria, whereas generic applications are only assessed on quality (with the additional requirement to show interchangeability). The approach to biosimilars is still evolving, but would seem to require data on all three criteria, at least to some extent. The intention appears to be to subject some CMs to a full assessment, on all three criteria, chosen on the basis of risk (safety), while allowing others to be assessed predominantly on quality. This appears to be close to the approach used in Australia, and the guidelines make repeated reference to TGA materials.
2. The next key move is to define CMs narrowly, as follows:
“complementary medicine” means any substance or mixture of substances that-
(a) originates from plants, minerals or animals;
(b) is used or intended to be used for, or manufactured or sold for use in assisting the innate healing power of a human being or animal to mitigate, modify, alleviate or prevent illness or the symptoms thereof or abnormal physical or mental state; and
(c) is used in accordance with the practice of the professions regulated under the Allied Health Professions Act, 1982 (Act No. 63 of 1982)”.
The last of these three requirements seems to be the most important – the guidelines circulated for comment make the targets clear: ” The CMs that will be subject to these regulations are those associated with those disciplines regulated by the Allied Health Professions Council of South Africa (AHPCSA). These are commonly known as Homoeopathic medicines, Western Herbals, Traditional Chinese medicines, Ayurvedic medicines, Unani-Tibb and Aromatherapeutic medicines/oils. As per the Act, the term “practitioner” refers to a person registered as such under the Allied Health Professions Act, 1982 (Act No. 63 of 1982).”
3. The guidelines give a hint of the risk-based approach to quality, safety and efficacy: “In general the categories (disciplines) of CMs are defined and can make high risk or low risk health claims. The CMs will be subject to compliance with Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP) and Good Dispensing Practice (GDP) as well as Good Regulatory Practice. In the process of complying with these practices the quality of the medicines is promoted and aimed at rendering them to be of acceptable quality, safety and efficacy. It is thought that quality and safety is non-negotiable, whereas, depending upon the discipline, proof of absolute efficacy might prove challenging (for a variety of reasons). The approach of these guidelines is to enable the applicant to present, to the MCC, an application free of errors and easy to review. Each discipline will have its own set of requirements governed by its own references and pharmacopoeias which are all subject to and compliant with the current science and knowledge of that particular discipline.”
4. The control of medicines and substances has also not been amended at all – section 22A will apply to CMs as it does to other medicines. The guideline states: “A complementary medicine may fall in Schedules 0, 1, 2 or 3 or higher. Medicines are not scheduled solely on the basis of toxicity. Although toxicity is one of the factors considered, and is itself a complex of factors; the decision to include a substance in a particular Schedule also takes into account many other criteria such as the purpose of use, potential for misuse, abuse, safety in use, the need for specialised (professional) knowledge in its prescription and the need for the substance.” For any CM included in Schedule 1 or above, access for “practitioners” will need to be assured via a listing in that Schedule for that specific category of person, as registered with the AHPCSA.
5. This line in the guideline is key: “Before submitting an application for registration of a complementary medicine, it is first necessary to establish that the product contains substances that are, in fact, complementary medicine substances. Essentially, if the substance is a designated active ingredient, as defined in the Regulations it is a complementary medicine substance.”
6. A new General Regulation 25A is inserted: “Medicines in category D are subdivided into such disciplines as may be determined by the Council after consultation with the Allied Health Professions Council of South Africa.”
7. However, the guideline is already prescriptive: “The following references (in addition to any further specified accepted references [ANNEXURE A] for each discipline) should be consulted for purposes of motivating that the product or substances used originate from the discipline indicated”.
“Herbal medicines or substances shall be described as herbal medicines or substances in at least one of the specified references on the herbal medicines reference lists or any of the following:
* Australian Therapeutic Goods Authority List of Substances
* German Commission C Monograph2
* German Commission E Monograph
* WHO Monographs on Selected Medicinal Plants
* ESCOP Monographs
* EMEA Community Herbal Monographs
* British Herbal Pharmacopoeia
* Formal Herbal Materia Medicae, or
* Other national or international herbal monographs, pharmacopoeias or materiae medicae”
“A Traditional Chinese medicine or substance must be described as a Traditional Chinese medicine or substance in at least one of the specified references or any of the following:
* the Traditional Chinese pharmacopoeia”
“An Ayurvedic medicine or substance must be described as an Ayurvedic medicine or substance in at least one of the following references
* The Ayurvedic Pharmacopoeia of India
* The Aurvedic Formulary of India”
“A Unani Tibb medicine or substance must be described as a Unani Tibb medicine or substance in at least the Unani pharmacopoeia or one of the specified references”
” The substance must be described as a homoeopathic substance in at least one of the specified Materia Medica, vade medicae, repertories or Homoeopathic Pharmacopoeiae or in any of the following:
* Australian Therapeutic Goods Authority List of Substances
* German Commission C Monograph
* German Commission D Monograph”
“The substance must be described as an aromatherapy substance in at least one of the specified references on the Aromatherapy Substances Reference List or listed in the “Accepted Aromatherapy Substance List”.
