Do-It-Yourself Medicine

Patients are sidestepping clinical research and using themselves as guinea pigs to test new treatments for fatal diseases. Will they hurt themselves, or science?

Mar 1, 2013
Jef Akst

© KAMRUZZAMAN RATAN/ISTOCKPHOTO.COMOn August 10, 2011, Joan Valor Butler diluted a solution of 5 percent sodium chlorite in 1 gallon of slightly salted water, and slowly injected 1 liter of the mixture into her 42-year-old son’s feeding tube, at his request. Sodium chlorite is a chemical commonly used in low concentrations in camping water-purification kits and for municipal water treatment. Many also believed it to be the active ingredient of a promising drug in clinical trials for amyotrophic lateral sclerosis (ALS)—a disease Eric Valor has lived with for the better part of the past decade.

As the disease gradually paralyzed his entire body, Valor became an avid student of ALS, a degenerative disorder commonly known as Lou Gehrig’s disease and characterized by a deterioration of motor neurons. He had first learned about the intravenous drug, called NP001, in 2010, when its developer, Neuraltus Pharmaceuticals, announced it would soon be starting a Phase 1 trial and was recruiting ALS patients. Animal toxicology tests had demonstrated the drug’s safety, and a small study in an ALS mouse model suggested it may slow disease progression—most likely by reducing macrophage-initiated killing of neurons, a recently proposed mechanism for how ALS wreaks havoc on the body. Valor started a thread on an online ALS patient forum to discuss NP001, and several patients decided to inquire about taking part in the trial. But 7 years removed from diagnosis, Valor’s disease was far too advanced for him to qualify as a trial participant.

Though he has outlived the average ALS lifespan of just 2 to 5 years, Valor’s muscular paralysis is severe. Within 6 months of his diagnosis, Valor—once an avid surfer and snowboarder—had difficulty walking. He started using a cane, then a walker, then a wheelchair. Eventually the disease confined Valor to his bed, where a ventilator forces air into his lungs 6 to 8 times per minute. By the time NP001 was making a splash in the ALS community, his speech was barely intelligible, and he was unable to move any part of his body except for his eyes and some of the muscles of his face. In his condition, Valor was a risk for any clinical trial testing a treatment expected to slow progression: for the drug to show a noticeable effect, he would actually have to start getting better, rather than simply stop getting worse—something no drug had ever done for ALS patients.

So Valor looked into treating himself at home, scouring the Web through a computer linked to an infrared camera that tracks the movement of his right eye. (See photographs below.) Dozens of other patients who couldn’t get into the trial also searched for another way to try the experimental drug. On the basis of a literature search, a Phase 1 trial consent form, and a patent owned by Neuraltus cofounder Michael McGrath, the patients believed NP001 to be a formulation of sodium chlorite. Some purchased NP001’s precursor, WF10, which was known to contain just over 50 percent sodium chlorite and could be ordered from Thailand, where it was approved for treating the autoimmune consequences of cancer radiation. But for many, the cost of $12,000 for a year’s supply was prohibitive. Sodium chlorite, on the other hand, could be purchased from online suppliers for just $50 per quart—15 years’ worth at the dosage outlined in the patients’ documented protocol.

There’s a new model of medicine in my opinion. You see these DIY programs where patients are deciding, after doing an Internet search, that this is what they want to do; they go get the medicine; they take it; and they log their own output measures.
—­ Richard Bedlack,
Duke University ALS Clinic

Self-dosing patients went to great pains to ensure that what they were doing was safe. Because WF10 was already approved in Thailand, they knew that at least one form of chlorite had completed safety testing to satisfy that country’s regulatory authorities. Patients reached out to the drugs’ inventors, and spoke to their doctors and each other about the risks and the proper dosing. Even test engineer Tom Poast, who does not have ALS, chimed in on the patient forum with insights on the purity of chlorite solutions available for purchase, dilution and mixing, and the chemical’s behavior. More than 1 year and 1,000 forum posts later, some two dozen ALS patients decided ingesting sodium chlorite was worth a shot.

While the ALS community has taken do-it-yourself (DIY) medicine further than most, patients across the board are starting to play a noticeably bigger role in their own care. “There’s a new model of medicine in my opinion,” says neurologist and clinical researcher Richard Bedlack, director of the Duke University ALS Clinic. “Once upon a time we had a very paternalistic system, where patients would come, and they would have a set of symptoms, and doctors would ask all the questions and give all the answers. And in the past decade things have really shifted almost to the other side, where a lot of medicine is autonomous now. You see these DIY programs where patients are deciding, after doing an Internet search, that this is what they want to do; they go get the medicine; they take it; and they log their own output measures.”

