TY - JOUR
AU - Chan, Tracey Evans
AB - Abstract Developments in medical technology, healthcare delivery, and commercial interests in medicine have increased both the potential for conflicts of interest on the part of physicians, and doubts over the sufficiency of patient autonomy as a justification for administering innovative therapy. The legal and regulatory treatment of innovative therapy is therefore an important question, on which there is a current lack of consensus on a number of issues. This paper discusses recent developments in Singapore and uses them as a springboard to flesh out basic regulatory issues that arise from the deployment of innovative treatment: the distinction between innovative treatment and clinical research, the adequacy of the current post hoc scrutiny of innovative therapy under existing legal principles and the need for further specialised regulatory oversight. Innovative treatment, Research regulation, Medical negligence I. INTRODUCTION Patients suffering from illness that has no standard medical therapy,1 or who have exhausted all current therapeutic options are often in a desperate situation. They press their doctors in search of something new in the hope that it can offer them some chance of recovery. Their doctors, in turn, are thus motivated to experiment or innovate in order to develop alternative treatments. This therapeutic motivation, however, comingles in modern healthcare with other professional and commercial considerations such as enhanced reputation and profit. In addition, there is the potential for innovative therapy to generate knowledge that will spur its development and eventual adoption by the profession. However, this desire to benefit future patients may be at odds with the interests of the particular patient offered innovative treatment. Innovative medical therapy has thus been a matter of increasing concern internationally in healthcare, particularly where market forces are at play in the healthcare system. The concern stems both from the particular features of innovative therapy and its differential regulatory treatment—as part of the traditional therapeutic pathway in healthcare rather than the research ethics pathway.2 If innovative therapy continues to fall within the therapeutic paradigm, as it traditionally has, decision-making would remain subject to the confines of the physician–patient relationship and certain post hoc review processes such as medical negligence. Substantial faith is therefore placed on professional judgment and the informed consent process. Patients in such situations may, however, not be in the best position to size up the medical complexities and uncertain risks, and are thus more vulnerable to false hopes and overly optimistic assessments of the worth of innovative therapy. In contrast, activity that is classified as research stands on a significantly different ethical, legal, and regulatory footing, where the need for prior ethical review is the current international best practice. Ongoing developments in medical technology, healthcare delivery and commercial interests in medicine have increased both the potential for conflicts of interest on the part of physicians, and doubts over the sufficiency of patient autonomy as a justification for administering innovative therapy. The legal and regulatory treatment of innovative therapy therefore becomes an important question, on which there is a current lack of consensus on a number of issues. This paper proceeds as follows. Part II discusses the recent pertinent developments in Singapore and uses them as a springboard to flesh out basic regulatory issues that arise from the deployment of innovative treatment. Part III examines the question of how we should distinguish innovative treatment from research, and the significance of appropriate classification. Part IV examines the adequacy of the current post hoc scrutiny of innovative therapy under existing legal principles. Part V then considers if specialised regulatory measures are warranted given the deficiencies of a purely post hoc system, and how existing regulatory systems could be developed in order to best meet the challenges presented by innovative treatment. II. RECENT ENCOUNTERS WITH INNOVATIVE TREATMENT IN SINGAPORE A. What Is Innovative Treatment? As a preliminary, it is necessary to specify what we mean by innovative treatment or practice. Generally, this phrase refers to significant departures from standard medical therapy which has not been validated by reliable research methods, or where there is simply insufficient evidence to support the safety and efficacy of the innovative procedure, method, or device.3 The adjective significant emphasises a distinction from variations or adaptations of existing standard therapy to suit individual patient circumstances. Thus, in offering innovative treatment, the physician is working on a hunch or scientific theory that has not been adequately investigated or researched. Such medical procedures are administered for the benefit of a specific patient but have uncertain outcomes because they have not been adequately tested.4 Conceptually, a more comprehensive definition has been offered as follows: Innovative therapies generally represent uncontrolled, often single, interventions intended to manage or solve particular problems. They are not ordinarily designed to test hypotheses. Additionally, they are not undertaken in order to gain new knowledge beyond the needs of the patient. Although the use of innovative therapies may lead to new knowledge, this consequence is secondary to their primary purpose of benefiting patients.5 B. Innovative Treatment as a Legitimate Aspect of Medical Practice Between August 2009 and November 2010, the Disciplinary Committee (DC) of the Singapore Medical Council (SMC) convicted several physicians for offering various forms of novel treatment that were not adequately supported by sufficient clinical or scientific evidence.6 In addition these cases seemed to suggest that there was a sharp dichotomy between standard and innovative therapy. The latter should only be administered under the auspices of a clinical trial. The legitimate place of innovative therapy within in the context of medical practice was, however, recognised in Gobinathan Devathasan v Singapore Medical Council.7 A neurologist's appeal against a DC of the SMC's conviction of inappropriate administration of therapeutic ultrasound was allowed by a High Court of three judges. The novelty in Dr Devathasan's treatment of a patient's complicated neurological condition was actually in the combination of therapeutic ultrasound with repetitive transcranial magnetic stimulation (rTMS).8 However, as the court noted, the two charges proffered against him for inappropriate treatment did not allude to this novel combination, but rather focused discretely on the two forms of treatment.9 In this respect, the SMC's Ethical Code and Ethical Guidelines (Ethical Code) provides that: 4.1.4 Untested Practices and Clinical Trials A doctor shall treat patients according to generally accepted methods and use only licensed drugs for appropriate indications. A doctor shall not offer to patients management plans or remedies that are not generally accepted by the profession, except in the context of a formal and approved clinical trial.10 The DC had acquitted him in respect of rTMS even though it was not generally accepted by his peers in Singapore. It reasoned that: … Whilst the use of rTMS is not generally accepted in our local practice, Dr Devathasan's work may represent novel treatment and may aid the progress and innovation in medicine … In our view, these above stated studies and other studies do support the basis of the application of rTMS as an extended indication or auxiliary treatment for a patient with PD [i.e., Parkinson's Disease], especially one who has failed other treatment options.11However, the DC convicted him on the second charge related to therapeutic ultrasound as an inappropriate ‘extension from its normal use into clinical neurology practice’ that was not supported by any ‘experimental evidence or physical proof of the safety of [therapeutic ultrasound] on the human brain.’12 Neither had the appellant specialist ‘verified his assumptions or conclusions through expert consultation, in-vitro or in-vivo experimentation or test of any form.’ Devathasan's case was that therapeutic ultrasound was administered, not for an established use to treat acute stroke, but rather to augment the effects of rTMS through increased cerebral blood flow. He justified its use by extrapolation from such combined use in relation to patients with gait apraxia, which was described in a paper he co-authored on the subject. The High Court overturned this conviction on a number of grounds, the majority of which related to procedural and evidential deficiencies in the DC's conduct of the proceedings and grounds of decision. The substantive ground relevant to the present discussion related to the professional ethical requirements for appropriate extension of existing treatments such as ultrasound into novel uses.13 After reviewing the expert evidence, the court surmised that the test for ‘general acceptance’ (i.e. standard therapy) required the following critical factors to be satisfied: However, it was only in respect of ‘off-label’ treatment15 for unapproved indications that specific questions of patient safety and adequate scientific rationale became pertinent. As Dr Devathasan was charged with administering treatment that was not generally accepted in accordance with para. 4.1.4 of the Ethical Code, the court reasoned that the DC had thus applied the incorrect test.16 Questions of safety and the presence of scientific rationales for extrapolation to present use had a closer ‘nexus’ to when ‘off-label’ use of a particular treatment is allowed, rather than whether they were indicated and generally accepted.17 (a) there had to be at least ‘one good study’; (b) the results of the study can be replicated and reproduced under the same sort of like treatment parameters and conditions; (c) the study had been written up in publications and presented at meetings; (d) the study had received peer review; (e) the study had to have ‘clear-cut results’ and the sample had to be ‘statistically significant’; and (f) the study had to have some form of controls, such as randomised double-blind trials.14 C. Legal and Regulatory Issues Counsel for the SMC in Devathasan had argued that the neurologist ought to have administered the novel combination in the context of a formal clinical trial.18 This unfortunately collapsed two distinct issues—whether innovative treatments have any place in clinical practice, and whether what Dr Devathasan was doing, nevertheless, amounted to clinical research. The court only answered the former question, accepting the legitimacy of the activity as off-label (or innovative) treatment for a patient who did not respond to standard therapy. In fact, the broader context in Devathasan suggested the presence of some form of informal study. Dr Devathasan had in fact treated 200 other patients in a similar way prior to the complainant, a number that had risen to 700 by the time of the DC hearing.19 He had accumulated sufficient clinical data to assert to the Singapore Ministry of Health and the Agency for Science Technology and Research that his novel combination would benefit patients generally. Acknowledging that a double-blinded clinical trial might be desired, he thought that this was not necessary.20 The first issue therefore relates to how we determine the boundary between innovative treatment and research. The implications of classification are serious—it determines which of the existing two regulatory pathways apply. If an activity constitutes research, this confers on it a significantly different regulatory paradigm where the physician no longer has primary influence over whether the ‘treatment’ is offered to a patient. In fact, her status as physician is said to morph into an investigator or researcher. Prospective control intervenes in the form of peer review by institutional review boards (IRBs) or research ethics committees (RECs). Heightened informed consent requirements, often statutorily supplemented, also apply. However, if a practice is safely within the boundary of medical therapy, then the decision to administer it is primarily one for the usual, internal dynamics of the physician–patient relationship. Freedman et al observe: Ordinary therapeutic practice is managed within the health provider-patient relationship however dangerous the intervention or ambiguous the indication. The doctrines of patient consent to care and of professional autonomy are intended to ensure that the intervention in question is the product of joint deliberation and agreement between