In the first part of our joint event with the Institution of Civil Engineers, we hosted an hour long webinar on the 1st of December 2020 to discuss the ever-present issues with regulating manufactured chemical products.  Attracting a wide online audience, we learned from key regulators that from time to time, chemicals come back into the public eye, whether in the context of a disaster (e.g., the recent explosion in Beirut) or the need to rapidly develop new products (e.g., to tackle the Covid-19 coronavirus outbreak).  

Biocompatibility Specialist, Sophie Clewlow from Medicines & Healthcare Products and Regulatory Agency (MHRA) joined colleague, David Jones, the MHRA’s expert Pharmaco-Toxicologist, along with webinar chair, Ruth Wilkinson, a Hazards Forum trustee for an hour-long lunchtime presentation.

Overview

When it comes to regulating chemicals, the main concerns that the speakers addressed were risk management, in particular safety evaluation and manufacture through to distribution, use and disposal. The experts revealed that issues will also vary between single products (e.g., fertilisers, cleaning agents and drugs) and products in combination (e.g., implantable medical devices). 

As part one of two sessions, this first session brought together key regulators to discuss existing approaches and what future holds in relation to medical products and medical devices.

Biological evaluation of medical devices

“What is a medical device” was the opening question from Sophie Clewlow’s presentation ‘Biological evaluation of medical devices – The importance of input assessment’. According to the Regulator, she explained that a medical device is any instrument, software, implant, material or other article intended by the manufacturer to be use for human beings for one or more of the following: for treatment or alleviation of disease; for treating an injury or disability,  investigation of the anatomy, physiological or pathological process or state; used in vitro examination of human specimen which does not achieve its principle intended action by pharmacological, immunological or metabolic means.

In terms of biological safety, Sophie emphasised that the intended use and relevant endpoints are as key in determining the classification and regulation of a medical device, as for a medicine or a vaccine.

Medical device regulation

As outlined by Sophie, the MHRA’s main role is to regulate medical devices in the UK market, with UK Notified bodies (NB) designated and audited by MHRA. In turn, the NB issue CE certificates which adhere to the regulations for Medical Device Directive (MDD) that consist of essential requirements. The MDD take a risk based approach to new devices on the market, especially the concept of exposure. Whereas the regulation of chemicals takes more of a hazards based approach, Sophie explained that when it comes to regulating medical devices, they look at the risks, in particular the probability of harm and the clinical benefit. Therefore, classification of a medical device only considers the medical benefit and intended purpose, not the intrinsic chemical make-up.

A device must have a medical purpose, otherwise its is not awarded CE. For example, coloured contact lenses and tattoo needles are not applicable to MDD. Generally, the more invasive a medical device, the higher the risk classification and there is an increase in the number of regulations that it must conform to.

Toxicology Vs Biocompatibility

To understand how the regulator assesses medical devices, Sophie went on to highlight the importance of considering the differences between toxicology and biocompatibility. She described toxicology as “the study of the adverse effects of chemical substances/materials on living systems”, whereas biocompatibility “is the ability of a material to perform with an appropriate host response in a specific application”. The importance of  carrying out these tests means that responses to the same medical device can differ from patient to patient. Therefore, studying both the toxicology and biocompatibility of the medical device can determine how a patient’s body reacts.

Thus, the response in humans is usually evaluated for devices by means of a risk assessment process that is based on toxicological data and expert judgement, as well as in keeping with ISO standards. 

Biological evaluation

The relevant guidance for medical devices involves a “biological evaluation which aims to protect humans from potential biological risks arising from the use of medical devices.” ISO 10993 is a standard that evaluates the biological risks of medical devices by providing risk management principles to follow.

Sophie explained that biological evaluation commences with the categorisation of medical devices which helps the manufacturers identify the types of hazards they will be looking at, depending on their application. In particular, they will look at the nature of body contact and the duration of contact to inform their categorization of each medical device. The more invasive the body contact and the contact duration increases, the higher the number of endpoints for evaluation. Yet, irrespective of the type and body contact duration, chemical and physical information is always considered during a biological assessment. This is a crucial step in hazard identification.

