Tag: Quality & Regulatory Affairs

S.M.A.R.T. innovations for the food industry

April 5th 2019

Martha Hodgson 

Last month, I had the honour of speaking at the annual NSF International conference, held at the British Library in London. This year’s conference theme was focused on ‘Addressing New Realities’, looking at how mainstream food producers can take advantage of technology innovation to compete effectively and survive in today’s rapidly changing world. 

Alongside industry experts, academics and futurists, examples of what we mean by ‘smart’ technology and how it is influencing the food industry were explored. These included drones that assess harvest maturity, artificial meat cultured in labs and new packaging materials and waste infrastructures that are helping reduce plastic waste. The main message throughout the day was clear – as digital technology and other applied sciences are transforming the future, we need to ensure the future remains people centered! Future proof organisations will be those who clearly understand what their consumers really want.

My keynote centered on the belief that innovation happens where consumer insight, technology enablers and business opportunities coincide. While technology plays a vital role in enabling opportunities, innovation requires all three ‘stakeholders’ and, the most fundamental starting point is having a clear understanding of the consumer. Building on this belief, I was delighted to address the conference delegates and share with them a S.M.A.R.T approach to innovation:

S

Solve a problem that customers really care about: often human behaviour is driven by a desire to solve problems, which can be functional, emotional or social in nature. We adopt Jobs-to-be-Done (JTBD) to define and understand the ‘jobs’ consumers are trying to solve. Done properly it provides a clear, solution-agnostic understanding of customer needs and desires across complex markets. The advantage over conventional market research methods is that jobs tend to stay the same over the long term, while technologies come and go and enable different point-in-time solutions that may become quickly obsolete.

M

Measure your success: Generally, consumers seek the best solution that enables them to solve their problem, and by understanding their needs we can create a multi-dimensional analysis of how well this has been done. We monitor eight mega trends which also help us understand how consumers make choices and measure how successfully the solutions have solved their problem. For example, personalisation is driving consumers growing desire for new experiences, while provenance is driving consumers transparency and traceability expectations.

A

Attitudes to Innovation: We seek evidence to understand and adapt to different consumers innovation attitudes and bring them on a compelling journey. Often organisations try to innovate by starting with a technology, this can result in new products and services that appear to be ‘tech for tech sake’. In order to make innovation meaningful to consumers you can begin by understanding their established behaviours and rituals. Be mindful of who your audience is here, for instance Millennials are the ‘Instagrammable’ generation and I love the expression ‘if a millennial eats a meal but didn’t Instagram (or ‘gram’) it first, did it really happen?’ Think about what makes something meaningful and attractive to your target audience.

R

Right to Play: when exploring innovation opportunities, be sure not to lose site of the baseline expectations and requirements that exist in your industry. These may be regulatory constraints that should always be addressed first. Consumers also have a set of baseline expectations within the food industry, both tangible (e.g. premium food ‘codes’) and perceived (e.g. attitudes and expectations around single-use plastic). These expectations can create tensions for organisations to innovate around, and we are seeing brands (even those competing with each other) adopting innovative new ways to try and solve such problems.

T

Transferable learning: innovation usually isn’t unique, meaning you can learn a lot from adjacent markets, in terms of technology enabled innovations that work…and those that don’t! For the Food industry, boundaries are blurring with both Beauty and Health making these industries highly attractive to learn from. We can already see examples where simple NFC technology is making both Beauty and Food more convenient, and how DNA science is enabling tailored Health and Food solutions. By exploring adjacent industries, we can see how business models could empower new social economies within the Food industry, as well as new material innovations which can inspire us to start experimenting with single-use plastic alternatives, for example.

Technology set in the context of consumer needs can unlock innovation and by implementing a S.M.A.R.T. mindset, it will help ensure you make the right technology investments for your business: By truly understanding your consumers’ problems, giving consumers measurable proof points to show that you have solved their problem making your innovation both attractive and meaningful to your target audience, ensuring you deliver against the baseline expectations first and foremost, and looking beyond your direct competitors to learn about both what to do, and what not to do, when it comes to successful technology-enabled innovation.

For highlights of the NSF International conference, featuring comments from Martha, please watch the following video.

Is medical device regulation failing to ensure patient safety?

January 18th 2019

Louise Place 

For the last decade I have been part of the medical devices industry, most recently as part of a design consultancy firm specialising in medical device innovation. In the last few years our world has been shaken with reports of the failure of medical device implants and the insinuation of industry wide misconduct.  The headline statistics are certainly shocking, in the investigation recently published by the ICIJ, their research suggests that in 2017 nearly 300,000 patients were harmed by medical devices in the US alone. Clearly something is wrong.

However, personally I have never come across anyone in the industry who wishes to cause harm to a patient, in fact it’s completely the opposite. Where I work, it is our company’s primary policy to improve lives through innovation and the stories that have hit the headlines do not to make it clear that most people in the industry are diligently working towards making sure all new devices are safe.

