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Mark Jacunski, a medical student from King’s College London, is one of our three essay competition winners. His writing explores the medical and ethical issues involved in treating rare diseases with off-label prescriptions.

In 1999, Jesse Gelsinger became the first known case of death due to complications stemming from experimental gene therapy1. Just recently, in November 2015, Layla became the first widely-publicized successful recipient of gene-edited donor cells to remit an unyielding leukaemia2. As these two cases may suggest, more sophisticated techniques and deeper knowledge have allowed experimental medicine to progress substantially. Indeed, many believe that we are on the brink of a revolution of personalized medicine.

However, analogous to personalized medicine, using off-label drugs to treat patients with rare diseases is still controversial. On one hand, it is important both not to set a precedent for unsubstantiated treatments and also to acknowledge the greater risk associated with off-label treatments. On the other hand, patients with rare diseases have no other adequate options, in part due to research and development focus on more common, economically-disruptive conditions in society, such as obesity or cancer.

Fundamentally, we choose to consider using off-label drugs for rare diseases because on-label treatments are either unsuitable or inadequate. In some cases the lack of on-label treatments for rare diseases will be a consequence of a lack of understanding of the pathology; rare diseases may not be the subject of much academic research. Funding sources for academic research have made it strikingly clear that they favour topics which are translatable to treatments which will alleviate healthcare systems the most3. This may be a natural conclusion of their cost-benefit analyses, despite widespread agreement among scientists that riskier and perhaps less-directed research is often the most beneficial.

Many of these same scientists argue that the translation of basic research to clinical treatments falls under the direction of pharmaceutical companies. Indeed, another reason that on-label treatments for rare diseases do not exist is because pharmaceutical companies have concluded very similarly from their cost-benefit analyses. The cost of developing a treatment has by some estimates amounted to several billion pounds sterling4. With over a decade of development and only fifteen years of on-patent exclusive sales to make up for the astronomical costs, pharmaceutical companies understandably search superficially for the benefit. Furthermore, for rare diseases there may in fact not be enough people with the conditions to achieve the same rigour. Hence, the approach of pharmaceutical companies has generally been to target the largest market in which they will have the largest market share. In other words, they target common diseases.

Because of this, people suffering from rare diseases are at a tremendous disadvantage in finding treatment. Hence, it seems appropriate to at least consider the use of off-label treatments. The problem then lies in finding an appropriate off-label treatment in the first place. But there may not be enough data about potential treatments to confidently make a decision. One of the reasons that developing a treatment costs so much is that regulatory bodies and insurance companies demand rigorous testing of the treatment before it is used. Normally, these rigorous tests yield evidence that forms the basis of modern – that is, clinical evidence-based – medicine. In the case of choosing an off-label treatment, the paradigm of medicine will have to shift to a more hypothesis-based approach: even when no conclusive clinical research exists, scientists and healthcare professionals can conjecture based basic scientific knowledge.

Supposing that a choice could be made, the risks of using an off-label treatment must be considered. There will be far less data about the treatment’s action, and especially not about its dosing, its clearance from the body, its side effects, and its long-term consequences. Indeed, using an off-label treatment is in principle a riskier path to take. But only a patient can determine whether that risk is worth it for themselves. The informed patient is the best judge of the value of treatment5: do they value treatment at the ostensible risk of complications above living with the rare disease, or above dying with the rare disease6? Additionally, the patient may even choose the risky off-label based not on the value of improvement but rather on the virtue of actually trying to battle the condition. Evaluating these options is a highly subjective activity, and patients are autonomous beings that are capable of making decisions with the help of healthcare professionals.

Unfortunately, even if there is a promising off-label treatment and the patient has agreed to the risks, sidestepping regulations can set a precedent. As mentioned, the regulation of treatments is in place in order to make sure that treatments given to patients are scientifically-sound and medically ethical: treatments must actually work and the benefits should outweigh the risks. It may seem reasonable to sidestep the regulatory requirements if part of the healthcare community supports the treatment, and no adequate on-label treatments exist. But a line has to be drawn. There is no concrete line between an off-label treatment supported by extensive non-clinical evidence and a large team of doctors, and a magical potion supported by a couple of obscure scientific reports and a dogmatic physician.

