Issue:April 2021

BIOSIMILAR DEVELOPMENT – Guidance on Biosimilar Interchangeability: The Debate Over Drug Delivery Devices


In 2019, the US FDA issued its final guidance document titled Considerations in Demonstrating Interchangeability with a Refer­ence Product.1 The guidance document details the pathway for how biosimilar products may be deemed “interchangeable” and substituted for the reference biologic without the intervention of a clinical prescriber.

As early experience in following this guidance has matured over the past year or two, a number of issues have arisen that may impede best available outcomes for patients, one of which is the question of whether “interchangeability” guidance may sti­fle innovation (and therefore improved patient experience) in drug delivery devices.

Before looking at the US situation, it is interesting to note some differences when compared with Europe. EU guidance on interchangeability separates the drug from the delivery device, specifically making way for device innovation: “Some differences may be allowed if they have no effect on safety and efficacy – for example differences in the formulation of the medicine, presen­tation and administration device.”2 This is significant, because delivery device usability and comfort for therapies that require frequent administration can offer competitive advantage, either to biosimilar producers trying to gain market share, or original biologics companies seeking to retain their market position. Evi­dence for this assertion may be seen in a number of pharma companies that have for some years been making moves to seek exclusive arrangements with device manufacturers to gain com­petitive edge in the switching/retention process.3 Certainly, in Eu­rope, with its regime that separates drug from delivery device, the EU has approved more biosimilars for each reference biologic than the US – almost across the board.4

Whatever the significance of such comparisons, however, this short article plays out the situation and seeks to stimulate discus­sion and feedback from readers.


One of the FDA’s guiding principles is to enable the avail­ability of best therapies and facilitate the best patient outcomes. While the larger part of the FDA guidance focuses on matters of medical therapeutic science, “human factors” have in recent years become an equally important consideration – including a focus on drug delivery devices that ease discomfort, avoid pain, and facilitate dosage accuracy. The enhanced importance of these aspects (“human factors”) is exemplified in the FDA’s guidance that recommends involving patients as early as possible in the clinical evaluation of new products – precisely to embrace human factors (ease of use, pain avoidance, etc) and the total patient experience.5 One would therefore hope that guidance on the interchangeability of biolog­ical drugs and biosimilars would encourage the use of alterna­tives to the original (“reference”) biologic that are at least the same, if not better. Moreover, the room for improvement may be applied equally to the delivery device as the drug itself.


What, then, does the FDA guidance on interchangeability say, especially with respect to drug delivery devices? The guid­ance document states that, “FDA expects that sponsors will submit data and infor­mation to support a showing that the pro­posed interchangeable product can be expected to produce the same clinical re­sult as the reference product in all of the reference product’s licensed conditions of use.”6 This clearly focuses on the clinical outcomes – after all, in scientific terms, a biosimilar is not the same drug, but it does offer the same therapeutic benefit.

The purpose of interchangeability is to allow a biosimilar to be substituted for a reference (original) biologic by a pharma­cist, without reference to the prescribing clinician. According to the Biologics Price Competition and Innovation Act (BPCIA) in the US, a biosimilar can be designated as “interchangeable,” whereby it may be sub­stituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.7 However, the rules vary from jurisdiction to jurisdiction, and international harmoniza­tion of interchangeability policies has some way to go.

Further to the demonstration of inter­changeability from the perspective of biosimilarity, there are additional consid­erations for demonstrating interchange­ability for a combination product that includes a device constituent part (eg, a container closure system such as a safety syringe or an autoinjector) to deliver the biological product. This is pertinent for manufacturers of combination products and contract manufacturers of medical de­vices that produce integrated drug delivery devices on behalf of clients (pharmaceuti­cal companies) who incorporate them into a final combination product.


The guidance document includes a section on considerations for the container closure system or any device constituent. While not proscriptive, it contains enough pointers to identify inputs, such as per­formance testing, stability studies, shelf-life testing, useability, and risk management, for sponsors to prepare an approach that can be discussed and agreed with the FDA at the beginning of the design phases.

