Health

How a Controversial Medical Trial to Reverse Brain Death Slipped Through Regulatory Cracks

Himanshu Bansal wants to perform an experiment that will revive brain-dead people. However, he may have skipped some regulations while his previous research raises serious ethical and scientific questions.

Rebirth. Credit: Babe Fromars/Flickr, CC BY 2.0

Rebirth. Credit: Babe Fromars/Flickr, CC BY 2.0

A highly controversial clinical trial to revive brain dead people using a cocktail of interventions – stem-cell injections and infrared lasers directed into the brain (called transcranial laser stimulation) – has run into trouble with the Indian Council of Medical Research (ICMR). The trial, which made an international media splash, was questioned by doctors and medical ethicists who asked (here and here) if its lead investigator, Himanshu Bansal, an orthopaedic surgeon from Uttarakhand, had the expertise or scientific rationale to attempt such a project.

Even though the trial is registered with the Clinical Trials Registry, India (CTRI), which is hosted by the National Institute of Medical Statistics, a body under India’s apex medical-research organisation, the ICMR, the council now says that the proposed trial doesn’t meet regulatory requirements. It has asked Bansal for several clarifications, and says that unless the surgeon is able to answer these satisfactorily, his trial is liable to be deregistered. “We have registered the trial by mistake, and the CTRI can definitely withdraw it,” Geeta Jotwani, deputy director general at ICMR, told The Wire.

Bansal’s trial is an attempt to reverse brain death – defined as death of the higher brain, as well as the brainstem – in patients who have suffered traumatic head injuries. The Uttarakhand-based doctor, who runs several stem-cell research organisations, including the Dr Himanshu Bansal Foundation and Mothercell, plans to use a mix of methods including injections of unmodified stem cells, peptides, transcranial laser stimulation and median nerve stimulation (electrical stimulation of a major nerve in the arm) to attempt to revive brain-dead patients, who will be brought to his hospital after the family’s consent. The peptides for his trial will be provided by the American company Bioquark Inc. Bansal told The Wire that he expects his trial to start as early as next week, as soon as accident victims start arriving.

The debate over defining brain death

The definition of brain death has remained mostly unchanged for over 25 years now. The idea of brain death is premised on the belief that once a patient’s higher brain and brainstem stop functioning, a cessation of heartbeats and circulation is imminent even if the heart and other organs are kept functioning artificially. This is why organs for donation can be harvested from brain-dead people before life-support is withdrawn. Brain-death, in other words, is thought to mean death, or at least impending death.

Not everyone agrees on this, however. Some researchers have argued that the definition of brain death is inconsistent, dated and ready for a change. One reason for this is the rare cases of recovery from brain death which pop up now and again in the scientific literature. Most of these cases are of infants and young children who have returned to life after being declared brain-dead; the brains of young children are more resilient to trauma. But adults turn up in these reports, too. For example, in 1976, four doctors reported in a letter to the medical journal Lancet that a 60-year-old man who had been diagnosed as brain dead had recovered completely 24 hours later.

There is debate on what such anomalies mean because brain death can be misdiagnosed if doctors are not scrupulous in performing all the standard tests. Conditions such as barbiturate poisoning can mimic brain death, and anecdotal reports often do not clarify if all confirmatory tests such as the apnea test were performed. While full recovery, as in the Lancet case, almost never happens after brain death, there is evidence that the death of the brain and the brainstem does not lead immediately to the death of the rest of the body. So, brain-death is not necessarily death. A 1998 meta-analysis found over a hundred documented cases in which the bodies of brain-dead patients were kept alive for several weeks, with a child being kept alive for as long as 14 years.

Does this mean brain-dead people are not really dead? Technically, it seems that the body can, in some cases, remain functioning with aggressive support. But the prognosis for recovering brain function is terrible. Nearly none get this back and, eventually, even other organs cannot be maintained on life support. That is why the debate on redefining brain-death doesn’t really affect the diagnosis of brain-deaths in practice.

Bansal cites this body of evidence as scientific rationale for his project to revive such dead subjects. “When a young person is declared brain-dead after accident, all relatives want us to keep trying to revive him for a couple of days. We want to intervene at this stage because we have seen patients recovering after 72 hours,” he claims. When asked for evidence of his claims of having seen brain-dead patients recover all their functions (as opposed to staying alive on life-support), Bansal says he hasn’t published such anecdotes because he didn’t have permission to share the hospital data.