patient and doctor – moreover of sole agreement between them. No outsiders need be consulted. … Any third party involvement will come retrospectively. … 21External scrutiny of its merits is then largely post hoc via a medical negligence action or disciplinary proceedings (as was the case in Devathasan). At best, there might also be external peer review in the form of quality assurance reviews within institutional healthcare systems that are put in place to systematically review the outcomes of therapeutic interventions.22 Generally, none of these quality assurance or safety systems kick in prospectively to protect the interests of patients in determining if the risks of innovative therapy are worth the potential benefits, particularly where there is insufficient evidence of either. It therefore becomes important for physicians to know when they will cross the regulatory line between therapy and research. Second, assuming an activity is not research but innovative therapy, what legal or ethical requirements should apply? Devathasan provides a good indication of what the professional ethical expectations are, but the court also observes that the current professional ethical framework is lacking.23 Should innovative therapy be subsequently challenged in court, how would the medical negligence analytical framework apply to treatment that, by definition, is not supported by a responsible body of medical opinion because it is innovative in nature? These questions were not addressed in Devathasan. Finally, in the wake of such analysis, a larger regulatory question looms: is the current post hoc review of innovative therapy via tort law and the medical disciplinary system adequate in the interests of patient safety and public health? The efficacy and safety of any proposed innovative therapy is not only the concern of the particular patient asked to receive it, but also that of the larger public health interest in ensuring that innovative therapies are adequately investigated and evaluated before they move into main stream medicine. III. THE ELUSIVE BOUNDARY BETWEEN INNOVATIVE TREATMENT AND RESEARCH A. ‘Intention’ as a Classificatory Device The SMC's Ethical Code unfortunately does not provide sufficient clarity on the boundary between therapy and research. Para 4.1.4, clause 1 appears to draw a blunt dichotomy between generally accepted methods and untested practices, stipulating that the latter should only be offered in the context of a formal and approved clinical trial. However, clause 3 of the same paragraph elaborates further: It is not acceptable to experiment or authorise experiments or research which are not part of a formal clinical trial and which are not primarily part of treatment or in the best interest of the patient, or which could cause undue suffering or threat to the life of a patient.24The conjunctive and alternate clauses confuse the meaning of the paragraph, but a contextual reading suggests two distinct situations when experiments or research are ethical: (i) if they are part of a formal clinical trial conducted in accordance with prevailing legal and ethical standards; or (ii) if they are primarily part of treatment administered in the best interests of the patient. If this interpretation is accepted, this clause amounts to a qualification of the first in that it expands the reach of medical practice to encompass instances of experimentation if these serve the patient's best interests. It would also be consistent with the recommendations of the Declaration of Helsinki.25 Nonetheless, the Ethical Code does not offer a definition of experiment or research in order to determine when a particular medical activity crosses the threshold. Experimentation seeks to resolve unknowns in relation to a particular patient. It may also involve testing hypotheses and generate new information about that patient. But it does not, by itself, elevate an activity to ‘research’ unless the information is sought for its general, as opposed to particularised, value.26 Historically, the conceptual confusion between the two was noted by the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in its Belmont Report: The distinction between research and practice is blurred partly because both often occur together (as in research designed to evaluate a therapy) and partly because notable departures from standard practice are often called “experimental” when the terms “experimental” and “research” are not carefully defined.27More elaborate guidance is found in the Singapore National Medical Ethics Committee's Ethical Guidelines on Research Involving Human Subjects (1997). Paragraph 2.2.1 defines research as follows: … Research. Human research can be broadly defined as studies which generate data about human subjects which go beyond what is needed for the individual's well-being. The primary purpose of research activity is the generation of new information or the testing of a hypothesis. The individual patient may or may not benefit directly. The fact that some benefit may result from the activity does not alter its status as “research”. … 28In contrast, medical therapy without a research function is defined by the NMEC in a similar fashion to that adopted by the Belmont Report29: … When an activity is undertaken with the sole intention of benefiting the patient, the activity may be considered to be part of “therapy”. The progressive modification of methods of diagnosis and treatment in the light of experience is a normal feature of medical practice and should not be considered as research. There could be conflicts between research (intended to generate new information) and therapy (intended to benefit the individual patient directly). Their resolution rests on the integrity of the physician/investigator. The patient is always entitled to the best clinical management, and research considerations must never override this.30These definitions of research and therapy were endorsed in the subsequent Bioethics Advisory Committee Report, Research Involving Human Subjects: Guidelines for IRBs.31 Therefore, the BAC's recommendations in respect of human biomedical research do not apply to ‘therapeutic activities undertaken with the sole intention of benefitting the patient … ’32 Several observations are warranted here. The main distinction between research and therapy seems to be the purpose or intent with which an activity is undertaken. Activity is properly categorised as treatment only where its sole purpose is to serve the interests of the patient for whom it is administered. In contrast, the term ‘research’ seeks to demarcate activity that serves to either generate additional data that is not necessary for the treatment of a patient or ‘new information’. The former idea seems a rather narrow definition of research from the perspective of outcomes. It would seem to suggest that if scientific methods such as randomisation and controls were used in an activity, it would not amount to research unless additional data were generated in excess of what were needed for the clinical treatment of the patient—which is implausible. Thus, by using the term ‘new information’, it is more likely that the NMEC meant that the purpose of deriving or developing new generalisable knowledge captures the intended object of research—information that will serve not only the patient's interests, but that of future patients. This is consistent with the earliest recommendations floated before the US National Commission in 1978 that centred around the use of ‘intent’ as a device to draw boundaries between research and medical practice (and innovative treatment in particular).33 The device of intent is also used in the Royal College of Surgeons' Guidelines on the practice of ethics committees in medical research with human participants.34 However, the NMEC's ultimate recourse to the ‘integrity of the physician/investigator’ to resolve any difficulty in determining what is the operative intent suggests that this is a subjective phenomenon. Without further specification of criteria from which intent is to be inferred, its utility as a regulatory sorting device is the subject of much reservation.35 Without clearer objective criteria, a subjective state of mind raises validation difficulties and thus the potential for inconsistent results. Furthermore, regulatory reliance on the ‘integrity’ of the physician/researcher to identify relevant research intent is unrealistically optimistic, especially where the consequences of increased regulatory scrutiny may conflict with the individual's professional and personal interests. Secondly, exclusive therapeutic intent may be an unduly stringent standard. Administering innovative therapy has the inherent capacity to generate, at the least, anecdotal evidence which could ground future pilot studies or clinical trials. It is thus always possible to infer some secondary research intent in deploying innovative therapy, even if the primary purpose is therapeutic. Similarly, by referring to ‘primary purpose of research’, the NMEC definition acknowledges that much professional activity in healthcare can possess more than one purpose, whether to benefit the patient, test a hypothesis, and/or generate new information in the progressive development and improvement of therapy.36 The true difficulty then posed by these definitions above is that there are no criteria specified to determine when there is a primary research purpose, or in what proportions these must be to transform activity into research.37 Thirdly, even if by ‘new’ the NMEC meant ‘generalisable’ knowledge, what does this mean? Scientific knowledge requires a certain methodological rigour for general acceptance, with the randomised controlled trial (RCT) representing the gold standard.38 Knowledge on which physicians are prepared to act in adopting novel treatments does not always meet this standard.39 In the realm of innovative treatment, where new modalities or combinations of diagnosis or treatment are administered without sufficient validating evidence to support their use, the medical information thereby generated often confers clinical value both in particular and general fashion. This, it is argued, is the true source of the difficulty in distinguishing between innovative treatment and research, not simply a reliance on research intent. Finally, there is one criterion from which research intent can be readily inferred: the presence of procedures that impose burdens or risks on the individual patient without any compensating medical benefit. For example, RCTs may include additional interventions to measure study outcomes—such as blood draws, biopsies, lumbar punctures, and imaging procedures—which are not required for the purpose of providing any diagnostic or therapeutic value to the individual.40 These are procedures where it may be properly inferred that the sole purpose is research. Some difficulty of application arises, however, in identifying the presence of non-beneficial procedures (in the absence of a formal written protocol). This depends on the level of uncertainty about what the standard practice is, against which the presence of additional non-beneficial procedures can be identified. However, this criterion alone will not suffice in classifying a broad range of activity where procedures used may correspond with what is clinically indicated, for reasons which will be apparent shortly. B. Alternatives to ‘Intention’ Accepting the shortcomings of a subjective approach to research classification based on an ambiguous concept of new or generalisable knowledge, alternative approaches have been proposed that seek to identify more objective features of any clinical activity that would constitute research. 