Terminal Patients Need Better Access to Drugs and Clinical Trial Information
Editor’s note: This policy memo was written by Jake Seliger and his wife Bess Stillman. Jake passed away before meeting his child, Athena, born on October 31, 2024. Except where indicated, the first-person voice is that of Jake. This memo advocates for user-centric technology modernization and data interoperability. More crucially, he urges expanded patient rights to opt-in to experimental drug trials and FDA rule revisions to enable terminal patients to take more risks on behalf of themselves, for the benefit of others.
The FDA is supposed to ensure that treatments are safe and effective, but terminal cancer patients like me are already effectively dead. If I don’t receive advanced treatment quickly, I will die. My hope, in the time I have remaining, is to promote policies that will speed up access to treatments and clinical trials for cancer patients throughout the U.S.
There are about two million cancer diagnoses and 600,000 deaths annually in the United States. Cancer treatments are improved over time via the clinical trial system: thousands of clinical trials are conducted each year (many funded by the government via the National Institutes of Health, or NIH, and many funded by pharmaceutical companies hoping to get FDA approval for their products).
But the clinical trial system is needlessly slow, and as discussed below, is nearly impossible for any layperson to access without skilled consulting. As a result, clinical trials are far less useful than they could be.
The FDA is currently “protecting” me from being harmed or killed by novel, promising, advanced cancer treatments that could save or extend my life, so that I can die from cancer instead. Like most patients, I would prefer a much faster system in which the FDA conditionally approves promising, early-phase advanced cancer treatments, even if those treatments haven’t yet been proven fully effective. Drugmakers will be better incentivized to invest in novel cancer treatments if they can begin receiving payment for those treatments sooner. The true risks to terminal patients like me are low—I’m already dying—and the benefits to both existing terminal patients and future patients of all kinds are substantial.
I would also prefer a clinical trial system that was easy for patients to navigate, rather than next-to-impossible. Easier access for patients could radically lower the cost and time for clinical trials by making recruitment far cheaper and more widespread, rather than including only about 6% of patients. In turn, speeding up the clinical-trial process means that future cancer patients will be helped by more quickly approving novel treatments. About half of pharmaceutical R&D spending goes not to basic research, but to the clinical trial process. If we can cut the costs of clinical trials by streamlining the process to improve access to terminal patients, more treatments will make it to patients, and will be faster in doing so.
Cancer treatment is a non-partisan issue. To my knowledge, both left and right agree that prematurely dying from cancer is bad. Excess safety-ism and excessive caution from the FDA costs lives, including in the near future, my own. Three concrete actions would improve clinical research, particular for terminal cancer patients like me, but for many other patients as well:
Clinical trials should be easier and cheaper. The chief obstacles to this are recruitment and retention.
Congress and NIH should modernize the website ClinicalTrials.gov and vastly expand what drug companies and research sites are required to report there, and the time in which they must report it. Requiring timely updates that include comprehensive eligibility criteria, availability for new participants, and accurate site contact information,would mean that patients and doctors will have much more complete information about what trials are available and for whom.
The process of determining patient eligibility and enrolling in a trial should be easier. Due to narrow eligibility criteria, studies struggle to enroll an adequate number of local patients, which severely delays trial progression. A patient who wishes to participate in a trial must “establish care” with the hospital system hosting the trial, before they are even initially screened for eligibility or told if a slot is available. Due to telemedicine practice restrictions across state lines, this means that patients who aren’t already cared for at that site— patients who are ill and for whom unnecessary travel is a huge burden— must use their limited energy to travel to a site just to find out if they can proceed to requesting a trial slot and starting further eligibility testing. Then, if approved for the study, they must be able to uproot their lives to move to, or spend extensive periods of time at, the study location
Improved access to remote care for clinical trials would solve both these problems. First, by allowing the practice of telemedicine across state lines for visits directly related to screening and enrollment into clinical trials. Second, by incentivizing decentralization—meaning a participant in the study can receive the experimental drug and most monitoring, labs and imaging at a local hospital or infusion clinic—by accepting data from sites that can follow a standardized study protocol.
We should require the FDA to allow companies with prospective treatments for fatal diseases to bring those treatments to market after initial safety studies, with minimal delays and with a lessened burden for demonstrating benefit.
Background
[At the time of writing this] I’m a 40-year-old man whose wife is five months pregnant, and the treatment that may keep me alive long enough to meet my child is being kept from me because of current FDA policies. That drug may be in a clinical trial I cannot access. Or, it may be blocked from coming to market by requirements for additional testing to further prove efficacy that has already been demonstrated.