I spend my life around medical devices. These include items as varied as a surgeon’s scalpel, an insulin injection pen or a portable oxygen delivery system. They also include implantable meshes and spinal support systems and complex hospital equipment designed to keep extremely sick people alive.

Each device I work with is the product of many years of design and testing before it is allowed near a patient. During that time, it undergoes substantial testing to ensure that it works according to the design intent, for the conditions it is expected to experience and the intended life both on the shelf and in use. Biocompatibility testing is carried out to ensure that anyone encountering contact with materials does not suffer an adverse reaction and a robust risk management process, including medical professional opinion, underpins all this to attempt to account for foreseeable harms from the use of the product. At every stage in this development process the concern is for the patient and one of the most common questions asked is whether you would be happy for a close relative to use the final product.

If a device does reach a human being for clinical evaluation, and not all do, the use in that person is strictly controlled. The safety profile, as far as possible, needs to be determined and the risks of the use of the device, as well as the benefits, need to be established and controlled as far as possible. In the United Kingdom, this assessment is carried out by the Medicines Healthcare Regulatory Authority (MHRA) and it takes several months for agreement, during which this information is assessed. It is also usual for an independent Research Ethics Committee to confirm the well-being of trial participants and agree to the trial. Once agreement is obtained recruitment may begin and appropriate volunteers may start a trial once they have signed an informed consent form which details the potential risks and benefits of the study. All trial participants may withdraw from a trial at any time without needing to give a reason.

Prior to a device being launched on the open market in Europe and depending on risk classification (the lowest risk devices can be launched after the creation of appropriate technical document with limited oversight), the summary of all the development documentation detailed above, and more is assessed by a Notified Body. These organisations, whilst not part of governmental structure, are designated by their national competent authority (e.g. MHRA) as having passed a strict assessment which confirms that they have the relevant in-house knowledge to question and approve a device for use. Post market surveillance also takes place to ensure that as more information becomes available through use, appropriate changes are made to the design and even withdrawal of product if it is deemed necessary because of a safety risk.

Europe is currently poised to welcome an update to the Directives and Regulations governing the development and assessment of Medical Devices to the market. This is the culmination of nearly a decade of discussions from the European Commission downwards to ensure the safe development of medical devices. The new Medical Device Regulations (MDR) place stricter requirements on the in-patient testing of devices, the post market follow-up (especially with regard to implantable devices) and the re-classification of some devices into higher risk categories. All medical devices, both yet to be conceived and those on the market already, must meet these regulations as manufacturers will no longer be permitted to rely on historical approval.

I am not claiming my world is perfect and the statistics show this. But carefully implemented medical device regulation maintains and promotes high standards of safety and efficacy. I’m proud to say that here at Cambridge Design Partnership the focus is always on the welfare of the patient. I wouldn’t have it any other way.

The new medical device regulation & the applicability of article 117 to medicinal products

January 16th 2019

Louise Place 

This article was first published on Drug Development and Delivery.

“Those who expect moments of change to be comfortable and free of conflict have not learned their history.” For many involved in the medical and pharmaceutical industries within the last few years, this quote – attributed to American historian Joan Wallach Scott – has never been more true. From the impending switch to the Clinical Trials Regulation to the implementation of the Falsified Medicines Directive, and the evolution of the Medical Devices Regulation (MDR) or the current uncertainty around ‘Brexit’ in Europe, change is everywhere. With so many new developments in progress, it is almost impossible to keep track of all the required updates to procedures – with a very real risk of missing something critical.

Article 117 of the new MDR1, has the potential to be one such pitfall. Buried deep within the final chapter of the document, just before the annexes, is the somewhat innocuously titled ‘Amendment to Directive 2001/83/EC’. For many medical device manufacturers, this article is likely to be mostly disregarded, as Directive 2001/83/EC2 – also known as the Medicinal Product Directive (MPD) – has historically not been an essential part of placing a device on the market. For companies whose focus is primarily on the MPD – like many pharmaceutical and biotech companies – this update may pass completely unnoticed.

This article is primarily focused with the impact of Article 117 in Europe on the combination of a drug and a device, where the primary mode of action is performed by the drug and the two products are combined in a single, integral product which is exclusively for use in the given combination and not reusable. Some examples of products that would be categorised in this combination include a single-use, disposable auto-injector or a disposable pre-filled metered dose inhaler.

Differences between US and Europe

The US and EU have very different systems for determining assessment routes for drug (or biologic) and device combinations.

The US refers to these products as combination products and selects a lead division with primary jurisdiction based on the primary mode of action. The other division is also consulted for the relevant aspect of the product.

In Europe the process is slightly different since the term ‘combination product’ is not officially recognised – albeit more frequently used, even in the absence of an official “status”. Whilst products are still assessed based on the primary mode of action, this determines one of two primary assessment formats; either medicinal product or medical device.

