by Martin Naley
What to do when your cancer won’t wait for a drug approval
My friend, Jason, is a community oncologist near Philadelphia. He has a brutal job filled with ups and downs. His patients are counting on him to find the very best treatment. He works late nights doing desktop research to find trials for his patients. Sometimes he does find a trial for an emerging therapy that could help, but doctors like Jason have learned that most of the time, those trials are just out of reach.
Oncologists are frustrated when they learn their patient can’t enroll in a trial. Denial of access to a therapy is bad enough, but the harder part is having to tell their patient they are out of therapy options. That conversation happens far too often and it needs to stop. At the current rate of trial enrollment failure, many doctors are just giving up on clinical trials as a way to help their patients.
The frustration is the same for the patients. They are online, reading everything they can and talking with the incredible community of survivors who are eager to share their own experiences and advice. Patients have learned that the emerging therapies are only available via trials, which should be considered at every step of their care. They might learn about a trial for a treatment that is right for them, and then they just can’t get that new therapy because it’s locked in a trial for which they are not eligible.
I’ve dedicated much of my life to helping cancer patients. Along the way, I have met drug developers, oncologists, entrepreneurs, technologists — all walks of life trying to do their part to help people fight this horrible disease. They are united by hope. Progress in the last decade has resulted in therapies that target broken genes or unleash a patient’s own immune system, and these therapies are nothing short of miraculous in their effect. We all want patients to be able to access these therapies. No-one wants doctors to have to tell their patients they are out of options.
It is that hope and compassion that has given the Right to Try movement so much momentum. I praise its principles — that people who are out of options need a chance, a final stand against their illness, if a therapy exists. It is imperative that we mobilize to make access to new therapies happen much more often, as quickly and broadly as possible, to ensure patients that cannot get into trials still have a chance to potentially benefit from these new therapies.
My last venture, Cure Forward, was a company that helped cancer patients access clinical trials. The company didn’t make it, but we learned a lot. Partly due to our effort, patient awareness about clinical trials has grown in this decade from 15% to 82%. People wanted to participate in trials. We had a rigorous, data-driven process, where we would qualify candidates and present them to investigators for review. Our system worked — some of those patients enrolled in trials. But what we learned at Cure Forward was how rarely that patient enrollment in a trial actually happens.
Why Clinical Trials are hard to access
We didn’t keep hard numbers on this, but it seemed like less than 10% of patients seeking a trial were able to get into one. There were three reasons patients didn’t get into cancer clinical trials. The first was that some patients just didn’t match the trial. For instance, they were missing the biomarker target of the drug. Those exclusions were perfectly understandable.
The second reason was just bad luck — the “unlucky”. Sometimes they lived too far from an available trial site, or they applied when sites weren’t taking patients. Timing and geography kept them from trials. This was frustrating because those patients met all of the inclusion and exclusion selection parameters for the experimental treatment and may have benefited from it, or at least contributed to knowledge about how the drug worked.
There was another large group of patients who couldn’t access new therapies in trials because they were “almost right” but not a perfect for a trial. For instance, they met the biomarker criteria, and there was a site nearby that was enrolling patients. But we would find out that the patient had too many prior courses of therapy, or they were just too sick, or they had another condition like diabetes that affected their overall condition. These “almost right” patients seemed to be good candidates for the therapy, but just couldn’t get in.
Clinical trials are selective because they need to be. A trial is an expensive project, and drug manufacturers need these projects to be successful. Allowing patients who are too sick or who have complicated medical histories introduces some risk to the trials. The people running the trials feel bad when they say no to a patient, but it’s a necessary part of the drug development process.
A Failure to Treat
For both the “unlucky” and the “almost right”, there is a failure to treat. Those patients often have exhausted standard of care, or there is good reason to believe that the new therapy would be better than standard care. The patients are willing to try an experimental treatment, both for their own potential benefit and for the opportunity to contribute to scientific progress, and they are turned away from something that could provide them a good chance or increased hope.
