Crowdfunding to pay to be a research subject in a clinical trial: The case of Lily Wythe [UPDATED 1/23/2020—see addendum]

Given my long history of writing about the desperate parents of children with deadly brain cancers using online crowdfunding and persuading celebrities to help them raise funds to take their children to cancer quacks, a story spreading around the media, both old and new social media, the last week or two definitely raised my eyebrow. Once again, I encountered the tale of a child (in this case 13-year-old girl named Lily Wythe) stricken with a deadly brain cancer (in this case a cancer with which we’re well familiar, diffuse intrinsic pontine glioma, or DIPG), given how many times I’ve written about cancer quacks like Stanislaw Burzynski or those at Clínica 0-19 in Monterrey, Mexico or Hallwang Clinic in Germany, luring such families in with false hope and quackery. Once again, I got the sinking feeling that the crowdfunding campaign was being used to support a cancer quack.

This time, though, there was a twist, which has left me profoundly conflicted, and that twist is that it’s not quackery or a quack clinic for which funds are being raised. It’s a legitimate clinical trial at Seattle Children’s Hospital. However, unlike the usual case for clinical trials, in which patients do not pay for study-related expenses other than routine medical expenses that they would have paid anyway even if they weren’t on the study, that doesn’t sound like what is happening here, which is that Seattle Children’s Hospital appears to be requiring at least this patient to pay for the cost of being on the clinical trial. You might recall that “pay-to-play” clinical trials and fundraising for such trials are ethically very problematic, as I’ve recently discussed. This story resurrected those concerns and added the the even more troubling element of a family scrambling to pay for such a trial.

While I’m happy that, as you’ll see, Lily is doing so well currently and certainly would never discourage anyone from entering a clinical trial, least of all a patient with DIPG. However, the similarities between what I’m observing with the case of the Wythe family and what I’ve observed with, for example, Burzynski patients made me profoundly uncomfortable, and I’m not sure what the answer is to make such a situation less troubling.

Lily Wythe’s story

Lily’s story is heartbreakingly familiar to me (and certainly to regular readers). It’s told in articles with the same sorts of headlines that we’ve seen so many times before with Burzynski patients or Clínica 0-19 patients, such as this article in a UK paper, Teenager’s desperate bid to raise £300,000 for cancer treatment nears target:

A teenage girl has created a viral fundraiser in a bid to send her best friend to the US for revolutionary cancer treatment.

Lillie Cotgrove came up with the idea of ‘The One Pound Warriors’ Facebook group in which people donate at least a quid.

The grassroots fundraiser has now been backed by a host of celebrities, including Rachel Riley, Alfie Allen and Steven Gerrard, and is nearing its £300,000 target.

Lillie’s best friend Lily Wythe was diagnosed with an aggressive malignant brainstem tumour called Diffuse intrinsic pontine glioma H3 K27MK.

It is a tumour of the central nervous system that affects sight, hearing, speech, swallow, breathing and heart rate and has an average survival of eight to 12 months.

Lily, 13, has undergone radiotherapy but the family are pinning their hopes on a clinical trial in Seattle, USA.

The family created a GoFundMe page and Lillie, of Benfleet, Essex, also set up a crowdfunder to help.

The HJ3 K27MK mutation is a mutation in DIPG that is associated with particularly aggressive disease and early recurrence after radiation therapy, usually within 6-9 months.

I must say that, as I saw story after story like this, such as this story posted nearly a week ago, I was very much expecting the “punchline” of the family wanting to take Lily to Houston, or to Monterrey, or to Hallwang Clinic, or to some other dubious clinic of which I hadn’t yet heard. I decided that I had to look into the story in more depth because it brings up so many issues, some issues similar to those that come up with stories that I’ve written about before and some very different. All are difficult, and the overall situation leaves me very conflicted. Specifically, I was very curious what this clinical trial at Seattle Children’s Hospital involved such that it required £300,000 (~$391,590 US as of yesterday’s exchange rate) to enroll. After doing some searching, I’m pretty sure I know what trial it is. More on that in a moment.

