Is the desperation of patients with incurable diseases being exploited?
BMJ 2023; 381 doi: https://doi.org/10.1136/bmj.p1337 (Published 12 June 2023) Cite this as: BMJ 2023;381:p1337Linked Analysis
Considering tomorrow’s patients in today’s drug approvals
In a linked analysis article (doi:10.1136/bmj-2023-075000),1 Fernandez Lynch and Largent argue that regulators should balance the wishes of current patients for access to potentially innovative therapies with those of future patients who want to be certain of the safety and efficacy of medical interventions. Their proposals inform debates about which medicines should receive market approval. But they discount that commercial interests exploit the willingness of patients with incurable conditions to explore experimental treatments and underplay drawbacks that will affect the certainty and future of interventions.
Our experiences since one of us (James Flynn) was diagnosed with amyotrophic lateral sclerosis (ALS) show how people with life threatening and incurable illnesses, out of desperation, may be more willing to experiment with interventions with unknown efficacy and serious downsides. ALS is a progressive, neurodegenerative disease that has no known cure and an average life expectancy from diagnosis of two to five years.2 Hoping to delay disease progression, James has tried supplements, prescription drugs, and experimental medicines.
A documentary about someone who experienced a rare ALS reversal first convinced him to take a nutritional supplement.3 After reviewing entries from ALSUntangled—an expert assessment of potential treatments4—he discontinued that product but continued taking other supplements. In terms of prescription medicines, he began taking riluzole but not edaravone. We found studies stating that riluzole probably extends survival and is reasonably safe,5 whereas edaravone is not superior to standard therapy, requires complicated intravenous administration,6 and is too expensive.
James has also participated in clinical trials of experimental medicines. The first trial tested the benefits of antiretroviral drugs. During this study, he subjectively experienced one of his longest plateaus. The experience of the next trial was less favourable. To participate in this extended access study of AMX0035 (sodium phenylbutyrate-taurursodiol) he had to stop taking the supplements L-serine, theracumin, and taurursodiol. After discontinuing these supplements, he experienced his biggest decline in functionality, ambulation, and independence. We do not know whether these relationships are causal. AMX0035 was given accelerated regulatory approval with limited evidence of efficacy, ending free access and making it unaffordable. This, in combination with adverse reactions such as diarrhoea7 that affected his quality of life, led James to decide to stop taking it.
Because there are no known cures for ALS, access to off-label treatments, supplements, diet, or drug combinations has been crucial to providing James with hope for slowing progression of this disease. Aside from a small number of panels and review boards, the predominant access to this information is by “word of mouth” from other patients. We were susceptible to unsubstantiated claims but could also seek out peer reviewed studies on effectiveness when assessing evidence. Others with incurable diseases may not have our academic backgrounds in health and medicine to conduct this research.
Not only is the marketing of supplements not based on rigorous evidence, but economic interests prejudice the science about treatments that inform clinicians and patients.8 Strategies by pharmaceutical companies include designing trials to highlight benefits and minimise adverse reactions, hiring for-profit contract research organisations that depend on favourable results for future business, ruling out participants that degrade results, and using trial durations that can demonstrate efficacy but are not long enough to identify harms. Even patient organisations, many of which receive corporate donations, can be biased by those funding them.9
Better protection
Regulatory bodies should guard against commercial interests by demanding high quality science. Instead, current regulations allowing weaker evidence lead to the approval of orphan drugs with few clinical advantages.10 Beyond considering representation of future patients, more extensive reforms are needed. These include having independent, not-for-profit bodies design and conduct clinical trials and approving only those drugs that show superior efficacy and safety to the standard of care.
Additional policies could include labelling drugs as experimental until there is sufficient evidence to confirm their effectiveness, mandating company paid “compassionate use” programmes until the completion of phase 3 trials, and even using incentives11 instead of patents to fund development and make prices more accessible. Lastly, regulatory bodies should improve oversight of supplements by verifying ingredients and enforcing stricter guidelines on efficacy and safety labels to inform the public. While continuing to press for well designed, reproducible, and transparent randomised clinical trials, patient groups and their physicians should take advantage of the fact that people with serious illnesses are already self-experimenting by considering alternative designs such as natural experiments, propensity score matched or retrospective cohorts, and experimental crossover trials.
Desperate people with serious illnesses may be willing to try anything, but their decisions should not have to depend on as yet unavailable confirmatory evidence in medical journals. A larger platform exploring possible treatment options reviewed by experts is invaluable and needs to be readily accessible to all. Regulatory approvals should be based on confirmatory evidence not prejudiced by competing interests.
Footnotes
Competing interests: MF and JF are siblings; MF and AP are spouses and are part of JF’s group of caregivers. Georgia Southern University and the Georgia Southern University Foundation have received funds to support AP’s research from WW International. JF participated in the expanded access trial of AMX0035 sponsored by Amylyx Pharmaceuticals.