Safety and efficacy
Assessing the efficacy and safety of a treatment is a challenge when there is limited research evidence and little or no clinical experience of use, creating high levels of uncertainty. Factors that might be undetermined before clinical research has concluded include the appropriate dosage and other interventions required to make a drug safe and effective.52 A previous Nuffield Council on Bioethics report highlighted the particular uncertainty around safety and long-term effects of the use of novel technologies that intervene in the brain. Safety concerns have also been raised about the use of some off-label medicines in children – see Box 1.
For patients who have limited options, uncertainty about safety and efficacy may be outweighed by the possibility, even if very slight, that the treatment could be effective for them.54
Box 1. Unlicensed use of medicines in children: cisapride
By 1999, the drug Cisapride had been prescribed to over 36 million babies and young children worldwide to treat reflux, even though it had not been licensed for children under 12 years old.55 It was withdrawn from routine use in the UK in July 2000 because of concerns about rare but very serious adverse effects, including sudden death, death from cardiac arrhythmia, and serious nonfatal arrhythmia. A later review found no clear evidence that Cisapride had significant benefits compared with placebo.
Patient consent and decision-making
GMC and Department of Health and Social Care guidance state that when an experimental treatment is offered to a person with capacity, this fact must be clearly explained to them before their consent is sought. However, as highlighted in the section on surgery, this does not always appear to happen in practice. The Care Quality Commission recently found that a number of private online health services did not adequately inform patients when medicines were being prescribed off-label or were unlicensed.
Some of the situations in which experimental treatments are considered create challenges for decision making. Patients may be in pain, distress or in a potentially life-threatening situation which could affect their ability to weigh risks and benefits. They may feel under pressure to ensure they have tried everything.59 Power dynamics may be significant, and patients might be strongly persuaded by the opinion of their doctor or feel unable to question their judgment.60
These challenges can be particularly acute when parents or guardians seek to access experimental treatment for a child or person who lacks capacity to consent. According to professional guidance, experimental treatments cannot be offered to someone who lacks the capacity to consent, or to a child, unless it is deemed to be in their best interests. If there is disagreement about what is in the patient’s best interests, healthcare professionals might be seen as gatekeepers to new treatment options and conflicts can arise – see Box 2.62 There are differing views, both within the academic literature and wider public debate, about how parental requests for experimental treatments should be appraised.
Box 2. Disagreements about the use of experimental treatment in children: the case of Charlie Gard
Charlie Gard was a critically ill infant who had a rare degenerative condition. His parents wanted him to have experimental nucleoside therapy in the US and raised the necessary funds through crowdfunding. This therapy had never undergone a clinical trial, nor been used to treat this particular disease, but a US neurologist believed it might offer a small chance of improvement to his quality of life. Disagreement arose between the parents and Charlie’s medical team, who thought that having the treatment would not be in Charlie’s best interests. Following a protracted and high profile series of court cases, judges ruled that Charlie should not have the treatment. Life support was withdrawn and Charlie died in July 2017.64
The role of information and language
Patients are able to access large amounts of information online about emerging treatments. This can empower patients to explore what treatments are available and make informed decisions about their treatment and care. In situations where trust has broken down between patients and healthcare professionals, patients may be more disposed to look to unofficial sources of information.65
The Advertising Standards Authority enforces rules requiring that any efficacy claims in advertisements for medical treatments targeting a UK audience must be supported by robust clinical evidence, and that treatments are advertised in a socially responsible way and do not mislead about the service or product provided.