First, let’s examine Lily’s clinical history in a little more detail. Because I’ve written so much about DIPG patients over the years, her clinical history sounds sadly familiar. From an article shortly after the Wythe family launched their crowdfunding campaign in late November, £300k plea to fund vital trial for Lily:

The bright and bubbly Eastwood Academy student, who also has a brother, Josh, 12, was diagnosed at Great Ormond Street Hospital in October.

After returning from a family holiday in August, Lily started suffering from morning headaches, vomiting and double vision.

Soon after came speech and co-ordination issues. After visiting healthcare professionals on five occasions, Lily finally had an MRI which revealed a tumour on her brain stem.

Lily was immediately admitted to GOSH for five days and put on steroids before the dreaded diagnosis followed a few weeks later.

She has undergone radiotherapy, which has reduced her symptoms, and she has had a life-saving operation to reduce pressure from her brain.

The community has rallied round to help, and so far, more than £14,000 has been raised, but this is a far cry from the cash needed to get Lily to Seattle for the trials, which start next spring 2020.

This story from two days ago provides more information. Overall, Lily is doing well now, radiotherapy having shrunk the tumor, although I’m not clear from the news reports about whether the tumor shrank away to undetectable or whether there is still observable tumor left on post-therapy scans. She also suffered some complications:

The last few months have taken its toll of Lily. She struggled to walk and dress herself going through the radiotherapy as well as having to learn to eat again.

Not long after starting radiotherapy in October to shrink the tumour, Lily got the flu and suffered aspiration, when you swallow food into your airways.

While recovering, Lily then suffered from hydrocephalus, which is when the brain swells and fluid gets stuck and puts pressure on the skull. She had to undergo intensive brain surgery.

“It is very intense and you do worry. But she had to have it because it can kill you,” Diane added.

She also had a shunt fitted from the brain to the stomach for any fluid to move to.

Stories like this one tear me up. They always have, ever since I started writing about these sorts of situations, albeit from the perspective of decrying quacks making huge sums of money selling false hope to patients like this. I’ve said it before many times. I can’t understand the parents’ desperation from personal experience, but I can empathize and understand as a fellow human being imaging what I would do in a similar situation, with a child whom I love more than anything in the world facing imminent death from brain cancer. I decry quacks like Stanislaw Burzynski and the doctors at Clínica 0-19 because they prey on the desperation such parents naturally feel, their willingness to do anything, to go to any length to save their child.

BrainChild-03: The clinical trial

Having covered so many stories like this on this blog, I can’t help but get a whiff, a hint, of the same sort of issue here, this time from Seattle Children’s Hospital. The Wythes and their friends have accomplished some truly prodigious fundraising. They’re nearing the needed £300,000, and Lily’s friend Lillie Cotgrove came up with the idea of The One Pound Warriors, in which she raises funds by having lots of people donate just one pound each, with amazing success. Thanks to the involvement of celebrities like Alfie Allen, who played Theon Greyjoy in Game of Thrones, the fundraising total has surpassed £250,000.

Alfie Allen raises funds for Lily Wythe

What is this treatment being tested in a clinical trial that costs £300,000 for a year when travel and lodging are factored in? A hint came from the very first post on the Facebook page set up by Lily’s family to fundraise and publicize Lily’s plight:

The passage:

After extensive research there are currently two suitable Clinical Trials in the US that show very promising results for Lilys type of Brain Cancer, a drug that starves the cancer and a new Immunotherapy treatment at Seattle Hospital.

Based on this, I knew it had to be either antiangiogenic therapy (“starving the tumor” by attacking the new blood vessels that supply a tumor with oxygen and nutrients) or, more likely given the high cost, CAR-T therapy. It didn’t take much Googling to figure out that the immunotherapy must be CART-T therapy. A quick trip to ClinicalTrials.gov led me to two trials:

The second trial was, according to ClinicalTrials.gov terminated by design, specifically it was topped “if fewer than 3 cohorts by molecular classification were with 10 participants or only 1 cohort enrolled at least 15 participants of 50” and thus appears to be no longer recruiting. Indeed, its results are published on ClinicalTrials.gov, with a reported 9 month survival rate of 64%. Moreover, this story published yesterday confirms that the family wants to take Lily to Seattle for CAR-T cell therapy. So it must be the first clinical trial.

