Emerging cell and gene therapies herald immense clinical value for patients, society, and healthcare systems: carrying the potential to offer life-changing solutions for people with few or no alternative treatments. Given the limited amount of long-term evidence for these therapies due to their relatively recent development, however, bringing them to market remains fraught with challenges.


For many, the harnessing of real-world evidence (RWE) and real-world data (RWD) will be absolutely pivotal to overcoming outstanding uncertainties around these novel therapies: not only with regard to assessing long-term efficacy and safety profiles, but also in calculating comparative value for money and evaluating the optimum use of healthcare resources.

“We believe that there is an urgent need to incorporate real-world evidence and other kinds of tracking of patient data over the long haul, both to support ‘pay-for-performance’ kinds of reimbursement arrangement, as well as other regulatory needs,” explains Janet Lynch Lambert, CEO of the Alliance for Regenerative Medicine (ARM). “Doing this may well be fundamental to our ability to successfully take cell and gene technology mainstream and get it to the patients that so badly need it.”


Plugging in the Data Gaps

For a start, there a many data gaps and information asymmetries that RWE and RWD could go a long way to filling. “Since most cell therapies are indicated for rare diseases, they are usually approved based on Phase 2 studies data where there is no randomization. This means we neither have longer-term data on the patients, nor know what would happen with the patients not invited to participate in these highly selective studies,” explains Professor Nicolaus Kröger, President, European Society for Blood and Marrow Transplantation (EBMT). “RWE is going to be absolutely essential for regulators and other stakeholders to see how these therapies really work in a real life setting and context, outside of the artificial perimeters of clinical trials,” he adds.

America’s Federal Drug Administration (FDA) would appear to agree and has been granting accelerated drug approvals on the condition that further data from real life is subsequently collected and reported back. Already the agency has been busy building out a substantial database of clinical data gleaned from electronic health records (EHRs). “Gene therapy, regenerative medicine and cell therapy are all still in the phase where they need to work on safety and efficacy, which is obviously very important for us. It takes radical technologies like that time to settle down once they get into humans. There is a lot for companies still to do. It is not a slam dunk now,” affirms Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER) at the FDA.


RWE is going to be absolutely essential for regulators and other stakeholders to see how these therapies really work in a real life setting and context, outside of the artificial perimeters of clinical trials

Professor Nicolaus Kröger, EBMT


“Some geographies would automatically hand approval to certain drugs; for example, a drug for people with metastatic disease who have exhausted all other treatments, that shrinks their tumours and they remain shrunk for six months. At the FDA, however, we would probably look to give the drug an accelerated approval, because we regard that as an intermediate endpoint, not a final endpoint. We would be requiring more data on how good this drug really is afterwards,” she elaborates.

The drug developers pioneering cell and gene technology, also, tend to be very keen on leveraging RWE to support their claims for market access and reimbursement approval. “It’s unrealistic to expect the industry to do trials based on all the manifold requests that different payers or regulatory bodies have across the world. It would take us too long. It’s sometimes even unethical…However, we believe real-world evidence can help fill a data gap in a faster, more efficient and much more convenient way and, this reason, we firmly hope that regulatory bodies and payers will become more broadly accepting of RWE and RWD,” declares Novartis Oncology’s CEO Suzanne Schaffert.


Better Insight

Companies like hers have, of course, become buoyed by RWE that seems to suggest that revolutionary cell and gene therapies like CAR-T can work even better in the real world than under trial conditions as the clinical community becomes more accustomed to their workings. “In the case of Novartis CAR-T, we now have real-world evidence in addition to the randomized clinical trial data and not only has the new data collected confirmed the existing efficacy profile nicely, but it has suggested an even better safety profile, which can probably be attributed to the fact that doctors have now learnt how to handle the side effects earlier and better,” points out Stefan Hendriks, Global Head of Cell & Gene at Novartis Oncology.

Some sponsors have also been pointing to excellent RWD to make the case for therapies like CAR-T to be use as earlier line treatments, the argument being that efficacy would rise if these products were being used not just as a last resort for the extremely sick. Stakeholders such as Niklas Hedberg, Chair of the Executive Board, EUNetHTA, however, remain cautious.

“Over the past five to ten years, we are, on national and regional level, increasingly being asked to grant reimbursement for products where the data is based on Phase I studies, even though, traditionally these studies only included healthy volunteers. This is especially true of new products in oncology, orphan drugs and precision medicine.  This is of course challenging but we must not forget the basic tools with which we start every assessment. RWD must be used to create more robust evidence. It cannot be used to produce the first evidence. There must be some kind of traditional data to support the argument that a drug will be more effective or more cost-effective if used as a first line treatment,” he warns.


Towards a Common framework

Development of global RWE infrastructure and a common framework to support long-term evidence generation and procedures, however, is a prerequisite to being able to properly harness the insights generated by real-word data. “For this to work, there needs to be some consistency across, at least across the Atlantic, but if possible even more broadly, on the standards for RWE that regulators – and ultimately payers too – will find acceptable,” reflects ARM’s Janet Lynch Lambert.

Former US FDA Director, Scott Gottlieb very much agrees. “Now that the FDA is starting to make decisions on the basis of these kinds of datasets, they’re going to have to invest very heavily in building out a rigorous methodology for how you make regulatory decisions using this information… only by creating a standard methodology for using RWE for regulatory purposes  will we be able to provide a more-level playing field in the broader marketplace among payers, product developers, regulators, and clinicians who all want to use this information for decision-making,” he believes.

Already certain collaborative efforts are underway to create better and more systematic RWE in the sphere of cell and gene technologies. “We are witnessing discussions regarding the establishment of a new European Cancer Data Center, and we are strong supporters of this,” points out Professor Marius Geanta, Co-founder and President of the Centre for Innovation in Medicine, Romania. “It will be incredibly positive if clinicians, patients and authorities across Europe have the option to access such resources at the pan-European level if they are unable to access them at the national level, whether it is because the national health system lacks the necessary capabilities or capacity, for instance, to organize or handle national health registries. But in order for this to work, we have to create a pan-European model based on transparency and trust,” he notes.

Even some jurisdictions have been positioning themselves as destinations of choice for the gathering and collection of RWE. Norway is a case in point. “One of our most compelling factors is our ability to do long-term follow-ups. If you start a trial in the US, you have to recruit considerably more patients than you are actually aiming to get the data from. In Norway, you will get the data and the follow up for almost all participants. The reason for that is the strong national healthcare system with no private alternative. Even if people move around Norway, they will still be within the national healthcare system, so we do not lose patients. Our registries, including the Norwegian cancer registry, could also be useful for companies looking to extract real world data on patients,” muses Jon Amund Kyte, Head of the Department of Experimental Cancer Treatment, at Oslo University Hospital, Norway.

What is for certain is that RWE and RWD are going to play an increasingly influential role in bringing on stream state of the art medicines than don’t really fit the traditional clinical trial paradigm. “Regulators are having to get used to relating to new kinds of evidence which are structured in new ways. In recent years there has been a need to handle umbrella, basket, and single-arm trials as grounds for medical approval; meaning that the clinical trial paradigm has frankly been turned upside down,” concedes Niklas Hedberg. Commentators like Gottleib, however, are highly optimistic. “I think a very rich literature will grow out of this on how to use these data in a reliable fashion and ultimately it’s going to be to the great benefit of patients who will be receiving game-changing, breakthrough therapies with potentially curative effects faster than ever before,” he enthuses.