Embrace disruption: the changing landscape of clinical research
Georg Pirmin Meyer, Senior Vice President, International, at Blueprint Medicines, explores how precision medicine and personalised treatments can improve healthcare in Europe, and around the globe
Delivering on the promise of precision medicine in ‘one-size fits all’ health systems
Every day, new technologies are unlocking deeper insights into the molecular and cellular alterations underlying numerous diseases, and transforming our ability to diagnose and treat them. When these insights are paired with precision medicine, we can also pave the way for more precise, predictable, and powerful treatment approaches that underpin truly patientcentric care.
Researchers are now much more hopeful to treat diseases that have previously seemed untreatable, due to the lack of understanding around the underlying causes. Even some patients with certain common cancers, such as lung or breast, don’t respond to standard-of-care treatments in the same manner as other patients. Researchers and clinicians have made significant strides in the last decade to understand why changes at the genetic level may trigger an illness, and how better understanding these changes may lead to treatment options that hadn’t been there in the past. Recent progress from tools, such as genomics or big data, makes a direct contribution to care for patients living with cancer, or with rare diseases such as advanced systemic mastocytosis (advSM), which can become cancerous, or spinal muscular atrophy (SMA).
Within lung cancer, the introduction of precision therapies for patients with mutations such as Kirsten Rat Sarcoma virus (KRAS), Epidermal Growth Factor Receptor (EGFR), and Rearranged during Transfection (RET), have led to better clinical activity, supporting increased adoption of precision medicines. Historically, these patients may not have responded to standard treatments, and would have seen their disease progress with no further options. As more of these tools and technologies become available and enter into routine practice, researchers and physicians will be able to deliver the right health intervention, at the right time, and across more disease states.
Re-imagining treatment pathways
Realising the full value of these advancements requires a paradigm shift in the way medicine has been practiced for decades. Physicians have been taught that treatment approaches should be universally applied to every presenting patient. Until recently, a one-size-fits-all approach – aimed at the “average” patient, possibly with only minor, little understood variations – was the only option.
Precision medicine effectively turns this approach on its head. It recognises that complex diseases should no longer be considered as a single entity. One disease may have many different forms, or ‘subtypes’, resulting from the complex interaction of our biological make-up, and the diverse pathological and physiological processes in our bodies. This means that two patients who have the same clinical diagnosis, such as breast cancer, may really have two very different diseases, based on their genetic make-up and any mutations they have. This may impact not only the underlying disease, but also how the disease travels through their body. This also demonstrates why biomarker testing at diagnosis is essential to ensure each and every patient understands what is driving their disease, and has the potential to receive the best possible care right from the beginning of their treatment journey.
As we integrate and analyse genomics and other data, we can find common factors and causes of variation. This means we are constantly discovering new pathways and presentation of disease, and with those discoveries, changing how diseases are thought of and treated. It enables us to recognise that the same underlying change in our DNA or genome can lead to problems in very different parts of the body, which would not have been previously identified with a more traditional care approach.
An example of this is AdvSM, which, in 95% of cases, is driven by a D816V mutation to the KIT gene. The mutation leads to uncontrolled mast cell production across multiple organ systems, and is associated with poor overall survival. Symptoms are varied across the body and may include skin lesions, chronic anaphylaxis, hypotension, migraine, and bone and muscle pain. Individually, these symptoms would be treated by different physician specialties, and the connection may not be made to the underlying cause, which impacts time to diagnosis for the patient.
The emerging precision medicine ecosystem
While precision medicine represents incredible potential for physicians and their patients, we must also recognise the co-ordination needed to operate in a myriad stakeholder ecosystem. Joining the dots between patients, clinicians, laboratories, clinical information systems, and government or other industry research sponsors, is an incredibly complex and delicate balance of information systems, personal data, and best supportive care. As we continue to grow in our ability to execute on precision medicine, we will need further collaboration among the developers and regulators of precision medicine, professional societies who will train the next generation of researchers, providers, and the regional and national health technology bodies who provide recommendations on medicines, and the other health technologies that can be financed or reimbursed by the healthcare system.