Here is where we encounter a little confusion and potential conflict with pa­tient best interests. The guidance first of all seems to limit device improvement poten­tial when it states that “A sponsor develop­ing an interchangeable product generally should not seek licensure for a presenta­tion for which the reference product is not licensed. For example, if the reference product is only marketed in a vial and a prefilled syringe, a sponsor should not seek licensure for the proposed inter­changeable product for a different presen­tation, such as an auto-injector.”8

However, this is immediately followed by apparent encouragement to potentially seek delivery device enhancements or im­provements (which could benefit the pa­tient and provide commercial competitive edge). This guidance reads:

“However, if a sponsor is considering the development of a presentation for which the reference product is not licensed, this should be dis­cussed with the FDA. In such cases, the FDA will evaluate whether the proposed presentation could support a demonstra­tion of interchangeability.” Early interac­tion is clearly essential, as the guidance notes: “Sponsors are encouraged to con­tact the FDA early during product develop­ment to discuss the proposed presentation [delivery device] and specific considera­tions related to licensure of the proposed product as an interchangeable under sec­tion 351(k) of the PHS Act.”9


So where does this leave the issue? Because of the multitude of different prod­ucts and presentations, what is not clear – and will be the challenge for sponsors – is the line between “similar and not-similar.” As the guidance advises, the solution to this is to engage with the FDA early in de­velopment and agree a route forward.

The probable result, until the market’s experience proves otherwise, is that spon­sors (pharma companies) will split into “pi­oneers” and “followers.” At Owen Mumford, we know that pioneers exist, be­cause we’re already working with some of them on enhanced device “presentations” for biosimilar drugs to propose to the FDA. These biosimilar companies clearly recog­nize that device enhancements can offer patient experience benefits and, at the same time, provide an element of compet­itive edge to encourage switching. There is certainly a discussion emerging in the wider biologics industry over whether biosimilars and device improvements can more easily be introduced for naïve pa­tients.10

Nevertheless, the issue remains over whether current guidance may suppress device innovation – innovation that is to the patient’s benefit. Particularly with com­bination products that incorporate a de­vice-constituent, we can see a scenario of sponsors “playing it safe” and adhering very closely to the design of the reference product. This, of course, would stifle a body of innovation: why introduce features into the proposed product that are not present in the reference product, when it may increase the risk around gaining ap­proval and require more work to demon­strate that the proposed product is interchangeable? However, if those fea­tures are shown to be improvements over the reference product or have been intro­duced to address on-market issues, then this should be seen as a “positive differ­ence” that adds benefit and ought to be encouraged by the FDA.


In short, then, clarity around the issue is likely to develop rapidly over the next couple of years as the biosimilars “pio­neers” bring device developments in front of the FDA for approval. A positive out­come from those consultations and appli­cations is important to fulfil the FDA’s objective of increasing patients’ access to therapies with the greatest “safety, efficacy, and security” available.11 As an industry, we should encourage this discussion to make sure that developmental debate is completed with the minimum of delay.


  1. FDA, Considerations in Demonstrat­ing Interchangeability With a Refer­ence Product, May 2019.
  2. European Medicines Agency, Guid­ance, Biosimilars in the EU, 2019.
  3. In-pharma Technologist, Pharma turn­ing to injectable systems to protect bi­ologics, 22 Jun 2015.
  4. Biosimilars Council, Lessons for the United States from Europe’s Biosimi­lars Experience, June 2020.
  5. Center for Devices and Radiological Health (CDRH) and Center for Biolog­ics Evaluation and Research (CBER), Patient Engagement in the Design and Conduct of Medical Device Clini­cal Investigations, 24 Sep.
  6. FDA, Considerations in Demonstrat­ing Interchangeability With a Refer­ence Product, May 2019.
  7. FDA, Implementation of the Biologics Price Competition and Innovation Act of 2009, 12 Feb 2016.
  8. FDA, Considerations in Demonstrat­ing Interchangeability With a Refer­ence Product, May 2019.
  9. Ibid.
  10. Biosimilar Development, Could naïve patients be the key to US biosimilar success, 26 Sep 2019.
  11. FDA, What we do, 28 Mar 2018; European Pharmaceutical Review, Medical device design – a key con­sideration when entering biosimilars market, 25 Nov 2019.

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Darren Mansell is a Regulatory Affairs Manager with Owen Mumford Pharmaceutical Services, where he has worked for over 14 years and is integral in ensuring products meet regulatory requirements to facilitate compliance and sales in worldwide markets. He works in a cross-functional team with colleagues from Operations, R&D, and sales teams to deliver new and existing drug delivery and diagnostic products to customers.