The terms risk, benefit, effectiveness, and safety are key to the approval of all new medical treatments (and of previously approved treatments for new uses). However, there is a vast divide between the concepts of relative risk and relative benefit (for a well defined group of patients) and the concepts of effectiveness and safety. The distinctions between these concepts are particularly important in the world of rare diseases.

Imagine if you will that you belong to a family that carries the gene for Huntington’s disease. Huntington’s is a rare, inherited, autosomal dominant, neurological disorder, initially described in 1872. Its key characteristics include involuntary movements, dementia, and significant behavioral changes. It is incurable; there is no known treatment for the disease itself; it is normally an adult-onset disease; but we are able to tell that patients carry the gene for this disorder at the time of birth. (And juvenile-onset Huntington’s can and does occur in patients as young as 2 years of age.)

Some readers may know that the 20th Century folk singer Woody Guthrie had Huntington’s disease and died from related complications in his mid 50s.

One potential form of treatment for Huntington’s would be gene replacement or some comparable therapy that could be given long before any of the symptoms of the disorder started to appear. Let’s call this Treatment A. However, the symptoms of Huntington’s do not usually appear until a patient is 35-45 years of age. So, any effective treatment given before symptoms appear would be a treatment given to an otherwise healthy child or relatively young adult. Furthermore, let’s say that, to be effective, Treatment A would have to be initiated before the patient is 18 years of age.

A second potential therapy for Huntington’s (Treatment B) would be some form of disease modifying agent that could be administered at the earliest onset of symptoms of the disease, and would simply prevent or delay any further progression of the condition. In this case, treatment would be initiated only for patients with early stage, progressive, and symptomatic disease.

Now if Treatment A and Treatment B were both available and were both 100% effective and 100% safe, this would be just wonderful. Patients and their families could choose whether they wished to use Treatment A early or Treatment B later on, and Huntington’s would be a curable disease with no associated side effects of treatment. Unfortunately, to date, no one has ever been able to develop any type of drug for any disease that is 100% safe. Every known form of drug therapy has side effects in at least some people … and no drug is effective 100% of the time, either.

So … let’s look at the situation in which Treatment A is discovered to be effective in 50% of cases but also has one really serious adverse effect that occurs in 50% of all patients. Conversely, Treatment B is discovered to be effective in 35% of cases but has a different serious adverse effect that occurs in 25% of all patients. Therefore, if we use Treatment A in otherwise healthy young patients, we have a 50% probability of curing their Huntington’s disease and extending their lives (as well as the quality of those lives), but also a 50% probability of inducing a really serious side effect that absolutely will lower the quality of their life (and perhaps the extent of their life) immediately, some 15 or more years before they are likely to have any symptoms of Huntington’s at all. Alternatively, we can avoid using Treatment A and wait until symptoms of Huntington’s disease become evident. At that point in time, we can use Treatment B, which has a lower likelihood of curing the disease (only 35%) but also a lower likelihood of any serious adverse effect (just 25%).

Decisions about whether to approve Treatment A or Treatment B for use in patients with Huntington’s disease (or any other condition) are made by regulatory authorities like the Food and Drug Administration  – usually with significant input and advice from independent specialists (and often from relevant patient groups too). Decisions about whether to use such drugs are made by individual doctors and their patients. It is certainly not my (or NORD’s) goal to tell anyone what is right or wrong in either of the above two (very simplistic) scenarios.

However, what is important to understand is that efficacy and safety are not the same as risk and benefit. A drug like Treatment A is clearly effective in half the patients it is used to treat … but would you want to use this drug to treat your symptomless, otherwise healthy 17- or 18-year-old son with Huntington disease, knowing that you had a 1 in 2 chance of curing that disease but also a 1 in 2 chance of inducing a side effect that could seriously affect the remainder of his life (whether Treatment A was actually effective for him or not)? Or would you think that Treatment B might be the less risky option … even though it is less effective too?

For children born with some rare disorders, who are almost certainly going to die within a few years of diagnosis if no treatment is available, it is clear that some families will (appropriately) feel that greater risk for adverse effects of any form of therapy may be acceptable in return for the chance of extending the lives of those children. The willingness of regulatory authorities around the world to exert flexibility and to approve new treatments when the risk for early mortality is so high is increasingly apparent — even though the evidence of effectiveness and safety may be relatively low (because of the difficulty of conducting clinical trials that meet traditional standards of evidence for approval of drugs for common disorders). It is also entirely understandable that regulatory authorities need some reliable idea of the relative risks and relative benefits associated with a specific treatment for a specific disorder (however rare) before approving such a treatment for regular use. Doctors and their patients also usually want some degree of confidence that a treatment offers a greater likelihood of benefit than of risk. Such treatments may not have high efficacy and they may well come with significant safety issues. Despite these flaws, regulatory approval may be highly appropriate if there are no other therapeutic options. Regulatory approval with no clear understanding of the benefit to risk ratio in a well-defined set of patients is a much more serious issue.

The passage of the new Food and Drug Administration Safety and Innovation Act (FDASIA) earlier this year has laid out a series of opportunities for the rare disease community, the Food and Drug Administration, and the biopharmaceutical industry to work more cooperatively — and efficiently — on ways to gather and evaluate data that can help us all to assess the risks and benefits of potential new drugs for rare disorders. This will be a major area of focus for NORD over the next few years.

We absolutely need better tests (“biomarkers”) to be able to tell if specific drugs are working. We need greater willingness for all parties to work together to better define the risk-benefit ratios that will allow approval of new drugs for patients who have no (or only very ineffective) therapeutic options today. We need greater financial resources to invest in the necessary scientific and clinical research. We need more (and sometimes better) natural history and other types of registry data so that we can accurately compare the effects of drug therapy to the natural progression of a rare disease in untreated patients (when patient numbers are too small to even consider the possibility of randomized clinical trials). But, above all, we need to understand and to distinguish between a drug’s effectiveness and safety in the treatment of patients with a specific disorder and the potential risks and benefits of approving that drug for use and of actually using that drug in an individual patient. Drugs for many rare diseases may well have lower levels of effectiveness and higher levels of adverse events than drugs used today to treat common disorders like hypertension or otitis media, but understanding the potential benefits and the potential risks associated with the use of such drugs in well-defined patients remains a scientific, a medical, and an ethical priority.

Note: There is currently no known treatment for patients diagnosed with Huntington’s disease that can delay the onset of symptoms or prevent the progression of this disease. However, symptomatic treatment of patients may improve their quality of life and prevent complications. Those interested in ongoing research into potential treatments for this disorder may want to visit the web site of the Huntington’s Disease Society of America or that of the Huntington’s Disease Lighthouse Families.