The Seattle Children’s Hospital website describes the clinical trial, known as BrainChild-03, thusly:

In this trial, the patient’s own T cells are reprogrammed to recognize and target the protein B7-H3, a surface molecule that is on most CNS tumors.

The reprogrammed cells (now CAR T cells) will be put back into the patient’s body (infused) through a catheter, either into the place where the tumor has been removed or into the CNS ventricular system (intra-CNS). Placement will depend on the location of the tumor.

This study is open to all types of CNS tumors that have recurred or progressed and for children with DIPG.

This is the first CAR T-cell trial in the United States for children with DIPG and is open to patients with DIPG any time after radiation.

The principal investigator is Dr. Nicholas Vitanza.

For those not familiar with CAR-T-cell therapy, CAR T-cell stands for chimeric antigen receptor (CAR) T-cell. In brief, CAR-T cell therapy involves taking blood from the patient, isolating T-cells, and genetically modifying them, after which they are grown into large quantities of cells needed and reinfused into the body. This short video on the Seattle Children’s Hospital website provides a simple description of how these cells work suitable for a lay audience:

In this case, the cells will be injected either directly into the tumor resection cavity (for tumors that are resectable and therefore resected successfully, which is almost never the case for DIPG) or into the ventricular system through a catheter. This clinical trial is the third trial that’s part of an initiative by Seattle Children’s Hospital to cure pediatric brain cancer, called—you guessed it!—BrainChild, just as the studies are named BrainChild.

Lily Wythe: Crowdfunding for a phase I clinical trial

As I read the ClinicalTrials.gov entry for BrainChild-03 (ClinicalTrials.gov identifier: NCT04185038), it became apparent to me that requiring a patient’s family to pay for this particular trial is ethically problematic. Certainly, it’s not as problematic as for-profit stem cell clinics requiring patients to pay for phase I clinical trials of their almost certainly worthless therapies, which they then use more for marketing than anything else, co-opting ClinicalTrials.gov in the process, but it’s ethically problematic nonetheless. The reason is that this is a phase I trial. It looks like a scientifically sound phase I trial, but it’s still a phase I trial, and that means that it is not testing efficacy. It is testing safety

Here are its primary outcome measures:

  1. Establish the safety, defined by the adverse events, of B7H3-specific CAR T cell infusions delivered by a central nervous system (CNS) catheter into the tumor resection cavity or ventricular system. [ Time Frame: up to 7 months. ] The type, frequency, severity, and duration of adverse events as a result of B7H3-specific CAR T cell infusion will be summarized.
  2. Establish the feasibility, defined by the ability to produce and administer CAR T cell product, of B7H3-specific CAR T cell product infusions delivered by a central nervous system (CNS) catheter into the tumor resection cavity or ventricular system. [ Time Frame: 28 days. ] The proportion of products successfully manufactured and infused will be measured.

Here are the trial’s secondary outcome measures:

  1. Assess the distribution of CNS-delivered B7H3-specific CAR T cells distribution within the cerebrospinal fluid (CSF) and peripheral blood. [ Time Frame: up to 6 months.] The trafficking of B7H3-specific CAR T cell product through the CSF by measuring remaining CAR T cells from a prior infusion at the time of each infusion and the trafficking of B7H3-specific CAR T cells from the CSF into the peripheral blood will be evaluated.
  2. Assessment of disease response of B7H3-expressing DIPG and DMG tumors to B7H3 specific CAR T cell therapy delivered into the tumor cavity or into the CNS [ Time Frame: up to 6 months ] The response of DIPG and DMG tumors to B7H3-specific CAR T cell therapy delivered into the tumor cavity or into the CNS will be determined by evaluating CSF for tumor cells and by CNS imaging with MRIs.
  3. Assessment of disease response of B7H3-expressing refractory or recurrent central nervous system (CNS) tumors to B7H3 specific CAR T cell therapy delivered into the tumor cavity or into the CNS. [ Time Frame: up to 6 months. ] The response of refractory or recurrent CNS tumors to B7H3-specific CAR T cell therapy delivered into the tumor cavity or into the CNS will be determined by evaluating CSF for tumor cells and by CNS imaging with MRIs.

