There is arguably no disease area more dynamic than oncology. Over the past few years, scientific advancements have fundamentally changed (and continue to change) how doctors view and treat cancer. It wasn’t too long ago, for example, that immuno-oncology drugs seemed to dominate pharma news – but now much of the attention has moved towards the potential of T-cell therapies.
These rapid developments affect researchers as well as patients – and CROs like ICON have had to find innovative ways to remain adaptive and design trials that can push the boundaries of what is possible in cancer treatment.
For Andreas Dreps, ICON’s senior vice president, oncology drug development, many of the most exciting developments in oncology are in the area of cell and gene therapy.
“The results we’ve seen in cell therapy over the past few years have been quite stellar,” adds Martin Lachs, vice president, global project management at ICON, “particularly in liquid tumours such as lymphomas and leukaemias. Now we’re expanding into a broader range of tumour targets. The growth in the area is substantial, and when you’re looking at response rates of 60-70% – perhaps even 100% in some products – it’s hugely exciting.”
Nevertheless, cell and gene therapies present their own unique R&D challenges that CROs like ICON have had to adapt to.
“The logistics behind cell therapy are highly intense,” says Lachs. “Supply chains are no longer traditional – you have to take into account vein to vein chain of custody and cold chain shipment – and that means working with specialist groups who can facilitate all of those factors. The number of stakeholders involved in executing some of these complex trials has increased phenomenally.
“That means we’ve had to build in-house expertise to support that, both in clinical supplies but also in terms of feet on the ground in supporting sites.”
Dreps highlights biomarkers and precision medicine as others areas of oncology that are continuing to show amazing promise.
“With a biomarker you can identify the optimal target patient population very early on. Whereas 20 years ago chemotherapy agents were targeting many non-cancer cells with a lot of toxicities, we can now identify the subset of patients who express the targeted molecule and deliver a compound directly to the target.
“Biomarker testing for trials is becoming much easier and more widely used. That said, one of the challenges is that it makes clinical trials much more complex – meaning we might need innovative and novel trial designs like basket trials with multiple arms. As a sponsor, you have to look more into the molecular profiling of every patient and make sure that you have all the data available to select the right population.”
As cancer treatment evolves in surprising and dramatic ways so must cancer research – and innovative, adaptive trial designs like these have become more popular in recent years as drug developers realise their potential.
“The changing nature of approaches to oncology means that we are more often looking at a molecular target rather than a specific cancer – e.g. you’re looking for any BRAF mutation or ALK mutation, which cut across the numerous tissue types,” says Lachs. “This is where adaptive trials are particularly useful.”
Adaptive trial designs include:
“We’re involved in all kinds of adaptive trials, because they are all different and they all have their place,” Lachs says.
“That said, while these innovative trials are very exciting, we also have to proceed with some degree of caution so as to balance complexity and timelines with anticipated trial outcomes. We have conducted basket trials that have progressed over years and yielded little.”
Dreps adds that adaptive methodologies allow a much more flexible approach than traditional designs.
“A sample size re-estimation tool, for example, is a very flexible adaptive design that allows the sample size of the study to be reassessed mid-way through.
“One of the risks with oncology trials is treating too many patients with an ineffective new drug. If there are signals that the drug is very effective, you might not need to enrol more patients to demonstrate that you can add significant clinical benefit.
Of course, CROs also have to adapt their businesses to the increased complexities these trial designs bring.
“This involves both building expertise and creating new systems to be more flexible in coping with changes which are required for these protocols – for example taking into account that in basket studies cohorts will drop in and out as the trial progresses,” says Lachs.
“We’ve had to set up our data systems flexibly to facilitate rapid change, but we’ve also had to become much more adept at obtaining data rapidly to facilitate making decisions based on that data, so that we can progress with new arms of the study.”
Dreps adds that it’s important the company employs people with knowledge and expertise in the adaptive trial designs.
