When families disagree with experts

I wrote last week about the deliberations at an FDA Advisory Committee meeting about an innovative gene therapy treatment for Duchenne Muscular Dystrophy. I highlighted the disconnect between the comments made by parents and patients, who all reported that the drug was almost miraculously effective, and the objective data from studies of the drug showing that the drug had many risks and no statistically significant benefits. It was impossible to reconcile the two sorts of assessments. One either had to believe the parents and ignore the data or believe the data and ignore the parents. Scientists and policy makers tend to believe the data and, more importantly, to believe that their objectivity is a virtue. They feel bad ignoring the heartfelt pleas of the parents but, in their hearts, they are convinced that they are doing not only what the law requires but also what is best for patients and families. The patients and families, understandably, feel otherwise. The anger of patients and families has become a cultural trope, the moving stuff of movies like Lorenzo’s Oil and Dallas Buyer’s Club.

I just spent a few hours listening to the discussions at February meeting of the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) and was struck by the very similar narrative arc. That Committee is charged with making recommendations about which newborn screening tests should be on the Recommended Uniform Screening Panel (RUSP). The RUSP is a set of recommendations to the states, which run newborn screening programs, about which tests for which conditions meet the strict criteria of the ACHDNC and thus become some of the only diagnostic tests that are done without consent and free of charge for every newborn baby.

To meet criteria, a test has to be accurate and there has to be a treatment that is available and effective. So far, there are 35 test/condition pairs that have cleared the ACHDNC hurdle.

The February meeting focused on testing and treatment for Krabbe Disease, a rare genetic condition in which babies are born looking perfectly healthy and then, in infancy, start to develop severe neurological problems. Most are dead in a few years. The only treatment is a stem cell transplant, which can itself be life-threatening. To be effective, the transplant must often be done in the first weeks of life, before any brain damage has occurred.

The problem is that tests to diagnose Krabbe are not perfect. So some babies have positive tests but may not develop the disease. So the question is whether a stem cell transplant can, in some cases, be more risky than watching and waiting to see if babies will develop symptoms. If so, then screening for the disease will expose more babies to treatments for which the risks may outweigh the benefits.

The ACHDNC meeting followed a pattern so similar to that of the FDA meeting about treatment for DMD as to be a little eerie. The pattern is also one that is likely to occur for many future treatments or screening tests. These two meetings thus give us a glimpse of the future of personalized medicine for rare diseases in childhood.

Both meetings started with public comments. The public comments were so emotionally moving that, after hearing them, only a person with a heart of stone would vote against any intervention that might relieve the suffering of patients and families with these terrible diseases. In the Krabbe hearing, the first public comment was by 12 year old Michael Wilson. Michael has Krabbe. So did his brother Marshall. Marshall was diagnosed at 18 months of age, too late for a transplant. Michael watched his brother’s slow demise and eventual death in hospice. Michael himself was tested at birth, diagnosed with the disease, had a stem cell transplant at age 4 months of age, and did well. Today, he said, he runs three businesses – lawn mowing, a lemonade stand, and a car wash. He plays soccer and tennis. He told the Committee, “Without the treatment, I would not be alive today.” Then Stacey Pike-Langenfeld, President of Krabbe Connect, pleaded for newborn screening. “Immediate action is required,” She said, “The only way these children can live a normal quality of life is to undergo a transplant in the first 30-45 days of life.” We heard about Grace and Madison, sisters who both had Krabbe. Madison was diagnosed at birth, had a transplant, and was cured. Grace didn’t, and died at age 4. After, the parents, two of the physicians who were pioneers in screening and treatment spoke about the urgent need for newborn screening.

Then, the Committee heard the objective evidence. It was, at best, equivocal. The Committee’s experts ended up concluding that the potential benefits of universal newborn screening did not outweigh the potential harms. The experts acknowledged that they were deeply moved by the ordeals and suffering of the families. Still, had doubts about the safety and efficacy of screening for Krabbe did not meet criteria for a recommendation of universal newborn screening.

The FDA Advisory Committee evaluating treatment for a new treatment for Duchenne voted narrowly in favor of approving the drug. The ACHDNC ended up with a tied vote, meaning that they did not recommend that it be added to the RUSP.

The reaction of advocates for screening was swift. Hunter’s Hope, an advocacy organization for people with Krabbe, wrote, “It should not be this hard to save a child’s life. Despite the irrefutable evidence, there was a tied vote. Children with Krabbe will continue to suffer and die.” Annie Kennedy, of the Everyday Life Foundation for Rare Disease, angrily wrote “But somehow... mind blowingly... after decades of effort and hundreds of children’s lives lost - today's vote yielded a tie. Krabbe will NOT being moving forward for addition to the RUSP.”

The treatment of rare childhood disease is one of the toughest issues in medical ethics and health policy. Everybody wants to do what is best for children. It is extraordinarily difficult to do the sort of rigorous studies that generate robust data. Good data is difficult to come by. Ultimately, we will need a new paradigm for research, public policy, and the financing of testing and treatment for rare diseases in childhood.

More on this in future blog posts. Stay tuned.