TGA Evidence Guidelines
TGA Evidence Guidelines
TGA Evidence Guidelines
Copyright
© Commonwealth of Australia 2019
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if
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Contents
Guidelines on the evidence required to support indications
for listed complementary medicines _______________ 5
Who are these guidelines for? ________________________________________________ 5
Scope of guidelines _____________________________________________________________ 5
Part A: Evidence to support indications for listed
complementary medicines _______________________ 7
Indications for listed medicines _____________________________________________ 7
Evidence to support indications for listed medicines ___________________ 11
Traditional indications: what evidence do you need to
support your traditional indication? ______________ 15
Evidence of traditional use __________________________________________________ 15
Multi-traditional paradigm medicines _____________________________________ 16
What are the sources of evidence of traditional use? ___________________ 16
Assessing the relevance of evidence to your indication_________________ 19
What indication sub-type does your evidence of traditional use support?
____________________________________________________________________________________ 20
Choosing or deciding upon your traditional indication _________________ 21
How to compile a summary of the evidence to support your traditional
indication _______________________________________________________________________ 22
Scientific indications: what evidence do you need to
support your scientific indication? _______________ 23
What are the sources of scientific evidence?______________________________ 23
Assessing your evidence _____________________________________________________ 29
Balanced view of your scientific evidence _________________________________ 31
What indication sub-type does your scientific evidence support? ____ 32
Choosing or deciding upon your scientific indication ___________________ 33
How to compile a summary of the evidence to support your scientific
indication _______________________________________________________________________ 33
Cross-evidence base medicine: What evidence do you
need to support your medicine with a combination of
traditional and scientific indications? _____________ 34
Cross-evidence base ingredient (scientific and traditional) ___________ 34
Cross-evidence based medicine _____________________________________________ 35
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Scope of guidelines
These guidelines provide information on the type of evidence that is required to support
indications for medicines listed under section 26A of the Therapeutic Goods Act 1989 (the Act)
(excluding sunscreen therapeutic products). The document is comprised of two parts:
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Related information/guidance
• Refer to Permitted indications for listed medicines guidance for information on what
permitted indications for listed medicines are, including terminology and structure, use and
applying for new indications.
• Refer to the Australian Regulatory Guidelines for Complementary Medicines (ARGCM) for
information on the regulation of listed medicines and registered complementary medicines
in Australia.
• Refer to Assessed listed medicines evidence guidelines for guidance on evidence
requirements for AUST L (A) assessed listed medicines.
• Refer to the Australian Regulatory Guidelines for Sunscreens (ARGS) for guidance on the
regulatory requirements for therapeutic sunscreen products.
TGA disclaimers
• This document is a guide only. It is the responsibility of each sponsor to
understand and comply with the regulatory requirements contained in the
Therapeutic Goods Act 1989 and supporting regulations. You are
encouraged to seek your own professional advice to find out how
therapeutic goods legislation and other applicable laws apply to you.
• Indications used in these guidelines have been provided as examples only.
These indications do not relate to actual medicines and whether there is
evidence to support the indications has not been assessed by the TGA.
• These guidelines reflect the TGA’s approach to assessing evidence to
support indications for listed complementary medicines. However, there
may be specific circumstances that justify a departure from the evidence
guidelines and in this situation the TGA will consider the merits of each
case against the regulatory requirements.
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Indications included in the Permissible indications Determination have been assessed against a
set of criteria and determined to be appropriate for listed medicines. These criteria are intended
to ensure that permitted indications will only cover (and AUST L listed medicines will be limited
to making) indications relating to:
• health maintenance
• health enhancement
• prevention of a non-serious vitamin or mineral dietary deficiency
• a non-serious form of a disease, ailment, defect or injury
To be consistent with their low risk status, regulatory requirements are placed on the use of
certain indications in listed medicines. These are specified in the Permissible Indications
Determination.
See Permitted indications for listed medicines guidance for more information on: what
permitted indications for listed medicines are including: terminology; structure; use; and
applying for new indications.
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Whether using traditional or scientific indications, the specificity of your indication determines
the level of evidence required to support your indication (refer to ‘What indication sub-type
does your evidence of traditional use support?’ and ‘What indication sub-type does your
scientific evidence support?’).
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Indication qualifiers
When you enter your medicine in the electronic Listing Facility (ELF), you may also choose to
select indication qualifiers from drop down lists to make a permitted indication more specific
and align with the evidence you hold for your medicine. For more information see:
• Permitted indications for listed medicines guidance
• Listed medicines application and submission user guide for information on selecting
indication qualifiers
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As a mechanism of establishing that you have the evidence to support your indications, you
should consider completing the appropriate checklists for your medicine and associated
indications, before listing your medicine on the ARTG. You should hold all the information
contained within the checklists for your medicine and submit this information to the TGA when
requested to do so.
During a compliance review of your medicine, the TGA may request the evidence you hold to
support the indications you make for your medicine. At this time, you may include the
appropriate checklists (or similar information) as part of your response to the TGA’s request for
information. While presenting your information in the provided checklist format is not
mandatory, submitting information in this format will help facilitate and expedite the
compliance review process.
