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International Parkinson and Movement Disorder Society
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Off Label Prescribing of Disease-Modifying Therapies Under Investigation: Balancing Uncertain Risks and Benefits

Prescription DrugsDate: June 2018
Prepared by SIC Member: Connie Marras, MD, PhD
Authors: Roger Albin, MD; Samuel A. Frank, MD; Albert Hung, MD; Soania Mathur, MD
Editor: Stella M. Papa, MD



Advances in high-throughput drug screening techniques and artificial intelligence technologies (e.g. Benevolent AI or IBM Watson for Drug Discovery) are speeding up the process of drug repurposing.  Given the efficiencies inherent in repurposing drugs compared with developing new compounds tailored for specific therapeutic uses, drug repurposing is a hotly pursued avenue to identify new treatments for medical conditions and movement disorders is no exception.  When preliminary evidence is published considering the potential for an existing drug to be re-purposed for use in a movement disorder, clinicians are often faced with questions from patients about its use for them as an individual, and just as often with requests to facilitate access to the drug.  These requests pose ethical challenges as clinicians try to balance risks against benefits, and hope in as-yet-unproven therapies against adherence to evidence-based medicine.  Our threshold for acquiescing may vary depending on whether or not the patient has another medical indication for such a drug (such as hypertension in the case of isradipine in a patient with Parkinson’s disease).  In movement disorders we are not strangers to off-label prescribing, but in the case of re-purposed drugs we do not have the precedent of decades of use in our patient population.  To comment on this important issue we have invited three experts in the field, and then asked a clinician who also has Parkinson’s disease to give us the broader perspective of both sides.

Dr. Roger Albin:

“Off-label” prescribing of medications is common in clinical practice. Primidone, for example, is used widely for essential tremor treatment without an FDA approved indication. Recent early phase clinical research has led to pressures for off-label prescription of agents such as israpidine, nilotinib, and exenatide that might be disease-modifying agents for Parkinson disease (PD). Several of my patients requested these agents. Given interest in “repurposing” drugs, it is likely that such requests will become more frequent. I refuse these requests because such prescribing is unethical medical practice.

A cornerstone of ethical clinical practice is the principle of non-maleficence (Beauchamp & Childress; Principles of Biomedical Ethics, OUP, 2012). No medication lacks potential harms and prescribing in a patient population, such as PD, different from the original target population of an agent increases the risk of serious harms. An “off-label” patient population may experience known harms at a greater rate. Unknown interactions between the prescribed agent and the disease process might also result in previously unrecognized harms. Against the background of the miserably low ultimate success rate of agents (for all diseases) entering early phase trials plus the fact that our preclinical models of PD have no established predictive validity, “off-label” prescription of putatively disease modifying therapies for PD is taking unjustified risks with patient health.

At a community level, I believe this kind of “off-label” prescribing, however well intentioned, leads to an insidious form of intellectual and moral corruption. It is a truism that much of what we do in clinical practice doesn’t have firm scientific foundations. “Off-label” prescribing is one of the ways that inadequately evaluated therapies creep into clinical practice. It is very difficult to uproot established practice patterns. Applying rigorous standards for novel uses of established agents is critical to improve both the safety and efficacy of clinical care.

Dr. Samuel A. Frank:

Patients use many resources to identify available interventions that are “over-the-counter” and in development for other conditions looking for any possible remedy for an incurable disease.  When considering using therapies that are already approved for use in other disorders, we should distinguish between a potential disease-modifying agent versus an intervention with possible symptomatic improvement.  Unless there is clear evidence that an intervention changes the progress of a disease, we may be providing false hope for patients and potentially doing harm. 

If the off label use can provide some symptomatic benefit; we may be able to improve quality of life and functioning.  For example, if the disease-modifying potential of paroxetine for Huntington’s Disease is only based on in vitro data, but it clearly has benefits on mood, sleep, anxiety, etc., we may be justified in prescribing it for symptomatic therapy.  In that case, it would be critical to communicate with the patient that the primary purpose is symptomatic, not disease-modifying therapy.

I agree with Dr. Albin’s comment that we should focus on non-maleficence, but there are varying degrees of potential risks and benefits of off-label prescribing.  Take his example of a patient with essential tremor.  There are many patients with essential tremor who also have hypertension.  In place of simply adding another medication such as primidone, we may choose to change another hypertensive medication to propranolol, with little risk of harm.  The situation becomes more complex when we start to consider medications with more side effects or more invasive interventions; for example, a patient with cervical dystonia requesting a more “permanent” solution with deep brain stimulation for which there is limited evidence in focal dystonias. In these cases, we should consider steering patients toward evidence-based interventions that provide a better balance between harm and function or quality of life.

Dr. Albert Hung:

The lack of available treatments to slow down progression or modify the disease course presents the greatest unmet need in the management of Parkinson’s disease and other neurodegenerative disorders. Identification of drugs already FDA-approved for another indication or available without prescription presents an opportunity to speed up development of desperately needed therapies.  These repurposed drugs have the advantages of being readily available and having a generally recognized side effect profile (although not necessarily in PD patients). However, prior to clinical use, it is critical that these drugs be studied rigorously in randomized, blinded, placebo-controlled trials.  In the absence of this evidence, I do not recommend or prescribe these treatments. For appropriate patients, I encourage them to consider participating in clinical trials.