Translating the science into value
As healthcare systems aim to reset and accommodate precision medicine into daily practice, they have also needed to rethink access and reimbursement processes. Innovation uptake rarely coincides at pace, and bringing precision medicines into clinical practice in Europe has been gradual, given barriers to adoption among Health Technology Assessment systems in many European countries.
What might not be immediately recognisable is the value precision medicines can bring to the overall health system. When the right treatment is identified and deployed at the earliest possible stage of disease, it will naturally decrease the use of ineffective or inappropriate treatments, reduce hospitalisations and other costs associated with chronic conditions, and more efficiently deploy the use of healthcare resources. However, there are also a number of environmental and organisational challenges that currently prevent the effective uptake of personalised medicines, and potentially hinder their development.
Collaboration by a range of stakeholders including leading payers, policymakers, and healthcare professionals, is needed to drive patient access and reimbursement for new therapies, as well as to maximise their positive impact on health systems in Europe.
Embracing the disruption
Advances in our understanding of the genome and disease pathogenesis, combined with collaboration of families and carers of patients living with cancer, are changing the landscape for clinical research and drug development. However, to fully realise the disruptive potential of precision medicine will require a multipronged scientific, clinical, and policy agenda.
The speed at which breakthroughs in precision therapies translate into advances in European healthcare, and improve patient outcomes for debilitating diseases, will ultimately depend on how stakeholders collaborate to tackle some uniquely European challenges. Only a continuously evolving and connected healthcare system will be able to accelerate the advancement of precision medicine technologies.
Georg P Meyer, MD, SVP & General Manager International at Blueprint Medicines, brings nearly 20 years of industry and clinical experience in a broad variety of diseases from inline and launch products (cardiovascular, bone, cystic fibrosis), to rare diseases in early pipeline and peri-launch settings (inflammation, oncology). From 2018 to 2019, he served as Blueprint Medicines’ Vice-President & General Manager, taking strategic and tactical ownership of the region, including access strategies to prepare Blueprint Medicines’ long-term success in DACH region, with accountability for six indication launches and two launch products.
Prior to joining Blueprint Medicines, Georg served as General Manager Germany, Vertex Pharmaceuticals 2018 to 2019, with a business focus on cystic fibrosis stakeholders, including payer HTA and price negotiations. Georg was also tasked to drive strategic innovation for Vertex International, with a focus on digital and multi-channel customer engagements, as well as driving value-based healthcare projects.
Prior to that, he held roles of increasing responsibility related to clinical development in bone, inflammation, cardiovascular, oncology, diabetes and urology within Amgen, Sanofi-Aventis and Sanofi- Synthélabo. Georg holds an MD from Albert- Ludwigs-Universität Freiburg.
ONCOLOGY
A targeted approach to developing targeted blood cancer therapies
Edmond Chan, Senior Director, Therapeutic Area Lead, Haemato-Oncology for Europe, Middle East & Africa (EMEA) at Janssen, explores how precision medicine and targeted solutions can be utilised in the fight against cancer
Over the last decade, it has become increasingly clear just how heterogenous cancer is. Different cancers – whether they be multiple myeloma, chronic lymphocytic leukaemia, or beyond – have different unmet medical and patient needs, not just from each other, but also within their cancer type.
This has reinforced the critical need for a tailored, targeted approach to treatment and management, which have the potential to deliver individualised approaches to care – or, in other words, to target the right patient with the right treatment at the right time. These therapies hold the potential to change the standard of care trajectory.
On the other hand, the targeted nature of these new therapies brings with it an increase in the possible avenues for research and development, as we explore the many different genetic factors that could influence treatment. In the last five to ten years, we have already witnessed a significant growth in cancer research, particularly in the field of haematology. Ultimately, though, every organisation working within our industry has limits to its time and resources. We cannot simultaneously innovate in every treatment route for every cancer type.
There is, therefore, a need for us to take a focused approach to innovating in targeted treatments, directing our efforts to those areas where the challenges are and that we know best, to give us the greatest chance of success. By focusing on areas that harness our expertise and experience, we can deliver meaningful improvements to the lives of those living with cancer.
The power of precision medicine
Precision medicine has been one of the areas that is becoming more and more prominent in our work in haematology. By taking into consideration cytogenetics, disease type, health status, and disease characteristics, it equips clinicians with bespoke treatment options and combinations that are tailored to the individual, allowing for a highly targeted approach.