Diagram 1 provides a general flow chart on the steps for compiling your evidence package for
your listed medicine. Detailed guidance on compiling traditional or scientific evidence packages
is provided in:
• How to compile a summary of the evidence to support your traditional indication
• How to compile a summary of the evidence to support your scientific indication
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Diagram 1: Compiling an evidence package to support the indication/s for your listed
medicine
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Homoeopathic medicines
Homoeopathic medicine is a traditional paradigm where the manufacturing
process of serial dilution and succussion or serial trituration is a major
component of the tradition of use. Provided that a substance is prepared
according to principles described in a recognised homoeopathic
pharmacopoeia and safety requirements are satisfied, indications may be
based on traditional use. Evidence of traditional use for homoeopathic
medicines can include independent written histories of use in traditional or
contemporary homoeopathic literature.
Evidence package checklists will assist you in compiling an evidence package for your traditional
indication.
While the TGA does not have a list of approved sources of information, Appendix 3 provides
some examples of internationally recognised resources and texts.
Each item of evidence must be considered on its own merit in relation to your
medicine. An item of evidence can only be considered a primary source of
evidence if it establishes a tradition of use and is credible and relevant for your
medicine/indication.
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Can you use evidence in languages other than English to support your
traditional indication?
Evidence in a language other than English can be used, if you provide in your evidence package
a:
• copy of the relevant pages in the original language; and
• verified English translation of the relevant pages.
A verified translation is one that is accompanied by a signed statement from an accredited
translator, fluent in both languages, verifying that the translation is true and complete.
Are there any other evidence sources you can use to support your
traditional indication?
If the traditional indication is from an oral culture, video footage (stored in a digital format, not
on film) may be appropriate. To be regarded as high quality, oral evidence must be corroborated
from at least two separate sources in different locations.
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Traditional non-specific
Two primary sources of evidence of traditional use.
(general) indications
Traditional specific
At least two primary sources of evidence of traditional use as well
indications as other relevant and credible items of evidence to support the
specificity of the indication.
Examples
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present in the medicine was used in ancient times for symptoms such as ‘stomach fire with
rebellious stomach qi’. However, there is no information on the plant part of the herbal species
used, the method of preparation or the recommended dosage.
In this instance, the evidence item is not sufficient to support the proposed indication.
Compare your chosen indication with the reported health benefit and context of use in your
evidence of traditional use. Your indication should have the same meaning and intent specified
in the evidence (including any traditional terminology). The terms used in your indication
should be consistent with the specified paradigm to ensure that the indication is not misleading
and appropriately supported by the evidence you hold. The use of common English terms in
addition to traditional terminology may provide clarity to the average consumer regarding the
therapeutic use of the medicine.
You should ensure that each ingredient (for which a traditional indication is made) has been
prepared using a traditional method for that paradigm (for example: dilution and succussion of
mother tinctures for homoeopathic medicines). Where your medicine has been modified from a
classic formula or individual ingredient –you should show that the formula or ingredient, as
modified, is still acceptable within the specified tradition.
When choosing your traditional indication you should:
• select the traditional paradigm that supports the traditional formulation
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• ensure the evidence supporting the indication is based on experiences or theories specific to
the particular tradition, not on scientific clinical evidence
• ensure the indication uses the same logic and terminology (may be accompanied by English
terms on the medicine label) as the evidence of use in the specified traditional paradigm
• Traditional indications cannot refer to anatomical, physiological or pharmacological effects
that are not envisaged within the specified paradigm, for example: ‘raise haemoglobin levels’
• imply efficacy based on scientific evidence for the medicine, for example: ‘clinically tested’
• use specialist terminology that belongs to a different paradigm, for example: ‘damp heat’ is a
specific Chinese medicine term and would be inappropriate for an Ayurvedic medicine
• include indications that require scientific substantiation, for example: ‘assists to increase
bone density by 10%’; or’
• refer to conditions that cannot be diagnosed within the specified paradigm, for example:
‘Traditionally used in Chinese medicine to increase bone mineral density’ is inappropriate as
increased bone mineral density cannot be monitored or determined without conventional
medical intervention
If you are aware that there is conflicting evidence between the history of
traditional use and contemporary scientific evidence for your medicine, then it
is advisable to include a statement to this effect in any labelling and advertising
associated with the medicine, for example: ‘this traditional use is not supported
by scientific evidence’. This will ensure that the advertised information relating
to your medicine is truthful, valid and not misleading.
In choosing your traditional indication, ask yourself:
• Are the terms used to describe your indication the same as those in your
evidence of traditional use?
• If the terms are different from those in the evidence of traditional use, can
you justify the change?
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Scientific indications are usually supported with data from relevant controlled human clinical
trials, or studies. These studies may be supplemented by other sources of evidence. You may
also choose to conduct clinical trials on your medicine. For more information on conducting your
own clinical trials refer to the National Health and Medical Research Council (NHMRC) website.