Annexure A to the guideline already provides the “Accepted Aromatherapy Substance List”.
A footnote is also inserted: “In most cases medicinal products used within the anthroposophic medical tradition cannot be distinguished on the basis of their methods of production, as these are largely shared with other medicinal product groups such as homeopathic and herbal medicinal products. In case of overlap, anthroposophic medicinal products are legally qualified as either homeopathic or traditional herbal medicinal based on their presentation in the product.”
The origins, reflecting the intention of part (a) of the definition are also very clearly identified:Some guidance is provided by risk category:
“Herbal substance / preparation means all or part of a plant, fungus, alga, seaweed or lichen, or other substance (other than a pure chemical or isolated constituent or a substance of mineral, animal or bacterial origin):
a) that is obtained only by drying, crushing, distilling, freezing, lyophilisation, extracting, expressing, comminuting, mixing with an inert diluent substance or another herbal substance or mixing with water, ethanol, glycerol, oil or aqueous ethanol; or other permitted solvents; with or without the addition of heat.
b) that is not subjected to any other treatment or process other than a treatment or process that is necessary for its presentation in a pharmaceutical form, and
c) where part of a plant, fungus, seaweed or lichen refers to a structure such as a root, root bark, rhizome, mycelium, fruiting body, bulb, corm, tuber, stem, inner or outer bark, wood, meristematic tissue, shoot, bud, thallus, resin, oleoresin, gum, natural exudate or secretion, gall, leaf, frond, flower (or its parts), inflorescence, pollen, fruit, seed, cone, spores or other whole plant part.”
” Traditional Chinese, Ayurvedic and Unani Tibb substances may be of plant, animal, or mineral origin. They may include fresh or dried substances, extracts or derivations from these extracts.”
“Homoeopathic substances may be of plant, fungal, animal, mineral or other origin prepared in accordance with homoeopathic principles and may include starting substances as well as allersodes, isodes, sarcodes, nosodes, allergens, and allopathic substances all used in potentised form at acceptable potencies for use as a homoeopathic medicine.
Homoeopathic preparations are
a) formulated for use based on homoeopathic principles, which may include being capable of producing in a healthy person symptoms similar to those which it is administered to alleviate, or those principles related to classical, clinical or combination homoeopathy; or
b) prepared or purported to be prepared according to the practices of homoeopathic pharmacy including starting substances using the methods described in a recognised pharmacopoeia which may include
(i) serial dilution and succussion of a mother tincture in water, ethanol, aqueous ethanol or glycerol; OR
(ii) serial trituration in lactose.”
“Aromatherapy substances are essential oils, hydrolate or other aromatic extract of plant origin where reference must be made to the part of the plant(s) or the whole plant and method used to extract the essential oils.”
Although by no means a simple task, it should be possible to identify products that are on the market currently, which may have a registry number issued in terms of the 2002 audit, but do not fit the new definition of a CM, and should therefore either be registered as medicines or removed from the market.
8. The key issue will be the extent to which quality, safety and efficacy are assessed and the data required for each:
8.1 The guideline is detailed in relation to quality: “Information is required for a product’s active ingredients and its excipients. The data are evaluated to determine the quality of the product, including the identity, impurities and stability of the ingredients. The data assessment also takes into account information about the manufacturing processes and standards of good manufacturing practice (GMP), as required. Details of quality control measures are required to demonstrate that the product will be produced to a consistent quality. Stability data for the product are required to determine a shelf life over which the product’s quality is maintained. Should the results of any testing be outside the acceptable limits then appropriate action, which may include rejection or destruction, must be taken immediately. The animal or plant should not be listed on the IUCN Red Data List, (http://www.iucnredlist.org/technical-documents/categories-and-criteria) or South African Nation al Biodiversity Red List of South African Plants (http://redlist.sanbi.org/redcat.php), unless from a licensed cultivated, legal source and must adhere to the principles of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) of which South Africa is a member.”
There are detailed requirements for all GMP aspects. Some have been clearly adapted for the CM category (notably in relation to homeopathic products).
