Cover story

ARE YOU PREPARED?

AS THE DEADLINE FOR EUROPEAN MEDICAL DEVICE REGULATION (EU MDR) IS RAPIDLY APPROACHING, OUR EDITOR LAURA HUGHES PROVIDES A BRIEF SUMMARY OF THE REGULATION AND SHARES THE RESULTS OF MPN’S RECENT SURVEY.

WHAT IS EU MDR? EU MDR is scheduled to come into effect in EU Member States from 26th May 2020.

This regulation will apply to all manufacturers selling medical devices within Europe and aims to provide greater protection of public health and safety.

IS THERE POTENTIAL FOR EU MDR TO BE DELAYED? The United States issued a statement to the World Trade Organisation (WTO) in 2019 writing: “Our industry is worried about their continued access to the EU’s $125 billion USD medical device market, $20 billion USD of which is supplied by US products.” However, the EU commented in July 2019: “There are no grounds for the time being to explore any amendment to the transitional periods.” WHERE ARE WE NOW? To date the European Commission (EC) has designated nine Notified Bodies (NBs) against MDR. The EC previously predicted at least 20 NBs. The EU acknowledged that the final number of designated NBs could be “slightly lower” than originally anticipated. The US statement to the WTO explained how they do not believe this number is enough to, “ensure continued regulatory approvals by May 2020.”

Only one of the regulations that has been put forward has been adopted to date. This regulation involves the reprocessing of single-use medical devices.

Additionally, the EC’s draft standardisation has been heavily criticised. The US statement addressed the issue to the WTO stating: “Industry maintains that the product standards necessary for compliance with MDR cannot be completed before the deadline.”

COMMENTS Lots of key industry figures have shared their views on the topic.

Reiner Thiem, head of regulatory affairs, Raumedic “We have intensively worked over the last three years to gain an understanding of the new regulatory landscape.”

Peter Rose, managing director - Europe at Maetrics, a life sciences consultancy firm: “Three year transition periods are well established in our industry, but never have I seen a transition period being used to get the system ready.”

MPN CONDUCTED A SURVEY ON PEOPLE SELLING MEDICAL DEVICES WITHIN EUROPE. THE RESULTS OF THE SURVEY ARE DISPLAYED BELOW.

Did you use any consultancy service as part of your preparation? Q

50% 40% 10%

YES

NO

N/A

The survey was completed by people from the following countries:

32% 2% 2% 2% 2% 2%

2% 2%

15%

Spain Poland France Germany

39%

UK Ireland

On a scale of 1-5, (1 being not ready at all, and 5 being ready to go right now) how prepared are you and your business for the new EU MDR? Q

9.52% 26.19% 40.48% 19.05% 4.76%

1 2 3 4 5

Which class of medical device is your company primarily a manufacturer of? Do you think the implementation of EU MDR will have a detrimental effect on patient outcomes? Q Q 28% 55% 12% 5%

To date the European Commission (EC) has designated nine Notified Bodies (NBs)against MDR. The EC previously predicted at least 20 NBs.

Class I medical devices Class III medical devices Class II medical devices No response

60% 40%

What do you think are the most challenging aspects of these new regulations? Q

35.71% Unsure

When did you start making preparations for EU MDR? Q

54.76% 23.81% 9.52% 0.00% 11.90%

Within the last 12 months Within the last 6 months Within the last 3 months Within the last month Not started

Scott Whittaker, president and CEO, AdvaMed “We are now in the critical period of transitioning to the new system, which needs to be completed by May 2020 (and May 2022 for IVDs). Industry is concerned that while we are prepared, key elements of the new EU regulatory system will not be ready sufficiently ahead of these deadlines to enable industry to comply with the new rules in time. In particular, we believe the capacity of the “NBs” (approval bodies) will not be adequate to allow for the re-certification of tens of thousands of existing and new products ahead of the May 2020 MDR implementation deadline. Appropriate and urgent action by European institutions will be essential to ensuring continued access to existing life-saving and life-improving medical devices and diagnostics that hospitals, doctors, patients and families rely on every day.”

Sandi Schaible, senior director of analytical chemistry and regulatory toxicology, WuXi Medical Device Testing “The year of MDR is here. And device manufacturers are under more pressure than ever before. With so many questions about NBs, whether Europe will delay implementation, and EUDAMED, the uncertainty and stress is palpable. Device manufacturers, you are not alone. We’re in this together. But don’t sit idle and risk having your devices pulled from market. If you’re behind, it’s time to lean more heavily on laboratory testing partners, if they have capacity. Put your foot on the gas and approach partnerships with transparency. Being forthcoming with details and giving your lab partners visibility to forecasts, intervals, and timelines will help you make up for lost ground in these final months before the 26th May 2020 deadline.”

