Leonie Hunt, Therapeutic Goods Administration, Australia

Based on a presentation delivered by Leonie Hunt at the Tenth International Conference of Drug regulatory Authorities (ICDRA) held in Hong Kong SAR, China, June 2002.

In Australia, the Therapeutic Goods Act 1989 provides for a national system of controls for the regulation of therapeutic goods, including both medical products and medical devices. The Therapeutic Goods Act 1989 is administered by the Therapeutic Goods Administration (TGA), a Division of the Department of Health and Ageing of the Australian Government. The TGA is located in Canberra and undertakes a number of activities in administering the regulation of therapeutic goods in Australia. These include pre-market assessment of products, pharmacovigilance, enforcement of standards, enforcement of good manufacturing practice (GMP) requirements, manufacturing licensing and maintenance of a register of approved goods.

In carrying out its duties, the TGA adopts a riskbased assessment approach whereby higher-risk medicines, such as those available on prescription, are fully assessed for quality, safety and efficacy pre-market whereas goods considered to pose a low risk have an emphasis on quality and safety before market entry. Examples of low-risk goods include simple vitamin preparations where it is considered that there is not only an inherent low risk from use of the product but also that claims made about benefits of the product are restricted.

In undertaking the assessment of higher-risk medical products, the TGA adopts international guidance documents where possible. This is done to reduce the compliance costs for the industry and to ensure that international best-practice is followed. In particular, since 1992, the TGA has adopted many European Guidelines and International Conference on Harmonization (ICH) Guidelines. TGA’s policy on fixed-combination medicinal products is strongly influenced by the European approach to fixed-combination medical products as contained in EudraLex - the rules governing medicinal products in the European Union - Rules 1998 (3c) 3a 10a, pp.175 - 180.

Fixed-combination medicinal products cover the entire spectrum of medicinal products - though often people tend to think of fixed-combinations as a relatively new introduction. Many traditional formulations, for example multi-vitamins and minerals or the oral contraceptive pill, are in fact, fixed-combination medicinal products. Therefore, there should be a wealth of experience around the world in the use of these products. Nevertheless, there are some important factors to consider when assessing a new fixed-combination medicinal product.

Firstly, it is important to assess the potential advantages of fixed-combination medicinal products. These include an improvement in effectiveness of treatment, safety profile and simplification of therapy. There may also be cost advantages if a fixed-combination product can be manufactured and sold for less than a combination of individual products.

But there are also potential disadvantages. As the dosage is fixed in the combination, the doses of the individual substances cannot be easily adjusted to meet the needs of the individual patient. There may be unnecessary exposure to the second medicine for some patients and the combination may lead to additional adverse events. It is also not always true that costs will be reduced by a second agent if use of a single agent alone could have satisfactorily treated the patient.

It is therefore important that when considering a new fixed-combination medicine, there be a justification as to why that particular fixedcombination is acceptable and appropriate. This justification needs to address issues relating to the benefit and risk of the combination. Possible justifications for fixed-combination products could be that it is more effective. Examples of this could include better control than from either medicine used alone at the same or higher dose.

Combinations should also be rational so that medicines complement each other in their actions or potentiate the beneficial effects of each other. It is also important that combinations be rational in terms of the condition to be treated.

Commonly used fixed-combination products include widely-used cold and flu’ remedies. These often consist of an analgesic, anti-pyretic, a decongestant agent and perhaps an antihistamine. The combination is logical for selfmedication for many patients as the symptoms that are to be treated in these self-limiting conditions often co-exist. In contrast, if a product was to be developed that simultaneously treated the symptoms of a respiratory tract infection and managed diabetes, the combination would not be rational. Although there will be a small sub-set of patients with diabetes at any point in time who also have the symptoms of an upper respiratory tract infection, the majority of people with an upper respiratory tract infection are not those with diabetes. The addition of the other treatment would lead to an unnecessary exposure to a medicine.

Justifications may also be based on grounds of safety. There may be reduced side-effects if two medicines are used at lower doses than one medicine used alone at a higher dose. This is an entirely acceptable reason for using a fixed-combination. It may also be that fixed-combinations can lead to a reduction in adverse effects if one of the drugs in the combination reduces the adverse effects of the other medicine. Although, ideally, we would wish to see patients treated with medicines with no adverse effects, this is not always possible. Where alternative treatments with less adverse effects cannot be found, a combination that leads to a reduction in adverse effects may be important.

