New Australian biosimilar guidance takes up WHO naming proposal

Generic companies planning to market biosimilar medicines in Australia will have to apply to the World Health Organization for a unique INN identifying code, and all biosimilars will have to have a clearly distinguishable trade name, according to guidance just published by the Therapeutic Goods Administration (TGA).

This is the first time that advice on biosimilars has been issued in the form of a guideline, the TGA said. While it is based almost entirely on that produced by the European Medicines Agency over the past few years, and also allows the use of reference products registered in Australia but manufactured overseas, it includes a number of specific provisions on product naming, labeling, and pharmacovigilance.

Welcoming the guidance as "an important first step" to efficient market access for biosimilars, the generics industry body the GMiA said that all regulatory authorities and the WHO needed to harmonize their naming policies, and cautioned that the INN must not be used to identify drugs products or for traceability purposes. It also pointed out that the main issue for biosimilars is that there is still no clear reimbursement pathway for such products in Australia.

For some time now, the TGA has simply adopted the guidelines drawn up by the EMA on the requirements for demonstrating comparability between the biosimilar and the reference drug. This new guidance is intended to bring together the relevant regulations without imposing new or changed requirements, apart from those on naming. "Considerable consultation has taken place so that all stakeholders are aware of, and can work with, the requirements of the guideline," the agency told Scrip.

It says the guidance will help companies provide the data needed to support biosimilar applications and clarify the scientific and regulatory principles used by the TGA to evaluate those applications, noting that, as with new chemical or biological entities, the legislative basis for evaluating and approving biosimilars is section 25 of the Therapeutic Goods Act 1989. It also lists the EU guidelines on data requirements that it has adopted, as well as the ICH guideline on assessing comparability.

Filing the dossier

Companies planning a biosimilar submission can request a pre-submission meeting with the TGA's Office of Medicines Authorisation (OMA) to discuss the dossier. After that, a pre-submission planning form must be filled in, and once it has been accepted the application will be subject to milestones set by the TGA for submission, evaluation, feedback and decision.

If the evaluation fails to show that the proposed biosimilar is sufficiently comparable to the reference product, the application may be withdrawn and resubmitted as a new biological entity with full clinical and preclinical datasets. In this case the sponsor will forfeit the biosimilar evaluation fee.

The reference product used must be a biological medicine registered in Australia with a full data submission, and must have been marketed "for a suitable duration and have a volume of marketed use so that there is likely to be a substantial body of acceptable data regarding the safety and efficacy."

In line with recently updated EMA policy, a reference product manufactured and sourced overseas can be used provided the product is registered in Australia and a bridging comparability study is conducted. The bridging study can be abbreviated if the product marketed in Australia is sourced from the same manufacturing facility as that used for the reference product.

As for extrapolation of indications from the reference product to the biosimilar, the guidance refers to the EU guideline that says extrapolation is possible in certain cases, depending on factors such as clinical experience, available literature and whether or not the same mechanisms of action or receptors are involved in all indications.

INN naming based on WHO proposal

Where the Australian guidance departs from current practice in the EU is in the naming of biosimilars. It explains that, under the Therapeutic Goods Regulations (1990), all medicines must use the Australian Approved Name (AAN), which in the case of biosimilars will be drawn from the Australian Biological Names (ABN) list.

However, special provisions are needed for biosimilars, because they are not identical to the reference product, and "must be assumed to be different to any other biosimilar as no direct comparability study has been conducted," says the TGA. As small differences between biosimilars can produce differences in clinical behavior, in particular immunogenic effects, "certain additional nomenclature provisions are necessary to ensure that it is possible to distinguish between biosimilars and clearly identify the reference product."

It says the ABN for a biosimilar must be composed of the reference product ABN (in order to identify the reference product to which it has been shown comparable) together with a biosimilar identifier consisting of the prefix sim and a three-letter code issued by the WHO's INN Committee. The ABN for a biosimilar infliximab, for example, could be "infliximab simfam". The ABN must be used in full in all labeling and in each reference to the product.

This construction was one of a number proposed in the WHO's draft policy on biosimilars during the 55th consultation on INNs for pharmaceutical substances in October 2012, which was published as a working document in February this year. Noting that current practices vary widely among regulatory authorities, the WHO said that the naming issue needs to be addressed globally while the number of registered biosimilars remains relatively small.

To obtain a biosimilar ABN, the company will first need to apply to the WHO INN Committee for the three-letter code, and then to the Australian ABN Committee to use that code in the biosimilar identifier; finally it must apply for the identifier to be added to the list of Australian Approved Names.

This naming convention will allow prescribers to identify the reference product and to distinguish clearly between biosimilars, says the TGA, noting that such distinctions are also important for pharmacovigilance purposes. It stresses that the addition of a biosimilar identifier to the AAN list "does not in any way imply endorsement of acceptance by the TGA of the substance as a biosimilar, but only that the sponsor's application for the use of a biosimilar identifier has been approved."

As well as the identifier, all biosimilars must have their own trade name to distinguish them from all other products, especially the reference drugs and other biosimilars. It is not appropriate to use the construction "active ingredient + company" because it "may suggest that the biosimilar is a generic medicine, lead to confusion in prescribing and dispensing, and contribute to difficulties in traceability in the event of safety issues."

Following product launch, companies must notify the TGA as to who is responsible for meeting the sponsor's obligations, submit period safety update reports and adverse events to the TGA, notify the agency of any significant safety issues, and ensure that they reply to any requests from the TGA for additional information. Any provisions in the risk management plan imposed as conditions of approval should be fulfilled.

Labeling issues

The guidance outlines the wording that should be placed on the product information of biosimilar products, including a statement to the effect that the level of comparability that has been shown with the biosimilar is not sufficient to designate the product as a generic version of the reference drug, and that the reference product should only be replaced by a biosimilar "under the supervision of the prescribing medical practitioner."

It adds: "It is the TGA's view that it is not currently possible to determine a degree of similarity between a biosimilar and an already registered biological medicine sufficient to support a designation by the TGA of 'bioequivalence.'"

Guidance welcome, but access still a problem says GMiA

Welcoming the guidance as an "important first step", the GMiA said that market access for biosimilars would be further enhanced by global harmonization on key issues such as the definition of an acceptable reference product, consistent INN naming and system-based pharmacovigilance procedures.

But it said that its members "do not universally agree with the naming convention set out in the TGA guidance." National regulatory authorities need to harmonize their policies on INN naming, and these should be clear and consistently applied, it told Scrip. But the use of INNs should not be inappropriately extended to address other issues, it said: "The intent of an INN and ABN is to identify the drug substance, as a nomenclature for classifying and cataloguing pharmacological classes and as a means of communication to healthcare professionals. INN is not intended to identify a drug product, a statement of therapeutic equivalence and/or substitution, nor is it a means of establishing traceability for pharmacovigilance purposes."

It also said that the main issue for biosimilars in Australia is that there is currently no clear pathway for reimbursing them. Biosimilars do not fit into either the current F1 (original brands with demonstrated cost-effectiveness) or F2 (generic brands) formularies on the Pharmaceutical Benefits Scheme. "Therefore the fact that TGA issues a guidance will do little to spur development of these medicines in Australia unless there is a mechanism in place for funding," it observed.