This is already beginning to deliver successful treatments for those living with blood cancers, but the power of precision medicine is by no means exhausted. There remains significant potential to push the boundaries of current innovation, and we are seeing exciting new technologies in the field emerge all the time.
Of course, by providing a more nuanced approach, precision medicine is accordingly more complex to develop and deliver compared with traditional approaches, as it can involve many stages and stakeholders. Despite this added complexity, my view is that the potential advantages of precision medicine are worth it – and that we can give ourselves the best chance of success by taking a precise focus on developing treatments in certain disease areas where we already possess years of experience, and then apply the learnings in other disease areas in the future.
So where is precision medicine making a meaningful impact for people living with cancer? Chimeric antigen receptor T (CAR-T) cell therapy is one example – a therapy option that holds significant potential for people living with multiple myeloma who have few available treatment options, and are often faced with poor outcomes.1
Despite the advances that have been made in care, relapse is still considered inevitable for those diagnosed with multiple myeloma, and, almost 40% of patients do not reach five-year survival.2Working by harnessing the power of a person’s own immune system to target cancer cells expressing a specific antigen treatment, CAR T cell therapy is a novel and highly personalised treatment. 1 Unsurprisingly, it is a complex process, requiring close collaboration between stakeholders across the industry to deliver it in the most effective way possible. But the need to harness this kind of innovation is clear – so we must keep advancing to provide patients with this additional treatment option, as well as other ‘off-the-shelf’ targeted therapy alternatives such as bispecifics.3
Delivering targeted solutions for patients
We recognise the importance of giving patients an active role and voice in the research and development process, and precision medicine is no different.
Receiving a cancer diagnosis can be overwhelming and frightening, often leaving patients with limited time – time that is impacted by the physical and emotional burden of living with cancer. Moving away from a one-size-fits-all treatment model offers an opportunity to start to try and alleviate this burden.
As well as having the potential to deliver better outcomes for extending life, such targeted therapies may also give people living with cancer time to do the things they enjoy doing. For instance, providing treatments that can be administered more rapidly and increasing the availability of oral treatments or subcutaneous injections versus intravenous formulations, means more flexibility for patients, less time spent in the hospital, and more time to spend doing the things that matter to them.
Realising the potential of targeted therapies to transform quality of life requires putting the patient voice and experience at the heart of treatment development. This can be achieved by working closely with patient organisations at each stage of the clinical trials process, including patient perspectives in health technology assessment decision-making, or providing the forums for people living with cancer to discuss their experiences of the diseases and treatments more broadly.
Change through collaboration
As treatments become more targeted, and lead to a corresponding growth of options based on different mechanisms of action, therapeutic indications, and influencing factors, the amount of information being provided to clinicians grows ever larger as well. The knowledge and expertise required of them, and of researchers working in the field, can also become increasingly specialised. To maximise the benefit to patients of such a targeted approach, we must work in collaboration with these experts from across the world – working towards our common goal of having new, efficacious treatments for cancers with high unmet need.
In other words, precision medicine can only have the impact that we hope it can have if we’re collectively able to translate scientific discovery into clinical practice. Thankfully, we are already seeing examples of this. For instance, the machine learning ledger orchestration for drug discovery (MELLODDY) project brings together academic and industry partners, to collaborate on an machine learning tool that pools insights from data generated during drug discovery programmes across the world.4
This is particularly important for rare diseases, where individual clinical trials have a fixed number of patients involved, and often limited access to a larger patient pool. Projects that use increasingly sophisticated technologies to collate data more broadly, allowing healthcare professionals and researchers to identify trends within a greater population size that can have a direct impact on day-to-day clinical practice, are therefore incredibly useful. Other similar examples of this are the Haematology Outcomes Network in Europe (HONEUR), which is a secure, collaborative platform allowing the combined analysis of datasets in haematological malignancies, and the European Health Data and Evidence Network (EHDEN), another data-sharing system powered by data from more than 100 million records.5,6
Progress is already being made, but there is of course more we can do. Change can only come through collaboration and, with research and development only growing more ambitious and complex, working with the wider oncology and haematology community and utilising exciting new technologies, such as AI and ML, are critical for success.
