Introduction

The Breast International Group (https://bigagainstbreastcancer.org/) is the largest international network of academic research groups dedicated to finding cures and developing better treatments for breast cancer through clinical trials and research programmes, with over 50 member groups world-wide1,2. A review of the National Cancer Institute’s National Clinical Trial Network groups reported projected gains of 24.1 million life years by 2030 among 108,334 patients enrolled in phase III trials from 1980 onwards, at a cost of $236 per life-year gained3. However, more recently, a constellation of factors including greater awareness of inequities in cancer care4,5, lack of diversity and inclusivity in clinical trials6,7,8,9,10,11,12, the rising cost of new anticancer agents13,14,15,16,17 and practices to limit their affordability18,19,20, lack of alignment of research funding with clinical need21, fewer academic and patient centric pragmatic clinical trials22,23,24, declining academic freedom25,26,27 and the move to increasingly elaborate research28, have led to concerns about global inequity in democratising discovery and how this might be ameliorated.

While cancer is a global, race and age agnostic disease, our clinical research enterprise is not. Short term consequences of this range from lack of inclusion of ethnic minorities and elderly patients4,29,30,31,32,33 to incomplete toxicity assessments34,35. Lack of ancestral diversity in clinical trials today compromises the external validity of translational studies in the future, and will unintentionally lead to algorithm bias in health care36,37,38,39. While the research agenda for all countries is set in more affluent ones40,41,42,43, the African continent is home to 15% of the global population, shoulders 25% of the global disease burden, but produces only 2% of the world’s research output42. By 2040, 30 million new cancer cases and 16 million cancer related deaths will be reported in low- and middle-income countries44. There, access to standard therapies is limited45,46,47,48, the relative health burden is higher than in high income countries46, the costs of newer anticancer agents are prohibitive44,45, and the transgenerational impact of maternal cancer related deaths is profound49. A 2018 review of 6710 trials in breast, lung and cervical cancer conducted globally demonstrated that several low- and middle-income countries with the highest incidence to mortality ratios in breast, lung and cervix cancer had no clinical trials registered for these tumour types40. Only 8% of studies that enrol patients in low- and middle-income countries, are led by individuals based there41 and only 4% of global cancer research output is co-authored by individuals in these countries. Subsequent access rates to novel agents are also inequitable35. Access is lowest in African countries due to wealth inequality, lack of infrastructure and sovereign debt50.

Democratisation and accelerated integration of discoveries are necessary in an era when pandemic, and climate change related disruptions have and will lead to delayed cancer presentations and fragmented care51,52,53,54,55,56,57. Improved equitable integration is also needed at a time of rising breast cancer incidence in low- and middle-income countries46. These concerns prompted the establishment of a working group within the Executive Board of BIG to conduct a reflective analysis of the landscape of breast cancer clinical trials. Analogous to the reflective novella of Charles Dicken’s “A Christmas Carol”58, we envisaged our trial landscape through the lens of the past, present, and future, and how the current ecosystem could be re-imagined to maximise survival and quality of life for ALL of the over 2 million patients who will be diagnosed with breast cancer globally this year59,60.

The Impact of the Discoveries of the Past

In oncology therapeutics the development of targeted therapies in breast cancer – first hormonal and then genomic, marked a transformative era for patients with breast cancer. Tamoxifen, first synthesised in 1962 with recognised anti-oestrogen actions, was initially developed by Imperial Chemical Industries (now part of AstraZeneca) as a possible female contraceptive61. In 1969, a single-arm phase II trial reported similar efficacy to historical controls treated with other endocrine agents (stilbestrol or high dose androgens) but with less toxicity62, findings confirmed in a series of randomised trials63. This tolerable efficacy led to adjuvant trials – the first initiated 3 years after the drug was commercially available in the United Kingdom, but unlike today when a single large trial is conducted to determine efficacy, a series of trials were conducted to look for optimal treatment duration with 1 year64, 2 years65, and 5 years66. Earlier studies with tamoxifen suggested no benefit67,68, whereas larger, academic trials demonstrated clear advantages69. Further studies directly compared different durations70,71. However, it was not until the results of several academic and industry trials were combined by statisticians at the Early Breast Cancer Trials Collaborative Group that clear evidence of improved survival emerged72. Their work included the following prescient comment: “…the very high degree of statistical significance suggested by this overview shows that where many trials have addressed related questions, a semi-formal overview of their findings (in cancer, as in heart disease) may produce reliable evidence long before this would have emerged from the usual processes of separate analysis and publication. Since the future treatment of many women might be importantly affected by this…”, with these initial findings confirmed in a full publication73. Thus, tamoxifen joined the World Health Organisation Essential Medicines List (WHO EML)74, because academic-commercial partnerships around the world had demonstrated the optimal duration of therapy (up to 10 years) with clear evidence of improved survival, with many of the key data emerging after generic drug supply became available from 2002 onwards.