1. The Deviation Approach In a pilot paper for the US National Commission, Levine proposed to include innovative therapy within the definition of research, being activity which differs in any way from customary medical practice.41 He argued that, in general, innovative therapy should be conducted and reviewed as if it were research.42 However, given the inherent uncertainties even in standard therapy, there is always some element of ‘experimentation’ even in customary practice. Levine was probably alluding to the experiential modifications to existing therapies noted by the NMEC above, and he thus sought to confine research categorisation to ‘substantive’ innovative therapy in order to keep the research review manageable. His primary reason for doing so was to minimise the informal incorporation of ‘bad’ innovations into standard therapy which have not been tested adequately, by subjecting such activity to IRB or more specialist regulatory review in order to ensure they are systematic and properly designed trials.43 This more expansive approach to research classification thus focuses on significant deviations from standard therapy, and not the quality of the information generated. However, it was ultimately not accepted in Belmont Report, which decided that: When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is “experimental,” in the sense of new, untested or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project.44A couple of arguments against such an expansive approach would explain this position. First, including innovative therapy within the sphere of research would probably introduce an undue burden on the practice of medicine, and hinder a patient's access to timely medical treatment, albeit of an experimental nature.45 This would arise from the inherent bureaucracy and delay of the IRB review process.46 Second, there is likely to be a concomitant burden on medical innovation if this could only proceed on the basis of formal research. The latter would be dependent on factors not within the immediate control of the practitioner, such as funding and institutional support, in addition to important ethical constraints on clinical trials.47 2. Systematic Design Generating Scientific Knowledge A stricter approach to demarcating research from medical practice focuses on the presence of systematic design. The US Common Rule adopts this definition of research: Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.48The emphasis on design suggests the use of methodology that would generate information or knowledge that meets stipulated standards. The Common Rule, however, does not elaborate on what it means by generalisable knowledge, or what specific scientific or professional standards were envisaged.49 In respect of design, Miller argues that the distinctive purpose of clinical research is revealed by its ‘characteristic methods that are foreign to medical care’.50 These include: These methods are drawn from the characteristic features of the RCT. It is the RCT that is the core fount of conflicting moral demands made of a physician/investigator conducting it—routinely asking them to sacrifice the interests of their particular patients for the sake of the trial and the quality of information it will generate.51 Thus, implicit in the reliance on relevant RCT methodological features is the narrower reading of generalisable as representing knowledge that bears the acceptable hallmarks of scientific methodological rigour.52 (a) random assignment of treatments, (b) the use of placebo controls, (c) techniques to mask treatments so that investigators and patients do not know what treatment they are receiving [blinding], and (d) restrictions on the flexibility in adjusting doses of study drugs and use of concomitant treatments. An emphasis on systematic design also suggests an affinity for more formalised activity that involves written documentation that can be scrutinised as a research plan or protocol.53 It was envisaged by the Belmont Report that the common practice when an investigator formed a research intent was to formulate a written research protocol outlining this intent, which could then be used for seeking IRB approval.54 Indeed, for the most part, the clear cases of research relate to activity that is formally organised and reduced into a written protocol designed to test a hypothesis. However, confining research to formalised activity overlooks other less formal activities could also harbour a research purpose (whether wittingly or unwittingly). These activities may, nevertheless, be practically influential in moving innovative treatments into the mainstream, in spite of their scientific methodological flaws.55 A clear example of such activity is what Margo terms ‘investigational studies’ (particularly in respect of surgery) with the following characteristic features: Such informal studies, at least in a surgical context, serve a transitional role between the development of new surgical models in the laboratory and the conduct of formal clinical trials by developing preliminary data and allowing refinements and modifications through testing in humans.57 There is also evidence that they have been used in the context of other forms of therapy.58 The underlying imperative in such informal studies is, nonetheless, the testing of a hypothesis that is hoped will benefit future patients by improving on conventional practice. However, if we adopt a definition based on scientific methodological rigour, ‘investigational studies’ would not amount to research. (a) they consist of a series of patients; (b) outcomes measures are common clinical parameters, the type usually obtained during routine clinical follow–up; (c) effectiveness is determined by comparison with historical controls (d) formal written protocols do not exist; and (e) because the activities are viewed as clinical care, they are invisible to IRBs.56 3. Reiteration of Treatment and Dissemination of Clinical Data In response to the challenges posed by investigational studies of innovative treatment, Gladstein argues that the boundary between treatment and research is crossed when a physician offers a reiteration of innovative treatment, collects patient data on clinical outcomes and subsequently presents or publishes these data publicly.59 However, it is not clear what the rationale for Gladstein's proposed criteria is.60 The collection and public dissemination of clinical information by a physician (suitably anonymised) is equally consistent with good clinical practice, and it would seem to create a perverse incentive against the sharing of useful data with the medical community if public dissemination per se could transform innovative treatment into research. Similarly, the notion of reiteration of treatment is inherently ambiguous since innovative treatment could justifiably be offered to more than one patient if they happen to be in a similar situation where, for example, standard medical practice does not avail any beneficial treatments. If reiteration involves restrictions on the flexibility of treatment parameters in order to standardise the innovative treatment across the series, then this would seem to coincide with the fourth scientific method outlined by Miller above. Consequently, Margo offers an operational variation on this approach by focusing on the reiteration of innovative treatment after a scientific hypothesis has been made public by the physician: After a case series has been formally presented or submitted for publication, there can be no turning back. Any addition of new patients to enlarge an existing clinical database is a clear departure from just clinical practice to clinical research. After a scientific hypothesis is a matter of record, the physician who enters more patients into the same series needs to regard the work as research as well as himself or herself as a researcher.61The discernible rationale underlying this operational approach is that whatever the ambiguities of a prior case series of innovative treatment, the collection of further clinical data on the innovation (after a hypothesis about its safety and efficacy has been formulated) would generate relevant clinical data in support of it and thus operates for the benefit of future patients as well. This arguably amounts to an implicit, broader interpretation of generalisable knowledge that encompasses any data that could have clinical, and not just scientific, influence on the merits of the innovative treatment in question. C. A Proposed Way Forward The choice of more objective criteria to demarcate the zone of clinical research activity essentially involves a policy choice that balances competing concerns. There is the common thread of protecting vulnerable patients from unknown risks and suboptimal treatment, which has to be balanced against the need for preserving a healthy amount of flexibility in clinical practice to encourage innovation, and the practical competencies and resources of the research ethics oversight system. Working from dictionary definitions is unlikely to be helpful, as different quarters define the term ‘research’ according to their needs and priorities,62 and proffered definitions may not have taken into consideration the underlying rationales for the burdens imposed by research oversight that would follow.63 In this respect, the objective of regulatory guidelines demarcating research should be grounded in the history of research ethics and regulation—the experiential lessons learnt from historical research abuses that occurred not only under the ideological conditions of war, but also in everyday medical practice by well-meaning physician/researchers.64 At the core was a realisation that abuses were possible because of the blurring of duties created by the inherent conflict of interests held by a physician who was also conducting research.65 Regulatory definition of research should be guided by an objective of identifying activity where there is a deviation between serving the best interests of the patient and the interests in developing generalisable knowledge. Lewens puts it well: If we define treatment not merely as a series of events designed to promote the health of the patient, but as a series of events optimized solely for the promotion of health of the patient, then anything that is not optimized solely for the promotion of the health of the patient does not count as treatment. Some research does aim partially at the promotion of health of those who participate in the study. In refusing to label it treatment, we ensure that patients will be made aware of the ways in which health promotion may have been partially sacrificed for other ends, and we encourage a careful scrutiny of whether the promotion of health has not been unduly sacrificed in experimental design.66The focus on methodology, it is submitted, provides the clearest way forward in identifying objective features of any activity that would bear the relevant hallmarks of research, and would benefit from the distinct ethical analysis that the research ethics pathway has been developed to provide answers for.67 Reliance on more diffuse criteria such as greater uncertainty of risks and benefits, or professional conflicts of interest,68 would likely extend oversight across large swathes of medical practice that current processes are not optimally designed for.69 However, confining ourselves to the strict methodological features of the RCT would be unduly restrictive if there are other types of methodology that are practically influential, even if not scientifically rigorous.70 Any single recognised method or combination of methods that has the potential to compromise the individualised, optimal clinical management of the patient should count as research. Thus the use of any control, not just a placebo, could affect the optimal choice of treatment modality for a particular patient, and thus constitute a research purpose.71 A more purposive test for research should thus encompass any methodology with a real potential to place the best interests of the patient in tension with the physician-researcher's need to satisfy the rubric of the relevant methodology (and hence the expectations of the relevant professional or scientific audience). Therefore, turning to the ‘investigational study’ example, the use of historical controls (comparisons with a prior cohort of patients who received standard therapy) would raise a regulatory concern if that standard therapy was indicated for patients in the informal study, but they were offered the innovative treatment instead. This does not amount to randomisation, but it still puts the physician in a clear situation of conflict between his desire to help the patient, and his desire to acquire sufficient data to formulate and test a hypothesis.72 Where, however, the criteria for offering innovative treatment stipulate the absence of standard therapy for such patients, there is less of a concern that their care is not optimised since they have no other existing options. Further, there is no relevant conflict between the needs of the patient and the expectations of the audience the physician might later address. Thus, on the particular facts in Devathasan, at least in relation to the subject of the complaint, the patient was offered the innovative combination of rTMS and therapeutic ultrasound only because she had failed to respond to standard therapy and had requested alternative forms of therapy.73 If the series of cases in an informal study were enrolled on the same basis, then it is submitted that the exercise should remain within the realm of medical practice rather than research—notwithstanding the subsequent retrospective analysis of clinical data to support its continued use in future patients (which might itself constitute research under the absence of a therapeutic benefit test74). IV. THE LEGAL CONSTRUCTION OF INNOVATIVE THERAPY: POST HOC REVIEW Based on the foregoing analysis, there remains a distinct