A delicate balance27 April 2022
Regulatory and compliance requirements are seen as necessary hurdles that need to be cleared by manufacturers if they’re to bring products to the marketplace – especially in highly-regulated industries like the pharmaceutical and medical device sectors. But in times of emergency, even the strictest regulators must balance an enduring need for safety, quality and efficacy with both public and clinical needs. Regulatory expert Dr Gabriel Adusei explains the risk-benefit calculations regulators have had to make during the Covid-19 pandemic, and why relaxing the rules too much during a health crisis can be catastrophic.
To understand the regulation of technologies used in the diagnosis, treatment and management of Covid-19, a cursory look at past regulatory responses is helpful. It was the 2003 outbreak of severe acute respiratory syndrome (SARS) that mirrors this most effectively. Although SARS only lasted six months, it resulted in more than 8,000 infections, with an approximate 10% mortality rate. Given the potential danger it posed, especially if it were to mutate and become more transmissible, laboratories worked with regulators to isolate the SARS-CoV virus that was causing the disease.
The swiftness with which this virus was isolated was seen once again during the current pandemic. Scientists isolated SARS-CoV-2 and mapped the entire genome of the virus in mere days of it being declared responsible for a swathe of pneumonia cases in Wuhan, China. But although sequencing the genome of pathogens is crucial for the development of specific diagnostic tests and the identification of potential treatment options, it was legislation put into place in response to the 2001 terrorist attacks on US soil that gave rise to the Emergency Use Authorisation framework. This allowed those tests and treatments to proliferate – at least in the US. The Emergency Use Authorisation (EUA) authority allows the FDA to help strengthen US public health protections against chemical, biological, radiological, and nuclear (CBRN) threats – including infectious diseases – by facilitating the availability and use of medical countermeasures (MCMs) needed during public health emergencies. An EUA does not represent approval of a drug or device in the full statutory meaning of the term, but instead authorises use of an unapproved product, or an unapproved use of an approved product, during a declared state of emergency. The increased flexibility and fast-tracking of tests to the public have had a significant impact on the development of new technologies, as well as facilitating the speedy manufacture and supply of personal protective equipment (PPE) and medical devices to where they are needed.
Regulations governing the movement of goods for the diagnosis, treatment and management of Covid-19 may have been relaxed. But the regulatory aspects in relation to quality, efficacy and safety of products are stringently maintained, as their relaxation could ultimately lead to higher numbers of deaths. Another example of this is the temporary authorisation given in the UK under Human Medicines Regulations Section 174. This section permits the supply of identified vaccine batches based on the safety, quality and efficacy data submitted to the MHRA, but the authorisations do not constitute a marketing authorisation, and under Regulation 174, certain requirements must be met.
Similarly to the US and UK, in Europe, regulators have been praised for how quickly they moved to ensure the volumes of ventilators, IVDs, PPE, and later vaccines, were adequate to manage Covid-19. In response to the outbreak, the European Commission temporarily allowed the marketing of non-CE marked personal respiratory protective equipment (and other personal protective equipment) through Commission Recommendation (EU) 2020/403. The marketing of these devices is permitted if certain criteria are met, but this only applies to equipment intended to protect healthcare professionals from the SARSCoV- 2 virus. For example, Article 59 of the EU MDR (2017/745) can be used where the European Commission is responsible for identifying and authorising certain medical devices and PPE that may be sold without CE Marking during the public health emergency, and where market access is granted individually by the competent authority of each member state. In response to managing Covid-19 emergencies, the EU has issued an implementing act restricting the export of PPE from the EU, and recommended conformity assessment procedures within the context of the Covid-19 threat.
As mentioned earlier, regulatory authorities tend to provide additional resources to deal with pandemics, and on the same lines, the European Commission issued new guidance documents on the performance of Covid-19 test methods and devices, as well as performance criteria. With Covid-19, as the required IVDs are self-certified according to the In Vitro Diagnostic Medical Devices Directive (IVDD), it has been highly recommended that manufacturers placing these IVDs on the EU market review and apply these guidance documents, which include considerations on device performance and the validation of it.
A cautionary note on relaxing regulation
The level of regulatory flexibility seen since the pandemic began is unprecedented and has led many in the medical device industry to question whether the concessions made over the past few years should lead to a softening of the rules. If there is such a time for the relaxation of regulations, this might not be it. Although certain considerations and risk-based regulatory approaches can be adopted, this is simply because in any given pandemic, there are so many uncertainties around the situation at hand.
