ACCM extracted ratified minutes, Meeting 1, 5 March 2010

Abbreviations

Present

Members of ACCM present

Professor Alan Bensoussan (Acting Chair)
Dr Lesley Braun
Dr Gary Deed
Ms Patricia Greenway
Dr Vicki Kotsirilos
Ms Karen Martin
Professor Stephen Myers
Dr Richard Oppenheim
Mr Kevin Ryan
Professor Bill Webster
Dr Hans Wohlmuth

Present as an expert advisor

Associate Professor Tony Smith

Present from the Therapeutic Goods Administration (TGA)

Mr Michael Smith (Secretary)
Ms Diane Wilkinson

Present for part of the meeting

Ms Nicola Powell
Dr Linda Lenton
Ms Hongxia Jin
Dr Michael Dodson
Dr Don Boyer (National Health Products Directorate Canada [NHPD] observer)
Ms Michelle Boudreau (NHPD observer)
Ms Loretta Wong (NHPD observer)
Ms Rebecca Hughes (TGA observer)

1. Procedural Matters

1.1 Opening of Meeting

The Chair opened the meeting at 9:30 am, welcoming ACCM Members, TGA staff, observers from the Health Canada National Health Products Directorate (NHPD) and expert advisor, Associate Professor Anthony Smith.

The Committee acknowledged the resignation of Prof Smith from the Complementary Medicines Evaluation Committee and formally thanked him for his significant contribution to that Committee, which he has served as a Member and Chair for over 10 years.

1.2 Apologies

Ms Jenny Burnett
Dr Ruth Lopert (TGA Principal Medical Advisor).

1.3 Conflict of Interest

An Officer from the TGA's Office of Legal Services presented this item, outlining the impact of recent regulatory changes on the TGA's statutory committees. Members noted that the name of the 'Complementary Medicines Evaluation Committee' had been changed to the 'Advisory Committee on Complementary Medicines' which is consistent with the names of the other TGA expert committees and emphasises their 'advisory' nature. Members also noted that it is now a requirement that each of the TGA's statutory committees publish their recommendations on the TGA website.

In terms of conflicts of interest, the Legal Officer stated that it was the responsibility of each Committee Member to disclose direct or indirect personal interests that could potentially cloud their judgement. The Legal Officer provided the following as some examples of potential conflicts of interest: financial interests; research interests; or family interests.

Members were reminded of the three forms (used to declare conflicts of interest) which they are required to sign: a declaration of a Member's conflicts of interest upon acceptance of their appointment to the Committee; an annual 'broad' declaration of conflicts; and, at the commencement of each meeting, the declaration of any conflicts of interest specific to that meeting's agenda.

A Member questioned if there would there be any legal repercussions for Committee Members if a sponsor questioned a Committee decision. The Legal Officer responded that the obligation of a Committee Member was to act in good faith and provide advice to the best of his/her abilities, in which case the Commonwealth would support the Member. There would only be potential personal legal implications if a Committee Member was considered to have been negligent in their obligations. Discussion ensued in relation to Members' responsibilities for commercial-in-confidence information provided to them in the course of Committee proceedings. Members were reminded that they were not at liberty to disclose or use information obtained in this manner. Discussion continued as to the correct procedure for Members to store or dispose of Committee documents. The Legal Officer advised that it was prudent for Members to not keep Committee documents, in case laptops, etc, were stolen or misplaced. The Committee requested confirmation of their responsibilities in relation to storage or disposal of Committee documents and a TGA Officer undertook to confirm TGA policy in relation to this matter.

In relation to the current meeting, Members submitted conflict of interest declarations, specific to agenda items for this meeting, to the Chair.

OUTCOME

ACCM noted advice received from the TGA Office of Legal Services in relation to the revised conflict of interest forms.

2. Confirmation of Draft Minutes of CMEC 74 (4 December 2009)

Members accepted the Minutes of the seventy-fourth meeting of the CMEC as an accurate record of proceedings, subject to minor amendments as identified by Members.