“We will likely start seeing biostatistics experts helping us in creating new trial designs more often – which allows us to expedite the entire process and do analysis to decide whether or not to proceed very early on.”
In general, earlier engagement with all stakeholders is becoming increasingly important in order to increase productivity and success.
“More and more we are trying to identify early on the potential candidates for a trial from a pool of pre-screened patients,” Dreps says. “This might require much closer collaboration with investigator networks – as well as the use of data from a patient population that has already received one line of pre-treatment, where the molecular profile is already available.”
Part of this, Lachs adds, is ensuring that ICON is always working in partnership with database platforms, so that the company can build in flexibility.
“Data is going to be an evolving picture,” he says. “We continue to adapt our data collection and our endpoint protection processes to keep pace with the increasing complexity. We’re well set up to do that because of our in-house expertise, and we have an extensive staff training programme for oncology, which we’re constantly reviewing and revising.”
Many would argue that the biggest catalyst for change in cancer research has been the COVID-19 pandemic, which has forced a shift towards remote monitoring, virtual arms and other uses of digital tools as global lockdowns reduce the ability of patients to go to clinics.
Lachs, however, says it’s still too early to tell whether these changes will be permanent.
“I think everybody will have a slightly different take on it,” he says. “COVID has certainly brought to the fore discussions on how you operationalise trials. I don’t think it is at this point having any impact on trial design or endpoint selection, but there’s very healthy discussion going on about running trials differently, right from the patient experience through to how we manage data.
“Thinking about patient centricity, for example, some patients may be fearful to go into hospitals as a result of the COVID-19 situation, and those that do are finding the number of appointments available are reduced to ensure social distancing. You can see that there’s a benefit to the patient if they have to go into the clinic less – perhaps once every two months instead of once every four weeks. We just need to make sure we’re not compromising safety.
“All that is on the table and is being feverishly discussed. The actual application of it might be a bit slower.”
Lachs believes that the permanence of these changes will be contingent on a number of things.
He says, though, that there will always be a mixed model in oncology.
“The complex requirements of oncology studies – radiology, scans, imaging etc. – can’t be done in an individual’s living room. Neither can earlier phase studies that require hospitalisation for PK sampling.
“Hospitals also have to be amenable to having other bodies being part of the assessments and conduct of clinical trials, both from an economic and logistics point of view.
“Realistically, we have to know that the crisis is not going to completely turn over oncology studies to become completely different from how they are now. It’s going to be an adjunct as much as anything else.”
Nevertheless, Lachs says ICON has made sure to be geared up for increasing virtualisation in trials.
“For example, last year we acquired Symphony Clinical Research, a provider of in-home and alternate site services. We also work with a number of telemedicine platforms, and we have people within our group devoted to the virtualisation of trials.”
The other key factor in being prepared for these changes is making sure regulators are aligned with drug developers and will be open to more innovative trial designs.
“We keep in regular contact with the regulatory bodies to bring ourselves up to speed with regards to their thinking,” says Dreps. “It also gives us the opportunity to discuss our ideas on how to develop new trial designs.”
Dreps and Lachs note, however, that not all regulators are aligned on how to approach adaptive designs – in their experience, for example, the FDA has been more open than the EMA to innovative ways of approaching research.
“We’ve also got to consider Japan’s PMDA and the Chinese NMPA, because they’re also substantial markets, and they’re not all aligned,” says Lachs.
“COVID-19 has in some ways been surprising in marking out what different agencies are permissive of in terms of how we go about conducting clinical trials. For example, the EMA has been more restrictive about remote monitoring or remote access to data than the FDA have – partly due to data protection and GDPR considerations.
“Overall survival has always been the backbone to approvals in oncology, and we anticipate that it will be that way for some time to come. But it’s changing to some degree and I think the FDA is currently more progressive in that regard.”
Dreps notes that, above all else, the most critical driver of change is our increasing understanding of the molecular biology of cancer.
