And now for something completely… similar.

The market for both biological medicines and biosimilars is increasingly serving a growing healthcare need globally. As with generic pharmaceuticals, it is vital that companies intending to develop biosimilar products choose the right strategies for their devices and take advantage of the regulatory opportunities to produce innovative, robust, low-cost, user-friendly delivery devices.

Freedom to innovate

The burden that regulators place on the costs, certain risks, timescales, and ultimate success of a medical device development, though necessary, is substantial. However, exploitation of the regulatory environment up front can have startling impacts on the freedom to innovate in and succeed with medical device development programmes, drug delivery devices in particular.

Mary Hutchens, a regulatory specialist whose appointment to Coalesce was driven by a strategic decision to improve the integration of regulatory affairs into the entire development process, explains how key differences between the regulatory pathways for different medicines and their delivery devices can be exploited.

Recent draft guidance from the FDA for developers of generic versions of GSK’s Advair has received high profile coverage in the industry press. The FDA has explicitly left little room for improving on the reference product in order to ensure bioequivalence, or so it would seem. Coalesce has discovered ways in which a generic inhalation products could gain market advantage from subtly improved devices, but the freedom to improve has been fundamentally limited by the FDA.

In contrast, the regulatory pathway for biosimilar products offers very different prospects for innovation and differentiation in drug delivery devices.

What are biosimilars?

Biosimilar medicines are complex, large molecules, typically derived from living cells, which are developed to show the same safety and effectiveness as the existing “reference” biological medicines. In contrast, generic drugs comprise much smaller chemically synthesised molecules that must be identical to the existing “reference” drugs.

A biosimilar has a degree of variability, as does its reference medicine, but when approved, the variability and differences between it and its reference medicine are considered not to affect the safety or effectiveness of the medicine.

The expiry of the patents for many biopharmaceuticals has stimulated the development of biosimilars by companies responding to the opportunities to compete in this market. This in turn has led to the evolution of regulatory frameworks designed to address the particular challenges of biosimilar products.

Biosimilars – Opportunities for Distinctive Devices

So what makes biosimilars attractive?

• Increasing global market
• Lower development timescale and cost
• Guidelines for biosimilars that leave freedom to improve on the reference product’s delivery devices
• Growing freedom-to-operate (FTO) as patents for both biological medicines and delivery technologies expire
• Opportunity to access markets that have already been developed by the reference medicine.

Biological medicines’ molecule size and fragility usually rule out anything other than injection. In many ways, injection is a relatively simple delivery method in that it is relatively easy to deliver a specific volume into a particular target location in the body particularly when compared with (for example) inhalation, where the patient’s inspiratory flow and physiology  as well as slight variability in the device and formulation  can have a dramatic effect on drug delivery performance.

So, with injectable biosimilar products, there are opportunities to improve upon the reference product’s delivery device without affecting the safety and efficacy of the medicine. In fact, the Q&A section of the FDA guidance on biosimilars allows the possibility of the biosimilar having a different delivery device or closure system from the reference product.

Divergence from the reference drug delivery device can be acceptable for biosimilar drug delivery devices.

Divergence from the reference drug delivery device can be acceptable for biosimilar drug delivery devices.

Together, these factors open up the possibility of products that are easier to use, cheaper to develop and manufacture, optimised for particular patients or geographical or socio-economic markets, and ultimately, preferred over reference and competing products.

Regulatory Environment

Regulatory authorities around the world have seen the need to develop strategies to address the particular characteristics of biosimilars, encompassing the complex structures and manufacturing methods. The EU was the first to develop a regulatory framework, establishing a regulatory pathway in 2003, and in 2005 the European Medicines Agency (EMA) published guidelines for biosimilars, the first regulatory agency to do so. In 2006 the EMA approved its first biosimilar and currently shows 17 approved biosimilars on its website. Other countries around the world have followed, adopting broadly similar regulatory frameworks, and in 2009 the World Health Organisation (WHO) formally adopted its guidelines on biosimilars.

The Food and Drug Administration (FDA) in the US has been slower to formalise its regulatory structure for biosimilars but in 2010 the US biosimilar pathway became law as part of the Affordable Care Act, and in 2012 the FDA published draft guidelines on biosimilars. In 2014 the FDA received its first filing for approval for a biosimilar, submitted by Sandoz seeking approval for Zarzio a biosimilar version of Amgen’s Neupogen (filgrastim) a protein that stimulates the growth of white blood cells.

Biological medicine growth is now double that of total pharmaceuticals and this will increase in the future as worldwide demands on healthcare increase. Commercialisation of biosimilars provides an opportunity for offer more affordable biological medicines to patients as by 2020 leading biological medicines worth an estimated $81 billion in annual global sales lose patent exclusivity. In addition an ageing population around the world combined with emerging economies with increasing populations and wealth will result in increasing need for financially accessible biologics.

Delivery Devices – an important aid to product acceptance

Biosimilars have been developed in several therapeutic areas including oncology, rheumatoid arthritis, dwarfism, and diabetes. The requirement for self-administration and self-titration can lead to relatively sophisticated devices rather than simple syringes.

Delivery devices such as insulin pens and auto-injectors have long been an aspect of patient administered treatment and the delivery device is an important aspect of the patients’ experience of the drug regime.

The design of the delivery device affects the comfort and convenience of the drug administration and influences the adherence and outcome of the treatment. The device through which a biosimilar is administered must be able to match the reference medicine’s device for convenience and comfort. If the biosimilar’s device is less convenient to use, this could reduce the adherence to the treatment and reduce significantly the uptake of the biosimilar.

This may have been a factor in the initial slow uptake of Omnitrope (somtropin), the first biosimilar to gain approval in the EU. The initial delivery system was as a lyophilised powder form in a vial, which was a more complex delivery system than the predicates that were already in the market. The manufacturer subsequently introduced an injector pen with a ready-to-use cartridge, and the improved convenience to the user has since seen sales increase.

The design and user experience of the delivery device may therefore serve as a key market differentiator to the reference or competing products, even if they are clinically equivalent.

If you have any thoughts or questions, please contact Mary by emailing or calling on +44 (0)1223 421 855.