By Larry Ajuwon
More than ever, we — patients, care providers, drug developers, payers among others — are all participants in the new drug development and clinical research-to-care paradigm. As the COVID-19 pandemic demonstrated, the enterprise was propelled into the unknown at warp speed and patients became much more directly involved as participants in efforts to address the crisis. At the same time, clinical research has continued to evolve as the scientific understanding of disease biology deepens and promising treatment options with new modes of action (MOA) are discovered and developed.
There is growing awareness that clinical research can be considered as a care or treatment option 1 for patients with rare diseases, cancers, and deadly infections where no suitable interventions are available. Payers are also pushing for reimbursement models 2 which are based on patient-reported outcomes in real-world settings. In addition, new digital health technologies are enabling the use of decentralised approaches 3 for both clinical trials and patient care.
In theory, the use of decentralised methods has the potential to expand access for patients but also leads to study designs and protocols becoming more complex owing to additional risks and requirements 4 around things like data privacy, data quality and patient support/outreach.
In many cases, patients are faced with bearing the financial risk and burden 5 associated with study participation.
The confluence of these factors including the relationship between ethics of clinical research and compensation practices recreates a dynamic that limits access and results in a low representation of underserved populations. This lack of diversity also leads to poor enrollment and patient retention, which has a direct impact on the quality of the clinical findings that are produced and could otherwise influence clinical practice and patient care.
Regulatory bodies and industry are now collaborating to drive patient-focused drug development and they have launched various initiatives (see below) to transform different aspects of the process.
At this pivotal moment, addressing the issue of economic and financial burdens with candor to achieve wider patient access across all disease areas and geographies is critical.
Valuing financial burden
A pressing question for all stakeholders in the pharma/life sciences sphere is “Why and how to achieve zero financial burden in clinical research?”
That is the question we pondered during a recent conversation with a veteran industry leader, whose company offers a technology platform for running decentralised clinical trials. The heart of the matter is: “How does this novel approach benefit patients, sponsors, payers, and society at large?”
We postulated the value derived from this construct would:
1) Allow more people to participate in clinical research — hence, helping to address persistent barriers that undermine objectives related to access and diversity.
2) Give investigators greater assurance that patients’ economic well-being is being supported and key ethical issues are being addressed.
3) Allow money spent by sponsors to satisfy the study objectives — and help to enable the effective use of capital/resources.
This new paradigm — which considers the economics of the patient burden — seems to offer plenty of opportunities for making the system more effective and efficient but there is no global standard, framework, or method for calculating the amounts that patients may receive as compensation or remuneration. 6
At the local community, state, and national levels, there are many practices, and norms regarding financial compensation, from providing fixed stipends to covering patient travel expenses (or reimbursement for such expenses), and/or offering compensation for time and effort to providing nothing at all. For example, stipend compensation is more common in the US.6
This compares with direct travel cost reimbursement in most EU countries, time/effort payment in Sub-Saharan Africa 8 and SE Asia 9 and some travel cost in the Middle East and North Africa (MENA).
Some studies10 have shown that compensating patients improves trial enrollment, and patient retention, along with increased access, however, we think such measures are useful as a by-product of the process and will provide data and insight to deepen our knowledge of socio-economics, medical research, and health.
Medical and research ethics (From Ancient Egypt to Helsinki)
In trying to figure out a budget line item to estimate the cost of a patient’s burden using minimum hourly wage to devise an ethical compensation formula that does not leave patients short-changed, the search led us, unexpectedly, to the 5th Egyptian dynasty (24th century BC) when the Nenkh-Sekhmet, chief of the physicians, had what is considered the first recorded medical ethics code on his tomb.
'Never did I do evil towards any person’ 11
As a precursor to the Hippocratic Oath of “First Do No Harm,” this principle is enshrined in later medical ethics codes including The Principles of the Declaration of Helsinki,12 the Council for International Organizations of Medical Sciences (CIOMS), 13 and The Belmont Report, 14 all of which mandate the protection of a patient’s rights, dignity, and well-being.
In clinical research, well-being would cover such things as ensuring patient safety, defining an acceptable risk-benefit ratio, and limiting the burden (including physical, psychological, and socioeconomic burden) to which participants will be exposed.
If our collective vision is to attain health equity, which the World Health Organization (WHO) defines as achieved when everyone can attain their full potential for health and well-being,15 then it seems our “simple task” as a research-to-care enterprise is to ensure that we keep to our ethical foundational principles constant.
Can industry and society support this ideal by enabling everyone to have access to research opportunities as a care option without experiencing the adverse effect of financial toxicity16 or economic distress?
Today’s industry enablers and trends
Real-world evidence (RWE) and outcomes contribute to marketing authorisations and influences reimbursement decisions
Underserved groups are traditionally underrepresented in clinical trials17 due to several factors including the risk of loss of income. This has broader implications in that approved treatments may not be demonstrated to be effective in these populations in real-world settings, leading to poorer health outcomes. Now that reimbursement decisions by payers are increasingly directly linked to how well the treatments are performing in the real world, sponsor organizations will be putting forecast incomes at risk, if pivotal studies do not include adequate patient representation that will in turn produce representative data.
