In part two of our conversation with Aurora Research Institute Early Phase Cancer Research Program medical director Dr Michael Thompson, he talks about lessons learned from the Covid-19 pandemic in making cancer clinical trials run effectively, and the skillset among investigators in running clinical trials. He also talks about potential reasons why cancer patients don’t sign on to clinical trials, and access to biomarker testing.
Previously, Dr Thompson discussed trial designs that aim to dismantle bureaucracy in initiating early-phase clinical trials, and how to design blood cancer trials that may ease pressure on recruitment.
Reynald Castañeda: Has the Covid-19 pandemic become a catalyst for making cancer clinical trials run better?
Dr Michael Thompson: At our site, Covid-19 trials opened very fast, so I think it got us to thinking: if you’re not going through layers of committees there is a way to get things going. People have started to realise that the risk in running clinical trials is much lower than the potential benefit. We found out if we need to do it, things can happen fast – and the trick is to keep doing that.
One specific unnecessary delay is that in some cases, when institutional review boards (IRB) review a protocol, the delay doesn’t really relate to the trial itself. It can be as trivial as a style thing – flipping column A to column B – which doesn’t have anything to do with protecting the patient’s interest. And in some cases, these trivial issues can lead to weeks of delay.
With regards to decentralised clinical trials, I am a part of a cohort study called CCC19 (clinical impact of Covid-19 on patients with cancer). We communicated via Twitter and it was a bit of a crowdfunding initiative that happened very fast and was published very fast. The study characterised outcomes of patients with cancer and Covid-19 and identified potential prognostic factors for mortality and severe illness. The trial is valuable because cancer patients are often excluded from Covid-19 trials.
Another element boosted by the pandemic was telemedicine. Traditionally, if you’re reviewing a research protocol with someone like a patient this usually happens face-to-face but this wasn’t necessary and can be done via telemedicine. Of course, there are still issues like limited access for some people but overall, it has been positive. Some sites may have research staff that are confined to one state, but with telemedicine their reach has been expanded as they are not limited by geography. Telemedicine also opens reimbursement channels for oncologists who usually aren’t paid for these video calls to talk about laboratory tests with patients.
RC: Once a treatment graduates to later-phase clinical trials, more sites become involved in the trial. Is this a concern because these newly involved sites may not be as familiar with the investigated treatment, risking trial failure?
MT: I work at a site level not at a sponsor level but I would disagree with that to some degree. In Phase I trials where this is the first time a drug is studied in humans, we do want a specialised team. But this may not be necessary in drugs that are already FDA-approved and are being repurposed in a different disease. These approved drugs already have clear guidance on how they should be used – and investigators in this case are mainly looking for the pharmacokinetic and pharmacodynamic performance of the drug in a different disease.
In Phase II, this is currently the predominant phase in oncology trials, with many Phase II cancer trials recruiting under 100 patients. These trials are meat and potatoes for investigators, so they are quite used to them.
As for Phase III trials, these studies investigate a new drug or a new drug combination against standard of care. I would argue you don’t need a highly specialised site for these trials as they would be used to the standard therapies. The new drug or combination being tested has also gone through the other phases, and there is data providing clear guidance on efficacy and safety and on how to use them.
RC: Even if there are limited treatment options which makes recruitment in clinical trials more appealing, are there still patients who are hesitant to sign on to trials?
MT: In general, when patients are offered to go sign on to a trial, they often participate. A potential obstacle is that the physician caring for the patient may be skeptical of the drug or the trial and so the patient is not offered to join the study. The site may not have access to the trial. Also, trials that investigate me-too drugs are also a less compelling sell to patients.
Investigators often say patients that go on clinical trials do better than the ones that don’t, because they get more oversight from more experts. While this high level of monitoring is attractive to some patients, it may be a turn-off for others. These patients can find surveys and questionnaires a bit of a burden. If they’re not too used to seeing doctors, these trials are a turn-off. On the other hand, there are patients who are used to being monitored regularly because they’ve had the disease for a while, or are a part of patient groups, so they totally get it.
Even if the patient is interested, they need to be filtered to fit into the needs of the trial. But clinical trials should not be designed to find the perfect patient. If you filter out patients based on the need of having perfect laboratory test results, there will only be a handful of those patients that would fit the bill.
RC: Regarding oncology trials that require biomarker testing in recruiting patients, how accessible are these tests?
MT: In myeloma, cytogenetics [a test that evaluates chromosomes] and FISH [fluorescence in situ hybridization] should be done by everyone, everywhere – but whether this is the case is a different story. In solid tumours, there are large panel tests that may take some weeks to get done because they are not normally used – they are best saved for diseases that don’t progress as quickly. In both blood and solid tumour trials that involve proprietary biomarkers, they may not be as easy to access, and thus could delay trial progress.
There is standard testing involved in all cancer trials but there are existing obstacles in accessing them. While a test may be standard, certain sites may not be doing it regularly or there are pathology staff shortages. These shortages are due to what’s been called ‘the great resignation’, where staff don’t come back to work. There’s also the case of too much Covid-19 related work that’s delaying non-Covid-19 tests. Testing can take more time because people are more distracted by other work.
RC: What do you make of chimeric androgen receptor (CAR) T cell therapies that require samples to be sent off-site? What are the challenges in running these trials?
MT: There are CAR T cell therapies that are already commercially available and there are ones in clinical trials. With commercially available ones, companies can’t make them fast enough so even if there are patients ideal for this approach, they can’t even access it.
So, in that case, clinical trials are very compelling because it gives you access to the treatment as opposed to being on a wait list. Also, you get it for free versus paying for an expensive treatment [public information shows CAR T cell therapies have a list price of $373,000 to $475,000].
But It’s true that even in clinical trials there is a need for synchronisation, as it involves collecting samples, then sending them offsite to be modified, and then receiving them back on site to be administered to the patient. It involves a lot of timing and coordination – and this can add to trial costs.
The interview has been edited for length and clarity.