1‘Peer review’ is the evaluation of research by other people in the same field to maintain the quality of
work in that field.
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Database searches
Your database search should utilise MEDLINE/PubMed electronic databases
and include at least one other relevant database.
Web search engines are not considered appropriate databases or sources of
primary evidence.
During your database search, if a substantial number of results (hits) are received, you can
refine your search by reducing the date range to the last 5-10 years (a justification for refining
the date range should be recorded in your evidence package).
Your database search of the literature should be documented to best practice standards. The
Australian Regulatory Guidelines for Complementary Medicines (ARGCM) provides guidance on
appropriate search strategy standards. The search terms, databases and search interfaces you
use and the numbers of references retrieved should be documented in your evidence package
(Evidence package checklists).
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Table 5: Levels of evidence associated with clinical studies (adapted from NHMRC)
IV Case series with either In depth description of the factors related to a disease,
post-test or pre-test/post- disorder or condition in a specific individual or group of
test outcomes. individuals.
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Dosage
For scientific indications, the recommended dosage and duration or frequency of administration
of the medicine must be consistent with the evidence supporting the indication.
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Statistical analysis
A study that fails to show a statistically significant difference between test and control group
may indicate that the measured effects are merely the result of a placebo effect or chance. The
results should translate into a meaningful health benefit for consumers. Some results that are
statistically significant may still be so small that they may not provide a positive effect to
consumer health.
Filtering relevant evidence to those of high quality will involve, as a minimum, an assessment of
the following:
• characterisation of the ingredient/s
• study design/methods
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Specific indication You must hold scientific evidence to support the specific indication. Such
as
• Evidence obtained from well-designed controlled trials with
randomisation; OR
• Evidence obtained from well-designed analytical studies preferably
from more than one centre or research group, including
epidemiological cohort and case-control studies; OR
• Evidence obtained from multiple time series with or without
intervention, including within country and between country
population studies.
Sponsors must ensure they are compliant with any requirements relating to
the use of a permitted indication as included in Therapeutic Goods
(Permissible Indications) Determination.
Vitamin or mineral supplementation claims are only permitted where the
recommended daily dose of the medicine provides at least 25% of the
Recommended Dietary Intake (RDI) for that vitamin or mineral. The RDI in this
context refers to the Australian RDI. If there is no Australian RDI for a vitamin
or mineral, an RDI from another country may be used. Where vitamins or
minerals are the subject of other kinds of claims, the dose must be consistent
with the evidence to support the claim being made. Indications / claims should
not refer to the presence of vitamins or minerals unless they are present in the
recommended daily dose of the product to at least the level of 10% of the RDI,
unless there is evidence to support a therapeutic effect below this level.
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The use of the term ‘clinically proven’ in scientific indication infers a level of certainty in the
implied health benefit associated with the listed medicine in that it has been clinically trialled
and proven to be effective. These terms are not acceptable unless supported unequivocally by
robustly designed, published peer-reviewed clinical trial(s) conducted on the actual medicine
being advertised, or an identical formulation and dose (as a minimum). The use of the terms
‘clinical’, ‘clinically’, ‘scientifically’ coupled with ‘trialled’ or ‘tested’ implies a higher level of
certainty associated with the health benefit of your medicine and unless matched by well-
designed clinical studies on your specific medicine, may mislead consumers about the
effectiveness of your medicine.
You must compare your indication with the quoted health benefit in your evidence identified
from scientific sources. Your indication will refer to the same clinically significant study
outcomes as that reported in the clinical study.
In selecting your scientific indication you should:
• ensure that the medicine’s therapeutic benefit is demonstrated by the clinical study
outcomes
• ensure that any claims you make from your medicine imply only the same level of certainty
in clinical effectiveness as that reported in clinical studies, for example ‘clinically proven to...’
compared to ‘may assist to...’
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If you are aware that there is conflicting evidence between the history of
traditional use and contemporary scientific evidence for your medicine, then it
is advisable to include a statement to this effect in any labelling and advertising
associated with the medicine, for example: ‘this traditional use is not supported
by scientific evidence’. This will ensure that the advertised information relating
to your medicine is truthful, valid and not misleading.
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Scientific studies
Study populations
As indicated in Part A of this guidance, only human studies are considered sufficient as primary
evidence to support indications for your listed medicine. Studies used to justify the scientific
indications for your medicine should be conducted in populations that are representative of, or
can reasonably be extrapolated to the general Australian population.
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In general, data obtained from studies with participants who have serious diseases, conditions
or ailments cannot be extrapolated to a healthy population and, as such, are not relevant
evidence to support an indication for a listed medicine.
However, in circumstances where a positive modulation of a health benefit is noted in a diseased
study population, it may be possible to use these clinical outcomes to provide secondary
evidentiary support for your indication.
