Summary of Points To Consider arising during the Conversation
On Wednesday 14 July 2021 the Faculty of Pharmaceutical Medicine (FPM) hosted the online event, In Vitro Diagnostics – Companions or Not?, within the FPM Conversations series. The event was moderated by Dr Craig Hartforda. The main session’s Speaker-Panellists included Camilla Fleetcroft (MHRA)b, Patrick Fivey (AstraZeneca)c and Piarella Peralta (Inspire2Live)d, with pre-session special guests (FPM’s Medical Devices, Diagnostics and New Technologies expert group) Bob Hollande, Rob Hastingsf, Bruno Roseng and Tim Higenbottamh, also participating. The event Agenda details are located at https://www.fpm.org.uk/events/fpm-conversation-medical-devices-and-diagnostics-save-the-date/
IVDs - Opportunities & Challenges as a Sovereign Regulator
- There are many challenges and opportunities within in-vitro diagnostics (IVDs) regulation that necessitate different stakeholders in the industry to work collaboratively across health and social care.
- The passing of the UK Medicines and Medical Devices Act (2021) brings with it the opportunity to evolve the UK’s regulatory regime. Medical Devices regulations in the UK encompass IVDs’ regulation.
- Towards evolving UK Regulations, the Medicines and Healthcare products Regulatory Agency (MHRA) has published a 2021-2023 Delivery Plan. The plan intends a commitment to patient health by enabling early access to high-quality products that are safe, effective, and innovative. To this end it is important to ensure access decisions are data-driven and that the benefit-risk profile is always considered.
- The MHRA plan is to enhance the UK’s medical device regime by ensuring that changes in clinical needs, technologies, and patient views are key factors for consideration when developing legislation.
- As the new EU Regulations for medical devices (MDR) came in to force in May 2021, Great Britain and Northern Ireland will now be on different platforms, in that the rules for placing medical devices on the Northern Ireland market will now differ from those applicable to Great Britain (England, Wales and Scotland): the EU’s MDR and IVDR will apply in Northern Ireland, following the EU’s implementation timeline.
- The UK regulations now have to be updated using the powers of the Medicines and Medical Devices Act. They intend to take heed of the Independent Medicines & Medical Devices Safety Review chaired by Baroness Cumberlege (First Do No Harm report published in July 2020). This includes provisioning for the importance of the patient voice.
- In order to move forward as a flexible, responsive, and transparent regulator, MHRA needs to foster collaboration with key stakeholders. There are concerns about the GB market being large enough to stand on its own and whether country-specific regulations might be perceived as an additional burden. The MHRA will need to consider the impact that updating regulations involving IVDs will ultimately have on patient needs, innovation, research and clinical trials, while being cognisant of market needs.
Impact of EU In-Vitro Diagnostic (IVD) Regulation on the Pharmaceutical Medicine Industry
- The current IVD Directive will be replaced by the In-Vitro Diagnostic Regulation in May 2022. This regulation will raise the standard for medical devices and in-vitro diagnostics in the EU market, including laboratory-developed tests/in-house IVDs (LDTs/IH-IVDs). It presents a change in oversight for commercial diagnostics. The regulation will introduce new requirements for technical documentation, quality management, and post-market surveillance systems. The regulation will also change the classification for many IVDs, which will result in many IVDs newly requiring a Notified Body review prior to approval. It is predicted that Notified Bodies will face a significant workload increase following on this new regulation.
- A Precision Medicine approach is used for several development and marketed products – in some cases however the necessary diagnostic to support patient selection may not be immediately available. To account for this, companies collaborate with external diagnostic manufacturers to ensure that the required diagnostic requirements for treatment are met. In the European Union, many labs conduct routine clinical testing services in combination with precision medicines. In order to provide these testing services, the EU relies on commercially approved IVDs and LDTs/IH-IVDs.
- What is the potential impact of the implementation of the IVDR?
- On commercial tests:
- Increase in clinical data required in many instances – to demonstrate and support maintenance of scientific validity, analytical performance and clinical performance.
- Companion diagnostics will need to be directly evaluated by the European Medicines Agency as well as by Notified Bodies.
- Commercial shortages for IVD tests used with precision medicines seem likely to occur in some instances e.g. this may be expected where there has been insufficient proactivity in preparing for the new regulation. There is also a limited number of approval bodies or notified bodies, and some of these have indicated limited capacity to take on additional conformity assessments for IVDs (in part due to COVID-19 related demands).