Targeting better treatments for the future
Precision therapies have potential as a future mainstay of treatment for haematology. As we move away from a one-size-fits-all approach, there is such scope to continue improving cancer therapies – and it is only by taking a targeted approach to developing these therapies, and working with experts across the region, that we can give ourselves the best chance of success. As the pace of advancement in precision medicine continues to accelerate, we will continue in our focused approach, targeting the areas in haematology that we have strong heritage in, and facilitating partnerships with the scientific community and wider oncology industry. The European Haematology Association Congress in June will provide another milestone on this journey, and will also give us further insight into what precision medicine holds in the future.
The last ten years have seen us make incredible progress in understanding cancer heterogeneity. The next ten years offer an opportunity to turn this better understanding into better outcomes for patients – but only if we target this opportunity in the most effective way possible.
References
Teoh PJ, Chng WJ, CAR T-cell therapy in multiple myeloma: more room for improvement. Blood Cancer Journal 11, 2021
De Angelis R et al, Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000-2007: results of EUROCARE-5 population-based study. Eur J Cancer 51: pp2254-68, 2015
Zhou X et al, Bispecific antibodies: a new era of treatment for multiple myeloma. J Clin Med 9: pp2166, 2020
Edmond Chanjoined Janssen in 2012 and has led multiple different functions in the organisation, including R&D, local, regional and global Medical Affairs. He currently heads the EMEA Medical Affairs Haematology team, focusing on haematological cancers such as multiple myeloma and chronic lymphocytic leukaemia, and driving patientcentered solutions and treatment in areas of unmet medical need. He is an experienced, UKtrained pharmaceutical physician, specialising in renal medicine, and holds a doctorate in clinical research in solid organ transplantation.
ONCOLOGY
Supporting the challenges of innovative systemic treatments
Dr Stuart Hill, Medical Director, Merck UK & Ireland, highlights how the benefits of immunotherapy can be maximised to meet the needs of each and ever y patient
In recent years, we have seen significant innovation in the way that we treat cancer, as newer treatments such as immunotherapies, including CAR-T therapy and targeted therapies, have all brought with them a new set of challenges. These range from equity of access (stemming from practical issues around resources in hospitals hindering treatment delivery), to how best to manage complex immunorelated side-effects, and to the ongoing issues around biomarker testing. Many cancers have recently had new systemic treatments approved for use by the MHRA and recommended by NICE on the NHS, and brought to light these challenges faced by clinicians across the treatment pathway and throughout the healthcare system.
Service design adaptation is needed
As a result of the increasing number of patients being initiated on immunotherapies, for example, there is an increasing impact on overall clinic capacity. There aren’t suddenly more chemotherapy chairs and spaces that can be used to support these new treatments. Service provision and capacity needs to be addressed to accommodate the growing patient numbers. As more cancers are being treated with immunotherapy options, the number of patients treated with them will continue to grow. There is significant variance across the country on how service design is set up to support the provision of newer therapies – with some regions/models of care faring better than others.
There are also many ways immunotherapies are used, for example, as a single agent or as part of a combination treatment. This can also create challenges with the service capacity and timing of treatment. Patient experience also needs to be considered in terms of distance travelled to receive treatment, as well as the overall amount of time that they receive treatment.
While this will not change overnight, these issues need to be addressed and reviewed to ensure the potential benefits of immunotherapies can be fully unlocked. Although the pharma industry can’t necessarily offer support to improve service design, we have collaboratively worked with clinicians to bring to light the key challenges and needs, and will continue to do so. We’ve also raised awareness and understanding among key decision makers who can use the clinicians’ personal experiences to create solutions.
Biomarker testing is on the increase
In addition to service design and provision, we have seen an increased use of biomarker testing, which brings additional challenges across the UK in terms of speed of testing, lack of consistency in testing across the UK, and how testing is funded and positioned in the treatment pathway. These factors can impact how patients get the right treatment at the right time for their type of cancer. These challenges are not unique to any one tumour type, but are consistent across the board for immunotherapies, as well as the newer targeted therapies. Pharma has an important role to play in fully understanding the significance of testing, and in educating clinicians to ensure the best clinical outcomes.