Instead of giving me a chance to take calculated risks on a new therapy that might allow me to live and to be with my family, current FDA regulations are choosing for me: deciding that my certain death from cancer is somehow less harmful to me than taking a calculated, informed risk that might save or prolong my life. Who is asking the patients being protected what they would rather be protected from? The FDA errs too much on the side of extreme caution around drug safety and efficacy, and that choice leads to preventable deaths.
One group of scholars attempted to model how many lives are lost versus gained from a more or less conservative FDA. They find that “from the patient’s perspective, the approval criteria in [FDA program accelerators] may still seem far too conservative.” Their analysis is consistent with the FDA being too stringent and slow in approving use of drugs for fatal diseases like cancer: “Our findings suggest that conventional standards of statistical significance for approving drugs may be overly conservative for the most deadly diseases.”
Drugmakers also find it difficult to navigate what exactly the FDA wants: “their deliberations are largely opaque—even to industry insiders—and the exact role and weight of patient preferences are unclear.” This exacerbates the difficulty drugmakers face in seeking to get treatments to patients faster. Inaction in the form of delaying patient access to drugs is killing people. Inaction is choosing death for cancer patients.
I’m an example of this; I was diagnosed with squamous cell carcinoma (SCC) of the tongue in Oct. 2022. I had no risk factors, like smoking or alcoholism, that put me at risk for SCC. The original tumor was removed in October 2022, and I then had radiation that was supposed to cure me. It didn’t, and the cancer reappeared in April 2023. At that point, I would’ve been a great candidate for a drug like MCLA-158, which has been stuck in clinical trials, despite “breakthrough therapy designation” by the FDA and impressive data, for more than five years. This, despite the fact that MCLA-158 is much easier to tolerate than chemotherapy and arrests cancer in about 70% of patients. Current standard of care chemotherapy and immunotherapy has a positive response rate of only 20-30%.
Had MCLA-158 been approved, I might have received it in April 2023, and still have my tongue. Instead, in May 2023, my entire tongue was surgically removed in an attempt to save my life, forever altering my ability to speak and eat and live a normal life. That surgery removed the cancer, but two months later it recurred again in July 2023. While clinical-trial drugs are keeping me alive right now, I’m dying in part because promising treatments like MCLA-158 are stuck in clinical trials, and I couldn’t get them in a timely fashion, despite early data showing their efficacy. Merus, the maker of MCLA-158, is planning a phase 3 trial for MCLA-158, despite its initial successes. This is crazy: head and neck cancer patients need MCLA-158 now.
I’m only writing this brief because I was one of the few patients who was indeed, at long last, able to access MCLA-158 in a clinical trial, which incredibly halted my rapidly expanding, aggressive tumors. Without it, I’d have been dead nine months ago. Without it, many other patients already are. Imagine that you, or your spouse, or parent, or child, finds him or herself in a situation like mine. Do you want the FDA to keep testing a drug that’s already been shown to be effective and allow patients who could benefit to suffer and die? Or do you want your loved one to get the drug, and avoid surgical mutilation and death? I know what I’d choose.
Multiply this situation across hundreds of thousands of people per year and you’ll understand the frustration of the dying cancer patients like me.
As noted above, about 600,000 people die annually from cancer—and yet cancer drugs routinely take a decade or more to move from lab to approval. The process is slow: “By the time a drug gets into phase III, the work required to bring it to that point may have consumed half a decade, or longer, and tens if not hundreds of millions of dollars.” If you have a fatal disease today, a treatment that is five to ten years away won’t help. Too few people participate in clinical trials partly because participation is so difficult; one study finds that “across the entire U.S. system, the estimated participation rate to cancer treatment trials was 6.3%.” Given how many people die, the prospect of life is attractive.
There is another option in between waiting decades for a promising drug to come to market and opening the market to untested drugs: Allowing terminal patients to consent to the risk of novel, earlier-phase treatments, instead of defaulting to near-certain death, would potentially benefit those patients as well as generate larger volumes of important data regarding drug safety and efficacy, thus improving the speed of drug approval for future patients. Requiring basic safety data is reasonable, but requiring complete phase 2 and 3 data for terminal cancer patients is unreasonably slow, and results in deaths that could be prevented through faster approval.