And although Bedlack has concerns about the safety and effectiveness of patient-driven trials, he argues that patients’ greater involvement is a good thing—both for managing their own health and for deciding the course of drug development. “I don’t think anybody has more to gain or lose from all this than patients,” he says. “So I think they should be driving the agenda.”


A justified risk?

Eric Valor© ELIOT DRAKEThe sodium chlorite project was actually the third patient-initiated trial Valor had taken part in—and the second he had helped organize. The first well-organized and widely recognized patient effort to investigate a potential ALS therapy occurred in 2008, following a promising Phase 1 trial in Italy for the treatment of the disease with lithium carbonate. The 44-patient study suggested that lithium significantly slowed disease progression, as measured by two standardized rating scales, including a revised version of the ALS functional rating scale (ALSFRS-R)—and none of the 16 participants treated with lithium died during the 15 months they were monitored. ALS patient discussion boards began to spread the news. It could be years before lithium became approved as a treatment for ALS, but because the drug was already marketed for bipolar disorder, it was not hard for patients to get their hands on. Some 350 ALS patients began trying lithium to treat their symptoms.

Humberto Macedo, an ALS patient in Brazil, started a Google Docs spreadsheet to track self-reported ALSFRS-R scores. And Karen Felzer, a research scientist on the US Geological Survey’s Earthquake Hazards team whose father had ALS, built a website to host the project. At 3 and 6 months, Felzer, who has a background in statistics (normally devoted to analyzing earthquake aftershocks), examined the data. Both times, she found no evidence that lithium slowed progression. By November 2008, when Felzer posted her second report on the project’s website, most patients had stopped taking the drug.

It wasn’t until April 2011, however, that the broader scientific community took notice. That month, analysts at PatientsLikeMe, a social networking site that allows patients to input, track, and share data, published their own review, using the ASLFRS-R scores that ALS patients taking lithium had shared on their profiles (Nature Biotechnology, 29:411-14, 2011). The researchers had reached the same conclusion as Felzer: namely, that lithium doesn’t slow the progression of ALS—a finding confirmed by multiple formal clinical trials. But the report was met with immediate criticism, as concerned researchers questioned the validity of the PatientsLikeMe platform and how it might influence patients’ decisions.

As some people can attest, I have an ability to be a cold bastard. I just treat myself as another lab rat.
—­Eric Valor, ALS patient

“We gave [patients] the tools to evaluate things that are not going through the formal review process or are not approved or on market,” says Jamie Heywood, PatientsLikeMe cofounder and chairman, “so, at some level, you could be accused of empowering dangerous self-experimentation.”

Indeed, the most commonly cited concern about DIY clinical trials is safety. “I think it’s especially worrisome in [the ALS] field because of our history,” says Bedlack. “In 100 years of ALS research, we have found only one drug, which has a very small positive effect. We’ve found many things that don’t do anything at all, and we’ve found several things that actually are harmful to patients . . . things [that] actually wound up making people progress faster than doing nothing at all or taking placebo.”

With researchers and regulatory agencies unable to consistently predict when an experimental drug will do harm, many doubt that patients will do any better. Drugs like lithium, which are generally considered safe in their approved context, can cause unforeseen complications when taken by patients suffering from other diseases. Furthermore, drugs that have yet to receive the US Food and Drug Administration’s stamp of approval—or treatments that aren’t even in the clinical trial system, like ingested sodium chlorite—hold an even higher chance of doing physical harm. “I don’t think we know that any drug is safe in people with ALS until it’s gone all the way through extensive testing,” Bedlack says.

“There’s a reason that those safeguards exist,” agrees cardiologist Ami Bhatt of Massachusetts General Hospital. “Everything still has to go through the Phase 1-2-3 trial because at the end of the day what the patients and the clinicians and the researchers want is to be as systematic and safe as possible.”


A debate over value

BED-BOUND RESEARCH: Eric Valor views a screen above his bed. An infrared camera detects the movement of his right eye, allowing him to navigate the computer and type his thoughts, which he can e-mail or have the computer speak audibly to others in the room or over the phone.© ELIOT DRAKEBeyond the immediate safety concerns surrounding patient-led trials, the unregulated initiatives may alter the course of drug development. Clinical researchers already face precarious odds: fewer than 10 percent of novel treatments that enter human trials ever make it to market. In the face of such adversity, drug companies are understandably wary of any movement that could jeopardize their chances of success, including patient-initiated trials. Drug developers go to great lengths to control the variables in clinical trials, to optimize the dosing and the treatment window in order to reduce side effects while maximizing therapeutic gain, and to monitor patients’ health. If patients outside the clinical research system start taking experimental drugs on their own, the likelihood of something going wrong is greatly magnified. And if something does go wrong—something that may not have been caused by the drug at all—entire drug development programs could be shut down prematurely.