One of the examples he quotes in support of his project is the highly controversial case of the 13-year-old American adolescent Jahi MacMath, who was declared brain-dead in a California hospital in 2013. However, when her parents refused to believe she was dead, they were able to transfer the body of their daughter to New York, where laws allow life-support to be continued if religious belief contradicts the idea that the person is dead. MacMath continues to remain on life support today, but researchers have argued that this doesn’t contradict the diagnosis of brain-death, and that the decision of the California hospital to discontinue life support was correct. To use hospital resources to support a brain-dead patient indefinitely merely to indulge amateur misconceptions around the concept, when such resources are better utilised on patients who can benefit from them, is morally wrong, ethicists say. MacMath never regained consciousness since her brain-death diagnosis.

Questionable credentials

Even if Bansal’s rationale for the project was adequate, the problem is that the researcher’s credentials in stem-cell therapy for neuro-regeneration are unclear. His curriculum vitae says he has an MBBS and MS in surgery, has a particular interest in spinal cord injuries, and learnt about stem-cell research during several ‘visits’ to research organisations such as the Institute of Experimental Medicine in Prague. He has authored five publications documenting trials of stem-cell therapy for a surprising range of conditions: blindness due to methanol poisoning, autism, motor neuron disease, cerebral palsy and spinal cord injury.

All of these studies appear in the Journal of Stem Cells, published by a New York-based science publishing company called Nova Science Publishers. It has been flagged by academic bloggers as being a predatory journal: a journal which publishes articles by scientists without proper peer-review in exchange for a fee, and is frowned upon by the research community. Papers in such journals are usually fraught with methodological problems. Intriguingly, four of Bansal’s papers appear in the same issue of the journal for which Bansal is the editor.

One of his studies documents the cases of five people who became blind after consuming methanol and were purportedly cured by Bansal through the use of stem-cell injections. The case of a 22-year-old NRI among them received widespread attention in the mainstream media in 2011, while also raising eyebrows. But this paper throws up several red flags, says Dorairajan Balasubramanian, who researches stem-cell therapies for corneal repair at Hyderabad’s L.V. Prasad Eye Institute and is the chairman of India’s Task Force for Stem Cell Research, which frames guidelines for stem-cell research in India.

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Credit: D. Ashley/Flickr, CC BY 2.0

“There are several things wrong about that paper,” says Balasubramanian. For example, he says, the amount of concentrate containing stem cells which Bansal claims to have injected into the region behind the bulb of the eye is too high at 2 milliliters. “To put in 2 ml in the retrobulbar space is unheard of,” he says, because it could cause edema. The paper also says that 240 ml of bone marrow were harvested as a source of stem cells. Extracting so much bone marrow would be unwarranted when similar stem-cell transplants have used far smaller amounts, says Geeta K. Vemuganti, the dean of the School of Medical Sciences at the University of Hyderabad who previously worked as an ophthalmic pathologist at the L V Prasad Eye Institute. Vemuganti adds that a lot of critical information is missing from the paper. For example, the paper doesn’t say when the bone marrow was drawn and what the time lag was between this and the time when the stem cells were finally injected.”

“It is absolute errant nonsense,” Balasubramanian says.

Another big concern with Bansal’s work is how many of the trials listed in his five papers are registered with the CTRI, given that such registrations were made mandatory in India in 2009 to keep a tab on the quality of trials. In an email to The Wire, Bansal claimed that he wasn’t aware that this registration was mandatory. The CTRI website shows only three such trials by Bansal, but nothing on autism, cerebral palsy or motor neuron disease. This raises the question of whether these trials were illegal, given that India does not allow stem-cell use for treating any diseases – except for proven indications such as blood cancers and disorders. In all other indications, a clinical trial must be conducted. The ban was introduced in 2014 to combat the rampant exploitation of vulnerable patients by doctors offering unproven stem-cell treatments for a range of conditions such as hair-loss.

Bansal’s website makes dubious claims about having found stem-cell therapy effective in conditions such as autism and Parkinson’s disease, while suggesting experimental treatment for ageing, breast augmentation and penile enlargement. The ICMR has now questioned Bansal about these claims as well, although he told The Wire that these claims referred only to clinical trials and that therapy was offered“on compassionate grounds on an experimental basis only.”