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Table 7: Characteristics of study populations that are relevant to the target population
Helps increase weight loss when Male and female participants aged 18-65 years; generally
used in conjunction with a healthy population with BMI 25-30 kg/m2 socio-culturally
calorie or kilojoule controlled similar to the Australian population.
diet and physical activity or
exercise
Relieve pain Male and female participants aged 18-65 years; generally
healthy population with a range of painful (non-serious)
conditions.
Relieves cough in children Male and female participants aged 2-12 years; generally
healthy population with cough associated with a range of
(non-serious) conditions.
Maintains bone strength Male and female participants aged 18-65 years; generally
healthy population; dietary and lifestyle pattern similar to the
Australian population.
Study duration
Relevant studies should be of appropriate duration to validate a health benefit included in an
indication. Each study should be long enough to clearly demonstrate the health benefit. The
appropriate duration of studies depends on the nature of the health benefit. If an indication
refers to a short-term benefit such as acute pain relief, trials of several hours duration may be
adequate. Conversely, for indications where long-term benefits are implied, studies must be of
sufficient duration to establish a sustained response that is likely to be meaningful. This is
particularly important for indications relating to maintenance of health or risk reduction, and
those that produce favourable modulation of body weight, as the body’s homeostatic processes
may reduce early gains. Therefore, studies assessing cardiovascular risk factors, weight, or
changes in muscle mass or bone strength that are not long enough to establish a sustained
clinical benefit are not relevant.
For these reasons, the duration of each study is an important factor and must be considered
when assessing the body of evidence relevant to an indication. The minimum relevant study
duration should be determined and justified in relation to the relevant indication, and all studies
of insufficient duration should be omitted from the primary analysis.
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Study outcomes
reflection of effectiveness under real world conditions [Koepsell & Weiss (2003)]. When
dropouts are not accounted for in the analysis of results, attrition bias (exclusion bias) may
result.
The number of study participants required for a s
tudy to demonstrate c linical
significance depends on several factors: the study aim and design, the type and
sensitivity of the p
rimary end-point, how the data will be a
nalysed, the
significance l evel and allocation ratio of treatment to control as well as the
anticipated standard deviation or the anticipated results in the control group.
There are many published resources available in which these factors are
explained including good and bad practices for sample s
ize c
alculation.
Often high quality clinical studies have been designed to provide meaningful statistical
calculations. Study clinicians have considered the factors that are important to achieve the
desired outcome and have designed the study accordingly. If you choose to use a clinical study to
support a scientific indication, you are not expected to perform power calculations, but to
consider any limitations of the statistical calculations that the study authors have reported,
including the number of drop outs and the impact this may have on the reported study
outcomes.
Appropriate statistical methods must be used to compare the effects of treatment between
groups, and to compare the number of individuals achieving a clinically significant result in each
group. The analysis should also account for any potential confounders. An Intent-to-Treat (ITT)
analysis should also be performed, particularly when attrition rates are high. Previously
unplanned analyses undertaken after the completion of a trial (post-hoc analyses) are to be
avoided as they are unlikely to have been considered in power calculations and study design.
An indication can only be justified when the available evidence supports the described health
outcome. The balance of evidence should support an outcome that is:
statistically significant; and
clinically significant (or meaningful to the consumer).
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Clinical significance
Not all statistically significant differences are clinically significant (Berry (1986), Sackett etal.
(1985), Levitt (1981)). A statistically significant outcome indicates only that there is likely to be
a relationship between intervention and outcome. Clinical significance is more difficult to define
but is commonly considered to represent a degree of benefit that is worthwhile in real life to
justify intervention, and may consider factors such as cost, side effects and inconvenience.
A number of general principles can provide guidance about clinical significance. For listed
medicines, it might be regarded as a degree of benefit that is meaningful to the consumer. The
number of participants required to detect a clinically significant difference between treatment
and control groups depends on the type and level of health benefit, the standard deviation of the
health effect, the significance level (p-value) and statistical power of the study and the type of
hypothesis being tested.
In general terms, most research studies contain 0.8 sample power, meaning that there is an 80%
probability of finding a significant difference with a given sample size, if a real difference truly
exists and having excluded the role of chance. High quality studies will recruit many more
subjects than required in order to maintain adequate numbers in the trial even when there are
drop outs recorded throughout the study. The meaningfulness of a predetermined ‘significant
clinical benefit’ may then vary between patients depending on a number of factors such as state
of disease, comorbidities, personal circumstances, and alternative options for treatment.
Judgements about clinical significance are often made by experienced clinicians within a context
of ongoing monitoring and supervised care. Listed medicines, however, are freely available to
consumers and may not involve practitioner intervention or supervision. Determining the
clinical significance of health outcomes associated with listed medicines is particularly difficult
for the following reasons:
• Listed medicines are self-selected by consumers from a wide variety of backgrounds, with
varied expectations and variable educational and financial resources.
• The health outcomes provided by listed medicines may be modest, not readily apparent,
and/or achieved over long periods of time.
• Healthy consumers may be satisfied with smaller gains in health than individuals with a pre-
existing condition.
