F

rom my days in medical school, I vaguely remember learning about lysosomal storage disorders. They occupied at most part of a lecture or two in my second-year pathophysiology course. I memorized a few details about these rare diseases in preparation for my board exam, and then never gave them another thought. These diseases were treated by pediatric specialists and wouldn’t be part of my life as a cardiologist.

That changed a few weeks ago when my 28-month-old daughter, Radha, was diagnosed with a lysosomal storage disorder. Now I know far more about these diseases than I did in medical school. I’ve also learned a frustrating fact that no medical school teaches its students: While the FDA has a compassionate use program to allow people access to experimental drugs, it can’t compel a company to provide those drugs. The newly signed “right-to-try” law doesn’t either.

Radha’s birth went perfectly. She was a healthy baby and met all of her developmental milestones — until it came to walking. My wife, Sonal, a pediatric gastroenterologist, recognized this and we had Radha evaluated by several specialists. None thought anything was physically wrong and indicated that she would learn to walk with the help of some physical therapy sessions.

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They initially helped. Then Radha’s progress slowed. Just after her second birthday, additional testing, including an MRI of her brain and spine followed by a genetic analysis, revealed that our daughter had metachromatic leukodystrophy.

This lysosomal storage disorder is an autosomal recessive genetic disease that interferes with the body’s production of a single enzyme, arylsulfatase A. Not enough arylsulfatase A causes a buildup of fats called sulfatides inside cells. In cells that make myelin, the substance that insulates and protects nerves, an abundance of sulfatides destroys tissue throughout the brain, spinal cord, and other parts of the nervous system.

Children with the most severe form of metachromatic leukodystrophy develop symptoms like trouble walking or poor muscle tone before the age of 30 months. Once symptoms appear, the prognosis is grim. Radha’s health will decline rapidly over the next three to six months. She will soon lose her ability to move, speak, see, and eat, and will be prone to seizures. The disease will then plateau for several years, leaving her in a vegetative state and unable to communicate. Our only hope is that she’ll always understand us when we tell her we love her, but we may never know. Most children with metachromatic leukodystrophy don’t survive beyond their 8th birthday.

Because we live in an era of rapid genomic innovation, gene-editing technologies such as CRISPR, proteomics, and rational drug design, I assumed that a disease caused by a single-enzyme deficiency was treatable. In my search for ways to help my daughter, I came across enzyme replacement therapies being developed for a number of conditions, including metachromatic leukodystrophy.

Shire Pharmaceuticals has developed a therapy for the disease and has even found a way to deliver it across the blood-brain barrier, which is no mean feat. The company has even completed a multicenter Phase 1/2 trial of the drug, called SHP-611 (also known as HGT-1110) in Europe, with what appear to be promising results. There was enough of a signal of therapeutic benefit from this trial to move forward with another one, though it appears to be several months to a year away.

Children with metachromatic leukodystrophy who were involved in the original trial have access to the drug as part of an extension of the trial. Radha developed the disease too late to take part in the first trial, and too soon to join the second one (if and when it happens).

Even so, that discovery gave me hope. It meant that Radha should qualify for what the Food and Drug Administration calls its expanded access program, also known as compassionate use. It governs the use of an investigational medicine that has not been approved by the FDA outside of a clinical trial.

Here’s how it is supposed to work. A physician caring for a patient with a terminal illness who has exhausted all other treatment options and isn’t eligible for a clinical trial appeals to the pharmaceutical company to provide an investigational drug that has undergone at least a Phase 1 trial, which studies the safety of a drug. If the pharmaceutical company agrees, the treating physician applies to the FDA for approval for expanded access to the investigational drug.

Thanks to policy changes at the FDA, it has become easier than ever for physicians seek access to investigational drugs. The application form has been significantly simplified and now only one member of a facility’s institutional review board needs to sign off on the petition. The FDA approves more than 95 percent such requests, and does so swiftly, usually in a matter of a few days.

Radha’s physicians followed Shire’s protocol for applying for compassionate use exactly as directed on the company’s website. Within a day or two, their request was denied, without any legitimate medical reason given.

With my daughter’s life on the line, I shamelessly used every contact and connection I have to reach someone at Shire to ask about compassionate use of SHP-611. When that effort yielded no responses, I called and emailed the current and former FDA commissioners, the head of the pharmaceutical trade association, PhRMA, the former CMO of a major pharmaceutical company, and even the dean of the medical school I attended. Most were cordial, even supportive.

Sonal and I even started a Change.org petition to help us nudge Shire to give Radha and her doctors compassionate access to SHP-611.

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All of our efforts to get answers from Shire have been repeatedly rebuffed with vague, unsatisfying responses, leaving me to wonder why the company is denying my daughter’s only hope. In fact, Shire has refused to correspond with me directly, and has instructed me to direct questions to it via my daughter’s treating physicians.

Large pharmaceutical companies are notoriously risk averse when it comes to expanding access to medications that are still in the testing phase. Many refuse to grant access to investigational drugs outside of clinical trials, and efforts to lobby them to release the medication as part of compassionate use are often rebuffed.

One fear they have is that an adverse event, like an injury or death — even if it is not directly due to the medication — will derail a company’s ability to push a drug forward for FDA approval, something they argue would ultimately undermine efforts to develop drugs that can help other families.

