Sunayana Shah and Brendan Shaw
Cell and gene therapies promise great clinical value for patients, society, and healthcare systems.
They have the potential to offer life-changing solutions for those patients with few or no alternative treatments. Once almost considered science fiction in medicine, personalised medicine is increasingly becoming a reality today, with each treatment for a disease created specifically for an individual patient using their own cells or genes to fight difficult to treat diseases.
What are cell and gene therapies?
In cell therapy, cells are cultivated or modified outside the body before being injected into the patient and may originate from the patient (autologous cells) or a donor (allogeneic cells).
Gene therapy aims to treat diseases by replacing, inactivating or introducing genes into cells, either inside the body (in vivo) or outside of the body (ex vivo), while cell therapy aims to treat diseases by restoring or altering certain sets of cells or by using cells to carry a therapy through the body.
Some therapies are considered both cell and gene therapies which work by altering genes in specific types of cells and inserting them into the body. For example, in treating patients for lymphoma using CAR-T therapy, a patient’s T-cells are removed from their blood, genetically modified, and infused back into the patient. The new modified CAR-T cell then attacks and kills the patient’s cancer cells.
Access to cell and gene therapies provides many benefits to patients such as greatly improved health outcomes and improved quality of life. However, the relative novelty of these treatments and their complexity presents multiple challenges to ensure they reach patients. These therapies are an emerging field of medical technology and present some uncertainty for doctors and patients. As a result, there are several emerging regulatory issues concerning these advanced therapies.
Examples of cell and gene therapy
A big challenge for cell and gene therapies is that they often target conditions that affect a very small number of patients. For example, in the case of a genetic immune deficiency called ADA-SCID or ‘bubble boy syndrome’, for which there is an emerging therapy, there are only about 14 people per year in Europe and 12 in the US diagnosed with its target disease.
David Vetter was born into such a bubble boy syndrome world where he could not touch and as an infant, he was placed inside the protective plastic bubble that had been specially built in the 70’s. The outside world was so perilous for him because he had the rare genetic defect so dangerous that it could turn even the slightest cold into fatal consequence. Despite this separation, David’s ‘fish bowl’ life turned him into a symbol of hope and determination for the rest of the world and inspired a documentary and many movies. Research into future advanced therapies for the disease resulted in a new gene therapy.
This treatment targets the patient’s immature bone marrow cells and replaces the faulty gene with a copy that produces functional adenosine deaminase. These cells are then injected back into the patient and can develop into the cells of the immune system and blood. This avoids the problems of a donor match seen in traditional bone marrow transplants.
Earlier this year, the BBC showed a documentary film called ‘War in the Blood’ which followed two patients through their CAR-T treatment as well as the doctors trying to save their lives. It gave a powerful insight into the contribution of terminally ill patients to the world of clinical research. Benefit and risks had to be clearly explained by the doctor, balanced with professional ethics, duty of care, kindness, honesty, and acknowledging that there are risks, but the risks of not doing treatment may be higher.
Advances in personalised medicine require biomarker validation
These therapies require a biomarker to predict susceptibility to certain diseases, to diagnose the diseases, to assess the stage and the evolution of a disease and to predict the response to treatment. Biomarkers cannot be used in clinics or in medicine development if they do not meet the validation criteria.
One of the emerging regulatory issues in cell and gene therapies is that current biomarker qualification processes tend to lengthen already cumbersome procedures thus jeopardising access of patients to innovation. However, recent advances in genomics, transcriptomics, proteomics, metabolomics, cytometry and imaging in combination with bioinformatics and biostatistics have made it possible to accelerate the discovery and development of specific biomarkers for complex chronic diseases.
Effective translation of the preclinical biomarkers into the clinic will pave the way towards effective implementation of personalised therapies across complex disease areas for the benefit of patients. Key to success here is encouraging evolving regulatory frameworks for incorporation of larger and more diverse sets of data including biomarkers, patient-centred outcomes, real world data (RWD) and patient registries.
Specialist Training
Healthcare professionals play a vital role in the use of cell and gene therapies and important here is the investment in appropriate infrastructure, training and certification. The journey of both the patient and the CAR-T cell product are complex and require a multidisciplinary collaboration to provide safe and timely treatment.
The training required to use cell and gene therapies is broad and delivered across several disciplines. The training of staff and qualification of specialised treatment centres is essential. Training and certification ensure staff collect and provide the cells that are the starting materials for the final product which they subsequently administer to the patient.
Staff at these specialised centres are also supported throughout the whole manufacturing journey. Doctors are supported whilst navigating the prescribing and ordering through the IT platforms. Through doctors’ feedback, manufacturers adapt and update their processes to make the process as seamless as possible for the staff.
