A patient's perspective

In 2011 Les Halpin was diagnosed with motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS). Since his diagnosis, Les has been committed to accelerating the development, approval and licensing of novel therapies for people with life threatening illnesses. Two years ago he also founded Halpin Neurosciences, a privately owned biotechnology company, to focus on accelerating the development of therapies for MND. In 2012 Les formed a campaigning organisation, ‘Access to Medicine’ http://www.accesstomedicine.co.uk/, a platform to open up a wider debate about the lack of drug development for people with life threatening illnesses.

A very good friend of mine died of motor neuron disease (MND) 20 years ago, as did a non-familial uncle 15 years ago. They received no therapies which could slow the disease progress, and from my perspective not a lot has changed since that time. This disease has affected me in a profound way, leaving me unable to walk and to use my limbs for everyday activities, affecting my speech, swallowing and breathing and robbing me of independence. The single licensed drug for MND, riluzole, is having no measurable impact on the progression of my disease nor on my quality of life.

The current drug approval process is cumbersome—it can take years, and requires extremely large and risky investment, to take a drug from the development stage through to Phase III and beyond. As an example, no new drug has been approved for MND since riluzole, almost 20 years ago. The drug regulatory regime, therefore, must change in order to help people with life threatening and rare illnesses. For such individuals, the ‘risk-return ratio’ is different compared with patients with more benign conditions and drug regulations should be adapted to allow such people the opportunity to try out new combinations of drugs. Currently drug companies do not have a financial incentive to invest in developing new drugs for rare or ‘orphan’ diseases due to the small proportion of the population who are affected and the high costs and uncertain outcomes of the drug development process. If pharmaceutical companies believe that the drugs they develop might be applicable to a wider range of conditions, and that the testing regime would be simpler, this might help spur significantly more investment.

From a statistical point of view, it is necessary to maintain the gold standard of the double-blind, randomised controlled trial (RCT). However, in order to achieve faster results it will be necessary to adopt alternative statistical approaches to rapidly identify changes in patterns or trends arising from data, leaving the RCT for special occasions.

The internet has had a democratising effect, enabling patients and other interested parties, who would previously have been considered ‘lay outsiders’, to have access to the same information as professionals. The flow of communication among patients with rare diseases like MND and between patients and providers of healthcare is accelerating. Social networking sites like Facebook and Twitter allow people to bypass traditional channels of communication and set the news agenda. In this regard, the recent use of the website ‘Patients Like Me’ (http://www.patientslikeme.com/) by patients with MND on lithium treatment to ‘self-report’ their own disease progress was a landmark event.1 ,2

The medical profession should embrace this change and harness the additional power provided by access to greater numbers of patients around the world. Relatively inexpensive web-based technical advancements could help accelerate the speed of drug development by reducing the time and cost needed for clinical trials. Based on the traditional conservatism of the medical profession, one might anticipate resistance to this kind of change. However, the all pervasive nature of the internet could be a force for good in accelerating medical progress.

A physician's perspective

The pace of discovery in amyotrophic lateral sclerosis (ALS)/MND is mostly slow, with only occasional leaps forward to fundamentally advance understanding. The failure to identify drugs with significant disease modifying potential in ALS/MND has a number of causes, not least the immense biological complexity of the neurodegenerative process.3–6 Orphan drug legislation, targeting drug development in rare diseases, has not resulted in significant advances in therapies for ALS/MND in nearly 30 years since its inception.5 ,7 ,8 This is no comfort to a patient living with ALS/MND today. The first major problem has been the lack of a specific therapeutic target integral in the pathogenesis of the disease.8 ,9 This is compounded by the lack of a biomarker to objectively monitor onset and progression of ALS/MND.10 ,11

Physicians enrolling a patient in a phase III trial for MND do so without much solid encouragement from preclinical data that the trial will significantly help the individual concerned. Our justification is that trials serve the greater good and that incremental improvements in outcomes will ultimately lead to therapies that make a difference to patients, in terms of survival and improved quality of life. We are comfortable working within the context of accepted methodologies, principally relying on the robustness of the RCT. However, given the time course of disease progression in MND,12–14 individuals randomised to the placebo arm may not directly benefit from participation in the trial. Participation in RCTs for patients and their families is problematic in that they have to gamble they will get the active drug.6 With the extraordinarily slow progress of the current orthodoxy of medical research in rare lethal diseases we need to be open to new methods of analysis. Can methodologies be developed which allow drugs to be robustly tested by observational means is a worthy question. This is not a matter of abandoning the RCT but rather investigating the utility of population based analysis of the effects of therapies with the active participation of patients themselves, reserving the RCT for situations that require further analysis.

Les Halpin raises the important issue of whether a systematic change in how patients with incurable diseases access drugs might accelerate the pace of discovery. He cites the recent case of lithium carbonate in the treatment of MND, which demonstrated the potential for patients to take an active role in managing their own disease by sharing experiences within social media networks to determine the efficacy of an already licensed drug.15 The ‘Patients Like Me’ social experiment may well lead to a shift in the way patients engage with experimental therapies.16 Patient reported outcomes are already being studied. Using the ALS Functional Rating Scale-R, the correlation between self-online and on-site assessments of severity has been demonstrated to be highly significant.1 While this type of methodology may introduce data biases and needs further study, the answer may be to create data linkages which harness the power of the patient's own observations to population based disease registries and hospital outcome data.