Patients are engaged as partners in drug development and evaluation.
The patient-focused drug-development approach18 — supported by conscientious engagement efforts by regulatory bodies, industry, and patient advocacy groups — is increasingly being embraced, with the primary goal of better incorporating the patient voice into drug development and evaluation.
Over the last 10 years, patients and patient groups have been playing a bigger role in the clinical research enterprise through expanded patient-engagement initiatives, such as consulting patients on clinical study design, usability testing of information materials,19 and contributing to protocol development.
The National Health Council (NHC),20 the Patient Focused Medicines Development, 21 and the European Patients’ Academy (EUPATI)22 are developing principles, practices, and patient compensation tools including having a fair market value (FMV) fee calculator, remuneration framework, and activities under a cross-industry initiative.
To go from being labeled subjects (the patients) to becoming partners in the healthcare ecosystem is a vital consideration.
The COVID-19 pandemic expanded clinical research and accelerated new operating models
The intense search for COVID-19 treatments resulted in a 7% increase in the number of new trials registered on the Clinicaltrials.gov 23 database for the period 2020–2022 (111, 781) compared to the previous period 2017–2019 (92,646). This later period also saw the rapid adoption of decentralization models in which studies involved having patient visits and assessments conducted remotely or at home.
Between 2015 and 2019, the studies averaged approx. 50,000 trial participants per year globally based on analysis of the FDA Drug Trials Snapshot Report.24
One large global contract research organization 25 also reported that perhaps owing to COVID-19, for the first time in 2021, the aggregate number of study participants intended for new trials was expected to exceed 2 million, double the level seen before the trials for both COVID-19 and several very large Ebola virus vaccine trials.
That is a 40-fold increase in two years!
In addition, the emergence of new digital tools and technologies (such as telemedicine, mobile health applications, home health services, patient-reported outcome tools, and more) that support decentralisation objectives are designed to broaden access to clinical trials and improve patient diversity.
Solving for zero financial burden in clinical trials
Navigating the path forward — A few recommendations
The COVID-19 pandemic has redirected drug development and healthcare enterprises onto a new path and has also energized stakeholders to make changes to meet the challenges of the new global health reality. To help keep up the momentum, the following are some aspirational goals that we propose:
1. Patient: Agree to financial arrangements in which all costs resulting from participation are covered with no risk of incurring loss in the future.
2. Patient advocate: Assign a patient financial advocate to all trials to help ensure that an adequate budget is earmarked and each patient undergoes an economic health check to ensure that adequate support is provided.
3. Openness: Adopt the “Sunshine Act Principle” reporting code for patient payments to ensure transparency and bench-marking at the national, regional, state, and local government levels.
4. Ethics Review - Decision-Making Framework/Policy: Standardize and publish a framework and make it subject to periodic assessment by an independent body.
5. Adequate coverage: Provide economically viable way for standard-of-care charges, insurance payments etc., to be covered under special “clinical research-to-care” plans/schemes.
6. Informed Consent (IC): Specify financial compensation arrangements (such as minimum stipend and other payments) in consent forms and publish it on all primary clinical trials registries. (eg, EU Clinical Trials Register, Clinicaltrials.gov, Japan Primary Registries Network).
7. Fair Wage Value: In determining the appropriate remuneration decision method and amounts, use the average country/region hourly wage based on International Labour Organization (ILO) data, adjusted for purchasing power parity (PPP).26
Parting thoughts…
As the conversation with the veteran industry leader draws to a close, we both agreed to share two take-away actions: the first was to help focus more attention on this topic in our respective communities, and, the second, was to explore how we can build an open data-sharing platform together with all participants to steer having clinical research as a care option toward a more equitable and burden-free future for all patients. Q.E.D
©
Larry Ajuwon is the Founder and Director of RHIEOS, a clinical innovation consultancy focused on enabling better access to treatments and lowering barriers to building viable health systems. Email: lajuwon@rhieosventures.co.uk
Acknowledgements
My gratitude goes to many people (colleagues, friends, clients, researchers..) who have contributed in one way or the other to the writing of this essay. In particular, the insights shared by and discussions with the following people have encouraged bold thinking on the topic and enriched my perspective.
Kamila Novak, excellent article highlights the different payment practices across the world and makes a good case for improvement and review.
Eric Nier, we had an informative conversation on how technology is being used to simplify patient payments and reduce financial burden
Kimberly Richardson et al shared some insights during this roundtable discussion
Gunnar Esiason makes a good case for better pay and patient advocacy in this article
Suzanne Shelley provided valuable editorial assistance and critique during the drafting
Sources
Virtual Clinical Trials: Challenges and Opportunities: A Workshop
Decentralized clinical trials (DCTs): A few ethical considerations
Fair payment and just benefits to enhance diversity in clinical research
Clinical trial participant time, inconvenience and expense (tie) compensation mode
The Council for International Organizations of Medical Sciences (CIOMS)
Definition of financial toxicity
Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups https://nap.nationalacademies.org/resource/26479/CT_Highlights.pdf
Practices of patient engagement in drug development: a systematic scoping review