The Existing System

The MPD requires evidence of CE marking when it is applicable but does not detail requirements for non-CE marked devices.

Under Article 1 sub-part 3 of the Medical Device Directive (MDD)3, devices in which ‘the device and medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable’ were governed by the MPD with the additional applicability of the essential requirements of Annex I to the MDD with regard to safety and performance-related device features.

Devices which do not meet this clear definition were governed by the MDD, unless they were in vitro diagnostic devices or active implantable devices governed by Directive 98/79/EC4 and Directive 90/385/EEC5 respectively.

What’s changed?

Article 117 of the MDR legally amends Annex I, Section 3.2 point 12 of the MPD as follows:

‘(12) Where, in accordance with the second subparagraph of Article 1 (8) or the second subparagraph of Article 1 (9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (*), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer’s EU declaration of conformity or the relevant certificate issued by a Notified Body allowing the manufacturer to affix a CE marking to the medical device.

If the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a Notified Body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a Notified Body designated in accordance with that Regulation for the type of device in question.’

For many medicinal products this amendment will not introduce an onerous change as a device that is non-integral to the medicinal product will still need a CE mark with the appropriate conformity contained within the declaration of conformity.

The key element of this change applies to integrated, non-reusable products where the drug element has the primary mode of action. In essence, the device element of a medicinal product – when integral, non-reusable and intended exclusively for use in the given combination – needs to conform to the Annex I (MDR) general safety and performance requirements without the requirement to be regulated as a CE-medical device. As part of demonstrating this, a Notified Body opinion must be incorporated into the marketing authorisation application for the medicinal product.

What does it mean?

With an increasing shift away from small molecule drugs towards biologics and an increased desire for patient self-administration to reduce the burden on healthcare systems, the option to combine a drug formulation with an integrated delivery device seems increasingly likely. There are some key implications of the Article 117 requirement that will require careful thought and implementation, not least that, as of the date of writing, no decision has been made as to how a Notified Body would issue an opinion on the device element of a medicinal product.

The overall implication of the MDR is that the device element of the medicinal product would not be treated as a fully CE-marked device but the Annex I requirements would still need to be met – as indeed was the case with the MDD. It should be noted however, that Annex I of the MDR has been expanded significantly and as such, it is likely that application for a medicinal product device element would not be dissimilar to that for application of the CE-mark; with the declaration of conformity being the significant omission. This also allows for continuing to handle the product development under the MPD and pharmaceutical practices.

It is assumed that a Notified Body would not issue a CE-mark certificate and it is probable that a Notified Body would issue some form of report to the manufacturer, detailing an opinion of the conformity of the device. This report could be included either as part of the marketing authorisation application or as a separate communication to the competent authority.

The question then arises as to the format of any submission to a Notified Body and the information that would be assessed as part of that submission. For a CE mark applied to a medical device, this information would typically be presented as part of the summary technical documentation (STED) rather than in the appropriate section of the Marketing Authorisation Application (MAA) as for the device element of a medicinal product. It is possible that section 3.2.R of the MAA, containing the device elements could be submitted to the Notified Body however, it is likely that there will need to be some revision of this section to ensure it captures all of the required information. Alternatively, a new section could be created in the application to assess the Annex I requirements separately.

Clarification is also needed as to how a Notified Body would form an opinion on the device element of a medicinal product. Currently, medical devices are assessed on a risk-based principle, with the device classification determining assessment routes and additional requirements. Device elements of medicinal products are likely to automatically increase the risk classification due to the presence of the drug product. It should also be considered that even a device element that would be classed as a class I medical device – and thus subject to self-certification – would still need a Notified Body review and opinion.

Within the submission itself, it is worth considering that the system should not be simply split down the middle between the device element and drug. Whilst it is true that certain elements lend themselves to one route or the other – for example formulation versus material selection – many cannot be assessed in isolation. Certain attributes have relevance to both the drug and device elements. For example, the siliconization level in a pre-filled syringe may be impacted by the drug formulation but is also key when considering the mechanical forces required to operate an auto-injector, especially over a claimed shelf life. Therefore, it is important that assessment of any individual element also accounts for the interface and interaction of that element with other parts of the system. This is a critical element where the MAA and Notified Body evaluation may differ in their overall assessment of risk.

After Approval?

Post-market surveillance (PMS) is one of the most significant updates captured in the MDR. There is an increased requirement for manufacturers to take a more proactive approach to PMS and actively assess performance of medical devices once they are launched on the market, rather than purely relying on user feedback. Medicinal products are subject to their own PMS requirements but, it is likely that the device elements of medicinal products would have an increased requirement for PMS in line with the MDR.

