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Thursday, February 9, 2017

US draft guidelines on interchangeability of biosimilars require repeat switches – why doesn't Australia switch over too?

By Sarah Matheson and Ric Morgan

As we have previously reported, it has long looked like Australia is determined to take a unique stance on interchangeability of biosimilars. This was confirmed with the PBAC recommending the a-flagging of Brenzys in September 2016.  The recent release for comment by the US FDA of its much awaited draft industry guidance on demonstrating interchangeability of biosimilars reinforces that Australia is indeed an island when it comes to biosimilars.

If adopted, as seems likely, the separate assessment of interchangeability under US legislation will require specific clinical trials. For biosimilars intended to be administered more than once, dedicated switching studies will need to:



  • target the number and duration of switches between the reference product and the proposed interchangeable product to the clinical condition to be treated, the therapeutic dosing of the product, and the duration of the exposure interval to each product; this so that the greatest concern in terms of immune response and resulting impact on safety and efficacy can be evaluated;
  • have a lead-in period of sufficient duration to ensure an adequate baseline (eg steady state of pharmacokinetics) before randomization to the switching period of the study;
  • incorporate a switching arm at least two separate exposure periods to each of the two products (ie, at least three switches with each switch crossing over to the alternate product); and
  • include a final switch from the reference product to the proposed interchangeable product, with a duration of exposure to the proposed interchangeable product being sufficiently long to allow reference product wash out to enable a comparison between the pharmacokinetics of the proposed interchangeable product in the switching arm with the reference product in the non-switching arm.

Consistent with our previously endorsed approach, the draft FDA guidelines explain: 'switching studies are designed to assess whether one product will affect the immune system’s response to the other product, once the switch occurs, and whether this will result in differences in immunogenicity or PK profiles.' Standard studies designed only to assess a biosimilar for efficacy and safety, or comparability to the reference product do not address this issue.

The detailed US document can be contrasted with the guidance provided by the Pharmaceutical Benefits Advisory Committee (PBAC) in relation to whether biosimilar products should be 'a-flagged'. The PBAC expressly assesses products for 'a' flagging on a case-by-case basis. However, the factors to be considered are far from clear with the PBAC appearing to be prepared to accept interchangeability in circumstances where there is simply an absence of evidence of any identified risks.

The PBAC's approach has resulted in 'a' flagging in circumstances where the safety of switching between biosimilars has not been adequately demonstrated through the completion of multiple-switch studies such as those discussed in the US guidance. This has created significant concern amongst medical professionals, as shown by this joint letter to the then Minister of Health Sussan Ley on behalf of five medical associations.

The US draft guidance now provides the Australian government with a ready-made model for evaluating properly whether 'a' flagging ought to occur. This model would avoid the problematic aspects we previously have identified and detailed in our white paper Costs before Caution—Australia's unique approach to the interchangeability of biosimilars. It would also—rightly in our view—include evaluation as part of the assessment of safety and efficacy (by the TGA) and not simply reimbursement (by the PBAC).

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