As the Titanic was sinking, the story goes that those few lucky enough to be in lifeboats, relatively warm and dry, were singing songs to drown out the cries for help from people drowning in the cold dark Atlantic. The safe people were afraid to go back and try to save anyone because perhaps something bad would happen. Maybe their boat would get swamped by people needing help or they could not save everyone and would have to face the dying as they sink. Their fear of the risks caused them to sing songs and search for reasons that the status quo was best.
The situation then has some parallels to the current situation in developing treatments for rare diseases. Time and again, I hear songs about why the status quo works and everything is fine, and yet people know that the cries are out there, and the feeling of dying with an untreated genetic disease is not far off from drowning in the cold, dark Atlantic. I have heard so often,"Patients with genetic diseases deserve just as good a treatment as those with common diseases". This is a traditional suave applied to the wound of scientists and parents trying desperately to get their kids treated. When you are drowning, you don’t really have that much time to discuss the quality and design of various types of life preservers. The truth is that the standards for drug development of large market diseases cannot readily apply to rare diseases and often the barriers created, mean that no very rare diseases, and no diseases with complex biology can ever get a drug treatment.
The idea that the quality standard of large market drugs needs to be maintained is also arbitrary and hardly compelling. So, the standard of "just as good as the others" means that people treated for diabetes still don’t die from diabetic complications, or that heart attacks don’t occur for people on cholesterol-lowering drugs, or that cancer patients on chemotherapy are all being saved? The truth is that all drugs are part of an ongoing struggle to fend off difficult diseases. Rare diseases have the double burden of having less information and more complexity making the standard more onerous than for common diseases. The fact is, that for most rare diseases that lack any real treatment, the proposed treatments are a clearer attack on the disease biology, and the benefit to them is far greater than for treatments of most common diseases. But the regulatory and development process is far more difficult for rare diseases both because of the smaller numbers and variability and but also the lack of historical clinical data.
The fear that perhaps we might approve a drug that does not work as well as we thought, or that a drug that did not get a double-blind placebo controlled study is not as good as one that has, or a new surrogate endpoint that is unproven, might not be the best choice, are the type of fears that paralyze our ability to do something intelligent for rare disease pateints. During the early part of the AIDS crisis, the intense public pressure brought forth regulations (Subpart H) to allow a blood test for T4 cells to be used as a primary endpoint before we knew for sure this was right. From this "risky" step, numerous drugs started in development and were approved, and many more entered development, as the risk of development for companies was lowered by this change. A decade or so later, we have a substantial number of HIV drugs and guess what, we are using a different better surrogate endpoint now for HIV. Science progressed and in the meantime, investment occurred and many good HIV drugs were developed. The "cries for help" in this case were loud enough to get attention and that bold action has changed the path of HIV infection for many. The promise that came with the Subpart H regulations from that era, has not been as fully realized for rare disorders, because of the fear that without clinical validation, the new surrogate endpoints cannot be used. The fear of making a mistake and not using sound science to make reasonable decisions means that most rare diseases cannot use the accelerated approval Subpart H regulations. This is a mistake.
When someone is telling you in support of the status quo, that "Patients with genetic diseases deserve just as good a treatment as those with common diseases" make sure to ask them to finish the song with the words, "or nothing". They should say "Patients with genetic diseases deserve just as good a treatment as those with common diseases or nothing." Or nothing, unfortunately is what most are getting. Time to stop singing, and start rowing.