Stephen Byer of ALS Worldwide, an ALS support and advocacy group he founded with his wife Barbara, experienced firsthand the industry’s hesitancy to support the use of unapproved drugs outside a formally designed clinical trial. In 2010, 2 years after their son Ben lost his fight with ALS, the couple tried to convince Knopp Biosciences and Biogen Idec to initiate a compassionate-use program that would give ALS patients early access to their experimental compound dexpramipexole (“dex”), then in Phase 2 trials. “They listened very thoughtfully—it took almost an entire day for this meeting—and [in] the end, they said no,” Byer recalls. “They didn’t want to impinge upon their clinical trial.”

(Byer did eventually succeed in connecting a limited number of patients with the drug through an investigator-sponsored trial led by the drug’s inventor, James Bennett of Virginia Commonwealth University, who still holds the drug’s patent. And despite the recent failure of the formal Phase 3 dex trial, Byer and Bennett plan to carry on, citing differences in trial design. “We have a number of ALS patients who have stabilized or even improved on the drug, with responses lasting many months,” Bennett says—“very atypical for placebo responses.”)

Another concern is that patient self-experimentation will hurt enrollment in FDA-sanctioned trials, particularly Phase 2 and Phase 3 trials that include a placebo group to strengthen the analysis. Due to the risk of being randomly assigned to the placebo group, patients may be more inclined to obtain that drug on their own, so they can ensure that they get the active compound, than to join a trial.

In addition to the risks, critics argue that the data produced by patient-driven endeavors are unlikely to be of significant value. Innumerable biases can sully data that are self-reported by a self-selected population. Desperate patients may be more likely to unknowingly exaggerate their improvement, or see improvement where there is none, simply because they expect the treatment to be effective—the notorious placebo effect. Additionally, patients who choose to participate in such experiments are not necessarily a fair representation of the entire ALS population. “For instance, if the only patients who are taking sodium chlorite are patients that are very smart, and generally likely to be wealthier,” says Heywood, “[then] that population of patients is different than the rest of the patients”—they may have greater access to drugs, for example, or better supportive care. Patients resorting to self-experimentation may also, on average, be more progressed, skewing the data toward later stages of disease.

Patient-led trials diverge even further from scientific norms in their lack of placebo control groups—the gold standard of randomized controlled trials. Instead of placebo groups, both Felzer’s and PatientsLikeMe’s analyses of the lithium data matched treated patients with ALS patients in the PatientsLikeMe database who showed similar patterns of disease progression but did not take lithium. Such historical controls are often thought to be weak, as clinical care has changed over the years and other unknown factors inevitably influence analyses done on data collected for other purposes. But some ALS researchers argue that historical controls shouldn’t be so readily dismissed.

We gave patients the
tools to evaluate things
that are not going through
the formal review process
or are not approved or on market, so, at some level,
you could be accused of empowering dangerous self-experimentation.—­Jamie Heywood, PatientsLikeMe

Neurologist Robert Miller of the California Pacific Medical Center, head of the Western ALS Study Group and principal investigator on both the NP001 Phase 1 and Phase 2 studies, has been collecting placebo-group patient data from ALS trials conducted over the past 12 years. He first pulled controls from this placebo database of more than 1,200 patient records to analyze Phase 2 trial data on lithium for ALS. Miller then used the database to generate matched controls to analyze data from the NP001 Phase 2 trial, the promising results of which were announced in October.

“When you have a small group of patients, [especially] with a disease like ALS that has a lot of variation, and you have a lot of noise, then you have an imprecise measure of rate of decline,” Miller says. “When you add in historical controls, you get a much more precise placebo rate of decline, and it increases the power of the trial.” Though the FDA did insist on having a placebo group, the agency permitted Miller to use the historical controls to supplement those data.

Bedlack agrees that historical controls can be a powerful tool when used correctly. “We’ve got thousands of patients that we could use to adequately match every new subject and at least get an idea—is this safe, is this tolerable, is there any kind of borderline efficacy signal that means that this would be worth taking forward into a Phase 3 trial,” Bedlack says. “I don’t think we need a placebo-controlled Phase 2 trial to answer those questions.”

Still, he cautions, “you cannot go from [patient-organized] studies directly to a Phase 3 study. Diagnoses need to be properly validated; outcome measures need to be properly validated. . . . I think there needs to be a more traditional study.”