Post-approval changes to a medicinal product with an integrated device element would likely need to be captured via the medicinal product variation procedures and would be assessed by the competent authority. It is not clear at which point a Notified Body assessment would be required, although it is likely that significant changes to the device element would require Notified Body involvement. The question arises as to when changes to one element of the product cease to impact on the other element(s) and thus when the requirement for Notified Body opinion would be triggered.

Existing marketed products pose an interesting question under Article 117. The MDR has been very clear that ‘grandfathering’ of existing products is no longer permitted and new certificates need to be issued for all medical devices in class 2 or higher. The case is not so clear cut for medicinal products and their integrated device elements, as such products fall under the medicinal products system. It is possible that implementation of the MDR would not apply to products previously assessed by a competent authority as part of a MAA. If this were not the case and Article 117 changes were applicable, significant remediation activities would be needed across industry. As with much of the regulatory situation at the moment, the position is currently unclear and may not become so until it is too late to change without significant resource and cost expenditure.

What next?

One of the obvious major impacts of the introduction of Article 117 is the need for pharmaceutical companies to involve a Notified Body. This has implications given the other changes in the medical device world in Europe. With the implementation of the MDR and the potential loss of UK notified bodies due to ‘Brexit’, notified bodies are currently limited on resource and may not be taking on new clients for the foreseeable future.

Selection of a suitable Notified Body also involves the capability of that Notified Body to assess a specific product type with an increased requirement for that Notified Body to demonstrate the relevant expertise in a product type. The additional complication is that currently, designation of notified bodies under the MDR has not been completed, so it is unclear as to which product codes notified bodies may assess against, which a Notified Body has chosen not to apply to assess, or which are relevant for medicinal products with integrated device elements.

Conclusion

In the regulatory arena, regulations and guidelines are always open to interpretation and many regulatory professionals have been known to utter the words ‘it depends’ when called upon to clarify. This seems unlikely to change with the implementation of the Medical Device Regulation, especially with regard to Article 117. What is clear however, is that with so much detail currently undefined and likely to remain so until the date of application in May 2020, impact assessments need to be performed and companies need to have open discussions with notified bodies, if not already started, to ensure that appropriate support is available when needed. The time, effort and skills required to implement the coming changes should not be underestimated and, as ever, the clock is ticking.

References:
1. Medical Device Regulation. Council Regulation (EU) 2017/745
2. Medicinal Product Directive. Directive 2001/83/EC
3. Medical Device Directive. Directive 93/42/EEC
4. In Vitro Diagnostic Directive. Directive 98/79/EC
5. Active Implantable Device Directive. Directive 90/385/EEC

Medical Devices Regulation

Medical Devices Regulation (EU 2017/245) – Are you ready for 2020?

September 27th 2018

Caroline Marshall 

Head of Quality

More than a year has passed since 25th May 2017 and the start of the three-year transition period from the Medical Devices Directive (93/42/EEC) and Directive 90/385/EEC on active implantable medical devices (AIMDD) to the Medical Devices Regulation (EU 2017/745).

But what does this mean for businesses with products currently on the market or a pipeline of new innovative medical devices? The answer every project manager likes to hear…it depends!

For most devices currently certified to the MDD the rules of device classification will not dramatically change, however transition planning should start now to allow enough time to assess if devices conform to the MDR and ensure they are not removed from the market.

How long do you have?

The first step to planning your transition to the MDR is to determine what key dates in the implementation of the MDR apply to your device or business.

What class is the device?

Device classification is also a key consideration when planning and budgeting for implementation of the new regulations. Although device classification has not drastically changed and still follows classification levels 1, 2a, 2b and 3 – some devices will be affected by re-classification or if currently not regulated as a medical device may now fall under the scope of AnnexXV1 of the MDR.

The greatest impact can be seen in the following device types:

• Class 1 devices containing software e.g. medical apps
• Class 1 devices that are currently self-certified, that have been reclassified to a higher classification
• Aesthetic or implantable devices without an intended medical purpose e.g. non-corrective contact lenses or equipment for liposuction
• Devices manufactured utilising non-viable human tissues or cells
• Class II implants if they come into contact with the spinal column
• Substance based medical devices

A change in device class can lead to new submission requirements including addition of essential requirements, update to Technical Files and Declaration of Conformity, and generation of clinical evidence, with all of these adding significant time and cost burden to a project. Therefore, it is essential that the classification of the device is established as early as possible to allow time for any unexpected activities.

Is your notified body designated?

Not only does the update to regulation extend the requirements of manufacturers, the notified bodies will also see significant changes to their responsibilities. And with the new classification rules the number of devices falling under the control of these notified bodies is significantly increased.

Re-designation of notified bodies is currently in progress to ensure there are enough notified bodies available by 2020 when regulations start to apply. At this point in time, in September 2018, no notified bodies are designated, although some have been assessed and are awaiting formal designation; therefore it is essential to check the status of your notified body and ensure they are able to support your device launch strategy.