Members identified a number of issues arising from the Minutes and requested that the following issues be considered as future meeting agenda items:

• Discussion of the TGA practice of publishing compositional guidelines for new complementary medicine substances on the TGA website.
• Discussion on the implementation of the 'Draft Guideline for Levels and Kinds of Evidence for Listed medicines with Indications and Claims for Weight Loss'.

In relation to Item 7.1, a Member asked if the list of herbs identified for removal from the permitted ingredient list would be made public. A TGA Officer stated that this would be given careful consideration by the OCM, and would likely occur as part of the broader consultation for the list of permitted ingredients in Listed medicines (which is to be included in legislation).

Members made the following recommendation:

3. Actions arising from previous meetings

3.1 Papain and Carica papaya safety review

Background

A TGA Officer introduced this item reminding Members that, at CMEC 74 (December 2009), they had briefly considered a United States Food and Drug Authority (FDA) website statement (from September 2008) warning companies to stop marketing topical products containing papain. According to the public statement, the FDA is taking action against these products because it has received reports of serious adverse events in patients using products containing papain. Reports include allergic reactions that lead to hypotension and tachycardia. In addition, patients who are allergic to latex can also be allergic to papaya, the source of papain. Therefore, the FDA considered that patients with latex sensitivity may be at increased risk of suffering an adverse reaction to a topical papain drug product. At CMEC 74, CMEC agreed that the matter should be investigated further, particularly with respect to identification of any adverse events in Australia, determining the risk to latex sensitive individuals and if there were any implications for the regulation of Australian products.

The Officer advised Members that CMEC had reviewed papain at CMEC 19 (April 2000), in the context of switching the regulatory status of a number of substances from 'Registerable' to 'Listable'. Though that review did not specifically address topical products, it was noted that the majority of products available in Australia at that time were grandfathered, with no reported adverse reactions. It was also noted that papain was already available to the public in powdered meat tenderisers as well as papaya fruit. At CMEC 19, CMEC's position was that papain was suitable for use in listable therapeutic goods, with no substance specific restrictions.

Members were advised that the current review addresses CMEC's specific questions in relation to topical papain products, and that the review had been broadened to include products in the ARTG that contain the species Carica papaya, from which papain is derived. In addition, the earlier review on papain had been updated.

Members noted that currently there are 6 topical products on the ARTG that contain papain or C. papaya, one being a sunscreen and the others mostly indicated for the relief of symptoms associated with insect bites, minor burns, rashes and other minor skin complaints. Two are grandfathered products. In contrast, there are over 60 oral medicines that contain papain, and over 50 oral medicines that contain C. papaya.

As noted in the CMEC 19 review of papain, allergic reactions to this enzyme (or C. papaya) have been documented over several decades, particularly in workers exposed occupationally to papain through the inhalation route. Several published papers from the 1990s report the co-existence in some individuals of allergic responses to rubber latex and papain or C. papaya, but no reports of adverse reactions to topical medicines containing papain or C. papaya in latex-sensitised individuals were located, other than the one FDA report of anaphylaxis in a latex-sensitised patient treated with an unapproved topical papain product.

The TGA Officer stated that, in considering the need for a label advisory statement about the potential for allergic reactions to products containing papain, it is important to note that there are a number of differences between the situation in Australian and the situation in the USA. Specifically, the formulations of the products are different; the USA products are promoted to treat much more serious conditions than the Australian products; and further, the USA products were on the market as unapproved drugs, and had not been evaluated by the FDA.

Members noted that only one relevant ADR has been reported to the TGA, and this was a dermatitis-type reaction at the application site following topical application of a grandfathered product. A request to the International Regulatory Cooperation on Herbal medicines network yielded one similar adverse reaction report, but no others. In addition, overseas regulatory agencies do not appear to have taken any action in relation to the FDA's concern about allergic reactions to topical papain products.

As well as allergenicity, the CMEC 19 review of papain included a discussion of reproductive effects in animals. However, as a subsequent study using a pure preparation showed no such effects, the reproductive effects were attributed to impurities in the papain formulations tested, and therefore dismissed.

Members were advised that the literature search for the present review retrieved recently published papers from several research groups, which demonstrated highly specific and reversible antifertility effects of C. papaya seed or various seed extracts in male laboratory animals. Some reproductive effects of seed extracts have also been demonstrated in female rats. In some of these studies it is apparent that very high doses of seed equivalents were used, but for many of the extracts, the seed equivalent could not be determined from the information available.