8.2 The requirements for safety are less clearly outlined: “Safety may be established by detailed reference to the published literature and/or the submission of original study data. Any complementary medicine that is of animal origin must comply with the requirements of the Animal Diseases Act, 1984 (Act 35 of 1984).”
8.3 The requirements for efficacy data are also conditional: “The applicant must provide evidence (data) to support the product’s efficacy for the proposed indication(s) and any claims that the applicant intends to make in the product labelling to determine whether the data supplied adequately support the requested indication(s)/claim(s) as provided for in these guidelines.”
Here are some details from the guideline:
“Where an active ingredient is well described in standard sources it is possible to use these descriptions as the basis of the efficacy and safety information.
The following are examples of the reference texts that are usually acceptable as sources of information on the safety, efficacy and dosage regimen of ingredients:
* Martindale: The Complete Drug Reference, Sweetman SC (ed), Pharmaceutical Press, United Kingdom
* Handbook of Non-Prescription Drugs, American Society of Health System Pharmacists, United States;
* Remington’s Pharmaceutical Sciences, Gennaro AR (ed), Mack Publishing Company, United States;
* Handbook of Pharmaceutical Excipients, Kibbe AH (ed), American Society of Health System Pharmacists, United States; Other sources should primarily include evidence-based references, such as the Natural Medicines Comprehensive Database, and the Natural Standard Databases. Note that indications and dosage must be the same as described in these sources. Any use outside the documented indications and/or dosages, or any new route of administration, will require evidence of efficacy and safety.
Note also that anecdotal or limited clinical reports/mentions of efficacy alone (e.g. in Martindale, “xxx has also been used in …”) are not considered evidence of efficacy and safety. Applications for products with well-documented ingredients should include details of the relevant texts (photocopies or scans of the relevant pages are preferred) with particular references to the accepted indications, dosage and routes of administration of the active ingredients.”
This statement is self-evident, but difficult to apply: “The evaluation of high-level claims (i.e. for the use of medicines for serious illnesses) requires an assessment of the differential between the benefits of a medicine and the risks of its use. There is no simple measure for this: the acceptable level of risk varies with the nature of the benefits, the risk from taking the medicine and the risks of untreated (and undiagnosed) diseases. Generally, the more serious and life threatening the untreated disease and the greater the benefit, the higher is the level of acceptable risk. The benefit-risk profile is also affected by the availability of accepted (proven) treatments, the risk profile of those accepted therapies, and the risks of foregoing treatment where such a medically acceptable option is available. A benefits risk profile should be determined for every complementary medicine – even for so-called “minor” conditions.”
9. Some guidance is provided by risk category:
HIGH RISK:
Type of claim:
* Treats/cures/manages any disease/disorder.
* Prevention of any disease or disorder.
* Reduction of risk of a disease/disorder.
* Aids/assists in the management of a named symptom/disease/ disorder.
* Relief of symptoms of a named disease or disorder2
* Treatment of proven vitamin or mineral deficiency diseases.
Evidence required to support claim:
* Clinical data to be evaluated3.
AND
* Two of the following four sources that demonstrates adequate support for the indications claimed:
1. Recognised Pharmacopoeia4;
2. Recognised Monograph4;
3. Three independent written histories of use in the classical or traditional medical literature, or
4. Citations from other in vivo, in vitro studies, case reports or others.
LOW RISK:
Type of claim:
* General health enhancement without any reference to specific diseases or conditions 1
* Health maintenance, including nutritional support.
* Relief of minor symptoms (not related to a disease or disorder)2 Evidence required to support claim:
* Clinical data to be evaluated
AND/OR:
* Two of the following four sources that demonstrates adequate support for the indications claimed:
1. Recognised Pharmacopoeia4;
2. Recognised Monograph4;
3. Three independent written histories of use in the classical or traditional medical literature. 5,6, or
4. Citations from other in vivo, in vitro studies, case reports or others.
Notes:
1 Health enhancement claims apply to enhancement of normal health. They do not relate to enhancement of health from a compromised state.
2 All claims relating to symptoms must be accompanied by the advice “If symptoms persist consult your healthcare practitioner”.
3 Refer to section 5.1 i) – vi)
4 Refer to section 5.1 vii) – ix) and Annexure A
5 In cultures where an oral tradition is clearly documented, evidence of use from an oral tradition would be considered acceptable provided the history of use is authenticated. Modern texts that accurately report or confirm the classical or traditional literature may be used to support claims. Traditional claims should refer to corresponding traditional descriptions of the condition(s).
6 Terms used must be in accordance with the practice of the associated discipline registered with the AHPCSA.
10. This is the approach to efficacy in the guideline:
“The criteria to be considered in the evaluation of efficacy for all complementary medicines may include established traditional use, pre-clinical data and evidence from clinical trials in animals and human beings as well as those references specified below appropriate for the risk level of associated claim.