Training is also given to the wider team in specialist centres beyond medical, nursing and laboratory staff, such as on-call, critical care and neurology pharmacists. Pharmacists are often the first port of call when a specialist centre wishes to use a cell and gene therapy and needs to provide pragmatic guidance. The role of the pharmacist, in particular, has evolved and in working with these therapies is split into governance, clinical and operational areas. All of which require extensive training. As more cell and gene therapies become available, there will be more pharmacy departments ready to handle them. Hospitals and therapy centres will need to develop the expertise and facilities to deliver these treatments.
Real world evidence and monitoring for safety and efficacy
With technological development, cell and gene therapy is becoming a realistic and successful option for patients, albeit with the evolving benefit-risk evaluations. Following decades of research and development, better vector technology and the discovery of powerful gene editing tools such therapies can now be increasingly used to treat disease in patients much more successfully than previous treatments.
Given the limited amount of long-term evidence for these therapies due to their relatively recent development, continued collection of more data on effectiveness and their safety profile will improve our understanding as their use progresses.
In monitoring their safety and efficacy, regulatory agencies and manufacturers gather as much information as possible. Patients can play their part as well, by giving feedback based on their experience of the therapies. Such monitoring and evaluation will help address uncertainties and increase our understanding of the long-term benefit and risks of such therapy. Here, real world evidence (RWE) is pivotal to overcome remaining uncertainties in such therapies in issues such as long-term effect, safety, health-related quality of life and use of healthcare resources.
What is required to support this goal is the development of global RWE infrastructure and a common framework to support long-term evidence generation and procedures. This will enhance the quality of evidence collected specifically for cell and gene therapies going forward.
For example, one of the questions often raised by patients and their carers is whether cell and gene therapies used to treat disease today may affect future generations. Manufacturers have clarified that this is not expected to be the case because many of the pipeline gene therapies augment or supplement existing genes rather than edit germline DNA sequences.
Impact of COVID-19 pandemic on evolving cell and gene landscape
A supportive research environment from basic research through clinical trials to regulatory review is vital to ensure that scientific discoveries can be brought to market and provide new treatment options for patients.
Unfortunately, this process has been thrown into disarray by the current COVID‑19 pandemic. The pandemic has disrupted many areas of development of cell and gene therapy, including research and development, manufacture, delivery of treatments and commercial operations.
The pandemic has disrupted many clinical trials for different treatments, including those for cell and gene therapies, whilst the financing of trials has been disrupted due to the redeployment of funding to projects specifically to develop COVID-19 treatments. This has meant that plans to launch new cell and gene therapies have had to be modified or postponed due to global disruptions to clinical development, delays in the regulatory process, and an inability to commence treatment.
Cell therapy manufacturers have found themselves highly susceptible to disruptions in the pandemic, because the supply chains that support the manufacture and delivery of these products were long, complex, and highly controlled even before the current pandemic. Like many manufacturers, those developing cell and gene therapies have been affected by the collapse in global supply chains.
Manufacturers are maintaining supply in these challenging times of the pandemic by working with governments and health systems to identify solutions to overcome closed borders, reduced air traffic and delayed flights. These delays risk the viability of the material collected for these therapies as it is both time and temperature sensitive. Gene therapy manufacturers have also experienced issues in the timely delivery of therapies to clinical sites and patients, which has proved a challenge in continuing ongoing clinical research.
Administering cell and gene therapies themselves to patients has also been problematic. There have been reports from patients of cancelled or delayed hospital appointments due to the pandemic and of patients themselves not being able to visit treatment centres because of travel restrictions and bans. Moreover, these therapies generally need to be administered in intensive-care units (ICUs), however in many countries ICUs have been primarily reserved for COVID-19 patients in the current pandemic.
The pandemic has also meant that there have been difficulties in recruiting patients for clinical trials and there have been suspensions in clinical trials to minimise the risk of spreading COVID-19. This, in turn, has had a ‘domino’ effect with delays in activating new sites and the postponement of trials for these new therapies.
During the pandemic, innovative approaches to evaluate these new medical products, such as through master protocols, adaptive studies and decentralised trial designs have paved the way for a different regulatory model. Through a collaborative effort regulators, sponsors and healthcare professionals can develop and coordinate an efficient clinical trial framework tailored to the patients considering the fallout of pandemic restrictions and helping to alleviate stress on the healthcare system.
The future
Cell and gene therapies are growing their share of the biopharma industry’s development pipeline and this growth will accelerate as more products approach the market.
In the post-COVID era, patient perspectives and engagement in research and development programs can be better conveyed to regulators and developers of cell and gene therapies via digital platforms
In the future, regulatory processes for advanced therapies will need to evolve to prepare for the new era of commercial development of these therapies for patients.
Shawview Consulting co-authored and supported the development of the Cell and Gene Therapy Toolkit jointly released in September 2020 by the International Alliance of Patient Organizations and the International Federation of Pharmaceutical Manufacturers and Associations
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