With these key questions considered it may be time to put a plan in place or review existing project timelines.
To find out how CDP can help with your MDR transition, please get in touch.

Exploding some of the myths about product safety

Exploding some of the myths about product safety

July 16th 2018

Colin Plimmer 

Senior Consultant Electronics Engineer

Hardly a week goes by without the press or social media picking up on a story, often accompanied by dramatic video, of batteries overheating and even in some cases ‘exploding’ in a consumer product – raising serious concerns about product safety among both consumers and manufacturers. In reality, these incidents are quite rare compared with the number of products sold. But when they occur they are very serious – both at a personal level for the user and at a reputational level for the manufacturer – with a lingering impact from product recalls and loss of brand value.

The vast majority of cases are entirely avoidable through robust product engineering and manufacturing approaches. Many incidents are, in fact, due to failures of the lithium-ion batteries used to power the device. This technology has a long history of issues in products as diverse as the Boeing 787 Dreamliner passenger aircraft, where battery pack fires were widely reported, and laptops and mobile phones – in particular, the Samsung Galaxy Note7 where Samsung had to recall millions of the handsets due to widely publicised handset fires and it led to a ban on taking the handsets on aircraft in the US. The problems that cause lithium cells to overheat and eventually catch fire or explode are well known – but we continue to see these failures occurring in devices on the market, due to either circuit design issues, incorrect mechanical embodiments or poor cell manufacturing processes. Some instances have even been blamed on ‘user error’. But we disagree on this point – in a properly designed product, user errors should not lead to hazards.

For example, in the case of e-cigarettes, especially those where the battery is interchangeable and charged outside the device, ‘user error’ is cited as a major contributor – with cells being charged with whatever charger is to hand, potentially driving them at too high a voltage or current, or cells even being replaced with low-quality, under-rated or damaged cells. Some of the most dangerous battery failures occur when the device fails in the owner’s trouser pocket – for example, when unprotected spare batteries are kept in a pocket along with loose change and keys, which then cause a direct short across the cells. These failures, and subsequent high-profile reporting of injuries, would have been avoided with good design practices and understanding of common usage behaviours. Product design engineers have many tools to call on to make a product safe, including electronic protection within the circuit itself, physical design features preventing connection of incorrect chargers, and correct allowance of space for the battery within the product envelope.

Whilst the manufacturers of high-end brands understand how to safely build and manage lithium-ion cells, many companies still risk failures in the field when they source and rebrand low-cost products from manufacturers that do not apply the necessary design practices and manufacturing controls. These products are usually designed to be as cheap as possible and, as such, often miss out many of the key safety features that the high-end brands include in their products. One example of this is the lack of thermal management. Lithium-ion cells should not be charged at temperatures above 40-50˚C, which can easily occur if the device has just been used to drive a heater (such as in cordless hairstylers or e-cigarettes) or has been left on a car dashboard (for example, portable power packs to charge mobile phones). Safe products contain internal temperature sensors to check the temperature and delay charging until the cells have cooled down. But sometimes cheap products omit this feature – risking the cells overheating, which can lead to a fire or explosion, especially if done repeatedly.

Whilst some categories of products are required to undergo regulatory safety tests, most low-voltage, battery-powered products are exempt from this, so a product with lithium-ion batteries can be launched with little or no safety testing having been carried out. Standards do exist but they may not have been implemented. Even if a product has been tested to the most common safety standards, such as UN/DOT 38.3 or IEC 62133, these standards tend to focus on the cell itself and may not offer sufficient verification that the product-level design will not cause long-term damage to the battery cells, which may lead to them failing many months after being sold. Standards do exist for usage of cells in specific product categories – but again, this relies on the product being engineered appropriately, with safety and the guidance of the standard in mind.

We would recommend that companies sourcing battery-operated products from original equipment manufacturers check proper battery design and manufacturing requirements are met and that the product has suitable back-up safety circuits to shut down the device should the primary charger or discharge circuits fail. At CDP, as well as engineering products to safely use rechargeable cells, we can also quickly analyse and test other product designs and samples to advise brand owners as to their safety and adherence with best design practices – to help avoid the risk of in-field failures and damaging product recalls. Ultimately, this is a service we would not need to offer if all products were designed and engineered with safety in mind – but we have not seen a reduction in the flow of incorrectly engineered and potentially dangerous products going to market.

 

How embracing MDSAP could help your business

May 16th 2018
Jon Powell

Jon Powell 

Head of Manufacturing

The Medical Device Single Audit Programme (MDSAP) is starting to gain acceptance in the medical device industry. The outcome of more than five years of work by regulatory bodies from Australia, Brazil, Canada, Japan and the US, MDSAP allows a recognised auditing organisation to conduct a single audit of a medical device manufacturer, sharing the results across the participating countries.