11.9% Notified bodies

14.29% Required documentation

4.76% Available resources

19.05% Clinical data for existing products

14.29%

Do you believe the guidance for EU MDR is clear enough? 33.33% Q

NO YES

You expect precision. We deliver.

contract manufacturing injection moulding medical devices

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Therapy FOCUS

A cool idea

SCALP COOLING TECHNOLOGY PROVIDER, PAXMAN, EXPLAINS HOW ITS INNOVATION AIMS TO HELP PATIENTS MAINTAIN A SENSE A NORMALITY WHILST RECEIVING CHEMOTHERAPY.

WHO ARE PAXMAN? Founded in 1997, Paxman Coolers design and manufacture the Paxman Scalp Cooling System – a hair loss prevention system for cancer patients undergoing chemotherapy.

Hair loss is consistently ranked as one of the most feared and common side effects of chemotherapy treatment, and the damage that chemotherapy causes to the hair follicle can be alleviated by using scalp cooling treatment - also known as the ‘cold cap’. The cold cap which is manufactured from high grade silicone material works by reducing the temperature of the scalp by a few degrees immediately before, during and after the administration of the toxic chemotherapy drugs.

Paxman has enabled scalp cooling to be available for chemotherapy patients worldwide. The company’s aim is that every applicable cancer patient, no matter where in the world nor their financial position, has the opportunity to maintain a sense of normality by keeping their hair through chemotherapy treatment.

HOW SUCCESSFUL IS SCALP COOLING? In recent years the success rate for patients using scalp cooling has been around 50 percent (on average), with significant variations experienced between different types of chemotherapy.

A key factor in improving efficacy is Paxman’s research and development collaboration with the University of Huddersfield in the UK. The collaboration was formalised in 2019 with the Paxman Scalp Cooling Research Centre, a multidisciplinary research group that constitutes the world’s first research and development centre in scalp cooling.

HOW TO IMPROVE SCALP COOLING EFFICACY The target for improved scalp cooling efficacy has always underpinned Paxman’s company-wide strategy and continues to form a major part of the company’s research, development and innovation strategies. The launch of the 4th generation Paxman Scalp Cooling system in 2018 saw a complete re-design of the silicone cooling cap. The fit of the cooling cap is critical for successful hair retention outcomes for patients. Extensive research by academics at the University of Huddersfield into varying cultural differences in head sizes and shapes led to the latest 3D printing technology being used to produce the optimum shape and fit for the cooling caps. The Knowledge Transfer Partnership (KTP) for this most recent project was judged “outstanding” by the Technology Strategy Board.

CHASING ZERO HAIR LOSS: THE 80/20 VISION The 80/20 vision means that around 80 percent of patients using scalp cooling shall be able to keep most of their hair. In 2012 the benchmark for scalp cooling efficacy was 48% whilst in 2019 we saw a significant uplift in successful scalp cooling outcomes to over 56%. Paxman’s research and development programme allows the company to continuously refine the efficacy and user-friendliness of its scalp cooling system. The collaboration with the multidisciplinary research team at the University of Huddersfield brings together crucial industry expertise and know-how.

The Paxman Scalp Cooling Research Centre, the world’s first multidisciplinary research centre focused on scalp cooling will continue developing individual 3D-printed cooling caps, along with important biological hair follicle research as well as developing innovative scalp cooling-related treatments. Initially, the Centre will focus its efforts on three key projects: • Development of a novel, environmentally friendly ecosystem for 3D-printed individual cooling caps ready for mass production and ultimately a perfect cap fit.

• Biological research using the most clinically-relevant in vitro models: Cultivated human hair follicles.

• Development of a topical product with the potential to substantially enhance the effect of scalp cooling. The enhancement effect of the product has already been proven in initial in vitro tests.

Continuous innovation is vital to ensure that the personal cooling caps ensure a high level of comfort for patients, as well as enabling them to practice their cap fitting in the comfort of their own home, maintain good hygiene and remove the nursing burden.

Paxman ©

Five ways to optimally manufacture drug delivery devices

BILL WELCH, CHIEF TECHNOLOGY OFFICER, PHILLIPS-MEDISIZE LISTS FIVE BEST PRACTICES THAT CAN HELP ACCELERATE TIME TO MARKET AND OPTIMISE RETURN ON INVESTMENT.