Another important aspect of this process to take into account is that evaluation of a device does not equal testing. The medical device is only tested when data is gathered which is then subject to risk assessment.

Biological evaluation is a step-wise approach consisting of:

• Hazard identification
• Risk estimation
• Risk evaluation

Once this information is collected, it will then be fed into a risk assessment using exposure data on the chemical, biological or toxicological hazards Finally, the balance between clinical benefit and toxicological risk will be looked at during the acceptability phase. This overall process is known as an “iterative closed loop process”.

Hazard guidance

Sophie highlighted the following common misconceptions of the evaluation:

• Identification of trade names is sufficient
• Our material/device is biocompatible because it is constructed from medical grade material
• Commonly use materials require no evaluation
• Biological testing is essential
• Multiple devices can be evaluated in one document
• Assessment of biological risk is not possible due to propriety information
• Animal testing for sensation and irritation is gold standard
• Everyone is qualified to undertake a biological evaluation

Sophie gave an example of the importance of knowledgeable and experienced professional input when risk assessing medical devices, as mistakes have been made in the past resulting in urgent recalls.

To enhance the biological evaluation process and to avoid mistakes, ISO 14971 advises that a risk assessment system must;

1. Identify hazardous situations associated with a medical device;
2. Estimate and evaluate associated risks;
3. Control these risks;
4. Monitor the effectiveness of the risk control measures.

In the addition to these extra measures outlined by the standard, Sophie explained that MHRA have implemented training in relevant disciplines and employ staff with suitable qualifications and experience.

Sophie also explained that testing on animals is now only justified if there is no other way to test a medical device, such as skin sensitization. Non-animal testing does exist, like the in vitro methods, however this is not widely used at present.

Fast-track success

In conclusion, Sophie reflected on a recent success for MHRA –  the current fast-track approval of medical devices. Because the world is in times of unprecedented public health need (e.g., tests for Covid-19 coronavirus), fast-track approval of medical devices manufacture (eg., ventilators, PPE and test kits) can therefore go ahead based upon this process, so long as the input parameters are tightly controlled. 

Expert in clinical trials

In the second half of the webinar, MHRA’s senior expert Pharmaco-Toxicologist, David Jones joined the discussion with his presentation, ‘Regulatory Challenges for the Evaluation and Supply of Vaccines and Treatments for COVID-19’. David’s current role principally involves assessing non-clinical data for clinical trial authorisation applications and marketing authorisation applications both for non-biological and biological products.

To demonstrate how active the MHRA are worldwide as a regulator, David shared a survey from The Association of the British Pharmaceutical Industry (ABPI)’s ‘Clinical Trials’ report which points out that the UK ranked 2 globally for phase I and II clinical trials in 2020.

Roll-out challenges

One of the many challenges that comes with rolling out vaccines in today’s climate is the “disinformation being spread by ‘anti-vaxers’”. To combat fake news in relation to COVID-19, David shared that it was crucial for the MHRA to be very open to maintain public confidence. Since March 2020, the MHRA set up a dedicated website on Clinical Trial Authorisation (CTA) for COVID-19 applications, with David offering free advice. The team made it their mission to expedite applications as quickly as possible.

Early on in the pandemic, on 18^th March 2020, regulators from around the world met in a virtual summit under the auspices of the International Coalition of Medicines Regulatory Authorities (ICMRA). They discussed the rapid spread of SARS-CoV-2 and decided that rapid development timelines for vaccine candidates were required to enter expeditiously into Phase I clinical trials. The type and extent of nonclinical and preliminary clinical  data required to inform was weighed against the risk/benefit of the unmet medical need for vaccines.

