FDA baits biosimilar makers with switching guidance

The US FDA’s release of guidance for biosimilar manufacturers to achieve “interchangeability” at last sets the sector’s sights on how to get pharmacists directly to substitute their products for innovative biologicals. What it will not do is unleash a flood of such products into the world’s biggest drug market.

The data needed to support any claim of interchangeability are substantial, including proof that patients can be safely switched from the original product to its copycat rival, and evidence of effectiveness in all indications. The latter requirement could prove a problem for the approved agents Amjevita and Inflectra, which have only conducted switching trials in single indications.

To interchange or not

For the use of some products, such as those infused in hospitals, the interchangeability of biosimilars could have little influence. This is because the decisions are likely to be governed by payers or institutions’ pharmacy and therapeutics committees, which will determine whether to use the less expensive biosimilars based on a balance of price, safety and efficacy.

Such products would include the biosimilar of Roche’s Herceptin that Mylan and Biocon have submitted to the FDA, Remicade competitor Inflectra, from Pfizer and Celltrion, and the Neupogen competitor Zarxio. The last two of these have been launched.

But for self-administered products like Amgen’s Humira competitor Amjevita, achieving interchangeability would be a bigger coup, since the biosimilar could be substituted by a dispensing pharmacist without physician intervention in many parts of the US.

Thus release of the guidelines this week is an important step for Amjevita, as well as Novartis’s Enbrel biosimilar Erelzi, in that the FDA has finally opened the door to approving products as interchangeable.

Switch to pull even

The standards are high, however. This is to be expected in a space where neither the regulators nor the sector have a large amount of experience. The main requirement is a specific trial to determine whether the biosimilar is as safe and effective as the original when patients are switched.

The trial design does not appear to be demanding, with one arm remaining on the original drug and one switching multiple times between the two – a less complicated protocol than the four arms expected by Bernstein analyst Ronny Gal.

However, the switching trial alone might not be sufficient for complex biosimilars that have not shown a high level of analytical similarity. In these cases the FDA will want additional post-marketing safety and efficacy data.

While the agency has been flexible about extrapolating data in approving biosimilars for drugs with multiple indications, it might be more demanding when those same biosimilars seek an interchangeability designation.

Switching studies of FDA approved biosimilars
Agent Reference product Indication Trial ID
Inflectra Remicade Crohn's disease CT-P13 3.4 NCT02096861
Amjevita Humira Psoriasis 20120263 NCT01970488
Erelzi Enbrel (EU approved) Rheumatoid arthritis Equira NCT02638259

Amjevita has been approved for all the indications that Humira has been, but the sole switching study that can be identified through an analysis of clinical trials has been in psoriasis. Likewise, Inflectra’s switching trial with Remicade has been in Crohn’s disease. In both cases rheumatoid arthritis is the big target.

Meanwhile, the one switching trial identified for Erelzi is in rheumatoid arthritis. However, this is against the European authorised version of Enbrel; the guidance says use of non-US approved agents “generally would not be appropriate”.

The good news for the biosimilar world is that interchangeability guidance is now public, and makers can begin working towards these standards. However, implementation could take a while, as so often throughout this sector – after all, it took five years between the passage of the law that created the FDA’s biosimilar pathway and the agency’s first approval.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @ByJonGardner on Twitter

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