Complementary and Contrasting Aspects of Academic (or Government Funded) and Industry Trials

The following game-changing new development was the development of trastuzumab for HER2-positive breast cancer75. Much initial work was done by academic-pharma collaborations in the United States, with the pivotal registration trial for metastatic disease sponsored and led by Genentech76. However, the most important impact of this drug was improving overall survival in early breast cancer, with several trials led by academic groups working globally with Genentech and Roche. Again, the duration of therapy was tested in these trials77,78,79, before approval, with further shorter durations tested in academic led studies supported by United Kingdom, Finnish and French governmental funding79,80,81 demonstrating the complementary nature of such academic studies to those sponsored by industry (Table 1). Since the 1990s when these therapeutics were being refined, the 5-year risk of death from breast cancer has reduced in the United Kingdom from 14.4%, then to 4.9% by 2020, reflecting the transformative impact of these decades of discovery82. Similarly in the United States the overall death rate has declined by 44% overall between 1989 and 202283. A recent modelling study estimates that 47% of this reduced mortality is attributable to better treatment of stage I-III disease, and 29% to better treatment of stage IV disease83,84.

Table 1 Hallmarks of Clinical Trials
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The Therapeutic Landscape of the Present

Currently, the landscape of cancer clinical trial activity has been dominated by the integration of immunotherapy into cancer therapeutics. Between 2016 and 2020, 12.1% of global public and philanthropic funding for cancer research was allocated to immuno-oncology21. The awarding of the Nobel Prize in Physiology or Medicine to Tasuku Honjo and James Allison in 2018 reflected the therapeutic impact of their seminal work 3 decades earlier, which led to the widespread incorporation of immune checkpoint inhibitor (ICI) therapy into cancer care85. In 2019, the ICI pembrolizumab was added to the WHO EML, joining trastuzumab, which had been listed in 201586,87. This inclusion was based on the impact of ICI agents in melanoma and lung cancer management e.g.,88,89, and prompted similar studies in breast cancer90. The potential for patients with breast cancer was reinforced by data from the Cancer Genome Atlas, which assessed distinct genomic immune profiles across intrinsic breast cancer subtypes and demonstrated that all subtypes were immunologically actionable91,92,93.

The impact of the work of Honjo and Allison has been substantial. By 2022, over 2000 clinical trials evaluating these agents were being conducted worldwide94. By 2023, 43% of cancer clinical trials in some countries were ICI related95. Seven years after the Nobel award, 11 antibodies directed against PD-1 or PDL-1 pathway and more than 85 oncology indications have been approved by the FDA78,96,97. As reflected by the multiple companion diagnostic tests to detect PD-L1 expression98, the rapid expansion of clinical investigation has been largely uncoordinated99,100 and referred to as “The Wild West”94. Such divergence will likely accelerate as complex gene signatures are explored to predict treatment benefit and ICI agents are potentially combined with over 160 antibody drug conjugates (ADC) in development101,102,103,104, and integrated with bi, tri, and tetra-specific antibodies105,106.

In parallel with these developments the clinical trial landscape has evolved significantly in the past 2 decades. In an analysis of 26,080 cancer clinical trials in the United States, the enrolment ratio of industry sponsored versus government funded trials for adults increased from 4.8 during 2008–2012 to 9.6 during 2018–202224. While cancer incidence increased during these periods, enrolment counts for federally-sponsored trials were flat. This evolution has been associated with a shift away from demonstrating gains in overall survival to the use by regulatory authorities of surrogate endpoints such as progression free survival or change in biomarker level107,108 where the strength of association with overall survival may ultimately may be low (Table 1). Progression free survival is now the most common end point in oncology phase III trials109, and initial short term favourable results may dilute or dissolve with time. In one analysis the ultimate median overall survival gain across a portfolio which included breast cancer patients was less than 6 months22.