Again, imagine you, your spouse, parent, or child, is in a situation like mine: they’ve exhausted current standard-of-care cancer treatments and are consequently facing certain death. New treatments that could extend or even save their life may exist, or be on the verge of existing, but are held up by the FDA’s requirements that treatments be redundantly proven to be safe and highly effective. Do you want your family member to risk unproven but potentially effective treatments, or do you want your family member to die?
I’d make the same choice. The FDA stands in the way.
Equally important, we need to shorten the clinical trial process: As Alex Telford notes, “Clinical trials are expensive because they are complex, bureaucratic, and reliant on highly skilled labour. Trials now cost as much as $100,000 per patient to run, and sometimes up to $300,000 or even $500,000 per patient.” And as noted above, about half of pharmaceutical R&D spending goes not to basic research, but to the clinical trial process.
Cut the costs of clinical trials, and more treatments will make it to patients, faster. And while it’s not reasonable to treat humans like animal models, a lot of us who have fatal diagnoses have very little to lose and consequently want to try drugs that may help us, and people in the future with similar diseases. Most importantly, we understand the risks of potentially dying from a drug that might help us and generate important data, versus waiting to certainly die from cancer in a way that will not benefit anybody. We are capable of, and willing to give, informed consent. We can do better and move faster than we are now. In the grand scheme of things, “When it comes to clinical trials, we should aim to make them both cheaper and faster. There is as of yet no substitute for human subjects, especially for the complex diseases that are the biggest killers of our time. The best model of a human is (still) a human.” Inaction will lead to the continued deaths of hundreds of thousands of people annually.
Trials need patients, but the process of searching for a trial in which to enroll is archaic. We found ClinicalTrials.gov nearly impossible to navigate. Despite the stakes, from the patient’s perspective, the clinical trial process is impressively broken, obtuse and confusing, and one that we gather no one likes: patients don’t, their families don’t, hospitals and oncologists who run the clinical trials don’t, drug companies must not, and the people who die while waiting to get into a trial probably don’t.
I [Bess] knew that a clinical trial was Jake’s only chance. But how would we find one? I’d initially hoped that a head and neck oncologist would recommend a specific trial, preferably one that they could refer us to. But most doctors didn’t know of trial options outside their institution, or, frequently, within it, unless they were directly involved. ,Most recommended large research institutions that had a good reputation for hard cases, assuming they’d have more studies and one might be a match.
How were they, or we, supposed to find out what trials actually existed?
The only large-scale search option is ClinicalTrials.gov. But many oncologists I spoke with don’t engage with ClinicalTrials.gov, because the information is out-of-date, difficult to navigate, and inaccurate. It can’t be relied on. For example, I shared a summary of Jake’s relevant medical information (with his permission) in a group of physicians who had offered to help us with the clinical trial search. Ten physicians shared their top-five search results. Ominously, none listed the same trials.
How is it that ten doctors can put in the same basic, relevant clinical data into an engine meant to list and search for all existing clinical trials, only for no two to surface the same study? The problem is simple: There’s a lack of keyword standardization.
Instead of a drop-down menu or click-boxes with diagnoses to choose from, the first search “filter” on ClinicalTrials.gov is a text box that says “Condition\Disease.” If I search: “Head and Neck Cancer” I get ___________ results. If I search “Tongue Cancer,” I get _________ results. Although Tongue Cancer is a subset of Head and Neck Cancer, I don’t see the studies listed as “Head and Neck Cancer”, unless I type in both, or the person who created the ClinicalTrials.gov post for the study chose to type out multiple variations on a diagnosis. Nothing says they have to. If I search for both, I will still miss studies filed as: “HNSCC” or “All Solid Tumors” or “Squamous Cell Carcinoma of the Tongue.”
The good news is that online retailers solved this problem for us years ago. It’s easier to find a dress to my exact specifications out of thousands on H&M,com than it is to find a clinical trial. I can open a search bar, click “dress,” select my material from another click box (which allows me to select from the same options the people listing the garments chose from), then click on the boxes for my desired color, dry clean or machine wash, fabric, finish, closure, and any other number of pre-selected categories before adding additional search keywords if I choose. I find a handful of options all relevant to my desires within a matter of minutes. H&M provides a list of standardized keywords describing what they are offering, and I can filter from there. This way, H&M and I are speaking the same language. And a dress isn’t life or death. For much more on my difficulties with ClinicalTrials.gov, see here.