In response to this fear, FDA Commissioner Scott Gottlieb unveiled an updated policy on reporting adverse events that occur during compassionate use. It now requires reporting “only if there is evidence to suggest a causal relationship between the drug and the adverse event.”

Pharmaceutical companies also worry that if an experimental medication is given to one patient through compassionate use, it must be given to all patients who request it. In the case of rare diseases like metachromatic leukodystrophy — in the U.S., only about 60 children develop the late infantile form of the disease each year — this could mean that a company would have trouble enrolling enough patients when it eventually opens a clinical trial.

That’s a valid concern when access to the therapy is not time-sensitive. But in disorders such as the late infantile form of metachromatic leukodystrophy, the disease progresses so fast and irreversibly that patients who are denied access to the medication today will soon be so debilitated that they would not derive any benefit from it if and when it became available via a clinical trial, and so would not be able to enroll in the trial anyway.

The push for a federal right-to-try process culminated this week with President Trump signing a new law in a ceremony surrounded by patients with life-threatening illnesses and their families. In theory, this law will let patients and physicians bypass the FDA and go directly to pharmaceutical companies for access to investigational therapies that have undergone early testing. But it doesn’t require pharmaceutical companies to accede to these requests.

This new law requires drug companies to report clinical outcomes and adverse events, though it reduces their implications by stating that the FDA should not use this information to delay or adversely affect the approval of investigational drugs. As a physician, I believe that removing federal safeguards for experimental drugs is dangerous, and I believe that adverse events should be reported to the FDA as a way to prevent them from happening to other patients. As a parent desperate to help his daughter in any way I can, though, I hope this bill will allay Shire’s fears and encourage it to give SHP-611 to Radha.

I have never been one to malign pharmaceutical companies because I believe they are our best source of new and improved treatments. Yet Radha’s situation has made me cynical of a system in which pharmaceutical companies cater to investors and the physicians who prescribe their products rather than to the consumers of their therapies. I wish I could say that Shire is an outlier, but a quick internet search shows many similar situations where other pharmaceutical companies have denied compassionate use requests for what amount to business decisions.

Shire’s therapy represents the only reasonable hope for Radha and our family. If the company continues to refuse access to SHP-611 outside of a clinical trial, then why not open a new one? Its previous trial ended 15 months ago and yet there is still no sign of the follow-up trial that Shire claims it is working hard to start as soon as possible.

Much of what we do in medicine is based on analyses of benefits and risks. Shire has produced a drug that in early testing demonstrated safety with enough benefit to push forward follow-up trials. In Radha’s case, the potential benefits of SHP-611 clearly outweigh the risks, but only if we get the drug to her soon, before her condition deteriorates further.

Compassionate use and right-to-try are billed as ways to give hope to patients who have exhausted all other options. From Radha’s perspective, they are nothing more than a cruel joke, dangling a potential lifesaving therapy just out of her reach.

Vibhav Rangarajan, M.D., is a fellow in advanced cardiovascular imaging at Northwestern University’s Feinberg School of Medicine.

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  • Your story is not surprising to me. It appears that you have all but exhausted your possibilities for gaming access to Shire’s new drug. As an infusion nurse, I encountered a pediatric patient with intractable seizures that was repeatedly denied authorization for IVIG by the insurance company because it had not been approved by the FDA for his condition, despite letters of medical necessity & other please by the parents & medical providers because the seizures were becoming uncontrollable. In a list ditch effort to get their son IVIG treatment, which was not approved by the FDA for his condition but showed promise in treating his condition, they contacted our local state senator by writing a letter to him which described their son’s medical condition & the refusal of their insurance company to authorize payment with a plea for his help. A couple of days later, they received a call from their insurance company telling them that the IVIG treatment would be authorized. Perhaps contacting your state legislator(s) may help you obtain the drug—-after all, drug companies are huge donors to politicians & one hand washes the other in the world on politics. When you cannot reach a goal by yourself, sometimes you have to recruit assistance from “friends in high places”.

  • This is where I would love to see BioViva gain ground in the USA and create a center of care where Bioviva takes the risk of outcomes and off of the drug manufacturers, and use their own doctor network and help patients. Perhaps even, if the drug is well documented, make a version of the drug through a third party CRO.

  • There is a Non-profit organization Called The Spoonbill Foundation, check them out. They are out of the OSHU in Portland Oregon, they are currently developing a drug in house with the support of the FDA that can save many children’s lives and they are doing it all without help from the pharmaceutical company is being all done through Grant’s fundraising and donations. They want to use this method to develop more drugs for more issues affecting many people this is their trial they are bringing this drug from Discovery to cure and starting a trial this year and just a matter of a few short years. The trials going to be able to be done at people’s homes without costly trips the testing facilities this is saveing them so much money and able to bring this to the kids who need it faster. Do this Foundation they give updates on how much money they’ve received and where they are in the process they’ve always been open for communication and there’s no secrecy. For rare diseases this seems like a really interesting way to doing it cutting out the pharmaceutical companies and letting the people who need the drug on the truck while keeping the cost down cuz that’s their goal they said no one will get denied this drug do the money.

  • I also have a almost 4 yr old who suffers from a rare genetic disorder due to a missing Enzyme and most children die before 10. He has PKAN. There is also been a drug in trial for some time now and is finally in Phase 3, my son is too young to enter. However a few families with older sicker children asked for compassionate use through the FDA and Right to Try, both were denied by the pharmaceutical company.

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