The Cambridge textbook of bioethics

C, a newborn infant, develops persistent vomiting on the second day of life. X-rays show midgut volvulus, a condition in which the intestines have twisted around their blood supply. Surgical exploration reveals necrosis of all but 15 cm of his small bowel. The necrotic bowel is removed and total parenteral nutrition (TPN) is initiated. At one year of age, he is taking half of his nutritional needs through his intestinal tract; the other half is given intravenously. Blood chemistry tests show that he is starting to develop significant liver damage from the TPN. C’s remaining small bowel has become dilated and dysfunctional. You have recently read about a new operation called the serial tapering enteroplasty (STEP), an innovative technique, which may be able to lengthen the remaining intestine and permit it to function more effectively. A surgical stapler in common use is deployed to segment the dilated bowel into a tapered, lengthened tube more closely resembling the shape of the small intestine (Kim et al., 2003). This operation, first developed in dogs, has been undertaken in a small number of infants with short bowel syndrome. It is considered a non-validated innovation by most pediatric surgeons and is not yet accepted as part of standard surgical practice. You would like to offer the procedure to your patient, but you do not think that there is time to go through the full Research Ethics Board approval process at your hospital. Your intention is to try to help, and perhaps other patients like him. You do not have a formal research protocol, but will develop your approach to treatment of this problem as you gain experience with this new procedure.

You struggle to manage your patient, a young soldier with severe respiratory failure caused by a blast injury. Conventional ventilation, at the high levels of positive pressure now required to maintain adequate gas exchange, is further damaging the lungs. An innovative lung assist

device (ILA) has been proven in the laboratory and in preliminary human trials to remove carbon dioxide directly from the bloodstream, permitting ventilation at lower pressure and reducing treatment-related injury,

the device on a compassionate basis at no charge. The company will provide a professional support team to instruct and assist you and your team in introducing and managing the ILA.

What is innovation?

Innovation is a notional concept: there are many notions of its meaning and no widely accepted definition. For the purpose of this chapter, we will define innovation as ‘‘a new evolving intervention whose effects, side effects, safety, reliability, and potential complications are not yet generally known in the community of practitioners’’ (McKneally and Daar, 2003). As a practical matter, we also include cost, convenience, and impact on institutional resources and personnel among the important aspects of innovation that should be taken into consideration when an innovation is introduced.

We will exclude from this discussion incremental improvements in established procedures and evolutionary variations, such as stapled instead of sutured anastamoses. Such variations and refinements are generally accepted as implicit components of improving standard practice. They fit well

within professional and institutional practice and policies for quality improvement. An informal process of collegial oversight of practice and its innovative variations is already in effect, as operating rooms, hospitals, and clinics form moral communities of caregivers who share a commitment to safeguard their patients, colleagues, and institutions from unnecessary risks. Accreditation, ‘‘credentialing’’ (validating qualifications), peer review, and quality improvement practices strengthen this protection. When an innovation introduces unknown risks, potential side effects, complications, resource requirements, or costs, the protection of the patients, innovators, institutions, and device manufacturers can be enhanced by collegial review (McKneally and Kornetsky, 2003; Morreim et al., 2006).

Innovation is not formal research as defined by the Belmont Report (National Commission for the Protection of Human Subjects of Biological and Behavioral Research, 1979), which designates research as ‘‘an activity designed to test an hypothesis, permit conclusions to be drawn and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective.’’ Under the current regulatory ethics paradigm, ‘‘innovative treatments are regarded as questionable until they are framed in a research protocol with formal mechanisms of informed consent’’ and innovators participate in the exploratory phase that precedes formal research, working ‘‘in the borderland outside the regulatory ethics paradigm’’ (Agich, 2001). Hypotheses and protocols can only be developed after exploration by innovators to stabilize techniques and identify appropriate patients for study.

Why is innovation important?