Certain humanitarian considerations and concession provisions had to be made to expedite the transition of new technologies from research and development to regulatory approval and manufacturing – making them clinically available for the diagnosis, treatment and management of Covid-19. But inspiration taken from the swift response from the regulatory agencies in assessing the impact of the pandemic and offering concessions on humanitarian grounds should not be misconstrued as loosely applying the regulations. That would have led to unreliable IVD test kits and other medical devices reaching the public. The dangers of unreliable tests, unvalidated processes and loosely regulated medical devices reaching the public or clinical setting cannot be overstated. To put it bluntly, the deleterious effects of unreliable tests reaching the public or clinical setting could be catastrophically deadly and economically devastating.
A better question to ask is: how can innovation in regulatory science inform the regulatory process to facilitate the development of new vaccines and approval of new medical technologies? The balance of the urgency of developing and approving new technologies with rigorous evaluation in a robust but expedient manner to ensure the highest degree of safety, quality, efficacy and performance should be a multidisciplinary and multi-factorial approach – all taken while employing the principles of regulatory science. In this way, it is an all-hands-on- deck approach, focusing on the science of developing new tools, standards, and approaches. Lessons learned from the previous and current pandemics offer opportunities to adopt new regulatory strategies and change the way regulators manage medical device approval processes in a future pandemic.
The progress of research and clinical trials, including for vaccines, were hampered by a lack of diversity among participants. This has serious ethical and research consequences, including impeding our ability to generalise study results, preventing some populations from experiencing the benefits of research innovations and receiving high quality care.
In November 2021, the UK government announced that it has commissioned a review into the health impact of possible race and gender bias in medical devices, including pulse oximeters. The issues could be widespread in clinical research. The result of this review should be quotas to govern the recruitment of participants in clinical trials, as well as other requirements that must be met to address diversity and inclusion. This can also be part of the remit of the EU Ethics Committee as per the provisions of Directive 2001/20/EC in the ethical approval process of any clinical trial application submission.
Advancing regulation with regulatory science by building on the achievements of existing programmes, with the efforts to transform the way medical products are developed, evaluated, and manufactured is the key to a swifter response and more robust approach to regulatory practice. That said, it is encouraging to know that in coordinated efforts, the regulatory agencies and other related authorities are working hard to provide support for the medical device industry, to enhance the progression of new technologies to the point of use, while maintaining the strictness of the regulations. Credit should be given to the regulatory agencies and other related health authorities working diligently and taking the necessary measures to manage the pandemic and ultimately making products available for the management of the virus.
“Certain humanitarian considerations and concession provisions had to be made to expedite the transition of new technologies from research and development to regulatory approval and manufacturing – making them clinically available for the diagnosis, treatment and management of Covid-19.”
Dr Gabriel Adusei
A recent temporary authorisation under Regulation 174 issued under certain terms and conditions for physically supplying a vaccine in the United Kingdom was for Pfizer. The terms and conditions included:
- This temporary Authorisation under Regulation 174 permits the supply of identified product batch within specific time frame and specified region. For example, this authorisation applies to supply within the United Kingdom of Great Britain and Northern Ireland.
- As provided in Regulation 174A (2) of the Human Medicine Regulations, the sale or supply of this vaccine will not be deemed authorised if the supply is for the purpose of any use other than the recommended or required use, or if a condition in this authorisation is breached;
- Pfizer Limited and BioNTech Manufacturing GmbH will be jointly and separately responsible for placing the product on the market in the United Kingdom for the purposes of The Human Medicines Regulations including Reg 345(3) (hereinafter “Pfizer/BioNTech”);
- Pfizer/BioNTech are jointly and separately responsible, with the manufacturers of the product, for the conditions relating to the manufacture of the product and to product release to the market under the terms of this authorisation;
- Pfizer/BioNTech is not only responsible for compliance with the conditions expressly applied to it in this authorisation but also, where the conditions apply legislation or guidance that confers responsibilities on marketing authorisation holders, for compliance with any responsibility however worded that applies to a marketing authorisation holder in the applied legislation or guidance;
- Pfizer/BioNTech must promptly provide to MHRA any further data that is generated by them, or which otherwise come into their possession, which is relevant to the risk / benefit profile of the product;
- Pfizer/BioNTech must respond in a timely manner to any requests for further supplementary data relating to product;
- Any deviations from any of these conditions can only be made with the prior agreement of the MHRA;
- MHRA may review and adjust these conditions for temporary supply in response to any developments which it considers material, including any subsequent market authorisations that might be issued by other medicines regulators;
- This authorisation will be valid until expressly withdrawn by MHRA or upon issue of a full market authorisation by the MHRA.
Source: Conditions of Authorisation for COVID-19 Vaccine Pfizer/BioNTech (Regulation 174) www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19/conditions-of-authorisation-for-pfizerbiontech-covid-19-vaccine