There are many drugs, licensed and unlicensed, for which there is preclinical data, much of which is not in the public domain, supporting their use as potential disease modifying agents in neurodegenerative disease. Les Halpin challenges the research and clinical community to allow open access to these medicines and to develop new robust methodologies to measure the effect on disease progression. Given the historical failure of so many well-conducted RCTs to improve the outlook for patients with MND,3 this idea has considerable appeal. There are significant challenges in allowing unrestricted access to non-prescribed medications in rare diseases, not least the increased likelihood of harmful effects. To some, this will seem a move back to the bygone era of unregulated clinical experimentation, although unrestricted access to medicines may be technically no different to the current relaxed attitude to complementary therapies already used by a high percentage of patients.17 It would be important to at least capture and analyse this information as much for safety and quality as potential beneficial effects of complimentary medicines. Analysis of symptom management strategies using patient and formal disease registry data may be a powerful tool in gathering evidence for effective therapies for symptomatic treatment across the spectrum of ALS/MND.18

Although acknowledging that doctors are perceived to be defensive about ‘expert patients’, perhaps fearing relinquishing control of the research agenda, we suggest that many of our colleagues would share Les Halpin's belief in the positive power of collective patient action. Any physician who specialises in ALS/MND can be in no doubt that the only way to make meaningful therapeutic impact in what is one of the most devastating of diseases, is by forming a partnership with our patients. We witness the courage of those who are trying to live with MND and, in the knowledge that we do not have all the answers, encourage them to challenge our ways of working.

One ethicist's perspective

Les knows the facts and rationally wants to try unproven potential therapies. Respect for his autonomy as a person who can make choices for himself in risky circumstances speaks in favour of his accessing unproven interventions for his terminal condition. Les knows his life will be drastically shortened by MND. It is also in his best interests to try to prolong his life. So beneficence speaks in favour of trying new interventions, even if there are slim chances of success. As I have argued, it is rational to take a small chance of survival when the alternative is certain death.19Respect for autonomy and beneficence support Les’ call for greater access to experimental interventions at the end of life.

The ethics of justifying RCTs is complex and manifold.20 It is a fact that RCTs, as this dialogue illustrates, are at best in the interests of half of the patients and against the interests of the other half. This may not seem to matter much when the issue is a small statistical risk (though of course it can equate to the avoidable, foreseeable loss of large numbers of lives as very large trials continue for the sake of greater statistical confidence20). But when your own life is on the line, it matters as much as anything does. Although the information from a trial might benefit future patients, or even those who would benefit after the completion of the trial, for those who die receiving the inactive arm, the trial harms them to the greatest degree possible. The RCT in all probability will not serve half of the patients with rapidly fatal diseases.

People with lethal disease are the best research participants because they have little to lose.21 And they know that. The risk that research presents to them is truly minimal. And, of all research participants, they have the most to gain. So engaging in ‘less than gold standard’ placebo-controlled trials is legitimate since the harm to the dying patient would be minimal. We should allow patients with terminal illnesses to try risky unproven interventions outside a strict randomised controlled trial setting. Of course we should study the effects as scientifically and ethically as possible, monitoring side effects and quickly terminating such compassionate interventions when evidence supports their inefficacy or harm. But we should give it a go.

There is an ongoing problem in all areas of medicine of failure to publish negative results and publication bias which has the consequence that patients like Les might be exposed to unnecessary risk or harm, and fail to give fully informed consent when accessing ‘novel’ treatments.22 It is essential that patients are informed of all the results of clinical research and at least made aware of the problem of publication bias. But it would be excessively paternalistic to prevent them accessing unproven interventions when apprised of these problems.

A common objection is that offering dying patients unproven therapies will coerce them into participation in research, using them as guinea pigs. People who are dying, the objection goes, will clutch at straws and are not competent to decide because they will literally do anything to cling to life. Similar arguments asserting coercion or undue influence are mounted to object to the sale of organs or large payments for participation in risky research, and they are equally misplaced there23 ,24 Patients like Les are competent to decide what is in their interests and it is mere assertion that they are not. If a person like Les decides, knowing all the available facts, that it is worth taking some unknown risk to try to improve his condition, then provided he has the status quo (no treatment) as option, his choice to take the unproven therapy is based on his assessment that the risks are worth the benefits. It is an example of gross hard paternalism to deny him this option. An offer is not coercive if the person has the status quo as an option. To choose to move from the status quo to accept the option on offer is to make a rational choice that it improves one's lot.

A related objection is that making such offers exploits the person. For example, selling organs may be rational for a poor person in India, but what is wrong is the poverty which makes this person's choice rational. The sale of organs exploits poor people. Of course, this argument is premised on the assumption that the offer itself is unreasonable—very good offers don't exploit people. Nonetheless, even if this were a reasonable argument against sale of organs, it can't apply to people dying of lethal conditions. They are not dying through anyone's fault—their disease is not due to social injustice (at least in cases like MND), as is the case of the poor Indian selling an organ. They are just unlucky and the only way out of their situation is through innovative scientific advance, the very thing being offered to them. So offering unproven potential therapies is not exploitative.

Too often simple-minded ethics is bad for people, bad for innovation and bad for science. We should find ways of evaluating the effects of innovative treatments for lethal diseases outside of randomised controlled trials. What is important is that dying patients are presented with all which is known or could reasonably be inferred about the risks and benefits of any novel agent. But rational, autonomous choice can and must proceed under uncertainty.

Justice requires that publicly funded healthcare systems evaluate the cost-effectiveness of novel treatments allocated fairly. But this should not stifle innovation or novel methods for evaluating effectiveness quickly and compassionately. Randomised controlled trials will remain the gold standard, but they should not be the only standard of evaluation in rapidly fatal diseases.