category of innovative treatment that rightly remains outside the research paradigm. In the absence of a definitive regulatory regime for such innovative treatment, legal or professional reviews of complaints concerning the administration of such therapy are generally ex post where compensation is sought for injury or loss suffered as a result,75 or a complaint is made in respect of professional misconduct. Medical negligence law offers the most obvious cause of action with which to hold a medical professional to account, and innovative therapy is therefore likely to raise issues relating to a breach of the requisite standard of care and informed consent. The focus here is on these, although similar issues are likely to be raised in a disciplinary review. A. The Applicable Standard of Care By definition, innovative treatment departs in some significant way from standard therapy. Historically, such deviation was treated as proof of negligence itself, or at least put the defendant medical practitioner under strict liability for untoward consequences by reason of attempting it.76 That conservative approach has since changed with the legal recognition that deviations are part and parcel of innovation in medicine, a crucial aspect of medical development and progress. Thus, as early as 1935, US courts recognised that some departures from standard therapy should not automatically be faulted by the law: We recognize the fact that, if the general practice of medicine and surgery is to progress, there must be a certain amount of experimentation carried on; but such experiments must be done with the knowledge and consent of the patient or those responsible for him, and must not vary too radically from the accepted method of procedure.77Critics of US case law, however, point out that it has yet to develop any distinctive set of principles to evaluate innovative treatments, given that traditional malpractice standards have been formulated principally with customary practices in mind.78 While similar sentiments in support of medical innovation were made across the Atlantic in Hunter v Hanley,79 the court took an arguably more innovation-friendly stance: … To establish liability by a doctor where deviation from normal practice is alleged, three facts require to be established. First of all it must be proved that there is a usual and normal practice; secondly it must be proved that the defender has not adopted that practice; and thirdly (and this is of crucial importance) it must be established that the course the doctor adopted is one which no professional man of ordinary skill would have taken if he had been acting with ordinary care. There is clearly a heavy onus on a pursuer to establish these three facts, and without all three his case will fail. If this is the test, then it matters nothing how far or how little he deviates from the ordinary practice. For the extent of deviation is not the test. The deviation must be of a kind which satisfies the third of the requirements just stated.80Mason and Laurie interpret this to represent a general reasonableness test to be applied in the particular circumstances of the case, albeit that the court must be assisted by expert evidence ‘as it thinks fit’.81 However, this seems to ignore the emphasis on the onerous burden of proof that the pursuer bears in establishing all three elements, and in particular, demonstrating that no medical professional of ordinary skill would have adopted the innovative course.82 This Wednesbury-like irrationality test of negligence83 was, however, expressly disapproved in Joyce v Merton, Sutton, and Wandsworth Health Authority, where Hobhouse LJ considered that the introduction of such an administrative law concept was liable to confuse.84 It is not obvious that a distinct set of principles is necessary for innovative treatment.85 Subsequent US cases scrutinising innovative therapy in its many forms did not draw any categorical distinction in approach towards evaluating standard and innovative treatments.86 Likewise, in Waters v West Sussex HA,87 the court observed that the inquiry related to a specific medical decision to undertake an innovative surgical procedure, rather than a medical practice. Nevertheless, the traditional Bolam test could be adapted to evaluate such ad hoc medical decisions.88 In fact, the court arguably also anticipated Bolitho caveats89 in requiring that the expert medical opinion supporting the innovative treatment ‘stands up to analysis and was not unreasonable in the light of the state of medical knowledge’.90 In Singapore, the courts have also encountered innovative treatments through the lens of medical negligence, but have not fully appreciated the status of innovative treatment and its dissonance with customary practice. The Court of Appeal decision in James Khoo v Gunapathy Muniandy91 involved the evaluation of the ‘unproven, experimental or controversial’ application of stereotactic radiosurgery to treat the plaintiff's neurocytoma.92 Nonetheless, the court reaffirmed and applied the traditional Bolam standard of care to evaluate, inter alia, the appropriateness of the radiation treatment parameters. It went further by imposing a more narrow gloss to the Bolitho clarification of Bolam, emphasising that the court should restrict itself to analysing ‘the process and not the result of the [medical] expert's reasoning …’.93 In particular, the court restricted the interpretation of ‘a defensible conclusion’ in Bolitho to two specific factors: the internal consistency of reasoning and external consistency with ‘proven extrinsic facts’.94 Thus, the ‘defensible conclusion’ referred to in Bolitho should not be understood as ‘reasonable’ in a substantive, merits-based sense.95 This would otherwise be inconsistent with the prohibition on preferring one expert body of opinion over another in determining what ought to be reasonable professional conduct,96 even if the court was evaluating innovative treatment. Conceptually, decisions to offer innovative treatment tend to involve clinical judgments made in the face of even greater medical and evidential uncertainty. The same concerns about the epistemic limits of judicial scrutiny of clinical judgment and inhibiting of medical innovation would suggest that they should also be guided by Bolam/Bolitho considerations.97 On the other hand, the constraints of the Bolam/Bolitho test are rightly self-imposed in respect of standard treatments or practices that have moved into the mainstream of medical practice, supported by adequate empirical research, peer review, or collective medical experience. Persistent alternative or ‘minority’ practice standards should thus be treated with greater judicial respect. In contrast, innovative treatments would not have been subject to the same level of professional medical or scientific assessment under the various developmental pathways in medical science. There might also be features of innovative decision-making context that raise questions as to the integrity and reliability of the physician–patient relationship in promoting patient welfare—such as potential conflicts of interest and the vulnerability of patients (and their families) in life-threatening or debilitating situations without any standard, efficacious therapy available.98 These considerations point towards the need for a more careful judicial evaluation of expert evidence supporting innovative treatment, in the interests of protecting patient welfare.99 One potential difference in evaluating innovative therapy is that it invites more prescriptive requirements for the relevant factors that supporting expert opinion must consider. The decisions in Heppworth v Kerr100 and Devathasan101 draw out three broad criteria that courts would find useful in structuring a review of innovative treatments: (i) the presence of some scientific rationale for the innovative therapy, (ii) pre-clinical evidential support for the safety and efficacy of the treatment, and (iii) the lack or ineffectiveness of any available standard therapy.102 Nonetheless, it remains to be seen what Bolitho's ‘logical analysis’ properly entails in the judicial scrutiny of innovative treatments.103 In Hepworth v Kerr, apart from the absence of proper scientific validation and adequate evidential support, the court considered that the defendant's innovative hypotensive anaesthetic technique involved the taking of ‘unnecessary risk’ when weighed against the surgical requirements for a bloodless operating field.104 If Khoo v Gunapathy's proceduralist conception105 of Bolitho prevails, then it would seem to rule out any cost–benefit analysis of clinical judgement that supports risk exposure which is disproportionate to the benefit conferred,106 contrariwise to the approach taken in some cases concerning standard therapy.107 There will be cases where, it is submitted, a very thin line separates the failure to consider or weigh a clear risk or precaution (procedural defect) from a decision to expose the patient to disproportionate risk (representing mere substantive disagreement). On the whole, one can discern a judicial trend which has embraced innovative treatment as a legitimate aspect of medical practice (compared with historical reprobation), evidenced by the converging approaches to evaluating such conduct for a breach of duty in medical negligence. Such a development is equally conscious of the limits of judicial competence and the untoward implications of over-intrusive scrutiny on medical innovation in the regulation of such treatment. B. Patient Informed Consent An equally important aspect of post hoc review is whether a patient has given informed consent to receive innovative therapy. Informed consent is a well-established requirement in medical treatment, but the question of the nature and scope of disclosure acquires greater importance given the feature of greater uncertainty regarding the risks and benefits of proposed innovative therapy, and the possibility of a greater divergence of interests on the part of the physician when compared with the administration of standard therapy. In particular it has been recognised by common law courts that interests related to reputational prestige and increasing direct or indirect commercial interests in the administration of innovative therapy are important considerations in formulating disclosure standards.108 There are three possible approaches to the scope of informed consent in the context of innovative treatment. The first treats it no differently from informed consent in a clinical setting, and the scope of disclosure depends on professional judgement to be determined by a responsible body of medical opinion. This was first indicated in the important case relating to the first artificial heart transplant in Karp v Cooley, where the US Fifth Circuit Court of Appeals ruled that notwithstanding the experimental, laboratory tested nature of the device, the question of what should be disclosed was a medical one to be determined by what ‘what a reasonable practitioner of the same school of practice and the same or similar locality would have advised a patient under similar circumstances.’109 This non-distinguishing, profession-centred approach was also endorsed by the Singapore Court of Appeal in 2002, which affirmed in Gunapathy the profession-centred approach in Sidaway110 without taking into account the innovative application of X-Knife surgery in the circumstances.111 The court was content to accept professional testimony that disclosure of the typical risks inherent in radiosurgery was adequate,112 without any mention of the complete absence of empirical data indicating the appropriate radiation dosages for the patient's type of tumour, nor what uncertainties were created by this lack of evidence.113 Thus in that case, evidence that the patient was informed of the main (known) risks associated with the procedure was sufficient to exonerate the medical team from liability for inadequate disclosure. The second approach adopts a patient-centred analysis of reasonable disclosure based on materiality. Courts endorsing this approach have specified that, at the least, patients must be informed of the experimental nature of the surgery.114 This is a basic, material feature of innovative therapy that needs to be communicated irrespective of the particular nature of the therapy. Some courts have gone on to include the particular physician's individual experience with the procedure, given its relative novelty, on the grounds that this constitutes a material risk factor in the patient's evaluation of the desirability of undergoing the innovative procedure.115 However, apart from the contextual significance of material risks and alternative standard procedures (if any), these courts have not gone further to indicate that any higher standard of disclosure