OcyonBio

The long-awaited formal guidance for interchangeability has been issued by US FDA. Once again, the core resounding message is the need for scientifically sound analytical characterization.

Enter at your own Peril – YIKES !!!

Based on my multiple readings there is a lot here to contemplate. The bar has been raised and the sponsor who wants to achieve this level of approval has lot to think about. The clinical requirements coupled with patient diversity has significant potential to generate confounding data even with a well designed interchangeable clinical study. Failure in studies may have unintended consequences.

The path to approval has significant risk to an existing biosimilar ( what happens if an approved biosimilar fails interchangeability – Marketing Nightmare ). Significant financial risks for studies that must be powered for PK/PD and also the added complexity with the requirement to ensure patient drop outs are considered in the statistics ( How does this impact doing clinical studies outside first world ?)

There are many questions that will need to answer along the way. The following are what we believe are the top take aways from the new published guidance. These are intended to start a conversation and do not pretend to be the only take aways from this very complex guidance documents.

Top 10 – The beginning…..

(1) Interchangeability can ONLY be sought after Biosimilarity Approval

(2) FDA continues to propose step-wise approach – Discuss before you go ahead with new clinical studies

(3) Complexity of product determines the extent of the interchangeability trial.

(4) Immunogenicity considerations based on complexity and extent of immunogenicity of innovator molecule

(5) Sponsors should seek interchangeability for all Indications.

(6) Clinical design requires a minimum two switching and powered to support expected high drop out rate

(7) Real world experience helpful, but difficult to use to satisfy statutory requirements

(8) Immunogenicity and serious adverse events should be analyzed based on descriptive measures

(9) Immunogenicity assay must be validated and agency recommends review prior to use in clinical program

(10) Post Marketing data not sufficient and FDA recommends sponsors to provide data explaining switching scenarios.

While, the Interchangeability guidances have been sort off announced in various forums, the one the escapes me is number 6. How can a sponsor generate real world data, when the biosimilars approved to date were not deemed interchangeable? Does the FDA know something we don’t ( off-label interchangeability?)

The Value of Real-World Experience – Where to find it ?

To date the FDA has failed to recognized real world data from Europe, Japan, India, Latin America, Third World countries. How is a sponsor with a biosimilar approved in the US going to find “real-world used” data ? Confusing part of guidance… this is what it says…

“postmarketing data from a licensed biosimilar product may be helpful as a factor when considering what data is necessary to support a demonstration of interchangeability. For example, some sponsors may wish to submit postmarketing data describing the real-world use of the biosimilar product, including certain safety data related to patient experience with some switching scenarios. Such data may reduce uncertainty about interchangeability and thus the data needed to support a demonstration of interchangeability. FDA will evaluate proposals to include postmarketing data in applications to support demonstrations of interchangeability on a case-by-case basis”

Is it conceivable that FDA is extending its post marketing data from real world use to other countries? This part of the guidance is confusing and requires further clarity. How are sponsors to know that there were switching and alternating with their drugs unless there were either safety or efficacy concerns.

Post Interchangeability Surveillance – Affordability down the tubes ?

Now there is where interchangeability gets tougher. According to the guidance

“In certain situations, postmarketing surveillance data from the licensed biosimilar product in addition to data from an appropriately designed switching study may be needed to address uncertainty regarding a demonstration of interchangeability and add to the totality of the evidence to support a demonstration of interchangeability. Further, there may be situations where a postmarketing study, in addition to postmarketing surveillance data, from the licensed biosimilar product may be needed to address uncertainty regarding a demonstration of interchangeability”

Costly Post-surveillance studies

This bar will make the demonstration of interchangeability almost impossible without years of post-surveillance data and another significant expense that will further reduce the ability for smaller companies to enter the market.

Agency meetings to further clarify clinical plan & path required?

The road to interchangeability requires meetings with FDA which is a good suggestion as the guidances are written vague enough to allow the interchangeability to be achieved on a case by case basis. The guidance recommendations …..

“FDA recommends sponsors intending to develop a proposed interchangeable product to meet with FDA to discuss their proposed product development plan. Early discussions with FDA about product development plans, including adequate scientific justification for the proposed development program, will facilitate development of interchangeable products”

Integrated Clinical Study Core to Interchangeability – Innovators smiling to the bank…

“An integrated study needs to be adequately powered to evaluate the appropriate endpoint(s) to support the demonstration of no clinically meaningful differences for biosimilarity, where the primary comparison is between the proposed product arm and the reference product arm. In addition, the study needs to be adequately powered to evaluate PK and PD (if available) following the final switch to support a demonstration of interchangeability, where the primary comparison is between the switching arm and the non-switching arm”

“FDA recommends sponsors intending to develop a proposed interchangeable product to meet with FDA to discuss their proposed product development plan. Early discussions with FDA about product development plans, including adequate scientific justification for the proposed development program, will facilitate development of interchangeable products”

Pay Close Attention going to say this once : Its all about the CLINICAL DESIGN!!!!

“A switching study or studies should evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product.”

Clinical study population not only need to appropriately be powered by need consider the potential drop outs.

“Design of switching studies may be informed by how the proposed interchangeable product will be used in clinical practice, taking into consideration scenarios where alternating or switching products might cause the most clinical concern. For treatments that have a long course of therapy, sponsors should anticipate dropouts in the study and should use a scientifically justifiable method to address the increased possibility of missing date.

The comparison of PK and/or PD as well as the demonstration of no diminished efficacy or increased safety concern pivotal to establishing interchangeability.

“In summary, the primary endpoint(s) in a switching study or studies are recommended to be, in most cases, a comparison of PK and/or PD (if available) parameter(s) between the switching arm and non-switching arm following the final switch. In cases where PK and/or PD are not adequately sensitive endpoints (e.g., products with limited systemic exposure, or for which PD effects are not measurable), sponsors are expected to propose and justify selected endpoints other than PK or PD measures.”

The new published guidance are welcome, but in looking at the extent of the requirements achieving both biosimilarity and interchangeability designation is a tall order. The clinical, financial and risk to an existing biosimilar product should considered prior to determining weather the risk is worth the reward.

The simpler biologics with known route of administration and low immunogenic incidents stand a significant chance of achieving success. For complex biologics which most of them are, the trial sizes considering the potential drop outs could be a daunting task coupled with significant financial risks.

Money Money Money – Innovator Companies get another 5-10 years of free exclusivity

Another guidance that creates another hurdle for biosimilar companies to bring life saving medicines to USA and prolong the impact of reducing patient costs.

We at Biosciencescorp applaud the FDA for this guidance, just interested to understand how it can be implemented with reasonable speed and economic prudence coupled. While we understand the agencies hyper focus on the multitude of requirements. We ask the agency to look across the Atlantic for more reasonable methodologies to achieve the same end point. Both patients and our country are drowning from healthcare debt and this guidance prolongs the life of innovator products who already extent their monopoly through their patent dances. Proceed with caution for those who will pursue the gold at the end of the rainbow.

As always I welcome your comments and you can contact me at Robert.Salcedo@biosimilarsciences.com or Robert.Salcedo@biosciencesCorp.com