Challenges of selecting the most appropriate end point

The concerns regarding trial endpoints are reflected in the ICI journey in breast cancer therapeutics102. There, initially low response rates were observed in single agent studies90, prompting incorporation with cytotoxic chemotherapy in the metastatic setting in phase 3 studies (KEYNOTE-119, IMpassion130 and IMpassion131110,111,112). Initial study results led to FDA approvals, but more long term follow up led to subsequent withdrawal of 2 indications for atezolizumab113. In early stage triple negative breast cancer, the KEYNOTE-522 study incorporated pembrolizumab into neoadjuvant therapy for 6 months with an additional response agnostic 6 months of therapy post operatively110. A modest improvement in pathological complete response rates from 55.6% to 63%, and a significant improvement in 3-year event free survival from 76.8% to 84.5% led to FDA approval for this indication. Subsequently, estimated 5 year overall survival rates improved from 81.7% to 86.6%. The role of continuing pembrolizumab therapy in patients who have had a complete pathological response has been raised by many114,115,116,117 particularly given the favourable results of adaptive response approaches in other cancer types such as the completed investigator initiated NADINA trial118,119,120,121. However, in the pivotal KEYNOTE-522 trial, translational studies to optimise patient selection for treatment are not yet in the public domain. Such studies would facilitate right sizing therapy, and potentially reduce the long term ICI immune-related toxicities observed in real world studies34,117,122,123,124, and help address concerns regarding the risk of ICI induced accelerated atherosclerosis125,126,127 and potential gonadal toxicity128 in this adjuvant treatment setting.

The enthusiasm regarding the potential benefit of ICI for patients has also been subdued by the significant financial toxicity of this therapeutic class. In the KEYNOTE-522 study, the cost per relapse averted was $2.64 million15. High prices are a major factor in preventing patient access to cancer medicines even with some WHO EML agents, and even in high income countries129,130,131,132,133,134. As highlighted by a recent Medecins Sans Frontieres funded study135 these prices set the negotiation standard for other less affluent jurisdictions136. This strategy is compounded by the “cancer premium” whereby In high income countries cancer drugs are on average 3 times more expensive compared to non-cancer ones137,138.

Central to these high costs is the cost of clinical development. A single trial now has 3 million data elements, a 10-fold increase in the past decade22, and an estimated cost for a pivotal trial of US$48 million139. An analysis of research and development productivity of 16 leading research-based pharmaceutical companies between 2001 and 2020 revealed a $6.16 billion R&D expenditure per new drug140. Such figures are then used to justify the high drug costs that ultimately limit patient access141,142. The median price for a course of an oncology drug approved by the FDA between 2015 and 2020 was $196,000143, while the median price per patient for a complete course of recently approved adjuvant therapy was $158,00015. Globally this can result in catastrophic financial loss for patients in the wealthiest country, and suboptimal breast cancer care in most of the remaining ones. These high prices are perpetuated by patent thickets and patent ever-greening19,20. In the United States these costs contribute to 3% of cancer patients declaring bankruptcy, a rate almost three times higher than the general US population16,17. This cohort also have a higher death rate than those that remain solvent144. In low- and middle-income countries, only 1–2% of the population will have access to innovative agents145,146. For them to access to medicines on the WHO EML often leads to substantial out of pocket expenses147.

A Vision for the Future

In the present era of unprecedented discovery, less than 1 in 20 patients with cancer participate in clinical trials113,148,149. Consequently for many patients the discovery resulting from trials is not relevant to them as either their demographic is not included, or non- affordability of agents (including WHO EML agents) prevents access to the therapies. What should be a golden age of medicine has become a gilded one, with the appearance of a wealth of treatment options concealing actual poverty of access150. The human cost of this reality for our patients and their families is profound. Our industry partners are also vulnerable. Patient trust is central to clinical trial conduct. However in 2014 a survey of the US public reported that 37% believed that the FDA intentionally suppressed natural cures for cancer at the behest of the pharmaceutical industry151,152. Failure to optimise the translational potential of patient provided tissue samples as outlined earlier, compromises this trust.

It need not be like this. Our patients’ reality contrasts with the decision of Roy Vagelos, formerly Chief Executive Officer (CEO) of Merck, who in 1988 established a drug donation programme, in 30 countries, of the WHO essential medication ivermectin, an avermectin derivative, to treat river blindness. The programme is estimated to have prevented 7 million years of disability at the cost of $257 million153. In 2015 the Nobel Prize in Physiology and Medicine was awarded to Bill Campbell and Satoshi Omura for the discovery of avermectin, reflecting the impact of this agent. The decision to donate the anti-parasitic drug to eradicate a vector-borne disease which caused a major public health burden in West Africa, has been equated to the Volvo car company’s decision to freely share the 3-point seat belt patent with other manufacturers because of its humanitarian potential154,155. What would be the impact of a similar initiative with other WHO EMLs such as trastuzumab and pembrolizumab (vide supra)? What if biobank specimens and data bases could also be shared? Failure to do so at present with resultant lack of co-ordination and non-optimization of donated patient material will also be contrary to the recently updated World Medical Association Declaration of Helsinki on ethical principles for medical research involving human subjects156.