extending to all reasonably foreseeable risks applies.116 This third, more onerous approach has not yet been accepted by a common law court in relation to innovative treatment. Where one is clearly within the realm of research, various courts have indeed imposed a distinctly higher threshold of disclosure just mentioned.117 In addition to that, they have weaved this requirement of heightened disclosure into consent to battery as well.118 One clear underlying concern motivating this higher standard relates to the similarities that innovative treatment has with formal research—a greater uncertainty as to risks and benefits, and the influence of developing new knowledge concerning the innovative treatment or procedure on the motivations of the physician.119 Thus, some commentators read the Helsinki Declaration120 as requiring just such a standard even in respect of innovative therapy,121 or support such a principle on the basis of the altered nature of innovative therapy and greater risks accompanying them.122 If the distinction between research and treatment argued for earlier is accepted, it would seem to suggest that the primary therapeutic motivation in innovative therapy unconstrained by an imperative scientific or professional methodology would render a full and complete disclosure under the third approach rather excessive. Furthermore, such disclosure might be counterproductive if the patient (often already in a vulnerable situation without standard therapeutic alternatives) is overwhelmed by the minutiae of reasonably possible risks, and suspicions might be unduly heightened by perceived defensive posturing given such full and frank disclosure. In research, this is considered a good thing as it highlights to the patient that a different paradigm is involved, provided that the innovative, untested option does indeed present a reasonable alternative in the patient's circumstances. As the court in Zimmer v Ringrose observed: In the case of a truly “experimental” procedure, … no therapeutic benefit is intended to accrue to the participant. The subject is simply part of a scientific investigation designed to enhance human knowledge. … To hold that every new development in medical methodology was “experimental” in the sense outlined in Halushka v Univ. of Sask. would be to discourage advances in the field of medicine. …There may, however, be specific concerns about a direct conflict of interest where the physician also holds a financial interest in demonstrating the success of an innovative therapy.123 In such situations, it might be more pertinent to recognise a fiduciary duty to disclose the interest and allow the patient to seek a second opinion, rather than impose a blanket requirement of full and frank disclosure.124 Therefore, if we properly remain within the realm of treatment, the focus of informed consent should be on disclosure of material risks that would influence the judgment of a reasonable patient in those particular circumstances. If appropriately framed to focus on the needs and interests of a reasonable patient in the relevant circumstances, then this would necessarily entail a fuller disclosure than if the subject matter pertained to standard therapy. There is ample common law authority to indicate that materiality in these circumstances must, at the least, encompass ensuring patient appreciation that the therapy is experimental and has not been sufficiently tested and evaluated in order for it to enter within the bounds of standard therapy.125 By reason of its experimental nature, informed consent for innovative therapy would necessarily involve the disclosure and discussion of a wider range of potential risks simply because their likelihood or severity would not be known or fully understood. Nevertheless, it should be noted that a patient-centred materiality test will more likely require a higher level of disclosure and patient engagement in practice. Uncertainty of benefit and increased risks associated with innovative therapy would require a more involved disclosure and discussion when compared with validated standard therapy where a clearer profile of the risk–benefit analysis is available. What the present analysis highlights more acutely is the uncertainty over whether a profession-centred standard of disclosure will adequately capture the rationale underlying informed consent to innovative therapy. This is particularly a concern where, apart from the physician–patient communication dynamic, there is no other independent evaluation of the innovation proposed. This paper does not attempt to revisit the general debate over physician- and patient-centred standards of disclosure.126 However, in the particular context of innovative therapy, it becomes even more imperative that the physician actively engage a patient and her values at a level she is prepared for—her personal goals of care and acceptable risk thresholds. Respect for patient autonomy in the face of uncertainty aside, informed consent also forces the physician into a process of self-scrutiny in carefully investigating potential risks and articulating her case for the proposed innovation.127 This becomes a default, protective mechanism in a situation where no other regulatory mechanism is triggered and the decision is essentially a private one made in the confidential context of the physician–patient relationship. Giesen observes that physicians may also have a bias in favour of experimenting in order to advance medical development.128 Such medical ‘adventurism’ needs to be balanced by ensuring that individual patient's concerns and interests are not ignored or downplayed in that decision making process, particularly when all the uncertain risks associated with the innovation will unequivocally be borne by the patient, not the physician.129 Finally, given that innovative therapy is more likely to be offered in situations where there is no standard therapy available, failure to appropriately disclose and advise patients of the experimental nature of the proposed therapy would essentially deprive them of a meaningful choice on the misimpression that the option was effective and appropriate.130 Thus, whatever the merits of the profession-centred standard of disclosure, at least in respect of innovative therapy, its desirability is questionable given the interests at stake.131 V. FURTHER REGULATORY IMPLICATIONS A. Persisting Concerns over Innovative Treatment Left to current regulatory processes, innovative treatment that is not classified as ‘research’ escapes any external review and is dealt with by the internal dynamics of the physician–patient relationship and possible post hoc review in a medical negligence action or disciplinary proceeding. The latter are generally not considered sufficiently robust to provide adequate oversight for innovative treatment: patients may only sue if they suffer injury, may not actually bring a suit or complaint, and even when they do, face considerable hurdles in obtaining recovery.132 The question therefore is whether this generally hands-off approach is satisfactory, although it is certainly possible that conscientious, innovating physicians may voluntarily seek professional peer-review, especially if practicing within a healthcare institution or team-based practice. Several features of innovative treatment within the domain of professional discretion raise serious doubts over the status quo. First, the decision to offer innovative therapy is subject to an increasing potential for conflicts between the patient's best interests and the physician's personal and professional interests in profit and advancement. The potential intellectual property and commercial spin-offs related to the development of new medical technologies have the potential for influencing professional judgments concerning innovative treatments, given their nascent stage of development and potential capacity, once administered, to generate valuable information in advancing the physician's interests.133 Concerns over conflicts of interest are of particular concern in a system where healthcare is principally delivered through privately operated institutions and cost recovery (if not profit) is an overriding concern. Secondly, quite apart from financial considerations, there may also be an evaluative bias in favour of the soundness of self-produced innovation, with the risk of an overestimation of the potential benefits and underestimation of the risks. This may be difficult to determine, particularly in an area where there is a lack of supporting data.134 Thirdly, pressure to innovate comes not only from professional quarters, but also from patients themselves. Patients without existing alternatives, and their families, may place strong pressure on doctors to try something new in the hope of a miracle cure.135 They are increasingly well informed and may point physicians to the latest media-informed developments across the globe. The burden of providing a detached, objective evaluation of the innovative option currently falls on the shoulders of the individual attending physician or surgeon, which may often be an unrealistic aspiration.136 Finally, a different interest hovers over every decision to deploy innovative therapy—the public health interest in the development of safe, efficacious new therapies. The public health interest reflects the interests of future patients who are affected by the precipitous introduction of new therapies before they are sufficiently tested. There is currently no general mechanism to inject such considerations into decision-making at the stage of casuistic innovation, as the decision to deploy innovative therapy is made ostensibly solely on the patient's best interests, irrespective of the interests of future patients in having such therapy systematically investigated for safety and efficacy.137 Thus it has been observed that a large majority of therapeutic interventions in medicine have not been subjected to the gold standard of scientific proof represented by the RCT.138 These considerations point towards a need to introduce some form of upstream regulation in order to preserve the integrity of the physician–patient relationship and promote better processes for the development and adoption of innovative therapies. B. Appropriate Regulatory Responses 1. Protecting Vulnerable Patients Through Independent Peer Review There are several broad regulatory strategies that have been adopted or recommended as responses to the concerns raised by innovative treatment. The first and foremost is the recommendation or requirement for prior independent peer review of the proposed innovative therapy.139 This is seen as a means for review and oversight of the individualised professional decision whether to offer innovative therapy, and draws obvious inspiration from the requirement for ethics review in the case of human biomedical research. A key rationale underlying this approach is perhaps the impetus such a review creates for any medical professional to reflect upon the proposal for innovative therapy, and a more impartial evaluation of the evidence supporting it and the personal needs of the patient.140 However, there is a broad variation on the specifics of independent peer review of innovative therapy, such as the appropriate forum and thresholds for ethical review. For example, in New Zealand, the Ministry of Health's Operational Standard for Ethics Committees provides guidelines and ethical standards for committees to review both health/disability research and innovative practice in seamless fashion.141 The recommendations require that innovative practice be subject to the same systematic evaluation, ethical review, and informed consent requirements as with other health research.142 In particular, like research, the innovative practice's justifiability must be demonstrated in terms of both contribution to medical knowledge and its potential to be of direct benefit to individual consumers.143 This is in part explicable on the particular conception of innovative practice adopted: ‘a planned deviation from currently accepted practice … involving an untested or unproven clinical intervention intended to be used on an ongoing basis.’144 This definition is akin to the classificatory approaches based on intention and reiteration of treatments used to identify research activity.145 The New Zealand approach thus appears to reflect the philosophy that innovative practice is substantially akin to research, and should be governed by similar ethical review processes and documentation. The Final Bristol Royal Infirmary Inquiry Report in the UK similarly recommended that any clinician undertaking a ‘new and hitherto untried invasive clinical procedure’ should satisfy a local REC that it is justified in the patient's best interests. This expansion of REC jurisdiction, nevertheless, recognises