Most of the important advances in medical practice, from anesthesia and appendectomy to heart surgery

and transplantation, were introduced through an informal process we will call the innovation pathway. This pathway has become the major driver of increasing medical costs, as expensive innovative technologies for diagnosis and treatment are added to healthcare budgets. Generally motivated by strong financial incentives, biotechnology and medical device companies are constantly pushing out the boundaries of medical treatment. Since the passage of the Bayh-Dole Act (1980), clinicians, hospitals, and universities in the USA have had similar incentives to pursue patents and equity shares in industry. The biotechnology industry’s growth has been further accelerated by venture capitalists seeking investment opportunities in this volatile, high-stake market (Leaf, 2005). In this setting of dynamic growth in medical innovation, traditional safeguards may be overwhelmed. Research ethics boards (REB) and institutional review boards (IRB) utilize mechanisms to review protocols that are designed to systematically generate generalizable data rather than strategies uniquely tailored to individual patients. There is a clear need for a nimble, informed, flexible mechanism of collegial oversight to protect the interests of patients, innovators, and institutions.

Ethics

According to Wilton et al. (2000, p. 49), ‘‘Continued innovation is necessary if there are to be future gains in our ability to serve patients.’’ Improvements in clinical care are dependent upon the development and integration of safe and effective innovations. The clinician’s ethical responsibility to act in the best interests of patients, and continue to improve his or her knowledge and skills, is consistent with the pursuit of innovation (Canadian Medical Association, 2004; American Medical Association, 2005). Establishing a pathway that minimizes risk to patients while facilitating the pursuit of innovation is consistent with these values as well as the principles of beneficence and non-maleficence.

In most ethical formulations of the issues that arise in health research involving human subjects,

196R. Zlotnik Shaul, J. C. Langer, and M. F. McKneally

research is defined by its ends: that is, what is to be learned (Lantos, 1994). Research is generally considered an activity designed to test a hypothesis systematically, permit conclusions to be drawn, and thereby develop or contribute to generalizable knowledge. By contrast, ‘‘[i]nnovation is focused solely on the benefit of the individual being cared for. If at any point it appears that any aspect of what is being done is not in that person’s best interest, the physician must change course’’ (Morreim, 2005, p. 42). These formulations have some overlap but they help to distinguish which frameworks should apply to a given intervention. In some cases, new practices should be introduced through the protective framework of research ethics and in others it is appropriate to have new or innovative practices governed by traditional medicolegal standards combined with professional and institutional policies.

The threshold at which innovation becomes accepted standard practice is not sharply defined. Many widely accepted procedures remain unvalidated, despite their acceptance (Levine, 1988). A commitment to accountability grounds the clinician’s ethical responsibility to evaluate innovative healthcare interventions. Conducting good research not only protects patients from unevaluated, potentially harmful interventions, it also fosters and maintains the integrity of clinical knowledge (Frader and Flanagan-Klygis, 2000).

Law

The fact that there may be unexpected harms resulting from innovative procedures does not in and of itself qualify them for the same type of review and oversight as research, but it does justify an increase in the level of safeguards to protect patients. The challenge is to delineate methods that offer protection to patients without stifling innovation (Strasberg and Ludbrook, 2003).

Canadian case law, for example, provides an articulation of standards clinicians will be expected to meet when providing innovative treatment. A clinician’s standard of care is often described as

‘‘the degree of care and skill which could reasonably be expected of a normal, prudent practitioner of the same experience and standing in the similar circumstances’’ (Lyne v. McClarty, 2001). When treating a patient, whether the treatment is innovative or standard practice, the clinician ‘‘ . . . owes a duty to the patient to use diligence, care knowledge, skill and caution in administering the treatment . . . ’’ (Lyne v. McClarty, 2001). In terms of reasonable precautions, it would be expected that a clinician using an innovative treatment would be able to show that others in the same field would have considered the precautions taken to be sufficient, that the clinician ‘‘ . . . could not have learnt how to avoid the accidents by example of another, that most probably no other practical precautions could have been taken’’ (Lyne v. McClarty, 2001).

While many forms of oversight for the introduction of innovative procedures have been proposed in the literature (Reitsma and Moreno, 2005), the best options are those mechanisms that are consistent with standards that have been generated through the law in the relevant jurisdiction and that operationalize the values of fiduciary responsibility and accountability.