Yes, the investigators are doing measurements (MRIs, etc.) to see if there is any tumor response, but that is not the primary purpose of the study. Yes, there’s a possibility of tumor response. OF course there is! The investigators wouldn’t do a study like this, much less a study of a treatment that costs so much money, if they didn’t have high hopes that it would be better than currently existing therapies.

Here’s where I have to be very delicate. I always assume that the family will likely see what I write because if there’s one thing I’ve learned it’s that families crowdfunding to save their child very frequently have Google Alerts set up to alert them whenever anyone posts something to the web about them, the very last thing I want to do is to be perceived, either by the family or anyone else, as criticizing the family. I am not. In fact, I admire their devotion and industriousness in raising such prodigious sums of money in such a short period of time. I understand why they do it. I applaud them. My question lies in the ethics of requiring the family to do that to be on the clinical trial, of making it a choice between doing what the Wythe family is doing and not being on the clinical trial.

Whenever I see a story like this, I always have to ask: What have the investigators told the family about the trial and its likelihood of helping Lily? There is an inherent tension between downplaying expectations because this is a phase I trial and hyping expectations in order to recruit. There is even more of a tension when you’re placed in the horrible position of the Wythes of having to crowdfund huge sums of money. Just Google Lily Wythe’s name and look at the headlines that come up. Read some of the articles. You’ll see what I mean:

I can only imagine what the TV coverage in the UK has been like, with all those celebrities involved in helping to fundraise for Lily. I also hate—hate, hate, hate!—the spin in the headline of the last story mentioning the NHS. The NHS most definitely does cover brain cancer treatment and certainly would pay for effective palliative treatments for Lily. It just doesn’t cover experimental or unproven treatment, particularly experimental treatment outside of the UK, which is not an unreasonable policy for a single payer health care system—or any government health care system. I’ve noticed that the press in the UK loves to spin stories like Lily’s to portray the NHS as the callous and uncaring, as “sending the patient home to die,” leaving the patient and family with no choice but to look overseas, where sometimes they find quacks like Burzynski and sometimes they find legitimate clinical trials like this one. This sort of spin sends a horrible message to patients and the general public by not-so-subtly implying that palliative care for cancer is not “real” care and that curative treatments are “real” treatments.

I also noted another thing about this trial that is very problematic and of a piece with criticisms of pay-to-play trials that I’ve discussed before. There’s no mention in its ClinicalTrials.gov entry that this trial is pay-to-play, at least none that I could find. It is true that FDA regulations do allow such “pay-to-play” clinical trials in “extraordinary circumstances.” An example of such “extraordinary circumstances” is a situation when a drug being tested has a price tag so high that the trial can’t otherwise ever be run. I’m assuming that’s how Seattle Children’s Hospital is justifying charging Lily’s family so much money to be on this trial, given how expensive it is to make and administer CAR-T cells. However, to reiterate my previous concerns, I still have a hard time envisioning such a scenario that wouldn’t be predatory, whether intentionally (as in the case of quack stem cell clinics) or unintentionally (as in this case), and the case of Lily Wythe illustrates why.

I also cite again ethical and scientific concerns raised in STAT News:

But experts say these trials are ethically fraught for a number of reasons: At worst, they run the risk of being a guise for an enterprise looking to profit from desperate patients. But even when intentions are sound, the trials are likely to only enroll those patients who can afford to participate, thereby skewing the results. There could also be a weak study design, without blinding or a control group, because patients would likely be reluctant to pay for a placebo. And they may reinforce the common misconception among patients that clinical trials are a route to accessing treatments that are guaranteed to help them.