Notwithstanding these factors, consideration should be given to the likely significance
(meaningfulness) of an observed health outcome to the intended target population. Table 8
provides a useful approach to the assessment of clinical significance for listed medicines.
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• the clinical trial duration needs to be sufficiently long to support indications that refer to
long term benefits, for example: sustainable weight loss is greater than 6 months; and
• the study should be carried out in a study group representative of the population group for
which the indication is made. Any extrapolation of results obtained from subjects outside the
target population group must be appropriately justified.
The use of qualifiers relating to the biological or clinical target of an indication restricts the
applicability of the indication to a specific type of a condition or process (such as mild pain
rather than pain more broadly) and narrows the relevant evidence base.
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Literature used to support low level biomarker indications should demonstrate therapeutic
effect in populations representative of, or can reasonably be extrapolated to, the healthy general
Australian population. This is difficult to substantiate when evidence is derived from a diseased
population. The extrapolation of study findings from a diseased study population to the healthy
population can be problematic and potentially misleading. A small change in a given biological
surrogate may be associated with negligible biological dysfunction and minimal increase in risk
of serious forms of disease, whereas larger changes are more likely to be associated with
pathophysiological processes and an increased risk of overt illness which requires health
practitioner involvement.
If your evidence uses study populations with baseline biomarker levels that lie outside normal
healthy levels it is unlikely to be considered relevant to support indications relating to low-level
biomarker indications for the healthy Australian population.
In addition, indications should only target healthy individuals with biomarker levels that lie
within the normal healthy range.
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The assessed listed-AUSTL (A)] pathway may provide an option for listed
medicines to make biomarker indications above those included in the
permitted indications list, when the efficacy of the medicine has been assessed
by the TGA. Refer to
Assessed listed medicines evidence guidelines
for more
information.
Because of the continuum between health and disease, all biomarker and risk reduction
indications should include a disclaimer that recommends consumers consult a healthcare
practitioner if they are concerned about their health status.
Indications that refer to the m
odulation of biomarker levels cannot be
supported by evidence of traditional use.
BMI unit) across a population could make significant impacts on the prevalence of obesity and
overweight individuals within the population. A mean body weight loss of 3% is likely to be
equivalent to a mean loss of one BMI unit in the population enrolled in a clinical trial. However,
the clinical study population will often include obese individuals which are different to a healthy
target population.
Obese people expend more energy for a given activity because of their larger body mass.
Therefore, for the same level of dietary energy and physical activity, the reduction in body
weight will be different for obese (BMI >30 kg/m
2) and overweight individuals
(BMI 25-30 kg/m
2). This difference may be negligible for small increments in BMI but is likely to
become increasingly significant as BMI increases.
Thus the degree of weight loss is likely to be different when comparing overweight and obese
individuals when given the same treatment protocol. As such, studies that include obese
participants with a BMI >30 kg/m 2 cannot be generalised to otherwise healthy overweight
individuals.
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It follows therefore, that in non-randomised controlled studies, the treatment group
(BMI 25-29.9 kg/m
2) should show at least a 5% greater weight loss than the placebo group to
counter for potential confounding. There must be a reasonable chance that meaningful weight
loss will be achieved in consumers investing in the medicine. Single mean values may be
misleading and it is important that the effect of an ingredient or medicine represents a
consistent effect across the whole target population. At least 50% of participants in the
treatment group must achieve a loss of at least 5% of initial body weight, making it ‘more likely
than not’ that consumers will achieve a clinically significant benefit from appropriate use of the
medicine.
For each clinical study used to support weight loss indications, the meaningfulness of the
observed effect to the general Australian population should also be assessed. Study outcomes
that report statistical significant changes in weight loss parameters must also demonstrate
clinical significance, or provide a meaningful health benefit to the consumer of your medicine.
Table 9 provides examples of terms that are often related to, or used to convey weight loss that
should not be substituted for the term weight loss in an indication. The evidence should support
your indication, thus if your evidence refers to the reduction of hunger, then your indication
could refer to reducing hunger, without extending this to weight loss or management.
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Table 9: Terms that should not be substituted for the term ‘weight loss’ in an indication
Increased metabolic rate
Fat loss
Weight Appetite suppression
maintenance
Enhanced metabolism Increased muscle Enhanced satiety
mass Weight control
Enhanced fat metabolism
Fasting
Cellulite Weight
Thermogenesis management
Slimming
Increased calorie burning
If a l isted medicine s tates that it is intended to supplement a named nutrient, it
must provide a t least 25% of the Recommended Dietary Intake ( RDI),
Adequate Intake ( AI) or nutrient reference value for that nutrient and the
nutrient should be i n a form that is available for absorption by the b ody.
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Examples
‘Helps to prevent dietary (state vitamin/mineral/nutrient) deficiency’
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Checklist 1: Evidence package cover page
Yes Yes
Checklist 2: Evidence search strategy
Yes Yes
Checklist 3: Evidence of traditional use filter
No Yes
Guidance to filter your evidence to identify those
items that are credible, relevant and of high quality
Checklist 4: Scientific evidence filter
Yes No
Guidance to filter your evidence to identify those
items that are credible, relevant and of high quality
Checklist 5:Evidence of traditional use summary
No Yes
Checklist 6: Evidence of scientific use summary
Yes No
The evidence which supports an indication for each ingredient is drawn from evidence of
traditional use, or from other scientific research into the ingredient. Refer to the Evidence
Guidelines for information on type of indications and evidence required to support them.