1. TAKE A TEAM APPROACH Pull together a combination of stakeholders, including design, marketing, finance, procurement and manufacturing, in the earliest stages of development. That way, you can work with front-end innovators to identify and refine the concepts that deliver the best features and usability for patients, caregivers and healthcare professionals, and also plan for the manufacturing and commercial realities that influence marketplace success. To maximise return on investment, it is critical to balance desirable design features with the cost of goods, production time, manufacturing complexity and scalability.

2. UNDERSTAND PATIENT NEEDS Patients have varied medication delivery preferences and dosing needs. For example, patients in paediatrics, geriatrics and oncology often require highly flexible oral dosing based on age, weight and other variables, and may find it difficult to swallow normal-sized tablets and/ or capsules. As a result, mini-tablets often offer a viable option, given their size and flexibility for adjusting dosing. To provide patients and caregivers with reliable methods to administer mini-tablets in variable quantities, Phillips-Medisize is commercialising an innovative, low-cost mini-tablet dispenser which mounts directly on a standard Ø38mm tablet bottle neck.

This makes it easy to safely and accurately dispense the exact number of minitablets needed per dose, without requiring a new or different bottle. Users of this device simply shake the mini-tablets into the preset dispenser dosing disk, rotate the lid and pour the mini-tablets onto a spoon, food or other option.

3. INTEGRATE MOULDING DESIGN EARLY In plastics manufacturing, the moulding design is typically added after the parts are designed for the mechanical application. However, for drug delivery devices, integrating moulding requirements early in the process is critical to addressing shrink, sink and multiple other factors caused by heating, forming and cooling. The resulting changes can affect the mechanical design and necessitate future adjustments to the overall device design in order to avoid moulding parts with unmanageable tolerances and quality issues. Meeting established plastics design standards, tolerance expectations and tooling design increases the overall design effectiveness, in turn reducing variability and furthering compliance with global regulatory requirements for product manufacturing.

4. DEVELOP CONNECTED DEVICES ON AN INTEGRATED PLATFORM Adding connectivity to drug delivery devices presents unique challenges along with numerous benefits. Developing these innovative products on an integrated core platform can accelerate time to market by using proven designs, existing infrastructure and repeatable manufacturing processes. Phillips-Medisize has created a scalable connected health platform that combines plastics components, electronic components, sensor technologies and software, and features a modular approach that is easily customised to multiple therapeutic areas.

5. CHOOSE YOUR DEVELOPMENT PARTNER WISELY Innovative partnerships that consider the entire opportunity lifecycle, facilitating a smooth flow through each stage, offer distinct advantages. These include increased production speed and reduced cost, as well as reduced risk once the product reaches the market. With the emerging trend of outcome-based reimbursement, combination products must continue to find ways to improve the entire therapy solution. Design development and user considerations, while important to consider, are merely aspects of the greater value proposition provided through design thinking and the committed implementation of device strategy.

These best practices provide a strong foundation for successfully developing, manufacturing and bringing drug delivery devices – both mechanical and connected – to market, quickly and cost-effectively.

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DELIVERY

The available market for biosimilar manufacturers seeking to compete with original reference biologics coming off patent between late 2018 and 2023 in the USA and Europe, is considerable. However, says Owen Mumford, even where clinicians encourage the use of biosimilars for the patient, there remain some key considerations to overcome. This includes clinical confidence in the biosimilar; competitive pricing of drugs through greater competition; and patient confidence in the drug delivery device. Owen Mumford’s study reveals the size of the near-term opportunity in competitive biosimilars markets for biologics coming off patent 2018-2023 and offers evidence that device design is a key differentiator in addressing patient adoption. In Europe, the estimated market opportunity for this five year cohort of patent expiries (factoring in competitive discounts and based on 50% market share) for biosimilar manufacturers is $3.12 billion per year based on current revenues; the equivalent market opportunity in the USA comes to