Without further research it is not possible to establish if the effects seen in these studies are of any relevance to the safety of complementary medicines that may contain papaya seed. No information was located for any adverse effects in humans exposed to papaya seed and a search of the ARTG did not identify any products that contain the seed per se. It can't be ruled out that products containing papaya fruit may include some seed, but given the amounts of C. papaya in products, if seed is present in proportion to the whole fruit, exposure is likely to be relatively minor.

The Officer concluded that overall, there does not appear to be a strong case for additional regulation of Australian products containing papain or C. papaya at this time.

Discussion

Difference in available data for Carica papaya and papain

A Member commented that it was unfortunate that the evaluation of papain and C. papaya had been combined, as there is not the same evidence available for the herbal species as for the single chemical entity. While there is no evidence of papain causing harm in pregnancy, there are a number of reports in the literature which strongly link preparations of C. papaya seed with the induction of male rat infertility. That given, the Member added that, while the seeds of C. papaya have been shown to have adverse effects in animals in pregnancy, it is difficult to establish the relevance or risk to humans, particularly in the absence of a risk/benefit analysis.

Conversely, another Member stated in their opinion it was useful that the review had been expanded to include C. papaya, as it had provided useful background information.

Topical or oral administration

The Committee discussed whether the safety concern related to topical or oral administration of papain. One Member stated that there does not appear to be much cause for concern in relation to topical allergies to papain/ C. papaya products. However, another Member stated that it is likely that adverse events (of latex sensitivity) are underreported to a large extent, but of those that have been reported, there does appear to be some evidence to assume an association. On this basis, it the Member suggested it might be beneficial for the public to be aware of a potential association with papain and latex sensitivity, perhaps in the form of a label advisory statement.

Conversely, Members noted that preparations of C. papaya are widely used, with no reports of adverse reactions. In addition, papain is also widely used in food processing and has GRAS status in the USA.

Members agreed that there did not appear to be significant cause for concern regarding topical use of papain or C. papaya.

Safety concern associated with C. papaya seed

Members noted the number of reports in the literature that strongly link preparations of C. papaya seed with the induction of male rat infertility, which raised concern for oral use of the seed. Members agreed it would be prudent to restrict the use of the seed, noting that this plant part does not appear to be present in any current medicines listed in the ARTG and therefore would have no regulatory impact.

Safety concern of unripe fruit or latex

A Member questioned whether consideration should be given to restrictions on the use of the unripe fruit or the latex of the plant, given reports of abortifacient activity for these preparations. Another Member responded that there were many preparations of herbal medicines that have been used traditionally in an attempt to induce abortion, e.g. slippery elm, and that traditional use did not necessarily infer that they were effective for this purpose.

Conclusion

Members agreed that preparations of the seed of C. papaya should not be permitted for use in Listed medicines, but preparations of other plant parts of C. papaya and papain remain suitable for use in Listed medicines.

3.2 Amended Regulations and criteria for ACCM consideration

Background

A TGA Officer introduced this item advising Members of the recent amendments to the Therapeutic Goods Regulations 1990 (the Regs) which aligns the names of the majority of TGA's expert advisory committees and clarifies details of their membership and operation. These changes are contained in Therapeutic Goods Amendment Regulations 2009 No. 6. The primary purpose of the regulation amendment is to emphasise the advisory role of the expert committees within the regulatory framework, to increase transparency and to provide consistency across TGA committee operations.

The function of ACCM is provided in Part 6, Division 1 E of the the Regs is as below.

(1)The committee's functions are to advise and make recommendations to the Minister or Secretary about the following matters:

1. inclusion of a complementary medicine in the Australian Register of Therapeutic Goods (the Register);
2. variation of an entry for a complementary medicine in the Register;
3. removal or continued retention of a complementary medicine in the Register;
4. any other matter concerning a complementary medicine;
5. any other matters referred to the committee by the Minister or Secretary (whether or not related to a complementary medicine).

(2) The Minister or Secretary may require the committee to give its advice to other persons or bodies.