Equivocal success

On August 15, 2011, after his sixth dose of sodium chlorite, Valor recorded his first positive effect. “Seemingly clearer speech,” he wrote in his openly shared patient log. He did note that “observations at this point inconclusive as no clearly documented baseline available,” and that the effect would have to be much more dramatic to convince him that it was indeed working—but he was “intrigued,” he recalls.

Others noted similar improvements. Excitement stirred on the group’s forum when one of the more curmudgeonly patients, Ron Schaffer, reported mild improvements in his energy level. “No placebo needed,” one commenter quipped—“if in the end Ron says the stuff works, that’s a 99.9 percent confidence level with N = 1.”

That September, Valor, using only his right eye, finished building the project’s website where those taking sodium chlorite could post their results. “Now we’re a year into it, and it looks like it does help,” says engineer Tom Poast. So far, however, the evidence is purely anecdotal. Because most are more interested in the success of NP001, which they suspect will be more effective than ingesting sodium chlorite, the patient community hasn’t yet completed any formal analyses of the data. And troublingly, NP001’s inventors say that sodium chlorite taken orally should not work at all because the chemical will be quickly converted to chlorine dioxide, which is not only ineffective at quelling macrophages, but could even be toxic.

Indeed, a report published by PatientsLikeMe investigators last October on found that “sodium chlorite has a potentially negative effect; we have more than 80% confidence that it is worsening patients’ progression rate.” A second report by ALS Untangled, an organization Bedlack founded to review alternative and off-label ALS treatments, came to a similar conclusion. NP001, on the other hand, continues to impress: in October 2012, Neuraltus researchers announced that the high dose notably slowed disease progression, and even stopped it altogether in a subset of patients.

While the company seeks a Big Pharma partner to launch a Phase 3 trial, Valor continues to push for early access to the drug. “Because of my late stage, how much [of the chlorite] response would translate to useful improvement [from NP001] is a large question,” he says. “Still, I am excited to try.” For Valor, there is no conflict in playing both researcher and patient. “As some people can attest, I have an ability to be a cold bastard,” he says. “I just treat myself as another lab rat.” 


Read about some of the initiatives and copmanies that are taking advantage of the patient data deluge. JPG | PDF© ARTVEA/ISTOCKPHOTO.COMAlthough fully organized patient-run trials are still few and far between, patients are taking a more active role in clinical research. Now, more than ever before, patients have access to scientific knowledge as it’s reported, and advocate communities are flourishing, thanks to the wide-ranging, faster, and more accurate communication provided by the Internet. This increasing patient activism, and an accompanying willingness to share personal stories, has resulted in a veritable deluge of patient data.

“When you have gigabytes of data, perhaps hundreds of gigabytes, for each patient, that’s more data than has existed in all clinical trials combined up until a couple of years ago,” says Marty Tenenbaum, who in 2010 founded Cancer Commons, a database that collates real-time patient data and up-to-the-moment basic medical research to inform cancer treatment.

The online networking site PatientsLikeMe, for example, has accumulated more than 175,000 users who are recording information about hundreds of diseases, treatments, and outcomes. Of the 200,000 customers of direct-to-consumer genetics company 23andMe, some 85 percent have contributed their genomic and phenotypic information to research—totaling more than 80 million phenotypic data points for more than 60 conditions. And the Personal Genome Project, launched by Harvard Medical School’s George Church in 2006, has accumulated about 200 full genomes and 400 partial sequences, with some 1,500 additional volunteers who have already made trait data available online and are willing to share their whole genomes.

But the availability of such data is only one side of the coin. Without expert analysis, patient-generated data would be useless to the drug development community. Fortunately, initiatives and companies are cropping up left and right to support and take advantage of this movement.

Among the benefits of such stockpiles of data is the ability to sift through the challenging heterogeneity of patients, their diseases, and their case information. “Clinical trials, especially as they’ve been traditionally constituted—large randomized trials—just are a disaster in cancer, because of the nature of the disease,” says Tenenbaum. “Every tumor is unique at some level.” Databases that collate genetic data, such as patient genomes or the genomes of their tumors, could facilitate the identification of biomarkers to help differentiate responders and nonresponders, speeding a drug’s path to the clinic. “It could literally slash years, if not decades, off the normal process,” Tenenbaum says.

Platforms that support patient input can also help researchers develop better benchmarks for assessing disease progression and more accurate measures of patient health, as well as point to novel indications for existing drugs and promising drug combinations. “We’re enabling a new partnership between the patients and the physicians,” says Jamie Heywood, cofounder and chairman of PatientsLikeMe, “and that new partnership should produce outcomes at lower costs with lower risks and better innovation.”


Editor's Note: The author of this article, The Scientist editor Jef Akst, has launched a blog about her research into this story. Read more about Eric Valor and other patients taking a more active role in their own care at DIY Medicine.