Photo illustration by Kerry Prugh
Do you have a movie you consider a guilty pleasure? A movie so bad that you are embarrassed to tell your friends about how you watch it every year?
For me it is Swordfish. It came out in 2001 and received many poor reviews, but I secretly like it and often fixate on one particular scene. Gabriel (John Travolta) gives Stanley (Hugh Jackman), a hypothetical: “You have the power to cure all of the world’s diseases. But the price for this is that you must kill a single innocent child. Could you kill that child to save the world?”
Stanley replies, “No!”
Gabriel: “You disappoint me, Stanley. It’s the greatest good.”
Stanley: “How about 10 innocents?”
And the exchange continues. It makes me wonder: Could I kill one innocent child to save so many?
Honestly, I could not.
This question is maddening for me, because I work in rare disease research. The Food and Drug Administration (FDA) confronts my colleagues and me with Gabriel’s scenario through its rigid regulatory reliance on placebo-controlled clinical trials.
The mission of the FDA is to protect human health. To fulfill that mission in the realm of pharmaceutical research and development, it is typically quite important to have placebo-controlled trials. Such trials, in which some patients blindly receive false, inactive treatments in place of the experimental drug, are the gold standard in demonstrating the effectiveness and safety of a given therapy, and they’re ideal for nonfatal diseases that affect large patient populations.
Rare diseases — defined as those that affect fewer than 200,000 patients in the United States — are different. A significant number of rare disorders are considered ultrarare and affect fewer than 1,000 patients, typically children, and are fatal. Most of these illnesses you have probably never heard of like Niemann-Pick Type C (NPC) disease. In studies of treatments for these diseases, the placebo control is an almost impossible standard. And yet it holds.
I run the Ara Parseghian Medical Research Fund at Notre Dame. It was formed in 1994, soon after the three youngest children of Cindy ’77 and Mike Parseghian ’77 were diagnosed with NPC.
NPC is a neurodegenerative disorder that leads to abnormal accumulation of cholesterol in a cell’s lysosomes, the organelles responsible for breaking down cellular material. Ultimately, this buildup leads to the degeneration of a person’s central nervous system and other tissues. Most NPC patients are diagnosed as children. Eventually they lose their ability to walk and talk, and most die as teenagers, although there are adults with NPC.
When the Parseghian children were diagnosed, scientists knew nothing about the disorder. But due to the resilience and hard work of the Parseghians and so many others, we now have a much better understanding of it. As of this writing, four therapies have completed late-stage clinical trials. One may soon become the first NPC treatment approved for medical use in the U.S.
The small patient populations for diseases like NPC mean relatively few people are available to participate in a clinical trial, which in a study of a drug intended to treat a more common disorder may involve tens of thousands of patients. Further, rare diseases affect each patient differently, making baselines hard to establish.
In the case of NPC, some patients may lose their ability to walk while their mind remains intact. Others can run sprints but have the mind of an infant. Without an identifiable biomarker — a biological indicator of a disease, which is unknown for most rare conditions — the only way to tell whether a therapy is working is time. And time is what most of these patients do not have.
Still, FDA regulations stipulate the placement of these patients into placebo-controlled trials that run for years — and that’s too bad, especially for those who are assigned the placebo.
That’s why I keep thinking about Swordfish. The federal government’s stance toward parents of children diagnosed with NPC might be phrased this way: “Your child may get the placebo and would then continue to get sicker and possibly die in order to demonstrate that a therapy is helping and save future generations.”
If this feels ethically OK to you, I have some families I would love you to meet.
One is the Andrews family of Austin, Texas. Both of their girls, Belle and Abby, have NPC. Belle was diagnosed at age 5 and Abby at 18 months. Belle was enrolled in a clinical trial for an experimental therapy and, unfortunately, received the placebo. Abby was too young to be enrolled, so she received compassionate use of the therapy (a way to access a treatment while it is in development). While children with the experimental drug stabilized, Belle declined. She declined so rapidly they removed her from the trial. Today, as a young teenager, Belle uses a wheelchair and needs 24-hour medical attention.
Belle and Abby came to our annual research conference this past June. We hosted a childcare room, and Belle spent her time mostly confined to her chair — and charming the volunteers — while Abby was busy running and playing.
My 12-year-old also came to the conference, and when I told her that Abby has NPC she was confused and frustrated. “Why is it so much worse for Belle?” she asked. Would this cruel disease start tearing away at Abby?
I, too, am confused and frustrated. I can’t stop thinking about the placebo group. Would Belle be running around like Abby if she had not received the placebo? Belle is not a piece of data but a little girl. She and her sister are the whole world for their mother and father.
What can we do about this?
Laws are in place that allow the FDA to provide regulatory flexibility and to encourage pharmaceutical companies to work on rare diseases: the Orphan Drug Act, the 21st Century Cures Act, the Right to Try Act.
These measures help. They provide clinical flexibility, but ultimately the FDA can still require a placebo-controlled trial. Today, a bipartisan bill called the Promising Pathways Act would allow for conditional approval for serious rare or progressive disease treatments based on early evidence of safety and efficacy. The bill would relax requirements for placebo-controlled trials, enabling patients with rare ailments to access treatments more quickly while still requiring pharmaceutical companies to provide further evidence — by monitoring patients in comparison to their medical history and other clinical data, for instance, in order to confirm long-term benefits and maintain patient safety.
Even if this legislation passes, the FDA and drug developers would not be mandated to use the flexibility the bill offers unless every person who feels that children like Belle should not receive a placebo makes sure the FDA understands that the patient’s voice comes first, that they should use the data they have without a placebo control whenever possible.
Maybe someday we will not have to answer the Swordfish question. Maybe instead of letting a few die to save the many, we can save them all.
Sean Kassen is director of the Ara Parseghian Medical Research Fund in the College of Science at Notre Dame, where he earned his doctorate in cell and molecular biology.