Generally acceptable evidence in support of efficacy include:
(i) Appropriately designed clinical trials using the product for which an application is being made.
(ii) Appropriately designed qualitative and observational studies preferably using South African-validated instruments/methods.
(iii) Published systematic reviews such as in the Cochrane database.
(iv) Published clinical trials
(v) Published case reports
(vi) Evidence-based databases (e.g. Natural Medicines Comprehensive Database, Natural Standards Database)
(vii) Accepted Herbal monographs or pharmacopoeiae.
(viii) Monographs from any other source equivalent in standard to any of the above.
(ix) In the case of homoeopathic medicines, justification of the use of the medicines from the relevant Materia Medica or Repertory listing.”
11. A “list of acceptable and authoritative texts for each discipline” is also provided in the guideline.
12. Any process such as this will take years to implement. The new general Regulations therefore make provision for a labelling style for all CMs that are as yet unregistered: “if the medicine has not received registration with the Medicines Control Council the disclaimer “This medicine has not been evaluated by the Medicines Control Council. This medicine is not intended to diagnose, treat, cure or prevent any disease“.
13. A risk-based set of deadlines has also been included in the General Regulations (even though these are the purview of the Council, not the Minister directly):
“48C. (1) Amendments addressing complementary medicines as per Regulation 8 Labelling of medicines intended for administration to humans, Regulation 9 Package inserts for medicines for human use, Regulation 10 Patients information leaflet, Regulation 40 Package insert for Veterinary medicines, Regulation 48 Labelling of veterinary medicines shall come into operation three months from the date of publication of this amendment.
(2) With effect from the date of publication of this notice, the Medicines Control Council has by virtue of powers vested in it by section 14(2) of the Act, by resolution approved by the Minister of Health, determined that-
(a)(i) complementary medicines falling in Category D and in the pharmacological classification 20.2.8 (Antiviral agents), 21.2 (Oral hypoglycaemics), 6 (Cardiac medicines), 26 (Cytostatic agents) are subjected to registration and shall relate to medicines that are available for sale in the Republic on the date on which this notice comes into operation and shall relate also to medicines that become available after the said date.
(ii) applications for registration of such medicines as per sub regulation 2(a)(i)that are available for sale in the Republic on the date on which it comes into operation shall be submitted to the Medicines Control Council within six (6) months of the date of this publication.
(b)(i) complementary medicines falling in Category D and in the pharmacological classification 32.3 (Slimming preparations) and pharmacological classifications 7.1, 21.7 (Male sex hormones), pharmacological classification 21.8 (Female sex hormones) and pharmacological classification 21.9 (androgen-oestrogen combinations) claiming sexual stimulation and sexual dysfunction available for sale in the Republic on the date on which it comes into operation shall be subjected to registration within 24 months of the date of this publication.
(ii) medicines as per sub regulation 2(b)(i) that become available after the said date shall be subjected to registration in terms of the Act.
(c)(i) complementary medicines falling in Category D and in the pharmacological classification 32.16 (Other) and claiming immune stimulation or expressions of similar connection and medicines falling in pharmacological classification 17 (Medicines acting on muscular system) and pharmacological classification 22 (Vitamins) claiming to be sport supplements and exceeding the upper limit of vitamins and minerals as published by Council that become available after the said date are subjected to registration.
(ii) applications for registration of such medicines as per sub regulation 2(c)(i) that are available for sale in the Republic on the date on which this notice comes into operation shall be submitted to the Medicines Control Council within 30 months of the date of this publication.
(d)(i) complementary medicines falling in category D and in all the remaining pharmacological classifications as per Regulation 25(2) and (3) that are available for sale in the Republic on the date of this notice shall come in operation on the date on which it is published which will not be later than December 2019.
(ii) complementary medicines falling in category D and in the pharmacological classifications as per Regulation 25(2) and (3) that become available after the date of publication of this notice shall be subjected to registration as per the provisions of the Act.”
That this is not designed to deal with the very challenging issue of African Traditional Medicines is clear. Whether that is an appropriate risk-based approach is open to debate. Certainly, the MCC cannot continue to allow the expansion of a unregulated and poorly defined CM category. If nothing else, this approach will identify medicines that cannot claim to be CMs and which should either be registered or removed from the market. How many fall outside of the AUS-L listing (or other recognised equivalents) and have claims that exceed the “low risk” category is not known at this stage.
Whether all of the rest can be dealt with by the end of this decade is an open question.
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