Is there a formula of risk tolerance to treat rare diseases?

Posted Monday January 06, 2014 by Melissa

Formula for assessing risk tolerance in rare disease

What risk would you take with your child’s life? What if the treatment had a 25% chance of death or serious injury, would you risk it?

The willingness of patients and caregivers to accept a level of risk when enrolling in a clinical trial or otherwise taking an investigational drug is different for every patient or family. However, there are some common factors that can be identified to create a model for how patients and caregivers often assess their risk tolerance.

I’ve developed a model for analyzing risk tolerance based on my discussions with families with different rare diseases and whose children are in different stages of those rare diseases. Hopefully this model, or something like it, could be useful by the FDA or others in analyzing the risk tolerance of patients and caregivers in enrolling in clinical trials, accessing investigational drugs via compassionate access (individual INDs or expanded access programs), or approving drugs for rare diseases.

For a disease that dramatically shortens a child’s life span, significantly impacts their quality of life, and for whom the continuation and perhaps increased intensity of these effects is fairly certain, when the current disease burden is significant, and when the child has progressed such in the disease that their lifespan is dwindling, the tolerance of risk in using an investigational drug is substantial.

Note that certain factors are disease specific, based on diagnosis alone, but they are affected and modified by the current effects and course of the disease on a particular patient.


What do you think? What would you add? What factors affect the risks you’d take to save your child?

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4 Responses to “Is there a formula of risk tolerance to treat rare diseases?”

  1. Leslie Phillips // January 6, 2014 at 10:32 am

    The primary consideration is that balance everyone hates to discuss: quantity versus quality of life. Of course, with an investigational treatment, there is the inherent risk of reduction in both…or the potential for an increase in both.

    The model of pediatric palliative care is one that focuses on the highest quality of life for the duration of life. Ideally, with a terminal illness, this should begin at diagnosis. When you have a rare disease with no (or limited) treatment options that generally leads to a dramatic decrease in the expected quantity of life, I agree that families (and the patients themselves, as appropriate) are more apt to have a higher risk tolerance, and understandably so.

    When you witness abrupt, rapid progression of disease, significant clinical change, and experience personal events (either witnessing changes in another patient, own life experiences, etc.), it seems more likely that you will take increased risk. I like the model, even though it is difficult to predict the nature of the disease specific factors.

    A large part of the FDA discussion this morning revolved around endpoints. For each patient and family, these vary; however, I believe it is important to discuss the markers that demonstrate measurable progress. Yes, this is something involved in a natural history study, but the prescribed endpoints may or may not be the things important to the patients.

    So, my expansion of this question is about what people think are the critical markers/endpoints for their families/patients/children?

  2. Carolyn Marie Keeney // January 6, 2014 at 11:37 am

    As the parent of a child with Hunter Syndrome, I have thought many times over the years about risk of the unknown (what I would find an acceptable risk were a clinical trial for a new treatment to be offered to us) versus risk of the predicted disease path. At the root of my decision, is a base formula that would be very similar to the one pictured. As I sit with an indescribable feeling of helplessness and watch my only child enter the age range of the average age of death for a child with Hunter Syndrome, and I watch the impact that the disease has on his quality of life, my risk tolerance climbs higher. When he was first diagnosed, my risk tolerance was much lower because in the denial of my mind, there was still uncertainty as to his prognosis; but, within two years time I would say that my risk tolerance had doubled when factoring in exposure to other children affected with his disease, a better education about the disease process, and his current impact of the disease. Since that time, it has grown even higher…

    Explain to me the risks; explain to me the possible benefits should I choose to accept those risks; explain to me the documented and predicted outcomes should I choose not to take the risks. Allow me to put the factors through my formula and decide for myself if it is worth it.

  3. Here is an interesting analysis of risk in the context of rare, degenerative disease performed by PPMD.;jsessionid=2C381495CB3753608053FD8DD624B686.app247d?docID=14503

  4. VERY complex topic as it is not purely an analytical decision but also an emotional one. Fear really plays a part in driving the decisions most people make, particularly when it comes to their children’s health. Not sure how you’d factor that in. That said, however, I’m a very analytical person and did actually put some analysis into our treatment decisions (along with heavy doses of judgment and faith). I looked at each treatment option and its potential outcomes. I assigned probabilities to each outcome (efficacy, lifespan, quality of life, risk of complications) to arrive at an expected value. I then factored in the probability of being able to receive each treatment option, the timing of receiving that treatment, and the expected time to benefit. Given the progressive nature of MPS II, the timing elements were really important. Finally I looked at the quality of life impact for our son, our other children and my wife and me for each treatment option. It took several months to gather all the relevant information, speak to the experts, and arrive at a decision. We ended up taking what many would consider a very high risk path, but after considering all the factors, it was not the highest risk option given our situation.