Collaboration and integration to progress clinical research

Here, Lucinda Cash-Gibson and Francesco Patalano discuss why the pharmaceutical industry is collaborating to develop protocols for patient-centric integrated platform trials and what the clinical research industry may look like in future.

close up of the hands of a group of business people piled together in the middle of a circle - idea of collaboration

Even before the COVID-19 pandemic, clinical research was evolving, driven by a need to reduce costs and expedite development. However, COVID-19 has accelerated transformation across the pharmaceutical industry, and clinical trial infrastructure has not escaped the sweeping trends of increased stakeholder collaboration, digitalisation and decentralisation. Aside from the shift towards decentralised and virtual trials, which social distancing regulations necessitated, clinical research for COVID-19 interventions was characterised by large platform trials. These collaborative research endeavours enable multiple interventions to be investigated under a single overriding protocol on an almost continuous basis. Some key examples include the US National Institutes of Health (NIH)’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) programme, the European Union (EU)’s REMAP-CAP study and the UK’s RECOVERY and PRINCIPLE trials.

To learn more about platform trials and why funding has been granted to a project to develop a tested and trusted framework to facilitate their routine use across various disease areas, called EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL),1 European Pharmaceutical Review’s Hannah Balfour spoke to Lucinda Cash-Gibson, the Scientific Project Manager of EU-PEARL at Vall d’Hebron Institute of Research (VHIR), and Francesco Patalano, Head of Novartis Centers of Excellence for Pediatric Development and Patients Reported Outcomes and EU-PEARL Project co-Leader.

Platform trials

Platform trials are not a novel entity. These studies are an example of master protocol trials – novel designs that investigate multiple hypotheses through concurrent sub-studies (eg, multiple treatments or populations or allowing for the addition or removal of arms during the trial).2 As of 1 August 2019, a study found that the number of master protocol trials had increased rapidly in the previous five years.2

Female doctor drawing a liquid from a vial into a syringe to give to elderly female patient - idea of clinical research/trial

According to that paper, there were approximately 40 master protocol trials in 2015 and about five platform trials; in 2018 this had increased to over 70 master protocol trials, with roughly ten platform trials. By 2019 this number had increased again, with 83 master protocol trials identified by the analysis, 16 of which were platform studies. In 2019, the majority of master protocol trials were being undertaken in oncology (76 of the 83 total); however, five platform studies had been designed for other indications, including influenza, Ebola, pneumonia and Alzheimer’s disease (AD).2 That analysis also found that the majority of the master protocol trials were undertaken in wealthy countries, such as the US (n=44), UK (n=25), France (n=23), Spain (n=17) and Canada (n= 13), with none identified in low-income countries and few occurring in middle-income economies.

In non-pandemic settings, several early-phase platform trials have been established to aid drug screening programmes,3 while late-phase uptake has been slower.4 The most notable trials with this design have occurred within the oncology indication, for example, the STAMPEDE trial (NCT00268476) which has so far contributed three changes to standard-of-care for prostate cancer patients since its initiation in 2005.5

Why use platform trials for COVID-19 treatment testing?

Indeed, platform trials are not a novel tool within the pandemic space – several such studies have been set up to combat global health emergencies in recent years, as well as to enable trials to be undertaken in resource-limited healthcare settings. For instance, for the 2016 Ebola outbreak in West Africa, the PALM study evaluated four different treatments, two of which were discontinued due to inefficacy while the others continued.

The MAMS platform design… is especially effective at maximising the number of people receiving active interventions, while prioritising recruitment, funding and clinical resources to the most promising arms”

In the COVID-19 pandemic, adaptive platform trials, also known as multi-arm multi-stage (MAMS) trials, continue to investigate multiple treatments simultaneously against a shared, standard-of-care control arm.6 They use interim analyses to ensure that only treatments showing promise continue to recruitment at the next stage of the trial. This ability to test a large variety of treatments at once and drop insufficiently active interventions significantly increased the rate at which best clinical practices could be identified and guidance implemented.6

Adaptive trials were chosen for many reasons, but efficiency was particularly key, especially in these instances where many interventions were/are expected to prove ineffective.6 In the context of a pandemic, the inefficiency of traditional two-arm randomised trials is three-fold: firstly, the design requires that each trial has a separate control arm, thus a huge number of patients only receive standard of care and are ineligible for recruitment into trials targeting a similar patient population; secondly, the interventions are tested based on limited available data, so many of the studies will end up being negative (ie, the treatment is deemed to be ineffective); and lastly, setting up new trials to evaluate emerging treatment options is hugely time consuming and inefficient.6 The MAMS platform design overcomes many of these issues and is especially effective at maximising the number of people receiving active interventions, while prioritising recruitment, funding and clinical resources to the most promising arms.

