Evaluating Global Regulatory Landscape for Driving Digital Innovation in Supply Management

Paul Ingram, PhD

The clinical trial supply space has many examples where current practices following traditional, conservative, historically proven, and perceived “safest” approaches to delivering medication to trial participants are being favored over newer alternatives that have become available. In recent months, regulatory bodies have provided guidance¹ and driven changes² that could spur clinical trial supply-chain digitalization and innovation initiatives. This will enable life sciences industry to deliver the greatest benefits to trial participants at the receiving end and help unburden operational teams who support the process throughout.

The movement towards trial decentralization has accelerated since the pandemic. We’ve also observed a rise in medication tracking across complex direct-to-patient supply chains and remote medication adherence monitoring. Although signs have been encouraging with possibility of studies now being more inclusive, fragmented guidance on direct-to-patient home services and remote medication adherence monitoring have potentially limited its adoption.

In late 2021, FDA issued draft guidance on digital health technologies (DHTs).¹ The DHT draft guidance attempts to clarify the kinds of devices and software that may be used for remote monitoring of clinical trial participants to ensure that the data is sufficient to support a product application. While the draft guidance overall was well received, multiple questions and feedback arose mainly seeking to clarify what exactly is included and excluded from being a DHT to drive greater diversity and inclusion by providing digital solutions to non-traditional sites that are more difficult to access.³ FDA is yet to comment on responses to the clarification questions on what technology is included and excluded from DHT guidelines. Once known, products that have digital technology and approaches that operate outside FDA DHT guidance will undoubtedly face uncertainty; and the only real choice is to follow the guidelines and ensure they are compliant regardless unless they can justify why their technology is not in scope.

Guidance on smart packages

The FDA guidance on DHT helps trial sponsors to feel more confident on how and where technology can be used in trials for unit dose level adherence monitoring and provide insights into participant’s medication adherence. It also clarifies how wearables and devices, providing digital endpoints can be used in defining outcomes of a trial.

With this, many manufacturers of packaging products that monitor and support participant medication adherence are considering ways to re-augment their products from being described as SMART packaging to being DHT compliant in US trials (with potential for these to be used across global trials). This may be a strategy to build clinical and regulatory stakeholder confidence in the compliance and validity of the technology and benefits they bring. The adoption of this approach also allows electronic drug reconciliation to unit dose level in a pack. This potentially unburdens clinical site and monitoring staff to a large extent. The future looks promising for unit dose level tracking for medication adherence especially as decentralized trials continues its growth trajectory and expands the activities that are not delivered via the physical attendance of participants at investigator’s clinical site.

Good manufacturing practices

The new European Clinical Trial Regulation (Regulation (EU) No 536/2014)² came into force in January 2022 and the EMA forward looking plans complementing the regulation shift outlined in the Accelerating Clinical Trials in the EU (ACT EU) initiative came into action in early 2022. The regulation provisions use of a single portal to process clinical trials data across EU. While there are clear benefits to good clinical practices (GCPs) with a streamlined central portal and process re-engineering to a more centralized clinical trial application approach are compelling. The new EU Trial Regulation also introduced more challenging changes to the long established GMP processes. It outlines the principles and guidelines for good manufacturing practice for investigational medicinal products meant for human use and arrangements for inspections thereof.¹⁰ It includes minor changes such as rechristening of the term non-investigational products (NIMPs) to auxiliary medicinal products (AMPs) and the pre-fix Authorized and Un-authorized if the product has Marketing Authorization under the European Medicines Agency jurisdiction.

The most challenging changes are with expiry date management and label text requirements. Central systems like the randomization and trial supply management (RTSM) system are no longer allowed to manage expiry date alone and further to this, under Annex VI, expiry date must now appear both on the product’s inner primary and outer secondary packaging.² This is particularly challenging given the rolling stability studies of the drugs as they are in clinical development. Consequently, expiry updates, traditionally performed only on the outer packs in distribution hubs and trial sites, will now be much more challenging. This new level of inner/primary container label expiry update makes it a higher risk activity outside the GMP facilities they were packaged in. Generally, the unblinded status of staff working in GMP packaging suites and the segregation procedures they have in place ensure minimal risk of mixing up of pack contents between different blinded medication packs as they are opened, re-labelled and then kits re-assembled and tamper sealed.

Digital labels

Some time ago, The EFPIA and ISPE released a position paper providing options on how best to manage the supply chain complexities presented by the new Annex VI. This took a risk-based approach using trial pack re-design and expiry date process work arounds more aligned to traditional concepts of packaging trial medication and printed label expiry updating. There are forward looking suggestions from both parties that emerging trends and technologies like ‘Just in Time’ and e-labels may be options in the future.^4,5

Given the passage of time from these articles, this is the future and e-label are becoming available, but their development timeline has slowed due to the global pandemic and key enabling technology around displays and batteries restricting their market readiness. E-paper display entry into use in trials has also been restricted by interoperability issues of needing proprietary antenna and cradles for updating the labels across the trial network. That said, since late 2018, when Apple devices opened near field communication (NFC), app developers⁶ could design apps on both Android and Apple BYO devices that can theoretically update e-paper displays used as clinical trial medication labels.