- Some supply issues might be anticipated for existing approved diagnostics used with precision medicines, as their current certificates will expire. These will need to be re-certified by a notifiable body by May 2022.
- New tests approved for commercial use with precision medicines may decrease, and they may also potentially increase in cost.
- On laboratory-developed tests (LDTs/IH-IVDs):
- Public laboratories using LDTs/IH-IVDs, who also then “export them” to other labs or who sell the testing services as a service, are likely to be impacted.
- While under the previous legislation public laboratories would be able to continue their use of LDTs/IH-IVDs in parallel, the IVDR introduces the need to justify why the lab within a health institution is using a LDT/IH-IVD over the equivalent commercially available CE marked IVD [Article 5 Paragraph 5(d) of the IVDR states “the health institution justifies in its documentation that the target patient group’s specific needs cannot be met, or cannot be met at the appropriate level of performance by an equivalent device available on the market”.
- If there are no IVDs approved for commercial use available, laboratories will need to follow strict exemption requirements under the IVDR to use LDTs/IH-IVDs.
- There is some risk that the need for patient testing with precision medicines may not be met in the short term if laboratories are not prepared for the new exemption requirements under the IVDR.
- On commercial tests:
- IVDR & Clinical Trials Regulation (CTR)
- The existing regulation for clinical trials using IVDs and the IVD regulation are currently separate, but this is expected to change with the introduction of the IVDR. When used in clinical trials, IVDs used for medical purposes will need to be labelled as CE marked, investigational IVD, or LDT/IH-IVD [see CTR 536, annex I, paragraph 7 (i)]. Some IVD Tests used in clinical trials, for example potentially those used as an inclusion criterion or for stratification for the planned primary endpoint, may need to be in compliance with the IVDR and CTR.
EU IVDR & the Patient Advocacy Experience
- The organisation Inspire2Live hosted a meeting to discuss the effects of IVDR on patients with laboratories across Europe (Inspire2Live is an organisation that brings together researchers, clinicians, and patient advocates together to drive initiatives aiming to propose new research and care from the patient perspective). While participants agreed that the introduction of the regulation would ensure high-quality testing, there are elements that should be considered by the European Commission and other bodies amidst the transition. Overall, it is considered important not to lose sight of the patient as technology advances are introduced:
- There is a reliance on companion diagnostics and LDTs/IH-IVDs across Europe that seems likely to be impacted by the new regulation. From a patient advocacy perspective, there are concerns about the infrastructure and available investment necessary for regulatory compliance. There will potentially be some shortages in the availability of diagnostics for patients. There have been attempts to mitigate some of the potential future risks of the regulation – some organisations have written to the European Commission asking for a possible delay, or phased implementation of the regulation.
- From the patient advocacy perspective, it is prudent to understand the effects of the new regulation on the management of public healthcare overall. The path(s) forward should be cognisant of what may be best for patients in general, such as which of whole exome, whole genome or gene panel testing is going to be preferable.
- Liquid biopsies and other technologies with bioliquids may need incentivisation due to costs.
- Reimbursement frameworks for IVD tests are fundamental to successful implementation of commonly used as well as rarely used IVD tests.
- When evaluating the experiences of the United States, Canada, and Australia, will those experiences shared by other countries be explored with respect to regulation?
- Yes, the MRHA wants to use the revision as an opportunity to identify and address current challenges on a global scale.
- There is clearly a rising interest in the necessity of increasingly engaging with patient advocacy groups. What should happen between industry and regulators with respect to increased interfaces with organisations involved with patient advocacy?
- This is a very complicated question to tackle. At the moment, there is a lot of participation asked from patients to increase the value of interventions and clinical trials. In Europe, there are a few organisations that work closely with industry to increase participation starting from the drawing board. However, there is no routine infrastructure to require such interaction between industry and patients. Regulation requiring patient advocacy groups’ participation/collaboration in the decision-making process is currently lacking. This should be assessed in the future, but with the message that patient involvement is not just a check box but mindful participation.
- From the patient perspective, why would increased access to diagnostics like genome sequencing be beneficial?
- These tests allow for more treatment options, particularly when it involves for example metastatic diseases. Studies have shown that patients undergoing genome sequencing may have a better quality of life. From the payer’s perspective, the investment of genome sequencing (in the Netherlands) prevents overtreatment. This is an important factor to consider as overtreating could result in unnecessary expenditures that offer no benefit to the patient.