However, online information can be misleading, complex and confusing, and might fail to alert patients to the limits or risks of experimental treatments. Misinformation can percolate quickly in online forums, and media reports can contribute to hype and misunderstandings.67 The way terms such as ‘innovative’, ‘proven’, ‘experimental’, and ‘novel’ are used or avoided can affect people’s understanding of an experimental treatment.68 These factors might adversely affect patients’ abilities to make properly informed treatment choices. The US Food and Drug Administration recently announced a clamp-down on clinics offering unlicensed stem cell therapies that were making deceptive assurances to patients about experimental products.69
The virtues of professional practice that are suggested to be important in the provision of experimental treatments include: responsibility in avoiding hype and false promise; humility in acknowledging the limits of current knowledge; and trustworthiness.70
While their primary duty is to offer the best possible treatments for their patients, healthcare professionals also might be driven by financial incentives, the desire to advance medical knowledge in the interests of future patients, and enhance individual or institutional reputation.71 Studies in the US and Australia have highlighted conflicts of interests arising from relationships between surgeons and medical device providers, which incentivise innovative uses of medical devices.72 Guidance on conflicts of interests has been published by the British Medical Association, and the Association of the British Pharmaceutical Industry.73 Professionals have a responsibility to report adverse effects of any medicines or medical devices, including those that are unlicensed or used off-label, to the MHRA or to the manufacturer who has an obligation to notify the MHRA.74
Equity and fairness
Access to experimental treatments is unequal. Not everyone can afford treatments that are available privately or abroad, and there are differences between and within European countries in how compassionate use schemes are used. How quickly patients can access experimental treatments also can vary, for example, between Scotland, England and Wales.76
Moreover, while manufacturers might be allowed to offer experimental treatments, there is no guarantee that they can or will offer them to all the patients who might benefit – see Box 3.77 Early access to expensive treatments might also raise questions of distributive justice if resources are diverted from elsewhere in the NHS without strong evidence of their benefit.78
Impact on research and knowledge generation
When experimental treatments are provided outside of a clinical trial, information about their efficacy and side-effects might not be recorded and shared, hampering knowledge generation.81 For example, while adverse reactions must be reported to the MHRA when an experimental medicine is supplied under the specials or hospitals exemption, there is no obligation to report other outcomes.82
Efforts have been made to ensure that the outcomes of experimental treatments are recorded. NHS Commissioning policy requires that any experimental treatments funded should contribute to the knowledge base, for example by requiring that data are submitted to clinical databases.83 The World Health Organization has developed an ethical framework for Monitored Emergency Use of Unregistered Interventions, which includes an obligation to collect and share meaningful data.84 In the UK, the Access to Medical Treatments (Innovation) Act 2016 proposes a register of experimental treatments provided by doctors in England.85 However, no such register has been set up and what purpose it might serve is debated.86
A separate concern is that healthcare professionals might offer experimental treatments to patients as a way of bypassing research, given real and perceived challenges and obstacles to initiating clinical trials, such as lengthy timelines, a lack of eligible patients, and a lack of support from funders.87
Box 3. Compassionate use of experimental treatments: HIV drugs in France
When French authorities allowed compassionate use of experimental anti-retroviral drugs for HIV patients in early 1996, manufacturers could initially only produce enough of the drugs to treat a small proportion of the 18,000 potential patients, and the national ethics committee recommended drawing lots to randomly allocate treatments.79 Eventually, 11,000 patients were able to access the drugs through the compassionate use programme, which is estimated to have led to a significant drop in hospitalisation rates and deaths. The drugs were given marketing authorisation later that year.80
50 Rogers WA, et al. (2014) Identifying surgical innovation: a qualitative study of surgeons’
views Ann surg 259:273-8.
51 McCulloch P, et al. (2009) No surgical innovation without evaluation: the IDEAL
recommendations The Lancet 374:1105-12.
52 London AJ (2017) Social value, clinical equipoise, and research in a public health
emergency Bioethics, published online first.
53 Nuffield Council on Bioethics (2013) Novel neurotechnologies: intervening in the brain.
54 EURODIS (2017) Early access to medicines in Europe: Compassionate use to become
55 Nuffield Council on Bioethics (2015) Children and clinical research: ethical issues.
59 See, for example, Bibler TM, Shinall Jr MC, and Stahl D (2018) Responding to those
who hope for a miracle: Practices for clinical bioethicists Am J Bioethics 18: 40-51.
60 This point was raised at Nuffield Council on Bioethics Roundtable meeting on Novel
medical treatments: innovation, hope and headlines, 19 April 2018.