Let’s then also be optimistic and imagine that all parties wake up to realise that it’s in everyone’s long term interests to reform the power balance in pivotal, practice changing trials. Researchers will develop new interventions (whether chemical, mechanical, electronic or health system) which need to be tested. There needs to be a forum for dialogue between the “owner” of new intervention, experienced clinicians, regulators, methodologists with clinical research skills, health care providers, AND the public/patients, who jointly define the questions. For example, with a novel endocrine therapy for breast cancer, we need to know what advances it offers: either in place of OR in sequence/combination with contemporary care and, for a cancer, with a long natural history such as hormone receptor positive early breast cancer, we also need to document the long-term effects, whether beneficial or not.

If the trial is for drug registration, then the regulators need to demand of the sponsor a design that meets ALL these criteria, not just the primary endpoint looking for a statistically significant improvement in recurrence after only a few years. If academics and patients and health care providers want to know if a whole population benefits or only a subset, then core translational research needs to be embedded in the trial. Such translational studies require a code of practice so that samples and data are not solely under one party’s control157. It is paramount that such correlative science is conducted AND reported, for the public good, whether or not it is of interest to the commercial OR academic bodies involved. If such additional data beyond an initial positive signal are of interest to the whole system, then perhaps the commitment to them needs to be a condition of marketing authorisation?

In late January 2023, the United States National Institutes of Health’s new Data Management and Sharing policy was activated158. This requires researchers to share data that was generated with institute support with immediate effect. Efforts to increase data sharing of individual participant data from clinical trials by pharmaceutical sponsors are also being made159,160. In 2024, the Japanese government launched an initiative that will make its publicly funded research free to read161 with data sharing as the norm rather than the exception. This vision would include information from translational data whether industry or academic related. It envisages leveraging real-world evidence from patients receiving standard therapy162,163, complementing pragmatic trials which have been globally impactful in the COVID-19 pandemic164,165,166.

Vaccine development strategies during the COVID-19 pandemic have emphasised the benefit of integrating real-world and clinical data to accelerate innovation. The use of such real-world data has been helpful in oncology, from assisting with estimates of ICI toxicity in Japan29, CAR-T-cell therapy toxicity in the United States167 through to assessing clinical use of cyclin-dependant kinase 4/6 inhibitors in patients with metastatic breast cancer in the Netherlands168. In Ireland during the pandemic a Geo-Hive live data base was established to provide daily guidance of COVID-19 infections169. This exemplar successfully collated data from multiple sources in the Irish healthcare system where data acquisition has historically been either delayed or incomplete, or both. A similar data base could be integrated into newly approved therapeutics with general data protection regulation compliance, mandatory registration by prescribers, and an “opt out” facility for patients analogous to that used in organ donation cards. Valuable pharmaco-genomic data could result and address the lack of ancestral diversity shortcomings highlighted by Duma and colleagues4, and the need for innovation highlighted by others170.

Analogous to beneficial impact of real world data integration into healthcare during the COVID-19 pandemic, pragmatic patient focused trial designs were also pivotal in reducing mortality during that time171. Similar benefits could be seen by employing pragmatic and sustainable trial designs in oncology. As the recent Lancet Breast Cancer Commission commented, “We identify the need to develop and facilitate novel, efficient, patient-centred translational clinical trials and enable a research culture and infrastructure to ensure these can be undertaken globally”. Extending access to appropriate clinical research into breast cancer across the globe must be part of our optimistic future: or the inequities in breast cancer care that the Commission highlighted will only get worse172 Figure 1.

Fig. 1: Challenges for breast cancer trials.
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Barriers to clinical investigation in breast cancer therapeutics include lack of co-ordination and lack of data sharing between trials, climate toxicity associated with research, entanglement between industry and investigators213 and growing trial complexity compounded by lack of funding.