Lack of living-cadaver research laws

The lack of a law on stem-cell research in India means Bansal’s previous research has, by and large, escaped scrutiny. But the decidedly controversial nature of his current trial to reverse brain death has turned the spotlight on him. Jotwani of ICMR says that the trial violates several regulations of clinical research in India. One of these violations is that the the ethics committee which gave permission to the trial isn’t registered with the National Apex Committee for Stem Cell Research and Therapy, as required under India’s 2013 guidelines for stem-cell research. Further, the trial is happening in collaboration with an American firm, which means it needs a go-ahead from the health ministry, and which hasn’t been received. Also, contrary to what Bansal has told the media, the trial is not exempted from receiving permission from the Indian drug controller.

Last month, Bansal told Scroll.in that he did not require permission from India’s drug controller because India does not have any regulations on clinical research on living cadavers, i.e. on the bodies of brain-dead people being kept alive by life-support. However, Jotwani says this is untrue, because Bansal never shared the protocol of his trial with the drug controller, opting instead to ask the controller through an RTI query if there were any regulations for research on living cadavers in India. When the drug controller responded saying there was no such regulation, Bansal took it to mean his trial was exempt. “This is misuse and misinterpretation of the RTI,” says Jotwani

Further, the problem with the argument that living-cadaver research is not regulated in India is that the trial attempts to revive brain-dead patients. In the eventuality that the trial succeeds, the subjects will not be living cadavers any more. “The hypothesis is they will get revived. Once they are revived, they will be human beings, won’t they?” asks Jotwani.

While Bansal is right about India not having any regulations for living-cadaver research, many other countries such as the US do not either, while others such as Canada apply the same guidelines for cadavers as they do for living subjects.

Living-cadaver research is useful in many cases. For example, researchers from the University of Pittsburgh, Pennsylvania, and the M.D. Anderson Cancer, Houston, have conducted such trials to test artificial lungs and to study how cells navigate the body’s blood vessels, after animal trials showed promise. The lack of government regulations, however, means that ethical guidelines need to be framed extremely carefully. A 2005 Nature Medicine paper lists some such ethical requirements: time limits on research, clarity on how the body will eventually be disposed, and the need for such research to answer an important clinical question.

In Bansal’s case, it isn’t clear if such guidelines were followed. He told The Wire that he had not thought of what he would do with the research subjects if he did succeed in reviving them. “We hadn’t thought of that. We had not planned for it,” Bansal said. Now, he says, after the media pointed out this flaw, he has purchased an insurance policy of Rs 50 lakh to treat and support the subjects if they do come back from brain-death. When The Wire pointed out that there may be other such ethical lapses in the consent form and asked to see it, Bansal said he couldn’t share the form because it was an “innovative” and proprietary document.

The chances of Bansal’s subjects returning to life, and regaining any kind of functionality, are extremely slim. Ira Pastor, the CEO of Biquark, the company supplying Bansal with material for the trial, acknowledges this. Responding to a question on how the trial could be classified as living-cadaver research when it was attempting to revive the cadavers, he wrote in an email to The Wire, “Frankly, if Indian authorities are actually even considering the eventual revival of patients at this juncture, even though we are quite far from that, then (aside from being flattered) we will deal with that eventuality in the appropriate manner at that time.” The real question, then is: what important clinical question does an experiment serve when it doesn’t expect to meet its own outcome?

Pastor has also defended his company’s decision to supply materials for a trial so beset with ethical issues. On the question of the lack of peer-reviewed research from Bansal, Pastor wrote in an email, “In an era of tens of billions of dollars wasted on irreproducible pre-clinical research each year, and tens of billions of dollars more of irreproducible clinical research, the peer-review process has its own demons to sort out.”

While the fact that Bansal’s trial was registered with the CTRI despite its gaping flaws points to major weaknesses in the CTRI’s functioning, it also raises bigger questions about the stem-cell regulatory regime in India. Balasubramanian says there are many other stem-cell researchers in the country today who carry out dubious research. This is because India currently only has guidelines for stem-cell research, and no law.

The only way to rein in the burgeoning industry of problematic stem-cell research is for the guidelines to become an Act of parliament. “Such researchers rule the roost because we only have guidelines. If you disobey them, (the regulator) can hit you with a wet noodle. That’s about it. That’s the problem,” Balasubramanian says. For now, it isn’t clear if the law will be here anytime soon.

Note: An earlier version of this article misattributed the quote about extracting too much bone marrow to Dorairajan Balasubramanian. It has now been correctly attributed to Geeta K. Vemuganti.