ACCM was asked to note the amendment to the Regs.

Discussion

General comments

A Member questioned whether the CMEC Members should have been re-appointed to the new ACCM. A TGA Officer responded that it had been agreed within TGA that the existing committees' memberships would transfer to each new committee.

Members noted the number of high quality papers that are presented to the ACCM and considered it regrettable that these papers are not available for wider distribution.

Members also commented on the number of applications that are rejected due to data deficiency and the frustration experienced by the Committee when they are not given sufficient information on which to base a decision. A TGA Officer responded that a review of the registration process is underway to increase efficiency, transparency and consistency. Further, the OCM is encouraging engagement with sponsors prior to applications being submitted. That given, the OCM cannot act as a de facto consultant for applicants and ultimately, the compilation of data is the responsibility of the sponsor.

Consistent criteria

The Officer stated that, as the resources of the OCM were limited, ACCM has a fundamental role in the evaluation of products, particularly in the provision of expertise not available within the OCM.

Strategic direction

A Member suggested that the Committee should have a more proactive approach and be instrumental in the development of strategic guidelines to enable the OCM to undertake its work. The Committee should be actively involved in the development of solutions, not merely informed of the process or outcome of the TGA's activities.

Expert Advisory Panel

The Member questioned how the revised Regulations affected the ACCM's expert advisory panel. A TGA Officer undertook to provide this information to the Committee.

OUTCOME

ACCM noted the amendments to the Therapeutic Goods Regulations 1990 and discussed the type of issues which should be brought to ACCM for the Committee's consideration and recommendations.

3.3

One matter was discussed under this agenda item.

4. Guidelines on Levels and Kinds of Evidence to Support Claims

4.1 Coded Indications Project update

This agenda item was not discussed due to time limitations.

TGA Addendum: This matter will be considered by the OCM-Industry Consultation Group (OICG) and referred to ACCM when appropriate.

5. International regulatory update

5.1 Regulation of natural health products in Canada -verbal presentation

A TGA Officer introduced this item, advising Members that the TGA has a number of Memoranda of Understanding (MOU) with international regulatory authorities to encourage strategic collaborations. One of those agencies is Health Canada.

The implementation of a MOU between the TGA and Health Canada enabled a valuable exchange of information between the two agencies. Three staff from Health Canada's Natural Health Products Directorate (NHPD), who were visiting the TGA on a technical visit, had been invited as observers to the ACCM meeting. The Officer invited the Canadian delegates to provide an overview of the Canadian Regulatory System for the information of Members.

Members noted that that the Natural Health Products Regulations (NHPR) are administered under the Food and Drugs Act. The NHPR came into effect in January 2004, and are administered by Health Canada's Natural Health Products Program which consists of three directorates: The NHPD; the Marketed Health Products Directorate (MHPD) and the Health Products and Food Branch (HPFB).

The NHPD was established in 2000 as the Office of the Natural Health Products and is the regulating authority for the commercial sale of Natural Health Products (NHPs) in Canada. All NHPs sold in Canada require a Natural Product Licence (NPL) (premarket authorisation). To obtain authorisation, all NHPs undergo a pre-market review to assure that they are safe, effective and of high quality. The individual/company with legal responsibility for the product must submit a Product Licence Application (PLA) which includes information about the products, proposed label text and evidence supporting the safety, efficacy and quality of the product.

The Canadian delegate briefly outlined the types and standard of evidence required for PLAs; the Product Licensing statistics from 2004 to 2010; site licensing requirements and statistics; the NHP Compliance policy; clinical trials for NHPs; and the 'NHP Online Solution' which is the electronic single product license application submission form.

Discussion

General comments

The Committee expressed their appreciation of the NHPD delegates providing an overview of the Canadian regulatory system.

A TGA Officer spoke of the value of the collaborative relationship between the two agencies and the opportunities presented to learn from each other.

Pregnancy warning statement on NHPs

One Member asked how the Canadian authority dealt with pregnancy warning statements on their NHPs. The Canadian delegate advised that there was a 'general' precautionary statement included on the medicine label of all NHPs for women who are pregnant or are trying to become pregnant.