This is a great step forward for companies who market in multiple territories. A single audit from the auditing organisation can now be used to check your systems for compliance with requirements from the five participating regulatory bodies alongside requirements derived from ISO 13485. This will potentially increase the speed at which devices can be brought to market and reduce the burden of hosting multiple audits. For example, if you are currently marketing in Europe, the US and Canada, adding Brazil to your intended markets will become easier as you can potentially provide evidence of good manufacturing practice from the one broad audit.

One of the key areas of focus for a quality team is hosting and preparing for audits. When I was a quality manager for a factory producing consumer healthcare products, audits were always at the front of my mind, whether it was an unannounced audit from our notified body or various regulatory authorities or scheduled internal assessments. In 2017, my team and I hosted more than 20 days of external audits and spent a similar amount of days in preparation. A huge burden on the team and the business.

For some businesses which market – or plan to market – in some or all of the participating countries, the requirements are not new, but the integrated audit approach of MDSAP may seem complex and confusing. Regulators are also starting to respond to the challenges highlighted by industry with the new audits. For example, Health Canada – in the first country to fully transition to MDSAP (by 1 Jan 2019) – has now clarified the transition process.

Here at Cambridge Design Partnership we have simplified the landscape by creating a gap analysis tool which maps the requirements of the MDSAP countries with those from ISO 13485. By comparing them against existing ways of working, gaps in a quality management system become more obvious – allowing them to be addressed. This ensures that embracing MDSAP isn’t just a regulatory check-box exercise but one that helps improve your business.

Brexit's potential impact on medicine regulation

Brexit’s potential impact on medicine regulation in the UK and EU

December 14th 2017

Louise Place 

Currently, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for just under a third of applications and updates for European medicinal product marketing authorisations – but on 29 March 2019 the UK will no longer be part of the European Union (EU).

I was struck by the enormity of the challenges ahead when I attended a recent meeting staged by The Organisation for Professionals in Regulatory Affairs (TOPRA). The title of the meeting was: ‘Preparing for the future: a conversation with the heads of medicines agencies’.

Change is nothing new in medical regulation – over the last year or so we have already familiarised ourselves with changes relating to European device submissions. For example, changes to the Medical Devices and In Vitro Diagnostic Directives (evolving into the Medical Devices Regulation and In Vitro Diagnostic Regulations respectively) as well as the pending Clinical Trials Regulation and update to the Falsified Medicines Directive. We’ve also adapted to changes to the Quality Management System standard for Medical Devices (ISO 13485) and are keeping a close eye on those being discussed for the Risk Management standard (ISO 14971).

However, this will pale into insignificance compared with the changes resulting from the UK’s decision to withdraw from the EU. Currently, on the departure date of 29 March 2019, the UK will become a ‘third country’ and the European Medicines Agency (EMA) is preparing for the worst-case scenario. There are two key aspects:

1. Continuing to market in Europe – companies that wish to continue to supply the EU, and currently hold marketing authorisations from the MHRA in the UK, would need to transition to a new European agency. Additionally, those based in the UK would need to appoint an authorised representative within an EU country, as non-EU-based companies are already required to do. I was surprised to hear that this may affect 6,000 medicinal products – no small task.

2. A new process for the UK – things won’t get easier, either, for those wanting to market in the UK. Currently, little is known about what the requirements for marketing in a post-Brexit UK might be – but there is likely to be some impact. My personal view is that, in the short term at least, the requirements won’t be too different from those in the EU. But what this will look like in the medium to long term, as viewpoints diverge, is currently anyone’s guess.

When, post Brexit, the UK’s MHRA can no longer authorise medicines for the EU market, there will be a significant additional workload for the remaining 27 member states. Add to this the recent announcement of the EMA’s relocation from London to Amsterdam – with the associated challenge of staff retention and recruitment – as well as the prospective implementation of a new process for the UK, and suddenly the 16 months remaining to Brexit don’t seem like very long at all!

Clinical Trials Scaled

Why do we need clinical trials for medical devices?

November 15th 2017

Helen Simons 

As part of our review of the new European Medical Devices Regulation (MDR) earlier this year, one of the topics that caught our eye was the expansion and clarification of the rules regarding clinical data for medical devices.

The difference between a clinical investigation and a clinical evaluation

Many people colloquially refer to “clinical trials” as the source for clinical data for efficacy of treatments, where the trial is the activity of testing a medical device with patients to confirm that it provides clinical benefits. In reality, this is what is defined as a clinical investigation within the regulations. The regulations also define a clinical evaluation as a wider scope activity, taking into account all scientific data as well as the data from a clinical investigation as a subset activity.

Where have we come from versus where we are headed

Previously, the European Union (EU) Medical Device Directive (MDD) acknowledged that clinical data is required to show that a device will comply with the essential requirements. It briefly outlined (in only nine paragraphs) the expectations of clinical investigations.