Perhaps one such concrete line can be drawn with standardizing non-clinical research. Advances in biology and its techniques now allow scientists to study physiology evermore faithfully. For instance, cell culturing systems using induced pluripotent stem cells can use blood taken from a patient and do countless relevant experiments on their own cells7. Moreover, advances in microscopic imaging techniques such as stimulated Raman scattering microscopy allow scientists to observe biological processes at a molecular level without needing to use dyes or stains that could interfere with those same processes8. With these techniques, and many others, much more has become possible in a laboratory setting. Having more concrete standards of basic science experimentation could make deliberations over off-label drugs more objective.

It is also important to consider that advances of biological techniques have given rise to unfathomable amounts of information that could be used in these deliberations. Information from the “omics” revolution, famously starting from the Human Genome Project completed in 2003, is slowly being untangled for practical use9. The untangling is being done in part by in silico approaches, that is, computational biology, that allows us to make predictions based on data that would otherwise comprise of an “impossibly large experimental burden”10. Standards in using computational approaches along with increasingly sophisticated experiments could allow us to know a great deal about drugs, making them much safer to use even without extensive clinical trials.

Despite these advances in treatment, there will have to be a little more care taken for every patient. For example, any information about dosing is likely to be less informative than the information coming from large clinical trials. There will have to be more gradual treatment implementation, and more monitoring. Since there are so few patients, each patient effectively ends up going through a sort of clinical trial on their own. In this way, the dilemmas that come with treating rare diseases probably foreshadow questions that will be raised about personalized medicine. Particularly since the Human Genome Project was undertaken in 1990, people ranging from politicians to journalists, from scientists to patients have been raging about the possibility of personalized medicine11. And yet many of these same people manage to shy away from what seems to be an early and specialized form of personalized medicine, that of treating rare diseases with off-label drugs.

The risks that come with treating rare diseases with off-label treatments can be discussed and managed by an assiduous team of healthcare professionals and the patient. This treatment and management will be imperfect. In fact, it may be unacceptable in reference to the painstakingly tested on-label treatments. But in a time of financial tumult for many research bodies, and soaring research and development costs for pharmaceutical companies, perhaps it is time to acknowledge that alternative approaches exist. In particular, since it is important not to set a precedent in allowing off-label drugs to be used, regulatory structures should be put in place that allow for scientifically-backed off-label treatments to be used on people for whom adequate options do not exist.



  1. Wilson, J. M. A History Lesson for Stem Cells. Science 324, 727-728, doi:10.1126/science.1174935 (2009).
  2. Reardon, S. Leukaemia success heralds wave of gene-editing therapies. Nature (2015). <>.
  3. Gewin, V. Risky Research: The Sky’s the Limit. Nature, 395-397 (2012).
  4. Herper, M. How Much Does Pharmaceutical Innovation Cost? A Look At 100 Companies. Forbes (2013). <>.
  5. Silverman, J., Kurt, S. & Draper, J. Skills for Communicating with Patients. 3 edn,  (CRC Press, 2013).
  6. Hursthouse, Rosalind, “Virtue Ethics”, The Stanford Encyclopedia of Philosophy (Fall 2013 Edition), Edward N. Zalta (ed.) <>
  7. Kunisato, A. et al. Direct Generation of Induced Pluripotent Stem Cells from Human Nonmobilized Blood. Stem Cells and Development 20, 159-168, doi:10.1089/scd.2010.0063 (2010).
  8. Liao, C.-S. et al. Microsecond Scale Vibrational Spectroscopic Imaging by Multiplex Stimulated Raman Scattering Microscopy. Light, science & applications 4, e265, doi:10.1038/lsa.2015.38 (2015).
  9. Best is yet to come. Nature 470, 140-140 (2011).
  10. Jacunski, A., Dixon, S. J. & Tatonetti, N. P. Connectivity Homology Enables Inter-Species Network Models of Synthetic Lethality. PLoS Comput Biol 11, e1004506, doi:10.1371/journal.pcbi.1004506 (2015).
  11. Collins, F. S. Medical and Societal Consequences of the Human Genome Project. New England Journal of Medicine 341, 28-37, doi:doi:10.1056/NEJM199907013410106 (1999).

There is more than one way to show a treatment works

by Guest Contributer time to read: 7 min