that the REC should be ‘re-formed’ as necessary so that they are capable of undertaking the requirements of ethical review for innovative therapy.146 However, RECs were not given jurisdiction over all new interventional procedures.147 Rather, medical practitioners intending to undertake ‘new interventional procedures’ should also seek approval from their NHS Trust's Clinical Governance Committee—which focuses on scientific safety and efficacy appraisal—before proceeding.148 Price thus observes that a regulatory gap exists within the parallel clinical governance and research ethics pathways in that no one is specifically tasked to undertake an ethical review of the innovative therapy offered.149 Other jurisdictions and institutions deploy adapted processes to cater to the specific needs of innovative therapy, rather than streamlining review within the research ethics paradigm. For example, various US hospitals such as the University of Pittsburgh Medical Centre and Boston Children's Hospital have created specific review processes to accommodate innovative practice. In the former, the Innovative Practices subcommittee of the UPMC's Technology and Assessment Committee (distinct from the University's IRB) was established to systematically evaluate innovative practice.150 It focuses on whether the proposed innovative therapy possesses a favourable risk–benefit ratio suitable for patient care, and its composition is carefully chosen to reflect this emphasis.151 In comparison, the Boston Children's Hospital divides review between unaffiliated departmental members (for assurance of patient safety) and administrative IRB review (for informed consent) in respect of innovative surgery.152 The oversight model also provides mechanisms for resolving ambiguities of classification between research and innovation.153 This preference for alternative models of review has also been the approach of various professional bodies such as the Surgical Innovations Team of the Society of University Surgeons,154 and the International Society for Stem Cell Research155 in their respective fields of innovation. Should existing research ethics review processes be expanded to accommodate innovative treatment, or are bespoke oversight mechanisms preferable? The optimal form of regulatory supervision should follow its specific function.156 Innovative therapy, unlike research, is focused on the care of a specific patient and not generalisable knowledge. Although the nature of the risks imposed and uncertainties involved are more akin to that experienced in the conduct of research, the ethical issues raised are different. Innovative therapy raises issues more focused on the needs and interests of the patient in electing for an innovative option. This is largely a clinically oriented issue which weighs the risks and uncertainties against the specific individual needs of the patient, and the clinical systems available to manage and mitigate those risks. Thus, Taylor argues that it requires ‘oversight tailored to the risks and patient implications actually presented by specific therapeutic innovations.’157 In particular, emphasis should be placed on (i) a review of the available data and scientific rationale support for the innovation proposed in the light of the patient’s needs and interests, (ii) adequate coordination and follow-up by the relevant clinical services involved in the particular patient's care, (iii) a rigorous, patient-specific informed consent process that conveys to the patient not only the uncertain risks and available options, but also the financial implications of innovative therapy, and (iv) an ethical review of the offer of innovative therapy given the risk–benefit analysis to ensure that it is not clearly inappropriate.158 In comparison, research ethics analysis performs a different sort of risk–benefit analysis that weighs the additional risks posed to the participants against the value of the knowledge to be derived from the research (in the light of its scientific design and on the assumption that clinical equipoise is satisfied where appropriate).159 Although research oversight may also focus on underlying scientific plausibility, this is for the different purpose of assessing the suitability of the proposed scientific methodology. The acceptable evidential thresholds may thus vary depending on whether the object is to develop generalisable data or to help a particular patient who has no other available options.160 The capacity of IRBs or RECs to review innovative therapies might be further limited in so far as their authority to undertake scientific review is restricted by the relevant regulations or ethical guidelines. For example, under the UK Department of Health Governance Framework for NHS Research Ethics Committees, RECs are not expected, nor are they appropriately composed, to review scientific aspects of a research protocol.161 Likewise, in Singapore, under the Ministry of Health's Operational Guidelines for IRBs, review boards are not responsible for the scientific review of research projects.162 These limitations do not suggest that IRBs or RECs, at least with their current mandates, are eminently suited to review innovative practice as well. Furthermore, Agich has observed that there is a lack of fit between the research regulatory oversight methods and the typical circumstances of innovative practice: The typical [research ethics paradigm] review is conducted by committee relying on the submitted application, protocol, and informed consent documents. The complex processes characteristic of clinical innovation are often not reducible to a scientific protocol. They typically involve intuition, experience, and an evolving knowledge about the treatment and disease processes and the interaction between treatment and pathology.163An insistence on conformance to the practices and expectations of the existing research ethics paradigm, or interposing multiple gatekeepers in the oversight process, may thus impede innovation in a rapidly evolving field of medicine. It is thus submitted that, consistent with more recent scholarship mentioned above, the form and routine in existing research ethics processes can inhibit appropriate understanding and review of the particular clinical and ethical questions raised by innovative treatment. In this respect, given the greater clinical ‘character’ of innovative therapy and the needs of the particular patient, a process more akin to clinical ethics peer review is necessary, with appropriate expertise drawn (whether internal or external to the institution in question) to address the underlying characterisation, scientific, and ethical issues. The quality of peer scrutiny on the underlying rationale and supporting evidence of innovative therapy would necessarily be influenced by the urgency of the patient's situation. Such a process would also have to be more flexible in terms of the necessary documentation and response times needed to make it viable in the context of innovative therapy. Informed consent review would also need to be more personalised, and should even consider independent peer involvement in communicating and explaining the necessary information, so as to obtain more meaningful informed consent.164 On this score, a related issue arises concerning the appropriate threshold for independent professional review. This is necessitated because of the wide ranging scope of potentially innovative practice within the practice of medicine, such that too low a threshold would likely overwhelm regulatory oversight and unduly impede access to innovative therapy to the detriment of patients. The Lasker Foundation Forum on Innovation in Medical Technology thus recommended that a high threshold be set in respect of the degree of deviation and potential risks involved.165 Indeed, the Belmont Report originally flagged out ‘significant innovations’ for possible research as soon as practicable.166 Useful starting points of reference are ‘innovations that provide diagnosis or treatment for a condition that previously had none, … that claim to provide a different stratum of effectiveness over standard treatments … or whose rationale is novel … signify a degree of novelty that is associated with uncertainty and the potential for significant risk.’167 Where this threshold is set may partly be addressed by professional guidelines, but should ultimately be left to the particular institutions implementing a system that should continue to follow an enforced self-regulation model.168 This context-specific classification would better adapt to the particular activities conducted by an institution, and its experience and capacity to manage different levels of risk associated with innovative practices. 2. Protecting the Public Health Interest Prescriptions are far less forthcoming in respect of regulatory measures needed to serve the public interest in the responsible development of new therapies. First, the ability of independent peer and ethical review of innovative therapy to regulate proper development is necessarily limited. The responsibility of such committees is conceived of as, first and foremost, protecting the interests of the patient in need. Innovative practice may thus be responsibly approved under such oversight even if it will not lead to generalisable (as opposed to anecdotal) knowledge that will accrue to the benefit of future patients under the RCT standard.169 If there is a sufficiently sound rationale for the innovation when balanced against the patient's medical need and lack of available therapeutic alternatives, then it could be unethical to deny the patient the choice solely because insufficiently rigorous knowledge would be generated. Certainly, prior ethical peer review would serve a useful function in screening out instances of quackery or unacceptable innovative risks in comparison with available standard therapy, and could encourage the physician or institution to undertake suitably designed research to compare the innovation with existing standard therapy. Independent peer review of innovative practice, nevertheless, cannot mandate the additional funding needed for, nor ethical propriety of, such research, let alone the professional desire to do so.170 A couple of regulatory mechanisms have thus far been used to complement independent peer review in improving the assessment of innovative practice in the process of development into standard therapy. The first is the use of clinical registries to improve the collection of data concerning the deployment of innovative therapy, thereby facilitating outcomes research in general and the deliberation of peer committees reviewing innovative practice in particular.171 This has most often been used on the field of innovative surgery, with examples of registries created by professional societies172 and the state agencies.173 They are not without their shortcomings, however, which range from the substantial cost of implementing them on a sufficient scale, to difficulties ensuring inclusiveness and validity, and ensuring respect for patient privacy.174 The need for careful selection and implementation of registries for innovative treatment points also to the need for some coordinating agency or professional society to provide a coherent strategy to protect both patients and the larger public health interest. This leads naturally to the second mechanism, which involves placing responsibility for oversight of the development process with a suitably equipped regulatory agency or institution. In respect of the systematic review of such therapies, various jurisdictions have agencies tasked accordingly. For example, the UK's National Institute for Clinical Excellence (NICE) maintains a compulsory register of interventional procedures. Its Interventional Procedures Advisory Committee assesses the available evidence on their safety and efficacy, and issues guidance on them.175 The NICE programme dovetails with the UK Department of Health's Interventional Procedures Programme mentioned above,176 which responds to notifications of new procedures with either fresh guidance or the commissioning of a systematic review of research on the procedure.177 A similar function is performed at the federal level by the US Agency for Healthcare Research and Quality in respect of new or as yet-unproven medical technologies that are being considered for coverage under Medicare and Medicaid.178 Such systematic review, however, also does occur at the institutional level: Witness the Massachusetts General Hospital Innovative Diagnostics and Therapeutics Committee, which reviews new medical technologies and determines whether they need formal research examination or can be introduced into practice without it.179 A substantial part of the regulatory complexity is rooted in the ongoing debate as to the proper conception