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ACSOM meeting statement, Meeting 27, 1 May 2015

Advisory Committee on the Safety of Medicines

7 July 2015

Role of the Advisory Committee on the Safety of Medicines (ACSOM) in the TGA's regulatory decision making process

The ACSOM is a statutory advisory committee established by the Therapeutic Goods Regulations 1990.

The TGA currently has ten statutory advisory committees from which it can obtain independent expert advice on specific scientific and technical matters to aid the TGA's regulatory decision making and other regulatory processes. The ACSOM provides advice to the TGA on, amongst other things, matters relating to the safety, risk assessment, risk management and other matters related to pharmacovigilance of medicines.

How this statement should be read

The advice provided by the ACSOM is an important element in the undertaking of the regulatory functions of the TGA. However, it forms only one part of the total body of information that is available to, for instance, a TGA delegate making a regulatory decision under the Therapeutic Goods Act 1989 (the Act). Therefore, while appropriate consideration will be given to such advice, it is important to note that neither the TGA nor a TGA delegate is obliged to follow it.

It should also be noted that details of the committee's advice may not become publicly available for some time after the committee has provided that advice. The purpose of this Meeting Statement is to describe in general terms the matters considered by the committee at each meeting and for it to be available as soon as reasonably practical after the relevant meeting.

Additionally, following publication of this statement, it is most likely that further work will be undertaken by the TGA to investigate, monitor and/or evaluate the medicines considered by the ACSOM; and this will continue for some time into the future. It is therefore possible that further information about the medicines will become publicly available at a later time and this will be pursuant to a regulatory decision under the Act being made and following further consultation with the medicine's sponsor and/or manufacturer.

Overview of the safety reviews and therapeutic goods referred for advice

The TGA continually monitors therapeutic goods supplied in Australia to ensure their ongoing safety, efficacy and quality. As part of this process, the TGA routinely undertakes safety reviews of therapeutic goods.

At this meeting, the committee’s advice was sought on the following safety review.

Combined hormonal contraceptive products and the risk of thromboembolism

The committee noted that currently there are over 60 medicines approved for supply in Australia that contain various strengths of various combinations of progestogens and oestrogens for hormonal contraception.

Combined hormonal contraceptives (CHCs) are associated with increased risks of venous thromboembolism (VTE) and arterial thromboembolism (ATE). In the course of both pre- and post-market assessment of CHCs by the TGA, it has been noted that the precautions for VTE and ATE in the Australian Product Information documents (PIs) have become overly long and confusing for prescribers, and there is a lack of consistency in the way this information is presented across the therapeutic class.

The committee also noted that the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) reviewed the risk of VTE and ATE with CHCs in November 2013. The PRAC concluded that there is good evidence for differences between CHCs in their risk of VTE depending on the type of progestogen, and that while the risk of ATE is increased with CHC use, there is no evidence for differences between CHCs in the risk of ATE1.

This conclusion was upheld by the EMA’s Committee for Medicinal Products for Human Use (CHMP). In January 2014, the European Commission signed a legally binding decision requiring PI documents for all CHCs to be updated with specified wording regarding the risk of VTE and ATE.
ACSOM agreed with the PRAC assessment that CHCs can be broadly ranked for VTE risk according to the progestogen. The committee found that research on drospirenone-containing CHCs2 published after the PRAC assessment was not inconsistent with the conclusions of the PRAC assessment for drospirenone.

The committee noted that higher doses of oestrogen are a factor that increases VTE risk, and that the PRAC assessment had only included contraceptives containing low doses of oestrogen. Oestrogen doses in CHCs have decreased over the past decades.

The committee also agreed with the PRAC assessment that the risk of ATE is increased with the use of CHCs and that there is no evidence for differences in risk between CHCs. A woman’s age is the major risk factor for ATE. The absence of a detected difference in the risk of ATE between CHCs may relate to very low event rates. The studies assessed by PRAC may not have had sufficient statistical power to identify differences between oestrogens. This may be an area of further research and understanding may improve over time.

Having agreed with the PRAC assessment, the committee supported harmonisation and clarity across the PI documents for CHCs available in Australia on the risks of VTE and ATE. The PIs should also provide context by inclusion of comparable information for the risks of VTE and ATE with other CHCs, pregnancy and in the post-partum period.