An indication may be related to one or more active ingredients, or to a fixed combination of
active ingredients. For each indication-ingredient relationship, you need to complete the
appropriate checklists to document:
your search for evidence
the findings from your search
the credibility of the evidence you wish to use to support the indication or claim
the relevance and consistency of the evidence, indication and medicine
Your evidence package should include a summary of the evidence you hold supporting all the
indications of your medicine and attached copies of evidence items.
If you have a traditional indication with evidence of traditional use
You are advised to include checklists 1, 2, 3 and 5 in your evidence package.
If you have a scientific indication with scientific evidence
You are advised to include checklists 1, 2, 4 and 6 in your evidence package.
If you have a both evidence of traditional use and scientific evidence
You are advised to include all checklists (1, 2, 3, 4, 5 and 6) in your evidence package.
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Next step
Complete checklist 2 to record your literature research.
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Search strategy
Provide the following information in the table provided:
• Source searched:
– identifying bibliographic details
– exclude duplicate sources; and
– include any website links.
• Date range of search: applicable for scientific literature searches.
• Search terms: include key words and specific exclusion terms.
• Type of evidence: Indicate if the evidence is scientific (such as: random control trial,
evidence based text, Cochrane review) or evidence of traditional use (traditional
pharmacopoeia, materia medica).
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Next step
The items of evidence that you have collated through this process should be filtered in checklist
3 (evidence of traditional use) or checklist 4 (scientific evidence). The filtering process will
determine the relevance and quality of each evidence item. This should be completed for all
items of evidence.
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Evidence item
Provide the details of the item of evidence that you are assessing.
Indication
Your evidence should refer to the same specific health benefit (with the same meaning and
intent) as your medicine.
If your indication is a specific traditional indication, the evidence should support this specific
health benefit and context of use, for example: target population.
Evidence of traditional use may be derived from populations that do not closely resemble the
general Australian population (which is the target population for listed medicines in Australia).
Further, some traditional medicine paradigms may specifically exclude certain subgroups of the
populations from using a particular medicine (for example: children, pregnant women). Your
indication should reflect this evidence.
Route of administration
How similar to your medicine is the description of intended route of administration (for
example: inhalation as opposed to a chest rub) to that specified in the evidence?
Dosage
The dose, dosage form, dosage range and dosage frequency of the ingredient/medicine should
be consistent with your evidence and the composition and preparation of the medicine should
be consistent with the principles of the tradition about which the indication is made.
Duration of use
How similar to your medicine is the duration of use specified in the evidence, for example: long
term, short term?
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If you answer ‘no’, ‘similar’ or ‘different or not specified’ to the majority of questions in checklist
3a, it is likely that the evidence does not support your indication and you should disregard it. If
you choose to include this item of evidence in your evidence package you should provide
justification as to why that item of evidence is included (see 3b).
3b Justification of evidence
It is recognised that it may be difficult to provide evidence for traditional indications that fulfil
all aspects of the credibility and relevance criteria.
Some sources of evidence may not include sufficient details to meet the majority of the relevance
and quality criteria in the traditional checklist filter (3a). In this situation, you should hold
several sources of evidence that meet most of the relevance criteria in the traditional checklist
and when these are combined, the collective source should provide all aspects of the evidence
for all concepts raised in the filter. That is the combined items of evidence should address data
gaps identified in 3a. This process allows you to use multiple sources of evidence of traditional
use to accurately support your traditional indication.
If the evidence summary table lists evidence items that are not relevant (and no justification has
been provided for their inclusion into your evidence summary), you may be asked for further
clarification as to why you have included evidence that appears irrelevant.
Next step
Once you have filtered your evidence to those references that are credible and relevant, or have
a justification for their inclusion in your evidence summary, then these references should be
included and summarised in Checklist 5: Summary table for evidence of traditional use.
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Use t
he s
cientific evidence f ilter to reduce t
he number of evidence i tems to
those t
hat are r
elevant and of high-quality, or to those that you can j ustify their
inclusion into your evidence s ummary.
You should also ensure that the evidence supporting your indications remains valid for the life of
the medicine, and this is best achieved using a body of evidence approach. As research advances,
the body of scientific evidence supporting a particular health benefit may change. Newer clinical
studies may enhance the strength of the evidence supporting your claim, or it may be
inconsistent with the strength of previous research. Having a body of supporting evidence will
allow you to ensure that the indications claimed for your medicine remain true, valid, not
misleading and consistent with scientific evidence for the life your medicine.
Evidence item
Provide the details of the item of evidence that you are assessing.
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Evidence item
Provide the details of the item of evidence that you are assessing.