of medical epistemology—whether medicine is essentially science or treatment.180 Adopting the former view would require the proper scientific assessment of innovative therapy before diffusion, while the latter would accommodate less formal and scientifically rigorous assessment in the development process.181 Add to this ethical and resource constraints on research and one is left with the impression that there is unlikely to be any standard regulatory solution to the challenge of protecting the public interest in the proper passage of innovative treatments into standard medical practice. A systematic resolution of this depends largely on the healthcare system in question, the profile of innovative practice within its institutions and healthcare professions, and the existing systems already in place that could be adapted to regulate innovative therapy. This larger discussion is beyond the scope of this paper; the point made here is that this regulatory interest cannot be adequately served simply by implementing an independent peer review mechanism for innovative treatments. VI. CONCLUSION In summary, innovative therapy is increasingly, and rightly, seen as a distinct category of medical activity that possesses features in common with both the therapeutic paradigm of the physician–patient relationship and the clinical research paradigm. It is most effectively distinguished from research by using both a methodological analysis (which searches for methodological constraints on the physician's judgement in serving the patient's best interests), or the absence of therapeutic benefit analysis (which complements the former by identifying the research purpose from the presence of procedures that are unnecessary for treatment). Streaming of innovative practice into the research ethics regulatory pathway would thus be put on a clearer footing. Legal oversight over innovative therapy exists in both medical negligence law and disciplinary proceedings, but greater analytical clarity is needed in first recognising the unique features of innovative therapy that distinguish it from standard therapy, and the appropriate standards of care in treatment and advice that should accompany it. Informed consent for innovative therapy needs to be more rigorously evaluated to respect the particular importance of patient autonomy in appreciating and accepting the uncertain risks and benefits associated with such therapy. Finally, post hoc legal scrutiny often comes too late, or not at all, in aid of vulnerable patients. It is also limited in its ability to systematically protect the public health interest in the development of safe and effective new therapies. Additional regulatory measures are necessary, which include, in particular, an adaptive peer oversight process that properly balances the interests of the individual patient and responsible innovation in medicine. The latter interest needs to be supported by other complementary regulatory mechanisms such as clinical registries and dedicated institutional oversight of the development process, because peer review itself cannot do this alone effectively. 1 A working definition of ‘standard medical therapy’ can be found in the US National Commission, The Belmont Report: Ethical Principles and Guidelines for Protection of Human Subjects of Research (18 April 1979), Part A, para 2 <http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html>: ‘interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable chance of success’. 2 See A Mastroianni, ‘Liability Regulation and Policy in Surgical Innovation: the Cutting Edge of Research and Therapy’ (2006) 16 Health Matrix 351, 370–1. 3 See, generally, R Levine, Ethics and Regulation of Clinical Research (2nd edn, Urban & Schwarzenberg, Baltimore 1986) 3–6. 4 S Verdun-Jones and D Weisstub, ‘Drawing the Distinction Between Therapeutic Research and Non-Therapeutic Experimentation: Clearing a Way Through the Definitional Thicket’ in D Weisstub (ed), Research on Human Subjects: Ethics Law and Social Policy ( Pergamon, Oxford 1998) 95; see n 5 at 621. 5 DH Cowan, ‘Innovative Therapy versus Experimentation’ (1985) 169 Torts Ins L J 619, 623. 6 SMC v Martin Huang, Singapore Medical Council (SMC), Kathmandu (2009) 26–8; SMC v Erwin Kay and SMC v Wong Yoke Meng, SMC, Annual Report (2010) 24–6; <http://www.healthprofessionals.gov.sg/content/hprof/smc/en/topnav/publication.html>. 7 [2010] 2 SLR 926 (Sing. HC). 8 Repetitive transcranial magnetic stimulation is a form of brain stimulation that uses a magnet instead of an electrical current to activate the brain. Unlike electroconvulsive therapy, in which electrical stimulation is more generalised, rTMS can be targeted to a specific site in the brain: US National Institutes of Mental Health, Brain Stimulation Therapies, <http://nimh.nih.gov/health/topics/brain-stimulation-therapies/brain-stimulation-therapies.shtml>. 9 Ibid at para 32. 10 2001, <http://www.healthprofessionals.gov.sg/content/hprof/smc/en/topnav/guidelines.html> [emphasis added]. 11 See n 7 at para 21 [emphasis added]. 12 Ibid at para 24. 13 Ibid at paras 42–60. 14 Ibid at para 46. 15 The court accepted expert evidence that ‘off-label’ use (i.e. innovative treatment) refers to the use of a therapeutic modality “which is not mentioned in the literature, or … is not approved by any of the [regulatory] agencies…”, ibid at para 49. 16 Ibid at para 60. 17 With respect, the soundness of this reasoning may be questioned. There was no doubt that both rTMS and therapeutic ultrasound were not generally accepted treatments for the patient's condition. However, as the DC accepted that innovative treatment was a recognised exception to the general standard of care required under para. 4.1.4 of the Ethical Code, the ethical requirements for off-label or innovative treatment became relevant for the purposes of determining an ethical breach of para 4.1.4 read in its entirety (see n 24 and accompanying text). In addition, it is difficult to see why patient safety is only relevant in determining the ethical propriety of innovative treatments, but not its passage into the realm of standard therapy. The quality of the clinical studies supporting adoption as standard therapy must surely encompass the basic clinical requirement of acceptable patient safety. 18 Devathasan, see n 7 at para 40. 19 Ibid at para 64. 20 Ibid at para 73. 21 B Freedman and others, ‘Demarcating Research and Treatment: a Systematic Approach for the Analysis of the Ethics of Clinical Research’ (1992) 40 Clin Res 653–60 at 654. 22 See D Cowan, ‘Innovative Therapy: the Responsibility of Hospitals’ (1984) 5 J Leg Med 219. 23 See n 7 at para 53. 24 See n 10. This particular clause in para 4.1.4 was quoted but not analysed by the court in Devathasan, see n 7. 25 World Medical Association, (2008), para 35 <http://www.wma.net/en/30publications/10policies/b3/index.html>: ‘In the treatment of a patient, where proven interventions do not exist or have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorized representative, may use an unproven intervention if in the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering.’ 26 See T Lewens, ‘Distinguishing Treatment from Research: a Functional Approach’ (2006) 32 J Med Ethics 424, at 426. 27 See n 1 at Part A, para 1. 28 (1997) [emphasis added] <http://www.moh.gov.sg/content/moh_web/home/Publications/guidelines/national_medical_ethics_committee_guidelines/1997.html>. 29 The Belmont Report's definition of medical ‘practice’ is found in Part A, para 2: ‘For the most part, the term “practice” refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individuals’. 30 See n 28 [emphasis added]. 31 BAC, Singapore 2004 at paras 3.21–3.23. 32 Ibid at para 3.24. The MOH's more recent Governance Framework for Human Biomedical Research (MOH, Singapore 2007) and Operational Guidelines for Institutional Review Boards (MOH, Singapore 2007) do not add anything further to these definitions <http://www.moh.gov.sg/content/moh_web/home/Publications/guidelines/human_biomedical_research.html>. 33 See R Levine, ‘The Boundaries between Biomedical or Behavioral Research and the Accepted or Routine Practice of Medicine’ (14 July 1975), in the Belmont Report, see n 1, Appendix A, Section 1 at 5. 34 (4th edn RCP, London 2007) at paras 3.4–3.5. 35 See, for example, I Goldiamond, ‘On the Usefulness of Intent for Distinguishing Between Research and Practice, and Its Replacement by Social Contingency: Implications for Standard and Innovative Procedures, Coercion and Informed Consent, and Fiduciary and Contractual Relations’ in The Belmont Report, see n 1, Appendix A at 14–4. 36 See also n 33 at 11–2. 37 See N King, ‘Experimental Treatment: Oxymoron or Aspiration?’ (1995) 25 Hastings Cent Rep 6 at 11. 38 J McKinlay, ‘From Promising “Report” to “Standard Procedure”: Seven Stages in the Career of a Medical Innovation’ (1981) 59 Millbank Mem Fund Q/Health Soc 374 at 392–3. 39 See L Noah, ‘Informed Consent and the Elusive Dichotomy Between Standard and Experimental Therapy’, Am J Law Med (2002) 361 at 400–1; N King and G Henderson, ‘Treatments of Last Resort: Informed Consent and the Diffusion of New Technology’ (1991) 42 Mercer Law Rev 1007 at 1023–4; J Lantos and J Frader, ‘Extracorporeal Membrane Oxygenation and the Ethics of Clinical Research in Pediatrics’ (1990) 323 N Engl J Med 409 at 412; cf V Miké and others, ‘Neonatal Extracorporeal Membrane Oxygenation (ECMO): Clinical Trials and the Ethics of Evidence’ (1993) 19 J Med Ethics 212, 216–7. 40 F Miller, ‘Ethical Issues in Surgical Research’ (2005) 15 Thorac Surg Clin 543, 545. 41 See n 33 at 6–7, 32. 42 Ibid at 35 [emphasis added]. 43 Ibid at 37, 41. 44 See n 1, Part A, para 3 [emphasis added]. 45 M Eaton and D Kennedy, ‘Innovation in Medical Technology: Ethical Issues and Challenges’ (Johns Hopkins University Press, Baltimore 2007) 31. 46 See N Frost and R Levine, ‘The Dysregulation of Human Subjects Research’ (2007) 298 JAMA 2196. 47 See Noah, n 39 at 406–7; S McKinlay, ‘Experimentation in Human Populations’ (1981) 59 Milbank Mem Fund Q Health Soc 308 at 320. 48 45 CFR 46.102(d). 49 See National Bioethics Advisory Commission, ‘Ethical and Policy Issues in Research Involving Human Participants’ (NBAC, Bethesda 2001) 35. 50 See n 40; S Strasberg and P Ludbrook, ‘Who Oversees Innovative Practice? Is There a Structure that Meets the Monitoring Needs of New Techniques?’ (2003) 196 J Am Coll Surg 938, 942. There is some support for this approach in Ancheff v Hartford Hospital 799 A.2d 1067 at 1071–2 (Conn. 2002), but it was framed as a factual question to be answered with the assistance of expert evidence. 51 See S Hellman and D Hellman, ‘Of Mice but Not Men: Problems of the Randomized Clinical Trial’ (1991) 324 N Engl J Med, 1585. 52 See n 40. Similarly, Lewens considers research to refer to activity designed to answer questions that the ‘medical research community would generally regard as scientifically important’: see n 26 at 426. 53 JK Mason and GT Laurie, Law and Medical Ethics (8th edn Oxford University Press, Oxford 2010) at 612, seem to prefer this definitional approach: ‘Research implies a pre-determined protocol with a clearly defined end-point. Experimentation, by contrast, involves a more speculative, ad hoc, approach to an individual subject’. 54 See n 1, Part A, para 2. 55 See n 38. 56 C Margo, ‘When Is Surgery Research? Towards an Operational Definition of Human Research’ (2001) 27 J Med Ethics 40 [emphasis added]. 57 M McKneally and A Daar, ‘Introducing New Technologies: Protecting Subjects of Surgical Innovation and Research’ (2003) 27 World J Surg 930, 931–2. 58 In respect of stem cells, see R Cash and others, Casebook on Ethical Issues in International Health Research (WHO, Geneva, 2009) at 12 and 44; in respect of the off-label use of a monoclonal antibody, see n 150 and HP Tan and others, ‘Living Donor Renal Transplantation Using Alemtuzumad Induction and Tacrolimus Monotherapy’ (2006) 6 Am J Transplant 2409; in respect of medical devices, Devathasan v SMC, see n 7, is potentially an example of an informal study. 59 E Gladstein, ‘What Is Research?’ (2001) 51 Int J Radiat Oncol Biol Phys 288. 60 Gladstein, ibid, argues that these criteria were supported by the Belmont Report, but a perusal of the relevant Part A of the Report does not support such a reading, unless he assumes that these are commonly taken as the essential elements of a formal research project. 61 See n 56 at 42 [emphasis added]. 62 See, for example, E Ahrens, The Crisis in Clinical Research (Oxford University Press, New York 1992) ch 3. 63 See N Fost, ‘Ethical Dilemmas in Medical Innovation and Research: Distinguishing Experimentation from Practice’ (1998) 22 Semin Perinatol 223, 224–5. 64 See n 45, ch 2, for a brief review of the modern history of human research ethics. 