The new MDR expands on this and takes up a whole chapter on the subject. Both the MDD and the MDR dedicate an annex to how clinical trials should be run but, again, the MDD only provided minimal guidance. Under the MDD, many people chose to look to the EU Clinical Trials Directive (and subsequent regulation) and the associated Good Clinical Practice guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Although intended for medicinal products, these gave a greater indication of the expectations for clinical investigations.

Here at Cambridge Design Partnership we were pleased to see that clinical investigation of medical devices has been recognised as an activity in its own right, and that equivalent instruction is now provided in the MDR. In particular, the MDR appears to have been well aligned with the Clinical Trials Regulation with the intention of using the same electronic systems to help with centralised processing of applications. This factor is particularly relevant when considering drug delivery devices or combination devices where both aspects (medicinal product and medical device) need to be considered.

Who needs to do what?

One particular aspect of the expansion and clarification of the requirements for clinical data which has been central to many discussions between us in the quality team are the articles and clauses pertaining to whether a clinical investigation is required.

The MDR is very clear that all products require a clinical evaluation, which comprises a review of relevant scientific literature relating to the safety, performance, design characteristics and intended purposes of the device; a review of all available clinical investigations data (i.e. not just your own but any published data); and a consideration of any currently available alternative treatment options for that purpose.

The MDR then goes on to lay out the rules to determine which classes of devices also require clinical investigations to be carried out. When you analyse the list of requirements, this results in quite a small subset of products starting from Class III and Class IIb (implantables only) and then narrowing down after that with various modifiers.

Compared with the MDD’s requirements – which covered long-term invasive devices as well as implantables, and Class IIa devices as well as Class IIb – we initially considered the MDR’s requirements a simplification. In addition, the MDD requirements were quite vague and didn’t actually specify which devices had to have a clinical investigation – and the listed devices had to wait 60 days before starting their investigation to allow for the competent authorities to have their say, which infers that they were required to have clinical investigation.

However, when we started to apply this to our projects and give guidance to our clients, we noticed something interesting. Although most of the products involved were not required to have a clinical investigation due to their classification, the reality was that as they were usually novel devices, there was not sufficient pre-existing clinical investigation data or scientific literature which the client was aware of to allow for a clinical evaluation to be carried out without a clinical investigation.

This is something that should be considered early in the project when developing the regulatory strategy to plan how this supporting information can be gathered and allow time for this activity.

It will be interesting to see what impact this has on an industry which is already predisposed to look to predicate technologies to allow 510k applications in the US rather than the expanded effort required for premarket approval (PMA) and how this will be resolved for products brought to the market in the EU.

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The end of grandfathering? What the latest regulatory changes mean for you

October 3rd 2017

The new European Medical Devices Regulation (MDR) introduced by the European Commission (EC) has led to a lot of discussion around the implications for getting products on to the European market. But what about products that are already on the market? What does the new regulation mean for these so-called ‘grandfather’ or legacy devices?

What are grandfather devices?

A grandfather or legacy device is a medical device that was already on the market and pre-dates an applicable standard, directive or regulation. Under the 1993 European Medical Device Directive, for example, some devices were exempt from meeting the new directive and allowed to continue being marketed.

In the US, the Food and Drug Administration (FDA) has a similar process with its 510(k) clearance route, which allows devices (e.g. blood glucose monitors) which are ‘substantially similar’ to a device marketed before 28 May 1976 to be marketed without going through the formal FDA approval process.

Why are grandfather devices a concern?

Best practice when it comes to developing medical devices has changed over time – each generation of regulation brings with it new requirements which need to be met. In recent times, the focus on human factors has been increased through the issuance of many FDA guidelines. Similarly, the MDR now brings more focus on to risk management and post-market surveillance. In addition to the general regulations, the technical standards which specific devices need to comply with also get updated regularly.

Previously, devices have not been required to be followed up on once they have been submitted and put on the market. This means that, even though best practice has moved on, devices can still be on the market for long periods without going through any scrutiny to ensure they are still safe and effective – as long as they have no serious incidents.

Similarly, where devices are submitted on a precedence justification – such as a 510(k) – then the original device which is being used as the basis of the submission may have been judged against a previous version of a standard or regulation. This means the original device may not be completely relevant to current standards and regulations – and so subsequent devices may not meet the full requirements for that type of product.

Of particular concern are devices which have a long history and hence each generation of devices is based upon the previous – a slow drift away from the first device which was analysed in full.

So what does the new MDR require?

As with most legal documents, the devil is in the detail. Hidden in the depths of the chapter on putting devices on the market there are two sentences of interest:

“Manufacturers shall ensure that procedures are in place to keep series production in conformity with the requirements of the regulation. Changes in device design or characteristics and changes in the harmonised standards or CS by reference to which the conformity of a device is declared shall be adequately taken into account in a timely manner.” Article 10, part 9.

This means that, once the MDR comes into effect, any devices placed on the market will need to be kept up to date with any changes in standards or regulations, rather than just submitted and placed on the market with no follow up.