When drugs are used “off-label”, the benefits of treatment need to outweigh the risks. In situations where these medications are intended to improve symptoms, the benefits of off-label use can be clinically determined (e.g., immediate release amantadine for levodopa-induced dyskinesias, or quetiapine for PD psychosis), and treatment can be discontinued in the absence of a positive response. However, response to putative disease-modifying treatments cannot be followed in the same way. Prescribing these medications can lead to sustained use without benefit and potential side effects. In some cases, patients who are motivated to start one treatment off-label may want to take multiple drugs in this way. This will potentially increase the risk of adverse effects and unknown drug-drug interactions. It can also lead to unsubstantiated hope, denial of symptom progression, excessive pill burden (all of which may keep patients from taking proven symptomatic treatments that may improve their quality of life), and unnecessary financial cost.

I think that the discussion of whether to use these drugs is more challenging and nuanced in patients who have completed participation in clinical trials. Recognizing the limitations of existing preclinical models and confounding effects of symptomatic treatments in current clinical trials, we are obligated as clinical investigators to approach these studies with equipoise. Subjects in randomized, placebo-controlled trials may have different motives for consenting to participate in these studies, but at some level, it is likely that they have some hope that treatment may be of direct benefit to them.  It is not surprising that after committing significant time and effort to a study – in some cases, up to several years – they may wish to continue a repurposed study drug as long as there is a potential for benefit, especially if the expected risk is low. For some drugs, safety and tolerability has been assessed in a scientifically rigorous manner (e.g., isradipine, Parkinson Study Group, Mov Disord 2013). In these situations, I think it is appropriate to discuss thoughtfully the pros and cons of off-label use with patients, with the understanding that its discontinuation should be considered if subsequent clinical trials fail to show evidence for benefit.

This is an exciting time for drug development in Parkinson’s disease. As we consider how to apply the use of repurposed drugs with potential but unproven benefit to clinical practice, it is important to weigh carefully both pros and cons.  Depending on the situation, it may be appropriate to consider whether patients may be candidates for clinical trial participation or if they have another indication to use the drug. Our challenge is to achieve a nuanced balance of patient-centered care with evidence-based practice.

Dr. Soania Mathur:

From the perspectives of both a physician and Parkinson’s patient, I have experienced the pervasive and unrelinquishing challenges that are an inevitable part of this disease. Patients are understandably driven by a sense of urgency to find more effective treatments and are increasingly frustrated with a drug development process that they feel is too slow, wrapped up in bureaucracy, and not aligned with the degree of immediacy that the Parkinson’s community feels. The field of drug repurposing with the efficiency of using treatments that have already passed safety and efficacy studies for other indications is of great interest to patients and a source of hope.  News of a potentially effective repurposed treatment that may be able to improve quality of life raises hopes of those in the Parkinson’s community, and in this age of technology and social media, access to information is the norm. But the news is often not from the research community directly. Many patients are not able to decipher and interpret the scientific language in clinical trial literature and they rely on interpretations of the data by other sources such as the media, which is often guilty of sensationalizing the information they relay. This can result in misled patients pursuing and demanding a treatment avenue that may not be valid or safe. Patients turn to their physicians hopeful that they will have access to what they feel is a breakthrough treatment.

How should a physician approach this issue? Personally, and as has been expressed by others in this discourse, I too have a personal ethical issue with prescribing medications for conditions other than those indicated for their use and made it a point not to do so while in clinical practice. Having now experienced this disease first hand however, my position is not quite so firm. There are several potential scenarios to consider. For example, using repurposed medications that have a known safety profile (in other patient populations) for symptomatic treatment may not be an unreasonable choice as the effects can be judged clinically. Or if there are co-morbid conditions in a patient for which the physician can justify prescribing a certain medication, such as Isradipine in a hypertensive person with Parkinson’s disease, then the decision is less difficult. However, unlike symptomatic treatments that can be given for a short trial period, the decision may become more complicated when it comes to disease-modifying treatments, which necessitate long-term administration thereby increasing risk of side effects and financial burden, and ultimately may not result in a positive outcome.

I know that as patients we live with the knowledge that there is currently no cure; that although maintaining quality of life is most important, the real unmet need in Parkinson’s is a treatment that can slow and ultimately halt its progression. But I am concerned about the off-label use of any of the repurposed drugs currently being studied for this purpose. At the very least I worry that in the case of potentially disease-modifying treatments, it gives false hope to a group of patients that are often grasping for any possibility in their desperation to slow this disease’s progression. And I also worry about the safety issues with regards to its actions in Parkinson’s patients specifically.  Are there potential side effects or consequences that we have yet to see in other disease states? Could we unknowingly do more harm?

Given that shared decision making is the expectation of patients, the key to approaching this scenario, I believe, is education. Mitigating hype, patients have to be engaged in truthful exchange, and educated about the status of the current research, whether or not the treatment in question has resulted in tangible, clinically relevant outcomes that are safe and likely to be effective. And most importantly, patients need to understand that the treatment in question, although it may have been successfully prescribed in other populations, is not necessarily translatable to the Parkinson’s population both in terms of safety and efficacy. This allows patients to make a truly informed choice or at least have a clearer understanding of the decision-making process.

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