$5.24 billion per year. To maximise on this opportunity, biosimilar manufacturers need to think seriously about drug delivery. Molecular size and viscosity create issues around the volume of drug being delivered, as well as potentially causing pain upon administration. We are seeing an increase in self-administration across the globe. As a result, precision dosing, ease of use, comfort, and convenience – all reliant on drug delivery device design – have become key in ensuring patient adherence. Familiarity and comfort with a particular delivery device also has to be taken into account as it can hinder switching from treatment despite the advice of healthcare professionals. George I’ons, head of product strategy and insights, Owen Mumford Pharmaceutical Services says: “This latest paper highlights some important issues concerning the key role of design for ‘combination products’ where delivery device and drug are seen as single entity by regulators. This highlights the supporting role of device design in ensuring that drugs, especially newly booming biosimilars, enter the market competitively.” LR: Why is device design for biosimilars so important in relation to patient adoption and what are the main considerations in drug delivery design for biosimilars compared with other drugs? GI: The device component is increasingly seen as integral to the therapy as a whole with biologics rather than a secondary consideration, especially since the design of the delivery device may have an impact on patient adherence. Testament to this is the position the Food and Drug Administration (FDA) has taken by creating a specific category for approval of combination products i.e. the device and drug. Biologics and biosimilars present specific challenges with respect to formulation development due to the nature of the molecular structure as these types of treatments are typically administered subcutaneously. Typical considerations are the trade-offs between medication volume, viscosity and injection frequency, and delivery time. Higher viscosity formulations may allow less frequent dosing for the patient but increase the complexity of device design. Higher volume injections may mean looking at different options in prefilled syringe and autoinjector design or even considering wearables as alternatives. Injection time, ease of use, lack of pain and needle protection are all key drivers for increased patient acceptance. HEAD OF CONTENT, LU RAHMAN, SPEAKS TO MEDICAL DEVICE MANUFACTURER, OWEN MUMFORD, ABOUT THE FINDINGS OF ITS RECENT REPORT SCOPING THE NEAR-TERM COMPETITIVE BIOSIMILARS MARKET IN THE USA AND EUROPE, AND ITS IMPACT ON DRUG DELIVERY DEVICE DESIGN.

It is now widely accepted that the design of a drug delivery device – typically an auto-injector or prefilled syringe device – is a crucial consideration. When switching to a new biosimilar, patients may experience difficulties if they are using a different device that is too unfamiliar. On the other hand, improvements in design and ease of use may be a persuasive factor.

LR: How can drug delivery designers and manufacturers seize upon the opportunities available in this market?

GI: A key element in device design is a thorough and robust Human Factors (HF) program. The HF process will test user acceptance of a new device and importantly determine the level of risk associated with each step in its use. Results from formative HF studies can provide key insights as to how device design can be modified to create more user-centric product features. Also important for device manufacturers is the ability to be able to offer flexibility in design so that different sizes and configurations of primary containers can be accommodated to allow for varying drug volumes and viscosities. With low volumes typical of biologics, the device also needs to ensure that the full dose is delivered to the patient and that the residual volume in the device is as low as possible. Another key consideration is the requirement to ensure that device designs comply with sharps injury prevention regulations and incorporate safety features that prevent needlestick injury and reuse. With many pharma companies creating different doses and formulations of the same molecule, as part of lifecycle management, the ability to have a platform device that can be used for all these variations with minimal design changes is a key factor.

LR: Is it important for device companies to collaborate with drug manufacturers and how easy is this process?

GI: The collaboration between pharma and device manufacturers is essential to developing and bringing a successful combination product to market. This relationship is key throughout the drug development process with horizon scanning for devices often taking place well before initiation of clinical studies. Most large pharma companies employ dedicated device teams who work closely with other internal departments such as formulation chemistry, clinical, sales and marketing as well as creating a close working relationship with the device suppliers. Smaller pharma companies without device teams often need additional technical support and guidance throughout the process so good collaboration - whether large or small - is central to a smooth launch.

LR: You highlight self-administration devices - how important is this market and what are the future opportunities?

GI: We’re seeing self-administration become increasingly important across the world. There are many drivers of this trend: In particular, self-administration helps to ease the burden on hospitals and makes treatment more convenient for patients. This is creating opportunities for manufacturers to favour the production of devices which prioritise ease of use and safety features. There is a growing demand for pre-filled syringes while safety-engineered devices can be seen to dominate the pre-filled market, with three in every four devices offering safety mechanisms. If we look at the market data for safety syringes specifically, an analysis of a range of key research sources reveals that the global pre-filled syringes market was estimated to be worth over $772 million in 2018, rising to some $1.137 billion in 2023: This amounts to a significant growth rate of 8.1%.

LR: Are there any differences between the US and UK markets?

GI: Approval of biosimilars is far more progressed in Europe compared with the US with over 60 approved by the European Medicines Agency to date compared to 25 approved in the US by the FDA. Both US and EU markets have well established regulations in place concerning DRUG DELIVERY

the requirement for employers to provide safety devices designed to prevent needlestick injury. These regulations apply to the employees regardless of the place of work and so cover acute and home settings. The US FDA has a specific combination product approval process for drug and device combinations. This has yet to be established in Europe and as such in this market the device still requires a CE mark for approval; however, the process will change with the introduction of the Medical Device Regulation (Regulation (EU) 2017/745) in May 2020. For Europe the drug is also regulated separately and a Marketing Authorisation Application (MAA) is reviewed and granted by the European Medicines Agency.

Precision dosing, ease of use, comfort, and convenience – all reliant on drug delivery device design – have become key in ensuring patient adherence.