When do you need to do this by?

Quite simply, every device available on the market must comply with the MDR by the date of application (26 May 2020).

There are certain exemptions or extensions attached to this deadline – as to be expected with any regulation which is trying to accommodate a large range of products.

But ultimately it comes down to the risk you want to accept. I would always recommend getting started as soon as possible to ensure you are ready when the deadline hits. The EC has provided a three-year implementation period because it knows that a lot of work is required to ensure all products are in compliance.

If you are affected by the changes and want to know more, get in touch with our team of quality and regulatory experts.

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Why you can’t afford to ignore post-market surveillance

September 6th 2017

The words ‘post-market surveillance’ (PMS) appear 129 times in the new European Medical Devices Regulation (MDR). This repetition is not accidental. The requirements for manufacturers to ‘actively and systematically’ gather, record and analyse relevant data for the lifetime of each device they market is work most companies had not been conducting effectively – and the European Commission wants that to change.

PMS is the proactive activities carried out by manufacturers to establish, implement and keep up to date a systematic procedure to collect and review experiences of their devices on the market. The purpose is to identify any need to apply corrective or preventive actions.

The MDR significantly increases the role of PMS, requiring a ‘post-market surveillance system’ to be an ‘integral’ part of a company’s quality management system.

And, in my opinion, PMS is integral to a successfully marketed device and business.

What does a successful PMS system need?

The MDR specifies that the manufacturer must plan, establish, document, implement, maintain and update a PMS system. The manufacturer is required to produce a PMS plan, specific to each of its products. This is key to the beginning of a successful, non-intrusive PMS system that can contribute to the development and long-term stability of a manufacturer’s device.

The plan must outline how to collect information from sources such as:

  •   information from vigilance, including trend reporting
  •   records referring to non-serious incidents and data on any undesirable side effects
  •   information from specialist or technical literature, databases and/or registers
  •   information from feedback and complaints, provided by users, distributors and importers
  •   publicly available information on similar medical devices

Reviewing of these sources of information must be systematic, and is required to be carried out within the manufacturer’s organisation by a person responsible for regulatory compliance.

A company can use existing processes, or implement new ones, to achieve the above. These could be:

  •   complaints procedures
  •   vigilance procedures
  •   checking of competent authority websites for information on adverse events or recalls of similar devices
  •   post-market clinical follow-up (PMCF) studies
  •   setting up key-word alerts on search engines
  •   social media
  •   feedback from users (via email/website/surveys)

The data gathered is to be used in ensuring the quality, performance and safety of the device. This is achieved through analysis of the information to assess for any significant increase in the frequency or severity of incidents that are not serious incidents or expected undesirable side effects. An assessment needs to determine if the new information could have a significant impact on the benefit-risk analysis conducted in the original risk analysis for the device. This is done by updating and improving the risk-management documents – for example, post-market data collected may indicate a risk has a higher probability of occurrence than first estimated. An update to the risk analysis may then initiate an update to the design, manufacturing process, labelling and/or instructions for use of the device. 

Challenges and consequences

One of the main challenges is the design of a quality management system which is conducive to the potential of multiple updates to processes, technical documents and even devices themselves. Speedy reaction to the possibility of adverse incidents will ensure any potential risk to public health is minimised.

Slow and reactive response to post-market data can be costly – in more ways than one.

The recent media coverage of court cases involving Johnson & Johnson’s pelvic mesh implants has shown what slow follow-up from manufacturers can lead to. The mesh had been predicated onto the market as the same material had been used for hernia repairs (see ‘The end of grandfathering?’ for insight into how the MDR is stopping devices being placed on the market without complying with the regulation). It is estimated that up to 100,000 women worldwide received the implant, which in some women has caused pain after the device began to erode into the surrounding tissue and organs, causing infections and complications. The mesh cannot be removed. A trial involving 700 Australian patients against three Johnson & Johnson companies continues in a federal court, as well as action in other countries such as the US. Johnson & Johnson has since stopped selling the product.

This is not the only case of devices being recalled after thousands of patients have been exposed to the device before any adverse incidents have been realised. In 2010, St Jude Medical stopped selling its Riata defibrillation leads after the silicone coating insulating the electrical conductor wires within the lead was found to erode prematurely – sometimes leading to a malfunction of the life-saving device. Also in 2010, DePuy removed its metal-on-metal hip implants from the market after the rate of failure of these implants was determined to be greater than the polyethylene acetabular hip implant.

What you need to do

The MDR’s emphasis on PMS could be seen as an additional burden on medical device manufacturers. But if you begin planning for the increased workload now, you can establish a PMS plan early, and revise and improve it throughout the three-year transition period. When the date of application (26 May 2020) comes round, you will then have an integrated, compliant system. And, in turn, a device that is safe, effective and performs as you intend it to.