“More or less every week we identify a new target, we learn more about pathways, about how to interact with these pathways and potentially how to stop cancer growth. This means the molecular profiling of patients will play a more and more important role.
“Most likely, this will also result in a situation where a new drug is only targeting a very small subset of patients. In contrast to 10 years ago where you normally had to design a trial with thousands of patients, today you often only need a few hundred participants.
“Molecular profiling might eventually allow us to identify those patients who will benefit from a new treatment very early on, such that you need only a very small group to demonstrate significant clinical benefit.”
“The elucidation of our immune system and immunology in general is growing exponentially,” adds Lachs. “Cell therapy is built on the idea of stem cell therapy; the idea of using the body’s own immune systems and immune cells isn’t that new, but the amount of information we’re learning as we do more trials is causing an exponential growth in understanding. That’s going to continue to gain pace.
Advances in technology are likely to have a similar impact.
“Our ability to use quantum computing to process huge amounts of data rapidly may actually facilitate more synthetic trials so that we can be even better at prediction, especially in combinational trials, where we can see what the best combinations might be,” says Lachs. “That means you can have a more focused approach to the real clinical trials, and it also cuts development time, cuts costs and improves outcomes.
“That’s an area ICON has been looking into for a few years – for example we were involved in the Cancer Moonshot Program headed by Joe Biden – but that concept still needs to be developed further.
“Let me be clear – you’re not going to get approval on the basis of some computer modelling. Rather, it’s about pointing us in the right direction. I think that’s yet to really take hold but I do see it as a real development, and our interest is in no way diminished. We need to have the best technology available for that but we also need to have an appropriate way of getting data, and data is expanding on a daily basis.”
Likewise, predictive analytics and artificial intelligence will help researchers analyse the huge amount of data becoming available.
Lachs again stresses the importance of early engagement with clients to all aspects of drug development.
“The earlier you engage with developers and help them design studies and take into account all the points we’ve discussed, the better. The divide between designing, conceptualising, and operationalising trials is going to blur – and we still need to keep endpoints and even pricing considerations in mind. Our continued investment in technology which supports that is going to be important.
“Meanwhile, with the increasing complexity of molecular targets and data, the relationship between CROs, pharmas and investigator sites needs to become less transactional. We need to be more embedded with what our principal investigators are doing and be a part of that operation.
“All those things need to be brought together and we have that capability and capacity within ICON.”
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Martin Lachs is vice president, global project management at ICON. With over 28 years’ experience in clinical development, Lachs has worked across a number of therapeutic areas whilst specialising in oncology. He is based in the UK and heads up ICON’s Oncology and Cell Therapeutics Project Management Group, lending operational and indication expertise across a group of over 260 international project management staff globally, dedicated to oncology and cell therapy drug development. Lachs has worked in developing key oncology site networks in the US and the UK and in 2020 was a member of a clinical trial review panel for University of Sydney affiliated hospitals.
Andreas Dreps is senior vice president, oncology drug development at ICON. Dr Dreps has over 25 years of clinical research and development experience in a variety of solid tumours and haematology diseases including breast, NSCLC, SCLC, pancreatic, gastric, ovarian, colorectal, head & neck and prostate cancers. He is co-author of the EMA submission dossier of Paclitaxel for ovarian cancer and the FDA/EMA Taxotere submission dossier for breast cancer and NSCLC. Prior to joining ICON, Andreas held positions at BMS, Aventis Medical, Merck/Serono and was responsible for the clinical development of Taxol, Taxotere, Campto and Gliadel, among others.
ICON plc is a global provider of outsourced development and commercialisation services to pharmaceutical, biotechnology, medical device, government and public health organisations. ICON supports programs across all stages of drug and device development, from endpoint selection and PRO development, through clinical trials, to post-approval and scientific publication. ICON delivers integrated market access, pricing, communications and health economics solutions to demonstrate product value and support brand success around the globe. For more information visit: www.ICONplc.com/access