David expressed the challenges in the evaluation and rollout of vaccines, especially with the recent need to expedite vaccine manufacture and clinical trials, as well as to repurpose medicines for COVID-19, has led to very wide collaboration between MHRA, pharmaceutical companies and academia, leveraging pre-existing knowledge and pathways, as well as using a rolling process of data review. 

Accelerate to develop vaccines

“Scientists from MHRA agreed that there were opportunities to leverage knowledge accumulated with “platform technology” to accelerate the development of SARS-CoV-2 vaccine manufactured using the same platform.” David explained that the MHRA already had the safety data for similar vaccines which could support the new proposed vaccines. He put forward a proposal to the ICMRA that COVID-19 was not the first, but in fact seventh Coronavirus and so it was a matter of altering the existing vaccines to create an effective vaccine.

Not all the Regulators agreed with David’s proposal, however participants generally agreed that some vaccine constructs for which there is adequate information and support from knowledge around the immune response elicited, may be permitted to proceed to First-in-Human (FIH) trials without first completing animal studies to assess the potential for enhanced disease provided adequate risk mitigation strategies are out into place in the FIH trials.

Open data

Regulators were keen to develop ongoing mechanisms that would allow sharing of data from animal model and clinical trials in order to alert the global Regulators of the outcomes of trials. Openly sharing information, David explained, would help with the quest to creating a successful vaccine. Also crucial in sharing knowledge was the co-operation and collaboration between Regulators, pharmaceutical companies, and academia.

Rapidly approved trials

In normal circumstances, it takes around 60 days to approve Clinical Trials. Currently, the MHRA have approved over 120 Clinical Trials (CTAs) for a COVID-19 indication, which includes 30% of all trials in Europe that come into the UK, and 5% of all global trials. David went on to say that the trials also included applications where multiple products have been tested. Incredibly, all of these applications were expedited and approved in less than a week.

The roll out of vaccines in the UK was a government decision, namely the Department of Health, not the MHRA. Until the end of December 2020, COVID-19 vaccine candidates were licensed and authorized via the European Medicines Agency (EMA), resulting in automatic validation in the UK. However, the MHRA are involved in evaluating data from any new vaccine candidates, rigorously examining for quality, safety and effectiveness to reach an independent, scientifically robust decision. The data submitted must include results from lab and clinical trials in humans; manufacturing and quality controls, product sampling, and testing of the final product.

Preventing severe cases

David also raised the issues with risk management in the re-purposing of medicines, along with the future challenges in areas of innovation in medicines.

David detailed further challenges with developing the vaccine, like the lack of a good animal model of the disease, few drugs created specifically for COVID, as well as the complexities of the immune system. He elaborated on the two pathological subsets that overlap, the first triggered by the virus itself, the second the host response. A minority of COVID-19 patients become severely ill, resulting in extra-pulmonary systemic hyper inflammation syndrome. Potential therapies aimed at different phases of the virus have been thanks to knowing how COVID-19 “plays out”. Drugs have been aimed at either mild or moderate disease to prevent the late stage where patients become severely ill.

In response to “Long COVID”, which was an increasing concern to the MHRA and the NHS, a number of specialist clinics were set up to help those with the debilitating effects of the virus.

Safety first

Most of the time, CTA applications for early trials focus on safety, however during the pandemic, David and the MHRA have requested robust justifications as to why a product might work in COVID. Due to unprecedented times, the MHRA have been faced with a myriad of applications for trials that are not beneficial.

In summary

As of 1^st January 2021, MHRA will be the UK’s standalone regulator of medical products, therefore the success of these approaches has meant that they and other initiatives will be fed back into how the agency operates. To get ahead of any new viruses, in particular looking out for any indications of COVID-20 or 21, they are using Horizon Scanning techniques so that the agency can be “future proof”.

About MHRA

The Medicines and Healthcare products Regulatory Agency regulates medicines, medical devices and blood components for transfusion in the UK.

Recognised globally as an authority in its field, the agency plays a leading role in protecting and improving public health and supports innovation through scientific research and development.