61 Department of Health (2009) Reference guide to consent for examination or treatment,
second edition 2009.
62 Birchley G (2018) Charlie Gard and the weight of parental rights to seek experimental
treatment J Med Ethics 44:7, pp448-52; Practical Ethics blog (5 July 2017) The moral of
the case of Charlie Gard: give dying patients experimental treatment…early.
63 Bhatia N (2018) Disagreements in the care of critically ill children: emerging issues in a
65 See, for example, Snyder J, et al. (2014) “I knew what was going to happen if I did
nothing and so I was going to do something”: Faith, hope, and trust in the decisions of
Canadians with multiple sclerosis to seek unproven interventions abroad BMC Health
Serv Res 14:445.
67 Nuffield Council on Bioethics (2013) Novel neurotechnologies: intervening in the brain;
Pullman D, Zarzeczny A, and Picard A (2013) Media, politics and science policy: MS
and evidence from the CCSVI trenches BMC Med Ethics 14:6.
68 See, for example, Richards B and Hutchison K (2016) Consent to innovative treatment:
no need for a new legal test J Law Med 23:938-48.
69 US Food and Drug Adminstration (2017) Statement from FDA Commissioner Scott
Gottlieb, M.D. on the FDA’s new policy steps and enforcement efforts to ensure
proper oversight of stem cell therapies and regenerative medicine.
70 Nuff’ said blog (7 August 2017) Making unbearable decisions about the care and
treatment of a seriously ill child – ethical reflections.
71 Swedish National Council on Medical Ethics (2016) Ethical assessments at the border
between health and medical care and research (summary in English). Keren-Paz T (2019) No-fault (strict liability) for injuries from innovative treatments: fairness or also
efficiency? Law, Innov Technol, in print.
72 Rogers WA and Johnson J (2013) Addressing within-role conflicts of interest in surgery
J bioeth inq 10:219-25; Johnson J and Rogers W (2014) Joint issues–conflicts of
interest, the ASR hip and suggestions for managing surgical conflicts of interest BMC
med ethics 15:63; Cohen D (2011) Out of joint: the story of the ASR BMJ 342; Tanne
JH (2007) US makers of joint replacements are fined for paying surgeons to use their
devices BMJ 335:1065.
73 BMA (2018) Conflicts of interest; ABPI (2016) Code of Practice for the Pharmaceutical
74 See https://yellowcard.mhra.gov.uk/.
75 EURODIS (2017) Early access to medicines in Europe: compassionate use to become a reality.
76 For example, the drug Orkambi for cystic fibrosis has been available through a compassionate use scheme in England, Scotland and Northern Ireland, but not in Wales. Cystic Fibrosis Trust News (17 May 2016) Lack of compassion risking lives in Wales.
77 See, for example, FDA (2018) Expanded access: information for patients.
78 Aggarwal A, et al. (2017) Do patient access schemes for high-cost cancer drugs deliver value to society?—lessons from the NHS Cancer Drugs Fund Ann Oncol 28:8, 1738–50.
79 CCNE (1996) Recommendation on making available an antiviral treatment for AIDS (1996-03-07).
80 EURODIS (2017) Early access to medicines in Europe: compassionate use to become a reality.
81 Nuffield Council on Bioethics (2013) Novel neurotechnologies; intervening in the brain.
82 MHRA (2011) Guidance on the UK’s arrangements under the Hospital Exemption Scheme; MHRA (2014) The supply of unlicensed medicinal products ‘specials’, MHRA guidance note 14.
83 NHS Commissioning Board (2013) Commissioning policy: experimental and unproven treatments NHSCB/CP/06.
84 WHO (2016) Managing Ethical Issues in Infectious Disease Outbreaks.
85 Access to Medical Treatments (Innovation) Act 2016.
86 See, for example, MRC (2018) Access to Medical Treatments (Innovation) Act.
87 Miola J (2019) Postscript to the medical innovation bill: clearing up loose ends Law Innov Technol, in print.