Further slowing a patient’s ability to find a relevant clinical trial is a lack of comprehensive, searchable, eligibility criteria. Every study has eligibility criteria, and eligibility criteria—like keywords—aren’t standardized on ClinicalTrials.gov. Nor is it required that an exhaustive explanation of eligibility criteria be provided, which may lead to a patient wasting precious weeks attempting to establish care and enroll in a trial, only to discover there was unpublished eligibility criteria they don’t meet. Instead, the information page for each study outlines inclusion and exclusion criteria using whatever language whoever is typing feels like using. Many have overlapping inclusion and exclusion criteria, but there can be long lists of additional criteria for each arm of a study, and it’s up to the patient or their doctor to read through them line by line—if they’re even listed— to see if prior medications, current medications, certain genomic sequencing findings, numbers of lines of therapy, etc. makes the trial relevant.
In the end, we hired a consultant (Eileen), who leveraged her full-time work helping pharmaceutical companies determine which novel compounds might be worth pouring their R&D efforts into assisting patients find potential clinical trials. She helped us narrow it down to the top 5 candidate trials from the thousands that turned up in initial queries.
- NCT04815720: Pepinemab in Combination With Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (KEYNOTE-B84)
- NCT03526835: A Study of Bispecific Antibody MCLA-158 in Patients With Advanced Solid Tumors.
- NCT05743270: Study of RP3 in Combination With Nivolumab and Other Therapy in Patients With Locoregionally Advanced or Recurrent SCCHN.”
- NCT03485209: Efficacy and Safety Study of Tisotumab Vedotin for Patients With Solid Tumors (innovaTV 207)
- NCT05094336: AMG 193, Methylthioadenosine (MTA) Cooperative Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, Alone and in Combination With Docetaxel in Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors (MTAP).
Based on the names alone, you can see why it would be difficult if not impossible for someone without some expertise in cancer oncology to evaluate trials. Even with Eileen’s expertise, two of the trials were stricken from our list when we discovered unlisted eligibility criteria, which excluded Jake. When exceptionally motivated patients, the oncologists who care for them, and even consultants selling highly specialized assistance can’t reliably navigate a system that claims to be desperate to enroll patients into trials, there is a fundamental problem with the system. But this is a mismatch we can solve, to everyone’s benefit.
Plan of Action
We propose three major actions. Congress should:
Recommendation 1. Direct the National Library of Medicine (NLM) at the National Institutes of Health (NIH) to modernize ClinicalTrials.gov so that patients and doctors have complete and relevant information about available trials, as well as requiring more regular updates from companies as to all the details of available trials, and
Recommendation 2. Allow the practice of telemedicine across state lines for visits related to clinical trials.
Recommendation 3. Require the FDA to allow companies with prospective treatments for fatal diseases to bring those treatments to market after initial safety studies.
Modernizing ClinicalTrials.gov will empower patients, oncologists, and others to better understand what trials are available, where they are available, and their up-to-date eligibility criteria, using standardized search categories to make them more easily discoverable. Allowing telemedicine across state lines for clinical trial care will significantly improve enrollment and retention. Bringing treatments to market after initial safety studies will speed the clinical trial process, and get more patients treatments, sooner. In cancer, delays cause death.
To get more specific:
The FDA already has a number of accelerated approval options. Instead of the usual “right to try” legislation, we propose creating a second, provisional market for terminal patients that allows partial approval of a drug while it’s still undergoing trials, making it available to trial-ineligible (or those unable to easily access a trial) patients for whom standard of care doesn’t provide a meaningful chance at remission. This partial approval would ideally allow physicians to prescribe the drug to this subset of patients as they see fit: be that monotherapy or a variety of personalized combination therapies, tailored to a patient’s needs, side-effect profile and goals. This wouldn’t just expand access to patients who are otherwise out of luck, but can give important data about real-world reaction and response.
As an incentive, the FDA could require pharmaceutical companies to provide drug access to terminal patients as a condition of continuing forward in the trial process on the road to a New Drug Application. While this would be federally forced compassion, it would differ from “compassionate use.” To currently access a study drug via compassionate use, a physician has to petition both the drug company and the FDA on the patient’s behalf, which comes with onerous rules and requirements. Most drug companies with compassionate use programs won’t offer a drug until there’s already a large amount of compelling phase 2 data demonstrating efficacy, a patient must have “failed” standard of care and other available treatments, and the drug must (usually) be given as a monotherapy. Even if the drugmaker says yes, the FDA can still say no. Compassionate use is an option available to very small numbers, in limited instances, and with bureaucratic barriers to overcome. Not terribly compassionate, in my opinion.
