Listed medicines with blood glucose and cholesterol indications

Background

What led to this review?

In 2016, we analysed data from our compliance reviews of listed medicines conducted in 2015. Of those indications which we found to be unsupported by the evidence provided to us by sponsors, the highest proportion was for indications relating to the:

• management;
• control;
• maintenance; and/or
• balance

of normal, healthy or improved blood glucose and cholesterol levels (ratio and/or range) - so-called 'biomarker indications'.

What did we do?

We identified 89 listed medicines with blood glucose and/or cholesterol biomarker indications for targeted review based on a high likelihood of the claims not being supported by evidence held by the sponsor. We asked sponsors of these medicines to send us the evidence they held in order to review the indications, labels and advertising claims for these products.

Findings

What did we find?

The sponsors of 87 medicines (98%) responded to our request for information:

• 11 advised that they had reassessed their evidence and removed unsupported indications from the ARTG and advertising materials for their medicines.
• 18 requested cancellation of their medicine from the ARTG.
• The remaining 58 (65%) provided us with evidence, which we reviewed.

We cancelled 2 medicines selected for review from the ARTG due to non-response to our request for information.

The evidence for all 58 (65%) medicines we reviewed was found to be deficient in supporting the blood glucose and/or cholesterol biomarker indications suitable for listed medicines. No issues were identified that represented a concern for the safety of consumers and no recall of products was warranted.

What was the outcome?

Of the 58 medicines we found to be deficient in meeting the requirements for listing on the ARTG:

• The sponsors of 46 medicines (79%) agreed to rectify the compliance deficiencies by removing the unsupported indications from the ARTG and advertising materials. These medicines remained on the ARTG. Any without deficiencies corrected by the due date will be considered non-compliant and we will move to cancel them from the ARTG.
• 12 medicines (21%) were cancelled from the ARTG by the sponsor during the review process.

What did the TGA do?

Since March 2018, indications available for use for listed medicines are now contained in a 'list of permitted indications' which is contained in the Therapeutic Goods (Permissible Indications) Determination. The list of permitted indications is maintained by the TGA and provides a comprehensive list of low risk indications currently accepted for listed medicines, provided appropriate evidence is held by the medicine sponsor. There is no longer a 'free-text field' for sponsors to enter their medicine indications when they apply to list their medicine in the ARTG.

Introducing the list of permitted indications provides transparency on what indications are suitable for listed medicines to help prevent sponsor non-compliance and provides greater protection for consumers from misleading and inappropriate claims. Indications referring to maintenance, management or control of biomarker levels, ratios and ranges are not included in the permitted indications list. Some lower level biomarker indications have been included where they meet the eligibility criteria for low risk indications, including that they do not imply serious diseases or those that cannot be self-diagnosed or self-managed.

We are also currently in the process of implementing several other enhancements to our post-market compliance monitoring program to address non-compliance in response to the recommendations from the Expert Review of Medicines and Medical Devices Regulation (MMDR). As consulted upon in our paper Business processes to support complementary medicines assessment pathways, these enhancements include improved transparency over the outcomes of reviews through publication on our website, greater targeting of sponsors found to have non-compliant products on the ARTG, and new online training modules for sponsors.

Information for sponsors

Sponsors of medicines who did not hold adequate evidence to support biomarker indications suitable for listed medicines were required to update the labels, advertising material and ARTG entry for their medicines to bring them into compliance. We are monitoring these medicines to ensure that sponsors make the required changes to indications to achieve compliance. If these changes are not implemented, the medicine will be considered as non-compliant and we will move to cancel the medicine from the ARTG.

From March 2018, any changes to a listing that constitutes a Grouping, such as the removal of unsupported indications, require updating the listing to draw all indications solely from the list of Permitted Indications specified in the Therapeutic Goods (Permissible Indications) Determination (the Determination). The Determination includes some indications related to blood glucose and cholesterol that sponsors may select if they hold appropriate supportive evidence. However, indications referring to maintenance, management or control of biomarker levels, ratios and ranges are not included in the permitted indications list. Sponsors of biomarker products we reviewed were permitted 12 months to update their ARTG listings to remove any non-compliant indications to align with the introduction of the list of permitted indications.