Indication
You must ensure that the research is relevant to your specific indication for your medicine. In
selecting indications, you should take care to make sure that they match the underlying evidence
you hold. Indications that do not match the science, no matter how sound that science is, are
unlikely to be supported. Indications should not exaggerate the extent, nature, or prominence of
the effects achieved in a study (the study outcomes), and should not suggest greater scientific
certainty than that which actually exists.
Specificity
Your evidence should refer to the same specific health benefit (with the same meaning and
intent) as your medicine.
If your indication is a specific, scientific indication, the evidence should support this specific
health benefit and context of use, for example: target population.
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Dosage
For scientific indications, the recommended dosage and duration or frequency of administration
of the medicine must be consistent with the evidence supporting the indication.
Route of administration
The evidence must relate to the whole medicine, the same active constituent(s) with a similar
route of administration to the medicine for which a claim is being made.
Duration of use
The recommended duration of use for your medicine should reflect the evidence.
Study methodology
The clinical research being used to support your scientific indication should be conducted in a
reliable manner to yield meaningful and reproducible results. The design, implementation, and
results of each piece of research are important to assessing the adequacy of the substantiation of
the health benefit or study outcome.
There are some principles generally accepted in the scientific community to enhance the validity
of test results. However, there is no single set protocol for how to conduct research. For
example, a study that is carefully controlled, with blinding of subjects and researchers, is likely
to yield more reliable results. A study of longer duration can provide better evidence that the
claimed effect will persist and better evidence to identify potential safety concerns.
You should critically appraise scientific studies in terms of methodological quality and the
possibility of bias and/or confounding. Studies that have been peer-reviewed are more likely to
be methodologically robust, but may not be.
Filtering to relevant evidence to those of high quality will involve, as a minimum, an assessment
of the following:
• characterisation of the ingredient/s
• study design/methods
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Participant dropouts
Attrition rates are commonly high in studies that evaluate health gains that are modest and
require long-term commitment. High attrition can introduce serious bias (attrition bias) into
these studies because the reasons for non-completion vary across initially randomised groups.
High attrition rates may also diminish the general applicability of the treatment to the Australian
population. The resulting data from a high attrition study should be interpreted with caution.
Confounders
Do any of the study’s confounders or variable affect the relevance of the evidence to your
indication?
Method of randomisation
Studies that incorporate randomisation process of assigning trial subjects to treatment or
control groups are often considered of greater quality due the reduction of potential for bias.
The randomisation method should be described in the study report and meet contemporary
standards (such as using post-study questionnaires’ of study participants to confirm that they
remained blinded). Similarly, the incorporation of good blinding methods in the study design
tends to result in studies that are methodologically robust.
Blinding protocol
Blinding protocols aim to avoid bias. A double blind protocol is where neither the experimenter
nor experimental subjects have knowledge of the identity of the treatments or the results until
after the experiment is complete.
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Statistical analysis
Statistical significance of study outcomes is important. A study that fails to show a statistically
significant difference between test and control group may indicate that the measured effects are
merely the result of a placebo effect or chance. The results should translate into a meaningful
benefit for consumers. Some results that are statistically significant may still be so small that
they may not provide a positive effect to consumer health.
Study limitations
You need to consider if any study limitation affect the relevance of the evidence to your
indication.
Clinical significance
You should assess the results of scientific studies for statistical significance and meaningfulness
(clinical significance) of the reported therapeutic benefit. Your evidence should demonstrate an
overall improvement in the expected health benefit that is statistically and clinically significant.
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To facilitate the assessment of balance view of evidence, both relevant non-supporting and
supporting items of evidence will need to be assessed for quality.
Checklist 4c provides a mechanism to determine the number of high-quality items that are
relevant to your medicine. You will need to have regard to irrelevant studies noted during the
search of the available literature to make an assessment of the balance of evidence for
supporting your indication. Only if the balance of high quality evidence is equivocal are the
outcomes of lower quality studies to be included in assessing the balance of evidence.
This checklist is designed to help you assess whether a reasonable person making an objective
assessment of all the relevant, high-quality evidence about your medicine would conclude that
the weight of high-quality evidence is in favour of your indication rather than against it.
When the balance of scientific evidence supports your proposed indication then complete the
Scientific Evidence summary. Otherwise, you should reconsider your indication and modify the
indication such that it is consistent with the evidence that you hold.
Next step
Once you have filtered your evidence to those references that are credible and relevant, or have
a justification for their inclusion in your evidence summary, then these references should be
included and summarised in Checklist 6: Summary table for evidence of scientific use.
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Does the Evidence summary table only include relevant, high quality
evidence?
If not, then you will need to provide justifications as to why you have i ncluded
these i tems in your evidence s ummary.
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Limitations of the IF
Generally, while high IFs are indicative of the (high) quality and "impact" of research published
by a given journal, low IFs do not necessarily correlate with low quality research. A given journal
may for example consistently publish 'good research', but have a low IF, if the field of research is
narrow and therefore has a small readership/ authorship base.