Probably the weakest justification on grounds for a fixed-combination is improved compliance. This is often cited as a rationale and is intuitively plausible but rarely in the experience of the Australian regulator do submissions contain data to support claims of improved compliance. It is certain that some patients are compliant with therapies but it is not known if someone who complies with taking several medicines every few hours will be less or more compliant if they only have to take the medicines once or twice a day. Similarly, if someone is not compliant when given clear instructions on taking medicines every four hours, it is not certain that their compliance will increase because they are required to take a combination medicine daily.

Development of fixed-combination medicinal products

In developing a fixed-combination product, it is important that the sponsor addresses certain criteria and the regulatory agency assesses the combination to ensure that these criteria are met. As always, the quality of the pharmaceutical product must be acceptable. It is also important that there be a logical combination of medicines in relation to pharmaceutics. As previously discussed, a combination of therapies for conditions that rarely co-exist or that have no obvious connection to each other is not rational or desirable.

The pharmacodynamics and pharmacokinetics of the drugs used in the combination must be fully explored as part of development. Indeed, an interaction between the two products may in itself be a rationale for the combination. It is important to establish the role of each medicine, alone and in combination. Interactions can and do occur within fixed combinations and with other medicines used commonly in the target patient group. The potential effects on the pharmacokinetics of both medicines must be investigated and understood before the product can be approved for marketing.

Efficacy

The indication for which the product is intended to be approved should be rational. Ideally, the ingredients of the product should be used in the same conditions, but use in usually concurrent conditions may be acceptable as discussed above. Conservatively, it has generally been recommended by many regulatory agencies that combination products be used as add-ons to single therapy. This would seem to be sensible as using a single therapy to control a condition is less likely to lead to over-prescribing, unnecessary adverse events and increased costs. However, there may be circumstances in which it is possible to demonstrate optimization of treatment with a combination as first-line treatment. These would be circumstances where a condition is important and serious, where either drug used singly at higher doses had significant adverse events or costs, and it was demonstrated that there was a low rate of success of treatment with one product alone.

The amount of information that the regulatory agency should require to demonstrate efficacy for a fixed-combination will vary. If two products have a long history of safe and effective use in combination, then it may be possible for documentation to be substantially bibliographic or based on a significantly reduced data set, relying on previous reviews of the individual products and published literature and other experience of use in combination. This would occur, for example, if two products were commonly taken at the same time each day and were used in the same patient group. Nevertheless, even given this circumstance, it is important that there be evidence of effectiveness. If effectiveness for the products used in combination is not greater that the effectiveness for one of the products used alone, then it is important this be identified for there is little additional benefit to be gained from such a fixed-combination and it is not desirable that it be approved for registration.

If a new combination of medicines is proposed, then it is important that a more substantial product development programme be undertaken and that similar information relating to the combination at varying doses in the intended patient group be generated as if the product was a new single entity. It is particularly important that the dose be well established. A fixed-combination allows the opportunity for the dose to be minimized and adverse events reduced. In order for this to happen, it is important that the minimally effective dose of the medicines, used alone and in combination, be established.

It is also important that the maximal dose response information is available. This is important because, if a minor increase in dose of one component of the fixed-combination leads to an improved dose response, then development of a fixed-combination using marginally lower dose of that substance may not be a rational development.

It is also important, when comparing a fixed combination, to look at effective doses of either medicine alone and other reference therapies used for the treatment of the condition. It may also be important to compare the fixed-combination with placebo in some cases.

Safety

As for any product, it is important that there be as much evidence as possible about performance in terms of safety of the medicine. For this reason, there should be some animal experience for the use of both medicines, singly and in combination, and human data should be available from use of the medicines, both singly and in combination. Again, if the products have a long history of concomitant use, documentation may be abridged.

Summary

Fixed-combination products can offer significant benefits to consumers and health systems. It is important in assessing the place of a fixed-combination product to consider the justification of the combination, as well as information on it’s quality, safety and effectiveness in patient management.