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Summary of submissions and TGA responses: Evidence required to support indications for listed medicines (excluding sunscreens and disinfectants)

25 March 2014

Consultation on Evidence required to support indications for listed medicines (excluding sunscreens and disinfectants) ('Evidence Requirements') closed on 22 October 2012. Prior to the consultation, the TGA proposed to embed the revised Evidence Requirements document into legislation. Implementation of this proposal would have required amendments to the Therapeutic Goods Act 1989 (the Act) and a Regulation Impact Statement.

In order to minimise regulatory burden, the revised document will be retained as guidelines only. The revised Evidence Guidelines: guidelines on evidence required to support indications for listed complementary medicines clarify the existing evidentiary requirements and do not impose any new regulatory requirements.

The revised Evidence Guidelines have taken into consideration, and where appropriate adopted, proposals included in the submissions received during this consultation.

The following table sets out in brief the broad issues identified from the submissions received and the TGA's response.

Summary of submissions and TGA responses to the second consultation on the evidence required to support indications for listed complementary medicines
Topic Summary of issue(s) raised in submissions TGA Response
General Comments The document is hard to read, is overly complex, is repetitive, contains ambiguities and contradictions and is not user friendly. The Evidence Guidelines have been revised to be a more user-friendly.
The document appears to be at variance to other comparable regulators such as Health Canada. Australia should harmonise with international standards. Where possible, the TGA aligns its legislative requirements with other comparable regulators achieving better harmonisation with relevant international standards.
It is not appropriate for advisory statements to be included in the evidence requirements document and instead they should be contained within the Required Advisory Statements for Medicine Labels (RASML).

The Evidence Guidelines do not 'mandate' label advisory statements for particular ingredients.

To be compliant with the existing regulations, information may be required on a medicine label to ensure that the presentation of the medicine is not misleading to the consumer.

Best practice regulation The legislative requirements should be principles based, consistent and concise. The legislative requirements associated with holding appropriate evidence to support indications has not changed. The Evidence Guidelines clarify existing regulatory requirements.
Concern was raised that the Council of Australian Governments (COAG) Principles of Best Practice Regulation have not been followed because no alternative options have been presented to address the 'perceived regulatory failure'. The Evidence Guidelines clarify the existing regulatory arrangements.
Consumer issues Consumers must be able to have confidence that the products they are purchasing are safe and effective and comply with TGA regulatory standards. The Evidence Guidelines clearly explain the evidence required to support indications and clarify the difference between traditional and scientific indications. The revised Evidence Guidelines, together with the revised Australian Regulatory Guidelines on Complementary Medicines (ARGCM) and information on complementary medicines on TGA website, clearly explain the regulatory requirements for listed medicines in order to inform consumers about the products they purchase and the level of regulatory scrutiny.
Impact on sponsors The current reforms will increase the bureaucratic and financial burden on compliant sponsors. The effects of this have the potential to adversely affect market availability and affordability of complementary medicines. Sponsors are required to certify that they hold evidence to support indications made for their products (as per section 26A of the Act). The revised Evidence Guidelines provide clarity regarding the evidence that a sponsor must hold in order to satisfy this certification.
Sources of established evidence (SEE) The 'Sources of Established Evidence' (SEE) list is not comprehensive enough. The revised document outlines the principles behind sources required for both evidence of traditional use and scientific evidence. This provides greater flexibility in the type of evidence used to support indications for a listed medicine.
Herbal Extracts The document includes excessive requirements for herbal extracts, including preparation.

The Evidence Guidelines, together with the Evidence package checklists, provide mechanisms to determine if a particular active herbal extract can be considered sufficiently similar to that in the evidence package. If there are differences in the method of preparation of the herbal extract then a justification will be required.

If an indication is based on a traditional preparation, the sponsor must be able to justify that their preparation is essentially equivalent to the traditional preparation reported in the evidence held to support the indication.

This requirement is consistent with 'Guidance on Equivalence of Herbal Extracts in Complementary Medicines' (TGA, 2011).