Learning from clinical experience
We now have 10 years of follow-up data from the melanoma trials where immunotherapy was first used, and there is a clear long-term benefit of these treatments, including an increase in overall survival. All the lessons that we have learnt can be directly transferable to Genitourinary (GU) cancers, such as how to manage the side-effects, and how to best manage the treatment pathway and decision-making by the multi-disciplinary team. Whilst we’ve got to wait and see the long-term outcomes in other cancers, we shouldn’t assume that because it’s happened in one cancer type that it’s going to happen elsewhere. However, the data as it stands does potentially indicate a similar trend. Whilst we wait for long-term data, pharma has an important role in collating real-world evidence to support the use of immunotherapies, and to continue to inform clinicians on the benefits of these treatments, along with how to interpret the data that is continuing to emerge.
Support required for all in managing side effects
Managing the side-effects of immunotherapy is one of the biggest clinical challenges. Successful management is critical to both patient outcomes and the patient experience. Managing side-effects appropriately can only be done if there is an understanding across the wider clinical team of who may encounter a patient during treatment, such as A&E and acute care. There are many healthcare professionals (HCPs) who need educating on understanding the toxicities associated with immunotherapies, and appreciating that they are very different from chemotherapy, where they may have more knowledge and experience. There is an opportunity for larger teaching hospitals who have more experience, to help support smaller regional/district hospitals in helping manage side-effects appropriately. This specialist knowledge is something that is only acquired through experience, and it’s important to recognise that with any newer therapy, education is key to ensuring the best patient care.
How pharma can help
At Merck, we are committed to providing good quality information for HCPs. With innovation comes some form of challenge, and there is a need to ensure that information is provided to ensure the best possible clinical and patient outcome.
It is our duty as an industry to help support and provide guidance to HCPs, who are part of a treatment pathway on how to manage care with these new systemic treatments, and how to best deal with the complex needs of patients.
There is a focus on sharing best practice to support some of the themes already mentioned around service design to deliver the best care to their patients. With there being such variance across the country in the way that things are done, anything that we as an industry can do to help bring equity of delivery in the care pathway is important. At Merck, we have several initiatives working closely with HCPs to capture key learnings and best practice. These are developed into resources and content that are shared across different audiences, to help drive discussion and address some of the areas where improvements to patient outcomes can be made.
With any new treatment innovation, pharma is instrumental in ensuring that the right studies and research are conducted that inform important clinical decisions – proving that outcomes will last in the real world, as we’ve seen in clinical studies. It’s also important that we set up trial designs that are innovative and forward-thinking – looking at how to best maximise the benefit of immunotherapy, using them as single and combination agents across different tumour types.
We must also ensure speed of access so that patients get the treatments as quickly as possible. We have a responsibility, to those patients who may potentially benefit to work closely with regulators and funding bodies, to minimise the time in those processes to speed up access.
NICE’s Innovative Licensing and Access Pathway process, launched last year, is a step in the right direction. The initiative allows companies to work with NICE and the MHRA much earlier in the development process, receiving advice and input on clinical trial design, to ensure optimal data generation for both regulatory approval and health technology appraisal. This process should lead to quicker market access for companies, and faster access to innovative medicines for patients.
With companies and key stakeholders in healthcare systems coming together to align quicker in decision-making and benefitrisk, clinical outcomes for patients should ultimately be improved.
Looking to the future
Given the body of evidence that is still emerging in long-term use of immunotherapies, closely evaluating the data to make sure we are personalising treatment, and understanding the drivers of treatment efficacy, is critical. Irrespective of what the systemic treatment is, the only way we are going to be able to do the best for patients in the future is by identifying the right oncogenic drivers that are causing the cancer to grow and develop, so that we can target the right intervention to stop it.
Dr Stuart Hillis Medical Director, Merck UK & Ireland. In 2010, Stuart joined Merck and has worked for the last 10 years in the Oncology Business, which he has led as Business Unit Director for the last 3.5 years. The heavy focus on translating science into improved outcomes for patients has inspired Stuart to now take up the leadership of the Medical Affairs team for Merck’s UK & Ireland operation.