Role of technology in the scheme of things

Options for using Bluetooth low energy (BLE) or NFC help make the process more interoperable than ever before. The ability to update the expiry date on an e-paper display label containing all the regulatory required text applied to medication kits without the need to return them for re-package to a GMP facility, while eliminating multi-page booklet labels, is hugely compelling. It remains a requirement in Annex VI² to have expiry dates and other items in human readable text physically on the packs. However, a digital copy of the most up to date label in a BYO device offers a convenient way to send updates to the e-paper display labels, on the product, and demonstrates a more patient centric label option to zoom and scroll in a participants preferred/approved language. While in app labels on BYO devices cannot replace the regulatory required text on the product label they can act as a digital supplement to drive patient engagement and protocol compliance.⁷

Also in early 2022, the UK Government’s Medicines and Healthcare products Regulatory Agency (MHRA) and Health Research Authority (HRA) teams set out post-BREXIT proposals to re-define clinical trial regulation.⁸

On a high level, it looks to remove obstacles to innovation, whilst maintaining robust oversight of safety of trials and ensuring the legislation builds international interoperability. This would eventually ensure that UK remains a preferred site to conduct multi-national trials. The running theme is to lower the burden of conducting low-risk trials across both areas of GMP and GCP and simplify things where possible. Proposals include requiring patient and public involvement in Research Ethics Committee review processes. To reduce barriers to participation, options to use a single front door for the Clinical Trial Application and Research Ethics Committee and a combined downstream review process (given the success of recent pilots) is vetoed. In addition, the proposal aims to simplify Informed Consent in cluster trials, reducing the burden of requirements for low intervention trial and as an alternative to the new EU Annex VI label regulations. The proposal also suggests that trials can be assessed as a risk-based approach to justify no physical re-labelling with trial information of some already commercially available medications being used in a protocol.

The option is to have medication management in a participant app to support kit level scanning of commercial bar codes and ensure the correct product is in the participants hands. This also presents an opportunity for participant apps with digital label or electronic packaging insert to support taking their trial medications correctly. Pilots of electronic product information using blockchain technology in the commercial supply chain are already under-way.⁹

In summary

Recent updates by regulators on how trials can be conducted and how digital health technologies can support them have created more confidence of integrating them into future trials. The need to try harder to include population diversity and flexibly support traditional, decentralized, and hybrid-trial designs is also a key driver to digitalization. Avoiding overwhelming trial participants with the number of potential apps to be used is a key consideration. The appetite of participant to use BYOD devices for medication management has grown and scanning of QA codes on own devices has become a new normal for a while. This may be linked to the adoption of COVID apps.

In some ways the UK has shown an appetite towards a slightly broader set of innovations to the drug development and clinical trial processes, and most regulators are now paying attention to how digitally enabled and innovative trial processes can be conducted to maximum effect.⁸ More needs to be done to ensure data interoperability for global trials fully benefit from the digitalization opportunities we now have. There is a big push to use data from electronic health records alongside clinical trial data with electronic health record to trial electronic data capture platform (EHR to EDC) links now expanding. If this can be achieved along with ensuring participant’s medication adherence, using a combination of Real-World Data and Clinical Trials Data sources, it will strengthen trial outcomes and benefit new medications being provided to patients that are being treated.

Paul Ingram, PhD, Industry Leader, TCS ADD™ Supply Management

References

1. Digital Health Technologies for Remote Data Acquisition in Clinical Investigations. 2022. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations
2. REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. (April 2014) Available at: https://ec.europa.eu/health/system/files/2016-11/reg_2014_536_en_0.pdf
3. Industry Stakeholders Respond to FDA’s Draft Digital Health Technology Guidance (2022) Available at: https://www.aardexgroup.com/2022/03/30/fda-dht-guidance/?utm_campaign=Quarterly%20Newsletter&utm_source=email&utm_content=Q1%202022%20Industry%20Insights%20Newsletter
4. Annex VI to Clinical Trial Regulation 536/2014 Risk assessment-based concept of an interim* solution on expiry date labelling of the immediate packaging of Investigational Medicinal Products (IMPs) (March, 2021) Available At: https://www.efpia.eu/media/589700/annex-vi-to-clinical-trial-regulation-536-2014.pdf
5. EU Clinical Trail Regulation: Annex VI Period of Using Labeling Requirements (March 2017) Available at: https://ispe.org/pharmaceutical-engineering/march-april-2017/eu-clinical-trail-regulation-annex-vi-period-using
6. WWDC: Apple’s NFC plan is a big developer opportunity (May, 2018) Available at: https://www.computerworld.com/article/3276649/wwdc-apple-s-nfc-plan-is-a-big-developer-opportunity.html
7. Accelerating Clinical Trials in the EU (ACT EU) Delivering an EU clinical trials transformation initiative. (January, 2022). Available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/accelerating-clinical-trials-eu-act-eu-delivering-eu-clinical-trials-transformation-initiative_en.pdf
8. Accelerating Clinical Trials in the EU (ACT EU) Delivering an EU clinical trials transformation initiative (January, 2022). Available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/accelerating-clinical-trials-eu-act-eu-delivering-eu-clinical-trials-transformation-initiative_en.pdf
9. Proposals for legislative changes for clinical trials (January, 2022) Available at: https://www.gov.uk/government/consultations/consultation-on-proposals-for-legislative-changes-for-clinical-trials/proposals-for-legislative-changes-for-clinical-trials#proposals
10. European Commission Website – Public Health- Clinical trials - Regulation EU No 536/2014 https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en