The benefits of this “terminal patient” market can and should go both ways, much as lovers should benefit from each other instead of trying to create win-lose situations. Providing the drug to patients would come with reciprocal benefits to the pharmaceutical companies. Any physician prescribing the drug to patients should be required to report data regarding how the drug was used, in what combination, and to what effect. This would create a large pool of observational, real-world data gathered from the patients who aren’t ideal candidates for trials, but better represent the large subset of patients who’ve exhausted multiple lines of therapies yet aren’t ready for the end. Promising combinations and unexpected effects might be identified from these observational data sets, and possibly used to design future trials.
Dying patients would get drugs faster, and live longer, healthier lives, if we can get better access to both information about clinical trials, and treatments for diseases. The current system errs too much on proving effectiveness and too little on the importance of speed itself, and of the number of people who die while waiting for new treatments. Patients like me, who have fatal diagnoses and have already failed “standard of care” therapies, routinely die while waiting for new or improved treatments. Moreover, patients like me have little to lose: because cancer is going to kill us anyway, many of us would prefer to roll the dice on an unproven treatment, or a treatment that has early, incomplete data showing its potential to help, than wait to be killed by cancer. Right now, however, the FDA does not consider how many patients will die while waiting for new treatments. Instead, the FDA requires that drugmakers prove both the safety and efficacy of treatments prior to allowing any approval whatsoever.
As for improving ClinicalTrials.gov, we have several ideas:
First, the NIH should hire programmers with UX experience, and should be empowered to pay market rates to software developers with experience at designing websites for, say, Amazon or Shein. Clinicaltrials.gov was designed to be a study registry, but needs an overhaul to be more useful to actual patients and doctors.
Second, UX is far from the only problem. Data itself can be a problem. For example, the NIH could require a patient-friendly summary of each trial; it could standardize the names of drugs and conditions so that patients and doctors could see consistent and complete search results; and it could use a consistent and machine-readable format for inclusion and exclusion criteria.
We are aware of one patient group that, in trying to build an interface to ClinicalTrials.gov, found a remarkable degree of inconsistency and chaos: “We have analyzed the inclusion and exclusion criteria for all the cancer-related trials from clinicaltrials.gov that are recruiting for interventional studies (approximately 8,500 trials). Among these trials, there are over 1,000 ways to indicate the patient must not be pregnant during a trial, and another 1,000 ways to indicate that the patient must use adequate birth control.” ClinicalTrials.gov should use a Domain Specific Language that standardizes all of these terms and conditions, so that patients and doctors can find relevant trials with 100x less effort.
Third, the long-run goal should be a real-time, searchable database that matches patients to studies using EMR data and allows doctors to see what spots are available and where. Pharmaceutical and biotech companies would need to be required to contribute up-to-date information on all extant clinical trials on a regular basis (e.g., monthly).
Conclusion
Indeed, we need a national clinical trial database that EMRs can connect to, in the style of Epic’s Care Everywhere. A patient signs a release to share their information, like Care Everywhere allows hospital A to download a patient’s information from hospital B if the patient signs a release. Trials with open slots could mark themselves as “recruiting” and update in real time. A doctor could press a button and identify potential open studies. A patient available for a trial could flag their EMR profile as actively searching, allowing clinical trial sites to browse patients in their region who are looking for a study. Access to that patient’s EMR would allow them to scan for eligibility.
This would be easy to do. OKCupid can do it. The tech exists. Finding a clinical trial already feels a bit like online dating, except if you get the wrong match, you die.
This memo produced as part of the Federation of American Scientists and Good Science Project sprint. Find more ideas at Good Science Project x FAS
The FDA has created a variety of programs that have promising-sounding names: “Currently, four programs—the fast track, breakthrough therapy, accelerated approval, and priority review designations—provide faster reviews and/or use surrogate endpoints to judge efficacy. However, published descriptions […] do not indicate any differences in the statistical thresholds used in these programs versus the standard approval process, nor do they mention adapting these thresholds to the severity of the disease.” The problem is that these programs do not appear to do much to actually accelerate getting drugs to patients. MCLA-158 is an example of the problem: the drug has been shown to be safe and effective, and yet Merus thinks it needs a Phase 3 trial to get it past the FDA and to patients.
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