- Overall, is the implementation of the IVDR a positive change, or is this an opportunity in the UK to diverge from the European IVDR approach?
- Patient safety is the most important factor of the new regulation. Some may consider that the quality of LDTs/IH-IVDs differs from that of CE-marked IVDR kits. Overall, the new regulation aims to increase the standard for the quality of diagnostics. This ultimately ensures patient safety, so some or many would/could argue that the change in regulation is a positive one.
- The EU IVDR transition has not been all plain sailing. The UK should use this opportunity to learn more about the setbacks in the transition process.
- Some companies have decided not to continue producing certain diagnostics given the strenuous process for approval introduced by the IVDR. Can the number of companies choosing not to provide the new tests be quantified? What will the pharmaceutical medicine industry do to help with the production of such tests? Will pharmaceutical companies invest in their production?
- Some manufacturers are not necessarily prepared for the change in regulation. This may be because they do not have the in-house capabilities to meet the IVDR’s various new requirements or because of the limited number of notified bodies.
- The funding aspects for the production of these products will be up to individual pharma companies and their partners. In some circumstances, the production might continue without additional funding.
- The industry may need to be more involved in the transition process, particularly in the interpretation of the new regulation on the production of diagnostics.
- Are there conversations about a possible grandfathering regulation like the 510K regulation in the U.S. that would ease some of the expected setbacks with the introduction of the IVDR?
- There are currently no plans for possible grandfathering regulations for the IVDR.
- Does the MHRA intend to time UKCA for companion diagnostics in line with marketing authorisation by the faster project route?
- The MHRA does not have the power to control this, but it certainly should be flagged. This topic brings in to question the roles and responsibilities of each organisation. What else should regulatory bodies be responsible for? For example, is there a role for the MHRA to license medical devices? This responsibility currently lies in the hands of notified bodies, but these are the type of questions that will surface during the transition process.
- The media has illustrated concerns about differences in data (information) collected for IVDs with respect to race and gender. Will the increase in the data needed for IVDs include different groups?
- Certainly, data samples must be reflective of the population in order to actually be branded as validated for use of the entire population.
- It is well recognised that genomic sequencing has been mostly conducted on populations with European ancestry. This brings a fundamental challenge to the interpretation of genomics from other populations as well as limiting opportunities in drug target identification from genetic diversity in other populations. Diagnostics may not be clinically as well validated in certain populations, and often laboratories will rely more heavily on in-house data.
- Some of the leading non-oncology precision medicines are targeted to genetic markers that are more common in non-Caucasian populations.
- The lack of diversity in data is a recognised challenge, even without the consideration of existing disparities.
- Real-world data is necessary for product development and product monitoring. While not currently always under good use, steps will be taken to ensure real-world data is considered.
Contributors and Contributors’ affiliations
This Summary of Points to Consider arising during the FPM Conversation event was Prepared by Craig Hartforda and Camila Pullizai for FPM, with contributions, review and approval by the FPM Conversation Speaker-Panellists.
Disclaimer: The views, thoughts, and opinions expressed in this Summary of Points to Consider are not necessarily endorsed by all of the Preparers/Contributors listed below and belong solely to those raising them at or after the FPM Conversation and not necessarily to the preparer(s)’/contributor(s)’ employer, organization, committee or other group or individual.
aCraig Hartford: Pharmaceutical Physician. Member of FPM Policy and Communications Group. Head of Specialty Safety at GlaxoSmithKline.
bCamilla Fleetcroft: Devices Regulatory Affairs Group Manager, Medicines and Healthcare products Regulatory Agency.
cPatrick Fivey: Senior Precision Medicines Policy Lead – AstraZeneca
dPiarella Peralta: Patient advocate – Inspire2Live
eBob Holland: Chair of FPM’s Medical Devices, Diagnostics and New Technologies (MDDNT) expert group. Senior Clinical Fellow, Heptares Therapeutics Ltd.
fRob Hastings: Member of FPM’s Medical Devices, Diagnostics and New Technologies (MDDNT) expert group. Precision Medicine Director, Astrazeneca.
gBruno Rosen: Member of FPM’s Medical Devices, Diagnostics and New Technologies (MDDNT) expert group. Accantes consult GmbH, Germany.
hTim Higenbottam: Member of FPM’s Medical Devices, Diagnostics and New Technologies (MDDNT) expert group. Advisor to Camcon Medical Ltd and Akari Therapeutics plc.
iCamila Pulliza: FPM Women in Pharmaceutical Medicine Project Intern.