Nutrient claims Dosage for essential nutrients doubled, from 25% to 50% RDI vitamins/minerals/ nutrients without justification. The requirements of the current guideline should be maintained. The Evidence Guidelines state that indications relating to supplementation with vitamins, minerals or other essential nutrients are permitted for listed medicines if the recommended daily dose of the medicine provides at least 25% of the Australian recommended dietary intake (RDI), adequate intake (AI) or nutrient reference value for that vitamin, mineral or nutrient.
Biomarkers Ranges too narrow e.g. a 15% upper limit of cholesterol does not take into consideration a 10% margin error, seasonal variations etc.

In general, the use of study populations with baseline biomarker levels that are outside the normal levels may provide support to indications of listed medicines when a suitable justification is provided and the safety of any modulation in the target population can be established.

Data generated from diseased study participants could be used to demonstrate positive pharmacological effects, however, such data (on its own) may not be appropriate to be extrapolated to support an indication that is intended to be used by healthy people to maintain normal biomarker levels.

Weight loss indications Weight loss indications should be specific so the consumer has a clear understanding of what the evidence supports. The Evidence Guidelines clarify the requirements for medicines implying a benefit to body weight and the appropriate evidence to support such indications.
The 6 month requirement for clinical studies is unreasonable and inconsistent with international agencies e.g. Canada and EFSA. This should be changed to 12 weeks. Relevant studies must be of appropriate duration to validate a health benefit included in a listable indication. In other words, each study must be long enough to demonstrate that a health benefit that is meaningful to the consumer has been clearly achieved. A reasonable timeframe to achieve a significant degree of weight loss is considered to be six months (clinical significance).
The statement '50% of participants achieving a loss of 5%' does not take into genetic variability in a study's participants.

The Evidence Guidelines requires that evidence (clinical results) demonstrate a therapeutic benefit that is meaningful to the consumer. In the instance of weight loss, the TGA has found that clinical significant is generally achieved if:

  • a mean overall loss of at least 5% initial body weight in the treatment group, which is at least 3% greater (for RCT) OR 5% greater (for non-RCT) than that of the control group. In both cases the difference must be statistically significant (p<0.05); and
  • at least 50% of participants in the treatment group must have achieved a loss of at least 3% or 5% of initial body weight, respectively.

By achieving clinical results that meet the above criteria it is likely that the therapeutic benefit is meaningful to the consumer. The '50% of participants achieving a weight loss of 5%' allows for both a genetic diversity and a level of scientific certainty.

Expert/author qualification

Industry welcomes the removal of the requirement for the evidence report author to be an expert.

Consumer groups consider the requirement for an expert author should be retained to ensure the balance of evidence is reported objectively.

The revised Evidence Guidelines provide 'Evidence package checklists' to assist sponsors to determine whether the evidence they hold reports a balanced view of evidence available to support indications.
Requirement for study population to be consistent with target population The requirement to examine whether the evidence can be applied to Australian population is unreasonable, given that Australia is a multicultural country and further, not all studies are conducted in Australia.

There are a number of factors to take into consideration when determining if a scientific evidence item is relevant and of high quality to support an indication. One factor relates to the similarity of the target population to the study population described in the evidence provided. This may include study participants that are socioculturally similar to the Australian population. If the majority of these factors are satisfied, then the evidence is likely to be classified as relevant and of high quality.

Sponsors should make sure that the research they rely on is relevant to the specific medicine being promoted and to the specific benefit being claimed.

NHMRC levels of evidence NHMRC levels of evidence should not be required as these were designed for prescription medicines and treatment guidelines. The Evidence Guidelines recognise that evidence used to support indications for listed medicines is often sourced from the available literature, rather than sponsor-initiated clinical trials specifically conducted with a proposed medicine. However, where a sponsor chooses to conduct clinical trials before listing a medicine, they should refer to the National Health and Medical Research Council (NHMRC) website for information on conducting such trials.
Transition Industry proposes a transition time of no less than 5 years to allow for sponsors to adjust to the requirements. Sponsors are currently required to hold evidence for the indications they make for their listed medicines. The revised evidence do not introduce new requirements, hence a transition period is not necessary. However, the TGA will continue engagement with industry over our approach to evidence reviews for listed complementary medicines.

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