Use of the term 'natural'

A Member asked why Canada had chosen the term 'Natural Health Products' rather than 'Complementary Health Products'. The Canadian delegate responded that this had been the subject of much debate and it was determined that 'natural' was the most accepted term for the general public.

Reporting of adverse events

The Committee asked how the Canadian system reported interactions or adverse events associated with complementary medicines. The Canadian staff member responded that it is mandatory that licence holders report to the MHPD all adverse reactions reported to them for their product. The MHPD coordinates post market surveillance, coordinates monitoring of health risks and manages adverse reactions involving NHPs. The HPFB inspectorate manages consumer and industry complaints, investigations and product recalls.

Assessment of evidence and Canadian industry compliance

Members noted with interest that the NHPD assessed efficacy in the pre-market environment. Members also noted the Canadian guidelines for clinical trials of complementary medicines, commenting that this would be a worthwhile tool for the TGA to develop for the Australian industry.

ACCM Members expressed their gratitude for the information provided to them and also the need for stronger collaboration between the two countries.

OUTCOME

ACCM noted and discussed the regulation of Natural Health Products in Canada.

5.2 Research funding with a regulatory focus in the USA-verbal presentation

This item was removed from the agenda, as the USA representative was unable to attend the meeting.

6. Evaluation of new substances

Nil items

7. Safety or efficacy reviews

Nil items

8. Herbal Safety Review/Plant part project

8.1 Herbal safety review update

A TGA Officer reminded Members that since June 2006, the CMEC have considered a list of herbal materials with potential safety issues, noting that the herbs that were prioritised for review have now been considered by CMEC.

At CMEC 74, Members noted that a full safety review of all the remaining herbal species not yet reviewed would be labour intensive and beyond the available resources of the OCM and the CMEC. As a way forward, CMEC noted the approach taken by OCM to expedite the completion of the herbal safety review project:

• Herbs that were considered 'not known' with respect to safety, will not be investigated further (unless an issue of concern arises in the future) as no safety concerns (such as adverse events) had come to the OCM's attention for these herbs. It was considered that full safety evaluations would not be a wise use of OCM resources.
• The remaining herbs identified as potentially requiring a restriction on dose or methods of preparation were briefly reviewed by the OCM. From this in house review:
  • A small number of herbs were considered eligible for removal from the ARTG as these ingredients had never been included in medicines in the ARTG; their safety had never been evaluated; and as a potential safety concern had been identified, their continued permitted ingredient status was not considered justified. It was reiterated that no current products listed in the ARTG would be affected by a change in the status of these ingredients.
  • A small number of herbs were herbs were considered to be suitable for homoeopathic use only. Again, it was reiterated that no current products listed in the ARTG would be affected by a change in the status of these ingredients.
  • Herbs identified to contain oxalic acid were flagged for further review with respect to potential safety concerns for oxalic acid in Listed medicines.
  • The remaining herbs were deemed to be listable without further restriction.

At CMEC 74, Members agreed that the OCM's approach to expedite the completion of the herbal safety review project was pragmatic and practical. However, in relation to the completion of the project, Members requested the following actions by the OCM:

• Provide clarification of the decision making process used to assess safety concerns for the herbal species included in the review.
  
  At ACCM 1, Members were provided with a decision flow chart summarising the OCM's approach to determining the suitability of the ingredients for Listed medicines, as well as a list of the references used in the project.
• Undertake a brief safety review of Ledum groenlandicum with respect to safety concerns associated with topical use of preparations of the herbal species.
  
  At ACCM 1, Members were informed that a brief review of the ingredient L. groenlandicum had been undertaken by the OCM in order to determine if ledol could be topically absorbed. Members noted that the review resulted in little new information being discovered about the plant, and failed to elicit any adverse reports relating to either ledol or L. groenlandicum. The traditional literature reveals that a long history of safe use is associated with a decoction of the leaves and twigs of L. groenlandicum. The literature warns that (oral) overdoses may cause violent headaches or symptoms of intoxication, and notes that the skin should be cleaned and rinsed between applications of the root powder or the decoction. A focused library data search including the terms "dermatological, skin absorption of ledol or ledum extracts" did not reveal any articles of significance to the OCM.
• Confirm that the herbal species tagged for removal from the list of permitted ingredients in Listed medicines do not have a history of homoeopathic use.
  
