A version of this article was originally published in the Journal of Australian Biotech October 2017, Volume 27(3). It was authored by Kim O'Connell and Suzy Madar.
Biological medicines (biologics) are agents derived from a biological source. As a consequence, they are complex and there is a high degree of variability between molecules of the same active substance. Biosimilars are medicines that are closely related, pharmaceutically and therapeutically, to their reference biologic. However, biosimilars are not identical to, and cannot be characterised as bioequivalent to, the reference biologic in the way that generic small molecules drugs are bioequivalent to the innovator drug. Regulatory approval of a biosimilar involves comparability, but not bioequivalence or necessarily substitutability, with the reference product.
In Australia, like most other jurisdictions, following registration of a biosimilar on the Australian Register of Therapeutic Goods (ARTG) it is necessary to overcome an additional regulatory hurdle in order for a biosimilar to be substituted for the reference product by a pharmacist. However, the regulatory drive in Australia towards substitution of biosimilars at pharmacy level is unique.
Australian regulatory position
In Australia, a sponsor of a generic product will be able to rely on safety and efficacy data relating to the originator product in order to obtain registration on the ARTG if bioavailability studies demonstrate that the generic product is ‘bioequivalent’ (that is, absorbed, metabolised and excreted in the same way as the reference product). However, due to the inherent variability of biological molecules, it is not possible to demonstrate bioequivalence between a biosimilar and its reference product. To register a biosimilar on the ARTG on the basis of safety and efficacy data relating to the reference product, clinical studies relating to the differences in biological responses to the biosimilar and the reference product must demonstrate that the biosimilar is ‘similar’ to the reference biologic in the sense that there are no meaningful differences in terms of safety and efficacy.
For a product to be eligible for public funding through Medicare in Australia, it is necessary for the product to be listed on the Pharmaceutical Benefits Schedule (PBS). For small molecule drugs to be ‘a’ flagged on the PBS and able to be substituted by a pharmacist, they must generally have been demonstrated to be bioequivalent. However, for biosimilar products where this is not possible, biosimilars are assessed for ‘a’ flagging on a case-by-case basis and an absence of evidence of adverse effects appears to be sufficient for a biosimilar to be ‘a’ flagged. Switching studies demonstrating the safety of repeated switching between biologic products are not required.
For more on the regulation of biosimilars in Australia, see our previous article in the BioScience Law Review here.
In Australia, nine biosimilars have been registered on the ARTG. Two of these (infliximab and enteracept) have been ‘a’ flagged on the PBS such that the biologic can be substituted for the reference product by a pharmacist without any supervision by the prescribing doctor. There is no limit on the number of times the reference product may be substituted such that it is possible that a patient could receive multiple different versions of the biologic they have been prescribed. As far as the authors are aware, this position is unique to Australia –biosimilars are not interchangeable at the pharmacy level in the US, EU, UK or New Zealand.
US and EU
In the US, drug products may be classified as either pharmaceutically equivalent or therapeutically equivalent. Products will be pharmaceutically equivalent if they contain the same active ingredient, are of the same dosage form and route of administration and are identical in strength or concentration. Drugs are classified as therapeutically equivalent if they produce the same clinical effect and are shown to have the same safety profile. Generic molecules must be classified as therapeutically equivalent to be substituted at pharmacy.
Generic substitution laws in the US are state specific. Some US states (e.g. Florida and Washington) require pharmacists to automatically substitute a generic unless the doctor has specifically indicated that there is to be no substitution. Most states allow, but do not require, pharmacists to substitute a generic however substitution is mandated by many health insurance plans. Under the Biologicals Price Competition and Innovation Act 2009, in order for a biosimilar to be substitutable at pharmacy, it is necessary to provide data demonstrating that the product has no clinically meaningful differences in safety, purity and potency from the reference product.
While four biosimilar medicines have been approved in the US, none have been found to be substitutable by a pharmacist.
The US Food and Drug Administration released draft Guidelines in January this year that contemplate sponsors being required to submit specific data from dedicated switching clinical trials that have been designed to assess whether the biologic will trigger a different immune response to the reference product.