Journals with high IFs (for example Science 31, for 2011) tend to have been established for many
decades, and accept manuscripts from a broad range of disciplines. Because they have a high IF,
researchers attempt to publish in them first, so they get "first right of refusal" on all the best
research. IF is dependent on net readership, and therefore journals that publish weekly or are
free to air have higher IF value compared to journals that are published monthly, but in general
a higher IF value the better the research.
0 ("not yet available") to < 5
Ambiguous/ uninformative
5 to < 10
Suggestive of "quality" research
(i.e. rigorous peer-review and high interest-value)
Highly suggestive of quality research
Various companies provide IF values as well as other information of all journals to provide
guidance regarding the level of quality of journals (website search for impact factors will find
this information).
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Monographs
• Blumenthal M et al. (eds) (2000) Herbal Medicine – Expanded Commission E monographs,
American Botanical Council, Austin, Texas.
• European Scientific Co-operative on Phytotherapy (ESCOP) series (1996) Monographs on
the Medicinal Uses of Plant Drugs, ESCOP, Exeter.
• World Health Organization (WHO) (1999) Monographs on Selected Medicinal Plants, Vol 1,
WHO, Geneva.
Pharmacopoeias
• British Herbal Pharmacopoeia, British Herbal Medicines Association, West Yorkshire.
• European Pharmacopoeia, Council of Europe, Strasbourg.
• Martindale: the Extra Pharmacopoeia, Pharmaceutical Press, London.
• The British Pharmaceutical Codex, Pharmaceutical Press, London.
• The British Pharmacopoeia, Her Majesty’s Stationery Office, London.
• The United States Pharmacopeia and National Formulary, USP Convention Inc, Rockville,
Maryland.
• Pharmacopoeia of the People’s Republic of China Vol 1
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Appendix 4: References
Benedict, M & Arterburn, D (2008). Worksite-based weight loss programs: A systematic review
of recent literature. American Journal of Health Promotion 22(6): 408-416.
CONSORT website (Consolidated Standards of Reporting Trials)
European Medicines Agency (2007). Guideline on clinical evaluation of medicinal products used
in weight control (CPMP/EWP/281/96). London.
Franz M, et al. (2007). Weight-loss outcomes: A systematic review and meta-analysis of weight-
loss clinical trials with a minimum of 1-year follow-up. Journal of the American Dietetic
Association 107: 1755-1767.
Franz, M, et al. (2007). Weight-loss outcomes: A systematic review and meta-analysis of weight-
loss clinical trial with a minimum of 1-year follow-up. Journal of the American Dietetic
Association 107: 1755-1767.
Heller HJ, Greer LG, Haynes SD, Poindexter JR, and Pak CY (2000) Pharmacokinetic and
Pharmacodynamic comparison of two calcium supplements in postmenopausal women. J Clin
Pharmacol Nov; 40(11): 1237-44.
Jull, A, et al. (2009). Chitosan for overweight or obesity (Review). The Cochrane Library 2009(1):
1-44.
Koepsell, T & Weiss, N (2003). Epidemiologic Methods: Studying the occurrence of illness.
Oxford University Press, New York.
National Health and Medical Research Council (2003). Clinical Practice Guidelines for the
Management of Overweight and Obesity in Adults. Canberra.
National Health Medical Research Council. levels of evidence and grades for recommendations
for developers of guidelines. 2009.
Note for guidance on good clinical practice (CPMP/ICH/135/95). Therapeutic Goods
Administration 2000.
Rose G and Day, S (1990). The population mean predicts the number of deviant individuals.
British Medical Journal 301: 1031-1034.
Sacks F, et al. (2009). Comparison of weight-loss diets with different compositions of fat, protein,
and carbohydrates. New England Journal of Medicine 360(9): 859-873.
Schulz, KF et al. (2010). CONSORT 2010 Statement: Updated Guidelines for Reporting Parallel
Group Randomized Trials. Annals of Internal Medicine. 152.
United States Federal Trade Commission's (FTC's) "Business Guide for Dietary Supplement
Industry Released by FTC Staff". (The full version of the FTC's guidelines are available from the
website.
Wu T, et al. (2009). Long-term effectiveness of diet-plus-exercise interventions vs. diet only
interventions for weight loss: a meta-analysis. Obesity Reviews 10: 313-323.
Laaser U, et al. (2001). Can a decline in the population means of cardiovascular risk factors
reduce the number of people at risk? Journal of Epidemiology and Community Health 55: 179-
184.
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Version history
Version Description of change Author Effective date
V1.0 Original publication
Therapeutic Goods October 2001
Administration, Office
of Complementary
Medicines
V2.1 Row 1,Table 6, page 41 correction
Therapeutic Goods July 2014
of BMI range to state 25-30kg/m
2 Administration, Office
of Complementary
Medicines
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PO Box 100 Woden ACT 2606 Australia
Email: [email protected] Phone: 1800 020 653 Fax: 02 6203 1605
https://www.tga.gov.au
Reference/Publication #