Precisely.

It’s also not clear to me from all my reading whether every patient enrolled on this trial has to pay or if Lily’s family only has to pay so much because they’re not from the US and don’t have US health insurance to cover the additional costs of treatment outside of the production and administration of the CAR T-cells. Some articles quote Lily’s mother as saying that the £300,000 is just for the treatment, a minimum amount of money needed, and that travel and lodging are extra. That doesn’t completely clarify the issue of how much is for the CAR T-cell treatment and how much for everything else or if every study participant is being asked to pay close to $400,000 to enroll in the study.

Incomplete narratives harm research and mislead patients

The press coverage for this story, as has been the case for pretty much every story I’ve ever covered of this type, has been an epic fail. More information is desperately required, and I don’t see it in any of the news stories about Lily. None of them that I’ve found thus far have bothered to look into this angle, in particular at why the Wythes are being required to pay so much money for a phase I clinical trial or at whether everyone is required to pay to be on this trial. No one has interviewed anyone at Seattle Children’s Hospital about the trial. Most stories, if they mention what the experimental therapy is at all—most don’t, other than to call it experimental, while some don’t even call it experimental, only “revolutionary” or “life-saving”—only refer to it as “immunotherapy.” (I’ve only found one story that even mentioned CAR-T cells.) None of them mention that the crowdfunding is for a phase I trial, explain what a phase I trial even is and that a phase I trial primarily tests safety and tolerability of the therapy, not efficacy, or asks Seattle Children’s Hospital why it is charging patients like Lily so much money to be on the trial. None of them explain what CAR-T cell therapy is, what’s known about it for brain cancer, or that CAR-T cells are not without risks, up to and including death, and it’s certainly not unreasonable to ask what additional risks there might be in administering them directly into the brain or cerebrospinal fluid. No one does.

In its hunger for feel-good stories showing a likable family do extraordinary things (and, make no mistake, the Wythes have done extraordinary things) to overcome incredible odds, the press hasn’t asked even the most basic questions to flesh out the rest of the story. They just present the story as a family heroically raising funds to save their brave daughter. That’s obviously the most appealing, emotional aspect of the story. However, it’s not the only aspect, and focusing solely on that aspect leaves unexamined the question of why: Why is this clinical trial set up so that it’s necessary for this family to go to such extreme lengths to raise so much money if they want to enroll their daughter on the trial, particularly given that it’s a phase I trial that is unlikely to help her? The family is likely aware of how long the odds are, even with this clinical trial, but the press sure doesn’t communicate that to the public. The press portrays this as Lily’s last chance and implies that there’s a good chance she’ll survive if only her family can come up with the money to pursue a treatment denied her by the “stingy” and “callous” NHS, the very same spin they put on stories of patients seeking treatment at the Burzynski Clinic, Hallwang Clinic, or Clínica 0-19. CAR-T cells are real treatment. Seattle Children’s Hospital is a top-notch academic hospital. We should expect better coverage.

I wish Lily Wythe and her family only the best. I hope they succeed in getting her on this clinical trial, and, as of when I wrote this last night, it looks as though they will. I hope she beats the odds. My purpose in writing this is not to dampen their optimism or criticize them in any way. My purpose in writing this is twofold. First, I want to take the press to task for not asking even just a little more about stories like this, to put them into proper context. I guarantee you that, even if the public knew what a phase I trial is and that this treatment had a small chance of curing Lily, they would still donate to fund a last ditch effort to save her life. More importantly, I ask whether a system of clinical trials that puts a family like the Wythes in the situation they’re in is ethical and what can be done to change its so there are no more families frantically raising money to save their daughter.

ADDENDUM: The PI of BrainChild-03 emailed me. I’m waiting to hear back from him, but he did wish to emphasize that the reason the Wythes are being charged is that they are international patients and do not have American health insurance to pay for the hospital stay. He states that the CAR-T cell therapy itself is provided at no cost. I’ll add more as I learn it.