The new assessed listed medicines pathway and the registered pathway for inclusion in the ARTG enable sponsors to make higher-level indications that are not allowable under the standard listing pathway. Although some listed medicines we reviewed used indications of this type, the sponsors did not hold appropriate supportive evidence in relation to healthy populations. Some of the evidence held by sponsors about blood glucose that we reviewed mainly related to unhealthy populations and may support indications that are suitable for the assessed listed pathway. For more information on the new pathway including suitable indications, please refer to Assessed listed medicines.

All sponsors of listed medicines currently referring to biomarker indications are encouraged to familiarise themselves with the compliance issues identified during this review to improve their compliance with regulatory obligations. Our advice to sponsors based on the outcomes of these reviews is:

1. Reconsider the indications made for your medicine.
2. Ensure that you hold high quality scientific sources (primary evidence) to support biomarker indications (refer to the case study below for further guidance on evidence requirements).
3. Remember that unacceptable presentation of the medicine includes:
   • referring to unsupported indications on the labels and any other advertising material
   • having a name that implies a therapeutic benefit not supported by evidence
   • having any statements on the label or any advertising material that may mislead consumers to believe the medicine possess characteristics it does not have.
4. Ensure prior approval from the TGA for reference to restricted representations in the advertising materials.

You can make changes to the listing of an affected medicine via TGA Business Services.

Please refer to the Listed medicines application and submission user guide for guidance on this process.

Any changes to your medicine's entry on the Australian Register of Therapeutic Goods (ARTG) must also be reflected on the medicine's label and any advertising material.

Case study: Blood glucose indications - What evidence is required?

The following indications are similar to those indications found to be unsupported by the evidence that was provided by sponsors:

1. 'may help maintain normal blood glucose levels within the normal range in healthy individuals'
2. 'may assist in the maintenance of healthy glycaemic controls in healthy people'
3. 'supports the control of healthy blood sugar balance in healthy individuals'

What evidence is likely to sufficiently support these indications?

Biomarker indications inherently require evidence with quantifiable data. As biomarkers such as blood glucose do not remain at constant values, the evidence must show how those values are maintained and prevented from going outside the healthy/normal range.

As such, biomarker indications almost always require evidence from high quality scientific sources (primary evidence). These include peer reviewed original clinical research in well cited journals, systematic reviews and unpublished studies where relevant.

Indications 1-3 relate to the maintenance or control of normal healthy blood glucose levels. The Australian Medicines Handbook^[1] and Royal Australian College of Pathologists^[2] specify the reference ranges for normal glucose levels (at 95% confidence limits in healthy adults):

The primary evidence should quantifiably show that normal healthy blood glucose levels are maintained or controlled in healthy humans.

For example, evidence that would likely support indications 1-3 would be from a clinical study that is:

• double blinded;
• randomised;
• placebo controlled; and
• sufficiently powered;

demonstrating that normal blood glucose levels (fasting 3-5.4 mmol/L and/or random 3-7.7 mmol/L) were maintained or controlled in healthy individuals when compared with placebo.

The Evidence Guidelines outlines the requirements for scientific indications such as those listed above.

What evidence is unlikely to sufficiently support these indications?

If the evidence does not quantifiably show how normal healthy blood glucose (fasting 3-5.4 mmol/L and/or random 3-7.7 mmol/L) is maintained or controlled in a healthy human population, then the evidence is unlikely to support indications 1-3.

In the absence of sufficient primary evidence, secondary sources of evidence, for example those from:

• reference texts;
• websites;
• databases;
• monographs; and
• descriptive studies;

are unlikely to support indications 1-3. Secondary sources of evidence primarily deal with providing an overview of published literature without undertaking a critical analysis. Whilst they do include references to clinical studies, it is not always clear how the literature quoted was chosen or if the assertions or quotes represent the balance of scientific literature. For this reason, they can only provide additional support to primary sources of evidence.

General evidence that refers to the Recommended Daily Allowance (RDA), Adequate Intake (AI) or Recommended Daily Intake (RDI) for an active ingredient does not sufficiently support indications relating to the maintenance or control of normal healthy blood glucose levels, especially in the context of healthy individuals. Healthy individuals would be consuming a normal healthy diet and would therefore already be meeting the RDA, AI or RDI for that particular ingredient. It is unlikely that the medicine would have any different effect than if a normal healthy diet was followed by normal healthy individuals.