It is because of this frustration, which pulls at all of our hearts, that efforts like Right to Try have gained so much momentum. It is a compassionate reaction to a gut-wrenching problem.
A Failure to Learn
I’ve been thinking a lot about the patients who are unlucky or almost right for clinical trials but who are turned away. This population is substantially larger than the population who actually gets into a trial, and may be a better proxy for the actual population the new therapy might serve.
When we turn patients away from clinical trials, we cause a failure to learn. If those patients were treated with the new therapy, we could learn from their experiences.
Clinical trials and the external validity deficit
Statisticians like clinical trials because they have high “internal validity”. The data is collected in a very rigorous and consistent way, and can therefore be analyzed effectively for statistical conclusions. However, it has been acknowledged by FDA that clinical trial data has low “external validity” — it is difficult to extrapolate from those data to the general population.
Real-world evidence, meanwhile, is a new kind of data that could help. By gathering information from electronic health records, scientists can start to see how drugs work in the real world. With real-world data, medical scientists can start asking new questions, such as “Does this drug work the same in the real world as it does in the trial?”, or “Does the drug work in older people, or people who are also taking blood pressure medication?” This examination of real-world evidence is being embraced by the FDA as a way to bridge what they call the “external validity deficit” of clinical trials.
Expanded Access: what to do when your cancer can’t wait for a drug approval
In the last few months, I have learned a lot about Expanded Access, sometimes called “Compassionate Use.” It’s a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use. Basically, it’s a mini clinical trial for an individual patient or small group of patients who couldn’t get into a clinical trial. The FDA receives and approves applications for these medicines, and the drugs are generally provided at no charge by the manufacturer.
The FDA has supported Expanded Access, and has streamlined its processes for it so that any doctor can initiate a request in a standardized way. There’s even a form to request access, called the “3926”. The systems are in place right now and have been used successfully for years in many parts of the world. It is a mechanism that governments, payers, and physicians are using to get patients the medicines they need.
Expanded Access Leads to Pre-Approval Insights
Real-world data is typically captured for treatments that are already approved. But what if we collected real-world data for patients obtaining treatment through Expanded Access?
We would create a new category of real-world evidence, which we could call Pre-Approval Insights.
Let’s go back to that terrible conversation that oncologists have with their patients. Their patient wasn’t able to access a potentially helpful therapy through a clinical trial. What if that doctor could deliver some much better news? The patient didn’t get into the trial, but they could secure the medicine through Expanded Access. That way the patient could access the therapy, and the patient could also have the opportunity to contribute to research that could help others.
I’ve started a new job, with a company called myTomorrows, a world expert on Expanded Access. They are active in 18 countries. You haven’t heard of them because they haven’t started yet in the US. That’s my job.
Drug development is terribly inefficient, leading to long development timelines, which compounds the need for pre-approval access. Furthermore, slow, expensive drug development has led to massive escalation of drug prices. Pre-Approval Insights can speed up drug development, lower costs, and halt this upward trend in drug prices.
In the coming months, my new team here in Boston will be working hard to introduce a service to facilitate expanded access for patients while also collecting data for Pre-Approval Insights. These insights can transform the drug industry, helping more drugs reach more patients at a lower cost, faster. We’ll start with cancer, but we don’t have to stop there.
I am encouraged that congress has taken up the compassionate cause of Right to Try. That legislation has brought about a consciousness that patients need every chance they can get when they are fighting a deadly or debilitating disease. The movement stems from core American virtues: compassion and freedom of choice. Expanded Access aligns with this same line of thinking behind Right to Try with the added benefit of the “learning loop” to create Pre-Approval insights, resulting in a complete solution to the problem.
The good news is that we don’t need any new legislative or policy changes to provide therapies through Expanded Access and to collect rigorous health data to support Pre-Approval Insights. The frameworks already exist. The challenge now is that they haven’t been applied systematically, using design thinking and product engineering principles. Meeting this type of challenge is where the health technology industry excels, and where a company like the one I have joined can make a real difference in people’s lives.