65 J Katz, ‘The Regulation of Human Research – Reflections and Proposals’ (1973) 21 Clin Res 785, 787. 66 See n 26 at 427 [emphasis added]. See also Belmont Report, see n 1 at Part A, para 4. 67 Innovative treatment raises distinct ethical issues within the realm of medical practice that would arguably require a different form of regulatory oversight: see the discussion below under Part V.B. 68 See, for example, Noah, n 39, 370–1. 69 See Part V.B.1 below. 70 Cf EH Morriem, ‘Medical Research Litigation and Malpractice Tort Doctrines: Courts on a Learning Curve’ (2003) 4 Hous J Health L Policy 1, 15–6: ‘If facts are not gathered in a consistent fashion according to specified rules, then they cannot add up to scientifically credible generalizations–and the project is unworthy of the name “clinical research.”’ 71 See n 21 at 658. 72 This was first suggested in basic terms by B Dickens, ‘What Is a Medical Experiment’ (1975) 113 CMAJ 635, 637. 73 Devathasan, see n 7 at paras 14 and 72. 74 See n 150 at 748. 75 The exception being prospective legal review by a court where innovative therapy is offered to a patient who lacks decision-making capacity and the court is asked to authorise it or confirm that the therapy is in the patient's best interests: see, for example, Simms v Simms [2003] Fam 83. 76 Slater v Baker and Stapleton (1797) 95 ER 860.  77 Fortner v Koch 261 N.W. 762 (1935) at 765 (S.C. Michigan) [emphasis added]. 78 M Greenberg, ‘Medical Malpractice and New Devices: Defining an Elusive Standard of Care’ (2009) 19 Health Matrix 423 at 433. 79 1955 SC 200 at 206. 80 Ibid [emphasis added]; cf D Giesen, ‘Civil Liability of Physicians for New Methods of Treatment and Experimentation: a Comparative Examination’ (1995) 3 Med Law Rev 22, 32: ‘The degree of knowledge and skill a doctor owes his patients increases, the further he departs from well established practice by applying new methods of treatment … ’ This seems to suggest a stricter standard of care based on the extent of deviation, which seems contrary to the more recent jurisprudence on standards of care in respect of innovative therapy. 81 See n 53 at 627. 82 See S McLean, ‘Regulating Research and Experimentation: a View from the UK’ (2004) J L Med Ethics 604 at 605. 83 Specifically proposed in Bolitho v City and Hackney HA [1993] 4 Med LR 381, 392 (CA), per Dillon LJ. 84 [1996] 7 Med LR 1 at 20. 85 J Robertson, ‘Legal Implications of the Boundaries between Biomedical Research involving Human Subjects and the Accepted or Routine Practice of Medicine’ (31 December 1975), in the Belmont Report, see n 1, Appendix B at 4–6, was of the view that the basis of tort liability for standard and innovative treatment is identical. Rather, the factual inquiry in each case differs. 86 See, for example, Hood v Philips 554 S.W. 2d. 160 at 165 (1977) (S.C. Texas); Mastroianni, see n 2 at 384. 87 [1995] 6 Med LR 362. 88 See also Simms v Simms, n 75 at paras 48–51. 89 Bolitho v City and Hackney Health Authority [1998] AC 232 at 242 (HL): ‘In determining what represents a responsible body of medical opinion, the court is not bound to follow expert evidence led by the defendant physician. It must be satisfied that that respectable body of medical evidence has a “logical basis”, which requires the court to ensure that the experts had “directed their minds to the question of comparative risks and benefits and reached a defensible conclusion on the matter’. 90 See n 87 at 365. 91 [2002] 2 SLR 414 (Sing. CA). 92 Ibid at para 99. 93 See n 91 at para 64. 94 Ibid at para 65. 95 Ibid. See also R Mulheron, ‘Trumping Bolam: a Critical Legal Analysis of Bolitho's “Gloss”’ [2010] 69(3) Cambridge L J 609 at 619. 96 See Maynard v West Midlands Regional H.A. [1984] 1 WLR 364 at 368. 97 See, for example, Baldor v Rogers 81 So.2d 658 at 660 (SC Florida, 1954). 98 See Part V.A. below. 99 In addition to respect for patient autonomy: see G Annas, ‘Cancer and the Constitution – Choice at Life's End’ (2007) 357(4) N Engl J Med 408 at 413: ‘The right to choose in medicine is a central right of patients, but the choices can and should be limited to reasonable medical alternatives, which themselves are based on evidence’; see MacNeil, n 134 at 480–1; cf Helsinki Declaration, n 25. 100 [1995] 6 Med LR 139 (QBD, Sheffield). 101 See n 7 at paras 53–7 (endorsing guidance issued by the UK General Medical Council and the US Food and Drug Administration on the off-label use of ‘medicines’ and ‘drugs, biologics and devices’ respectively); 62–7 and 72. None of these factors were explicitly considered in Khoo v Gunapathy, see n 91. 102 See also n 53 at 143, para 5.51. 103 For a discussion of the uncertainties relating to ‘logical analysis’, see H Teff, ‘The Standard of Care in Medical Negligence – Moving on from Bolam?’ (1998) 18 OJLS 473 at 480–1; R Heywood, ‘The Logic of Bolitho’ (2006) 22 PN 225 at 227–8. 104 See n 100 at 164–5. 105 See n 94. See also Mulheron, n 95 at 626. 106 See Heywood, n 103 at 234. 107 See for example, Marriott v West Midlands HA [1999] LLR Med 23 at 28: Mulheron, n 95 at fn 103, classifies this case as an instance of an expert opinion failing to consider the comparative risks and benefits. It is submitted that this is difficult to support on the express reasoning of the court. 108 See, for example, Zimmer v Ringrose (1981) 124 DLR (3d) 215; Estrada v Jacques 321 SE 2d 240 (1984) at 255 (CA, NC). 109 493 F.2d 408 (1974) at 419 (CA 5th Cir.). 110 Sidaway v Bethlem Royal Hospital Governors [1985] AC 871 (HL). 111 See n 91 at para 143. 112 Ibid at para 131. 113 Ibid at paras 99–105. 114 See n 108. 115 See, for example, Hales v Pittman 576 P.2d 493 at 500; see also P Healey and A Samantha, ‘When Does the ‘Learning Curve’ of Innovative Interventions Become Questionable Practice?’ (2008) 36 Eur J Vasc Endovasc Surg 253, 256. 116 See Noah, n 39  at 375–9. 117 See Halushka v University of Saskatchewan (1965) 53 DLR (2d) 436 at para 29; Whitlock v Duke University 637 F. Supp 1463 (1986); Weiss v Solomon (1989) 48 CCLT 280. 118 Halushka, ibid. 119 See Giesen, n 80 at 35; AM Capron, ‘Informed Consent in Catastrophic Disease Research and Treatment’ (1974) 123 Univ Penn Law Rev 340, 368. 120 See n 25 at para 32, read with para 22. 121 Healey and Samantha, see n 115. 122 Giesen, n 80 at 35; cf Noah, n 39 at 407–8. 123 P Taylor, ‘Overseeing Innovative Therapy without Mistaking It for Research: a Function-Based Model Based on Old Truths, New Capacities, and Lessons from Stem Cells’ (2010) 38 J L Med Ethics 286, 291–2. 124 See, for example, Moore v Regents of the University of California 793 P.2d 479 (1990) (SC Cal). 125 See, for example, Estrada v Jacques, n 108 at 254: ‘ … With experimental procedures the “most frequent risks and hazards” will remain unknown until the procedure becomes established. If the health care provider has a duty to inform of known risks for established procedures, common sense and the purposes of the statute equally require that the health care provider inform the patient of any uncertainty regarding the risks associated with experimental procedures. This includes the experimental nature of the procedure and the known or projected most likely risks.’ [emphasis in original]. 126 See, for example, P Schuck, ‘Rethinking Informed Consent’ (1994) 103 Yale L J 899. 127 See P Freund, ‘Legal Frameworks for Human Experimentation’ (1969) 98 Daedalus 314 at 323; Capron, n 119 at 371–3. 128 Giesen, n 80 at 35. 129 See also King and Henderson, n 39 at 1032; 1044–5. 130 Ibid at 1044, 1048. 131 The analysis here is based on a private law conception of the issue. For a human rights centred discussion on patient consent and experimental treatment, see A Plomer, The Law and Ethics of Medical Research: International Bioethics and Human Rights (Cavendish, London 2005) ch 3. 132 Robertson, n 85 at 20. 133 Taylor, n 123 at 291–2. 134 Ibid at 296; P MacNeil, ‘Regulating Experimentation in Research and Medical Practice’ in H Kuhse and P Singer (eds), A Companion to Bioethics (2nd edn, Wiley-Blackwell, Oxford 2009) ch 39, at 471. 135 See, for example, W Dondrop and G de Wert, ‘Innovative Reproductive Technologies: Risks and Responsibilities’ (2011) 1 Hum Reprod  4. 136 H Edgar, ‘Regulating Psychosurgery: Issues of Public Policy and Law’ in W Gaylin and others (eds), Operating on the Mind: The Psychosurgery Conflict (1975) ch 5 at 128. 137 This was a major concern of Levine in his report to the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research; see n 33 at 37. 138 M Dublinsky and JH Ferguson, ‘Analysis of the National Institutes of Health Medicare Coverage Assessment’ (1990) 6 Int J Tech Assess Health Care 480 at 487. 139 See for example, Eaton and Kennedy, n 45 at 104, reporting the consensus at the Lasker Foundation Forum on Innovation in Medical Technology. 140 Edgar, n 136 at 128 and 132; MacNeil, n 134 at 483. 141 New Zealand Ministry of Health, Operational Standard for Ethics Committees: Updated Edition (Ministry of Health, Wellington 2006). 142 Ibid at 25, para 123. 143 Ibid at 25, para 123(iii), 26, paras 127, 129, 131, and 132. 144 Ibid at 24, para 121 [emphasis added]; which resonates with the ‘reiterative’ definition of research considered above: see Part III.B.3. 145 See Parts III.A and III.B.3. 146 Bristol Royal Infirmary Inquiry, Final Report: Recommendations (2001), paras 100–1; online: <http://www.bristol-inquiry.org.uk/final_report/>. 147 D Price, ‘Remodelling the Regulation of Postmodern Innovation in Medicine’ (2005) 1 Int J L Context 121, 135. 148 UK Department of Health, Health Service Circular HSC 2003/11: The Interventional Procedures Programme (12 November 2003); online: <http://www.dh.gov.uk/en/Publicationsandstatistics/Lettersandcirculars/Healthservicecirculars/DH_4064922>. 149 See n 147 at 136. 150 C Ryan and DP Swanson, ‘Clinical Research, Innovative Practice and IRB Review’ (2007) 7 Am J Trans 748–50. 151 Ibid at 749. 152 Mastroianni, n 2 at 440–1. 153 Ibid. 154 W Biffl and others, ‘Responsible Development and Application of Surgical Innovations: a Position Statement of the Society of University Surgeons’ (2008) 206(6) J Am Coll Surg 1204 at 1207–8. 155 ISSCR, Guidelines for the Clinical Translation of Stem Cells (ISSCR 2008) at 15–6; online: <http://www.isscr.org/GuidelinesforClinicalTranslation/2480.htm>. 156 Taylor, n 123 at 293. 157 Ibid at 295. 158 Ibid at 296–8. 159 Freedman and others, n 21 at 656. 160 Taylor, see n 123 at 296. 161 UK Central Office for Research Ethics Committees, Governance Arrangements for NHS Research Ethics Committees (Department of Health, London 2001); online: <http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4005727>. See also S Holm and E Cave, ‘New Governance Arrangements for Research Ethics Committees: Is Facilitating Research Achieved at the Cost of Participants’ Interest’ (2002) 28 J Med Ethics 318 at 320. 162 MOH, Operational Guidelines for Institutional Review Boards (December 2007) at para 7.10.1; online: <http://www.moh.gov.sg/content/moh_web/home/Publications/guidelines/human_biomedical_research.html>. 163 G Agich, ‘Ethics and Innovation in Medicine’ (2001) 27 J Med Ethics 295, 296. 164 See King, n 39 at 13; MacNeil, n 130 at 483–4. 165 Eaton and Kennedy, n 45 at 104. 166 See n 44. 167 Strasberg and Ludbrook, n 50 at 944. 168 I Ayres and J Braithwaite, Responsive Regulation (Oxford University Press, New York 1992) ch 4, 102–6. See also Cowan, n 22 at 250. 169 See Taylor, n 123 at 295–6. 170 See Noah, n 39 at 406–7. 171 Strasberg and Ludbrook, n 50 at 946. 172 For example, the registry established by the American College of Surgeons in respect of surgical innovations: Biffl, see n 154 at 1208. 173 In the UK, a voluntary register, Safety and Efficacy Register for New Interventional Procedures (SERNIP), was initially set up by the royal colleges. Australia followed suit with its own ASERNIP for surgical procedures: B Campbell and G Madden, ‘Safety and Efficacy of Interventional Procedures: Scrutinising the Evidence and Issuing Guidelines Without Stifling Innovation’ (2003) 326 BMJ 347–8. SERNIP's functions were subsequently taken over by the National Institute for Clinical Excellence (NICE) in February 2003: Price, see n 147 at 135. 174 Strasberg and Ludbrook, n 50 at 946. 175 Price, n 147 at 135–6. 176 See n 148 and accompanying text. 177 Ibid at 2. 178 Eaton and Kennedy, n 45 at 103; AHRQ <http://www.ahrq.gov/about/profile.htm>. 179 Ibid. See also Cowan, n 22 at 246, 248–51. 180 King and Henderson, n 39 at 1023–4. 181 See Noah, n 39 at 400–7. © The Author [2012]. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com
TI - LEGAL AND REGULATORY RESPONSES TO INNOVATIVE TREATMENT
JO - Medical Law Review
DO - 10.1093/medlaw/fws025
DA - 2013-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/legal-and-regulatory-responses-to-innovative-treatment-sYYbPV2Ujn
SP - 92
EP - 130
VL - 21
IS - 1
DP - DeepDyve
ER -