Similarly, in the EU, biosimilars follow a different and more onerous path to regulatory approval than bioequivalent generic drugs. “Interchangeability” in the EU generally refers to prescribing of the biosimilar in place of the reference product by a physician (rather than substitution by a pharmacist). Some EU health authorities such as that in Finland recommend that biosimilars that are shown to be interchangeable with their reference biologic be prescribed to naïve patients and this has resulted in a much greater uptake of biosimilars in those jurisdictions. However, even the Finnish regime contemplates that substitution will be under the recommendation and guidance of a physician rather than by a pharmacist independent of clinical supervision.
The notable European outlier is France. In January 2014 it was proposed that French pharmacists be permitted to substitute biosimilars for reference biologics when initiating a new course of treatment in a particular patient, provided the prescriber had not marked the prescription as non-substitutable. This proposal has not been implemented due to the extent of opposition it has met. However, even in France, the proposal would only apply to treatment of naïve patients such that issues of multiple switching would not arise. The potential for multiple switching is a position that is truly unique to Australia.
Why is Australia unique?
The Australian regulatory position appears to reflect a stronger push towards the timely uptake of biosimilar medicines. This is of course driven at least in part by the fact that six of the ten most expensive PBS-listed medicines in 2015-16 were biologics, with a combined cost to the Australian Government of AUD 1.28 billion.
Most recently, a Strategic Agreement between Medicines Australia and the Commonwealth (the Agreement) was released with the 2017-18 Budget in recognition of the potential cost benefits that biosimilars represent and an observed lack of uptake of biosimilars that is thought to reflect a perceived lack of data relating to the safety of switching between biological products. The Agreement provides that the Pharmaceutical Benefits Advisory Committee (the body responsible for decisions relating to the PBS) may recommend that a biosimilar should be preferred (although not mandated) for new patients and permits lower prescriber authority requirements for biosimilars over reference biologics (however the Agreement has been publicly criticised on the basis that it is not clear what “lower prescriber authority requirements” means). The proposed changes relating to biosimilars are accompanied by other measures designed to reduce the cost of the PBS, including a proposed increase to the statutory price reduction for first new brands of pharmaceuticals from the current 16% to 25% and a 10% statutory price reduction on F1 drugs that have been on the PBS for 10 years or more (and a further 5% reduction for those drugs that have been on the PBS for more than 15 years).
The Agreement also foreshadows a move away from brand name prescribing for both small molecule and biologic drugs.
What is the concern?
The comparatively pro-substitution position for biologics in Australia, and the recent Agreement in particular, has attracted criticism from a range of groups, including the Australian Medical Association and the Australian Rheumatology Association, on the basis that there has been a lack of consultation with clinicians and consumers, particularly in relation to the recommendation that naïve patients be treated with biosimilars rather than the reference biologic in the first instance. The key concern for specialists appears to be that prescribers should retain control over whether a patient is dispensed the reference biologic or the biosimilar on a case by case basis. For example, a US-led survey of 160 Australian biologic-prescribing doctors by the Alliance for Safe Biologic Medicines (and co-sponsored by AbbVie) determined that 89% of respondents believed it critical or very important that they be notified in the event of a pharmacy-level substitution of biologics/biosimilars. The primary concern however, appears to be the safety of multiple switching where a patient may be switched between different versions of biologics each time a script is filled. It has also been suggested that multiple switching between biosimilars may promote the development of neutralising anti-drug bodies and a consequent loss of efficacy.
The Australian regulatory position relating to substitution of biosimilar medicines is unique. Not only is Australia the only jurisdiction in which a biosimilar may be substituted for the reference biologic by a pharmacist without prescriber supervision, it is also possible that a patient may be switched back and forward between different biologic products that are not ‘bioequivalent’. That the PBAC – traditionally the arbiter of cost efficiency – has been charged with the assessment of biosimilar interchangeability, is itself unique.
Of course, concerns about switching from reference biologics to their biosimilars apply equally in reverse when a patient is moved from a biosimilar back to a reference product. Some vocal proponents of biosimilar uptake also suggest that because of inherent variance in biologic medicines, differences between batches of a reference biologic can be significant enough to trigger differences in immune responses.
We anticipate more regulatory activity in this area that will no doubt be accompanied by significant public debate.
 PBS Information Management Section: Pharmaceutical Policies Branch, Expenditure and Prescriptions Twelve Months to 30 June 2016, 2016 <https://www.pbs.gov.au/statistics/expenditure-prescriptions/2015-2016/expenditure-prescriptions-report-2015-16.pdf>.