The information on VTE and ATE risks should be presented in an easy to understand manner, noting that current formats of dense pages of text were not easy to use. The quantification of risk in the PRAC public statement seemed a particularly clear way to present the information3. ACSOM also advised that the changes in information for prescribers required by the EMA were a suitable model for changes to the Australian PIs.
The committee also noted that CHCs were subject to ongoing research and study and that PIs ought to evolve with emerging knowledge. Especially, ongoing attention to the effect of the oestrogen dose on VTE would appear to be important.

The PRAC assessment had been unable to assign a relative risk for VTE for two progestogens. Where the risk is uncertain due to the lack of pharmacoepidemiological studies, this should be acknowledged in the PI document. The precautionary principle would suggest that where the risk for a particular progestogen is uncertain, then the risk of the class should be used in determining the risk for the individual patient.

The committee advised that all CHC PI documents should have the same basic information regarding VTE, including the comparative risk with pregnancy and the post-partum period. Risk factors for VTE change over time and the PI should highlight that an individual’s absolute risk should be re-evaluated periodically.

The committee advised that all CHC PI documents should have the same information regarding ATE. Current data suggest that the risk of ATE with CHCs is very low and there are no data to demonstrate a different risk with different active ingredients in CHCs.

The committee highlighted that as well as the Consumer Medicine Information (CMI) document being consistent with the PI, consumers need an outline of all the issues and risks. These issues include the need for regular review of risk factors, including the age of the woman; the risk of VTE during pregnancy and post-partum; and consideration of non-hormonal contraceptive options.

Soon after this meeting, the BMJ published research by Vinogradova et al4 on 26 May 2015 that investigated the association between use of combined oral contraceptives and risk of VTE, taking the type of progestogen into account. The study concluded that risks of VTE associated with combined oral contraceptives were, with the exception of norgestimate, higher for newer drug preparations than for so-called 'second generation' CHCs. Out-of-session comment from members was that this newly published study reinforced the committee’s view on CHC risks.

Risk Management Plans

A Risk Management Plan (RMP) is a set of pharmacovigilance activities and interventions designed to identify, characterise and manage risks relating to a medicine. At this meeting, the committee’s advice was sought two RMPs for medicines with proposed indications relating to:

  • haematological disorders and
  • neoplastic disorders.

For these medicines, the committee was asked to provide advice on matters including:

  • the adequacy of the safety concern list provided by the sponsor;
  • the adequacy of the pharmacovigilance plan to address all safety concerns and what, if any, additional pharmacovigilance activities would be appropriate to monitor the risks of the medicine;
  • the adequacy of the risk minimisation plan to mitigate all the safety concerns, in particular, the adequacy of routine risk minimisation through the proposed Product Information to manage a specified important potential risk and missing information; and if it is not considered to be adequate, what other additional risk minimisation activities might be required; and
  • whether there were any specific safety concerns associated with the medicine compared to other products modulating the same pathway.

The committee’s advice will shortly be provided to the TGA for consideration as part of the TGA’s regulatory decision making processes.

Following complete assessment of the application, information on the RMP evaluation will be included in the Australian Public Assessment Reports (AusPAR), which is published on the TGA website once it is finalised.

Further information

Meeting statements are made publicly available after each meeting.

For further information on the ACSOM, please visit the ACSOM web page or contact the ACSOM Secretary: Mr Craig Davies by phone on 02 6232 8641 or email:


1. EMA/739865/2013: Assessment report for combined hormonal contraceptives containing medicinal products (pdf, 332KB)

2. Dinger J, Bardenheuer K, Heinemann K. Cardiovascular and general safety of a 24-day regimen of drospirenone-containing combined oral contraceptives: final results from the International Active Surveillance Study of Women Taking Oral Contraceptives. Contraception 2014; 89(4):253-63. doi: 10.1016/j.contraception.2014.01.023.

3. PRAC confirms that benefits of all combined hormonal contraceptives (CHCs) continue to outweigh risks(pdf, 80KB); page 2.

4. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015; 350