  At ACCM 1 Members were informed that following CMEC 74, the list of herbal materials has been reviewed to capture any ingredients traditionally used homoeopathically.
• Undertake a safety review of the herbal component oxalic acid to determine if any regulatory control is required to control the use of herbal species that contain this component
  
  At ACCM 1 Members were informed a literature search has been commenced by the OCM in relation to the potential safety issues of oxalic acid and the oxalic acid content of seven (7) identified species of herbs. It is anticipated that the results will be presented at ACCM 2.

Discussion

Members considered that the 'decision flow chart' was a useful summary of the OCM's approach to determining the suitability of the ingredients for use in Listed medicines.

In relation to the herbal species (never included in medicines in the ARTG) identified for removal from the permitted ingredient list due to safety concerns, a Member asked if this list would be made public, in the interest of transparency. A TGA Officer stated that this would be given careful consideration by the OCM and would likely occur as part of the broader consultation for the list of permitted ingredients in Listed medicines (which is to be included in legislation).

OUTCOME

ACCM noted the finalisation of the Herbal Safety Review Project.

9. Registration applications

Nil items

10. Regulatory reforms

10.1

One matter was discussed under this agenda item.

11. Matters referred from within TGA

11.1 Adverse Drug Reactions Advisory Committee (ADRAC) meeting

Members noted the Minutes of ADRAC Meeting 319 and discussed, in detail, case reports of interest.

Members also noted that this was the last meeting of ADRAC as the Committee had been replaced by the Advisory Committee on the Safety of Medicines (ACSOM). The Committee stated that, to date, the open communication between the ACCM and the ADRAC had proven valuable and expressed the hope that this communication would continue under the ACSOM. In particular, Members acknowledged the significant contribution that Dr Vicki Kotsirilos had made to the communication between the two Committees, as a member of both the ACCM and the ADRAC.

OUTCOME

ACCM noted the Minutes of ADRAC Meeting 319

11.2

One matter was discussed under this agenda item.

11.3 Consultation on TGO 80 Child resistant packaging requirements

A TGA Officer introduced this item advising members that the Therapeutic Goods Order No. 80 Child-Resistant Packaging Requirements for Medicines (TGO 80) is an Order made by the delegate of the Minister for Health and Ageing under section 10 of the Therapeutic Goods Act 1989 (the Act). Members noted that the TGA was inviting submissions on proposed amendments to this document. The closing date for submissions was Friday 19 March 2010.

Members noted that the proposed amendments would update the list of substances which, if present in a medicine, necessitate that the medicine has child-resistant packaging (CRP). The objective of the proposal for amendment to TGO 80 is to ensure that Schedule 1 to TGO 80 continues to reflect currently approved medicines and an appropriate risk management approach to the identification of substances warranting CRP, based on the criteria for CRP described in the 'Introduction' to TGO 80. In turn this will ensure that TGO 80 remains a useful tool in assisting in the prevention of accidental poisoning in children.

ACCM was asked to note and comment on the proposed amendments to TGO 80.

OUTCOME

ACCM noted the proposed amendments to Therapeutic Goods Order No. 80 Child-Resistant Packaging Requirements for Medicines (TGO 80).

12. For information

Nil items for consideration

13. Sponsor representations to ACCM

Nil items for consideration

14. Other business

Nil items for consideration

15. Recommendation record

Item 2 Confirmation of Draft Minutes of CMEC 74 (4 December 2009)

Recommendation 1.1

CMEC confirms that the draft Minutes of its previous meeting CMEC 74 (4 December 2009), as amended, are a true and accurate record of that meeting

Item 3.1 Papain and Carica papaya safety review

Recommendation 1.2

ACCM recommends to the TGA that preparations of plant parts other than seed of the herbal species Carica papaya remain suitable for use as ingredients in Listed medicines.

Recommendation 1.3

ACCM recommends to the TGA that the ingredient papain remains suitable for use as ingredient in Listed medicines with no restrictions.