What is EU-PEARL?

EU-PEARL is a strategic alliance between the public and private sectors to transform the way clinical trials are conducted. Funded by the EU’s Innovative Medicines Initiative, EU-PEARL is a project, running from 2019 to 2023, to develop a reliable framework to facilitate the running of multi-company platform trials in any disease area. Lucinda Cash-Gibson explained that the goal of establishing these sustainable and reusable integrated research platforms (IRPs) is to encourage and support collaborative drug development and expedite the testing of therapeutics. “Platform trials can take a lot of time and money to set up and run and we would like to make this process more streamlined and efficient,” stated Gibson. “This project adds value for all stakeholders, not just pharma, because patient engagement is a key aspect. In fact, as part of our work, a patient engagement platform or repository will be developed… we are also moving towards more collaborative approaches in research, so integrating different perspectives and really co-creating knowledge is what we are trying to do.”

Fundamentally, we are working to completely change the paradigm of critical research”

Francesco Patalano added: “The goal of this project is to promote the use of these studies for the testing of multiple active agents in parallel within a single study, rather than in different protocols, and putting in place not only the study itself, but also a network of investigators and a way to treat the data. A collaboration of multiple companies or institutions, testing their actives in the same study increases the efficiency and probability of success. Fundamentally, we are working to completely change the paradigm of critical research and move away from the system where everybody is independently testing their own compounds. While I am not saying that this is applicable to every drug and every indication, I see these collaborative platforms becoming a lot more widespread than they are today.”

Why is industry working to apply platform trials more broadly, outside of pandemics?

Patalano explained that in a non-pandemic setting the same benefits of speed and efficiency are also beneficial, particularly for rare diseases where there may be a limited population of patients to recruit from. “By testing multiple agents in the same model, in parallel, you can get to a faster answer as to whether something is working in a certain condition. These designs are more efficient and ultimately more beneficial for the patient,” stated Patalano, continuing that the process of running traditional randomised controlled trials is not difficult, just time consuming, since a new protocol must be designed and run each time.

In Modern Laboratory Senior Female Scientist Has Discussion with Younger Male Laboratory Assistant

“If we consider the number of compounds that are being tested in early-stage clinical trials and fail, each of these needs a new study to be set up, protocols to be written, patients to be recruited and, when the study closes, results to be analysed and so on. However, platform studies basically run almost on a continuous basis, where new interventions can be included at almost any time. Not only is this very advantageous in terms of getting a quicker answer about whether something works or not, but shifting to this approach may also change the overall paradigm of clinical research,” expounded Patalano.

How is EU-PEARL facilitating the adoption of platform trials?

EU-PEARL is initially focusing on developing a patient-centric, collaborative IRP framework that is disease-agnostic as well as ones in four key disease areas. Cash-Gibson and Patalano explained that these indications – major depressive disorder (MDD), tuberculosis (TB), non-alcoholic steatohepatitis (NASH) and neurofibromatosis (NF) – were selected because they represent four very different medical problems. Thus, by setting up trials in these diseases, it would give “almost the full spectrum of disease that you could actually address by implementing an integrated collaborative platform study”. Treatment-resistant TB was selected as the infectious disease because it is an emerging problem; treatment-resistant MDD was chosen to represent the neuropsychiatric sector; NASH as an example of a chronic long-term disease with no effective treatments; and NF as a rare genetic disorder with a limited pool of patients to recruit from.

Patalano added: “If we can explore the boundaries of what can be done with a collaborative platform studying these four conditions, we can begin to cover more diseases from there. We are trying to get these trial designs utilised away from the emergency-use situation of a global health crisis or pandemic and into more routine application.”

EU-PEARL’s work is based on five key pillars:

  1. Making the IRP design patient centric by using patients as key collaboration partners
  2. Establishing clinical networks of hospitals to run the trials, led by centres associated with the European University Hospital Alliance (EUHA)
  3. Developing the operational framework – a comprehensive set of tools and methods for the planning, implementation and analysis of platform trials
  4. Building a data governance system that integrates data sources to promote transparency, engagement and utilisation
  5. Addressing regulatory issues and working in a way that complies with European and national data protection and ethical regulations & legislation, to one day obtain regulatory endorsement for IRPs.

Final thoughts

Overall, the EU-PEARL project seems to exemplify the desire of the clinical research sector to adapt, evolve and grow to suit the needs of drug development. While platform trials may not be applicable in all indications, and traditional randomised controlled trials remain the gold standard, the benefits afforded by platform trials – and for rare disease indications in particular – make them an attractive option for future use in both pandemic and routine settings. Additionally, concluded Patalano, the collaborative multi-company approach, in the presence of a well-established framework, will increase the probability of an early detection of an effective approach to combatting challenging medical conditions.


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