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What would a trial addressing the concerns raised in this commentary look like? In Table 2 we have outlined many of the suggestions integrated in this paper which would increas access for patients and integrate them as partners in trial design and conduct. In our group The Optima Young /Path4Young Trial is an exemplar of a digital approach to the challenges we face. As demonstrated in Fig. 2 many activities across the trial pathway can be digitised. Such digital technology can encourage a more global and equitable reach of clinical trials and also empower patients to participate in co-creation of clinical research protocols. Artificial intelligence algorithms and natural language processing models can be activated to facilitate the screening and recruitment phase of a clinical trial to determine patient eligibility with relative accuracy173,174,175 and use of matching algorithms to reduce potential provider bias176. Patients can provide consent through digital platforms (eConsent)177,178 which reduces geographical constraints179,180. Patient data can be collected remotely at different time points during the clinical trial in several ways: electronic capture of active and passive patient-generated health data (PGHD) through the deployment of electronic patient-reported outcomes and biosensors; automated data collection via the patient’s electronic medical record and personal health record; and through telemedicine visits181,182,183,184. Other trial activities that can be digitised include the research intervention itself, the digital transfer of imaging and lab results, adverse event AE monitoring, data analysis, and the eventual sharing of results with participants185,186,187,188,189,190,191,192. Many oral, subcutaneous, and intramuscular therapies with established safety profiles and some infusions have been adaptable to successful remote administration185,186,187. Other advantages included real time feedback for patients and staff193,194 and patient empowerment195,196,197,198. Challenges to implementation include digital literacy199,200, cybersecurity and privacy concerns among others201,202. Oncology trials are often characterised by multi-site participation and manual data collection, digitisation of data collection can greatly ease the clinical burden associated with many trials. Such studies are also more environmentally sustainable with up to 90% less carbon emissions203. The aim is to realise many of the hallmarks of equitable trials which optimise the benefits of both academic and industry trials (Table 3).

Fig. 2: The use of digital tools in the path for young research pathway (EU funded international chemotherapy de-escalation trial in pre-menopausal women with breast cancer (BC)) – Figure adapted ref. 199.
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The trial includes digital information resources for patients, family members and the general population to improve trial understanding and real-time communication; workshops with patients representatives regarding study procedures, recruitment, results, and monitoring of inclusion metrics with automated alerts relating to the risk of under-representation of patient groups, an equity toolbox to boost and support diverse participation hosted in WeShare, and implicit bias training programs for investigators.

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Table 2 Strategies to increase access to clinical trials for patients
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Table 3 Hallmarks of Equitable Trials
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Building on Charles Dickens’ acute social observations, as a healthcare community, we have a role in determining if the outlook for our patients represents “Great Expectations” as illustrated in Fig. 3, rather than “Bleak House”204. In 2022 the US NIH funding for clinical research was $18 billion205, a figure exceeding that of all other government funded research combined206. However it is only a fraction of the $100 billion expenditure of the US pharmaceutical industry205. This expenditure had doubled in a decade, a trend that will be reflected in a growing industry-funded clinical trials arena in the future. In this regard, a “Bleak House” ending that Dickens could have written might look like the following: The total control of clinical trials sits with commercial bodies which only test therapeutic approaches that will reap financial rewards for their shareholders, with no regard for the broader community in which they and their employees live. Regulators are emaciated into bodies that just review submitted data and can only reject studies that do not meet the endpoint chosen by the sponsor, which may have little or NO relevance to patients, hospitals, health care providers, or clinicians. Then, in the face of severe financial pressures, such new interventions are only accessible to the rich, further exacerbating the inequalities in the world until mass migration driven by famine, climate change, and lack of access to good medicine overwhelms even those rich health care systems. That nightmare scenario is perhaps unimaginable; but it is surely in no one’s interest to inch in that direction.

Fig. 3
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Opportunities to Optimise Patient Benefit and Integration in Clinical Trials in Breast Cancer.

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We need to recognise and manage the hazards posed by prioritisation of shareholder returns over patient welfare and value for money in healthcare207. To realise the “Great Expectations” outlook that our patients and communities need, we would ask that the power balance shifts back to genuine partnership between all the parties involved: patients and the public, academics, health care providers, funders, innovators, commercial enterprises, and regulators, with the right clinical questions asked over the relevant timescale for everyone’s benefit208,209. The COVID-19 pandemic outlined where such a partnership was transformative for our societies. While the pandemic was an acute pivot point that facilitated rapid transformational change, our current reality in oncology research doesn’t. George Bernard Shaw, a Nobel Laureate for Literature, wrote “Progress is not possible without change”210. To harvest the current crop of discovery210,211,212 for ALL patients, we ALL need to change. We hope this manuscript will catalyse the necessary conversations required to enable such globally relevant re-democratisation of drug discovery and medical innovation.