The legal standard of informed consent requires that patients and substitute decision makers not only understand and appreciate the potential risks and benefits of a procedure but also the innovative nature of the procedure (Coughlin v. Kuntz, 1987). The law of informed consent requires that the consent be voluntary; that the patient be capable of understanding and appreciating the potential risks, benefits and impact of the intervention in his or her own life situation; and that the patient be informed

– must be told and comprehend all that a reasonable person would want to know about the risks, benefits, and impact of the proposed treatment. In the consent discussion, clinicians need to discuss the kind of information that a ‘‘reasonable patient’’ might consider material information for making an informed decision about whether or not to consent to the innovative procedure (Coughlin v. Kuntz, 1987).

Professional standards are developed within professional bodies and healthcare institutions and are relevant to innovative practices. Maintenance of professional standards through continuing education and examinations are intended to help to ensure that clinicians have the skill level and knowledge to meet the challenges of rapidly changing technology and scientific information.

Policy

Surgeons are constantly exposed to new procedures and devices through medical journals, conversations with colleagues at meetings, and through advertising and promotion by representatives from the companies making new products. Most hospitals do not have a specific policy in place for surgeons to follow when introducing innovative procedures, other than the REB, which is infrequently used for this purpose (Reitsma and Moreno, 2002). A policy for the introduction of innovative procedures and devices should have a number of attributes if it is going to be used by surgeons. These include ease of use and a short timeline between application and approval or rejection. The policy should provide transparent accountability, patient protection, and legal protection for the surgeon and the hospital.

We have developed a policy at The Hospital for Sick Children, Toronto, for the introduction of innovative procedures and devices that attempts to address as many of the relevant issues as possible, and have implemented and carried out a preliminary evaluation of the policy. At the time of this writing, the policy addresses only procedures or devices that have been introduced previously at other institutions but are new to this hospital. An on-line form contains 10 points about the proposed innovation (Table 26.1) that the surgeon must address and then submit to the surgeon-in-chief, who has three options: approve of the proposal, request for expert advice, or recommend submission to the REB/IRB. The process is evaluated using structured interviews and a compliance review as part of the hospital’s quality assurance program.

Table 26.1. Ten points to be addressed and submitted to the surgeon-in-chief by a surgeon who is hoping to use an innovative procedure or device

1.Description of the innovative procedure or device

2.Evidence of effectiveness/rationale for request

3.Evidence of collegial endorsement and suggestion of advisers (internal or external) with whom The surgeon-in-chief may consult

4.Potential risks and benefits to patient

5.Special consent considerations

6.Initial number of patients to be treated

7.Expected impact (positive or negative) on resources, for example for procedure time, device costs, postoperative care

8.Assurance of device safety and approval (may include ‘‘special’’ approval) for use in the jurisdiction

9.Evidence of necessary skill or training on the part of the surgeon and the interdisciplinary team

10.Plans for collecting and reporting quality assurance and outcome data

Over a one-year period, 14 applications to perform innovative procedures were submitted through this policy. All were approved, two after expert consultation, and 23 procedures were performed. Case review revealed perceived benefit to the patient in 78% of the cases, and lower cost in 56% of the cases compared with the standard approach. Surgical innovators strongly supported the process. Compliance review indicated incomplete written documentation of the innovative nature of the procedure/ device in 10% of the cases. Experience with this policy suggests that innovative procedures and devices can be introduced through a user-friendly process that promotes accountability and responsible resource utilization, intending to protect patients, surgeons, and hospitals, but that the evolving consent process needs further improvement.

Empirical studies

Reitsma and Moreno (2002) identified 59 published papers that described surgical innovations, then

198R. Zlotnik Shaul, J. C. Langer, and M. F. McKneally

surveyed the corresponding authors: 15 of 21 authors did not submit their protocol to an REB/IRB; seven mentioned the innovative nature of the procedure on the consent form. Although 14 authors described their work as research, only six sought prior REB/IRB review.

In a subsequent study, Reitsma and Moreno (2005) surveyed surgeons for their definitions of innovative surgery and research, and for their attitudes toward regulation, the need for specific informed consent, and IRB review of surgical innovations. The surgeons’ responses differentiated routine surgical variation from research requiring IRB review by two criteria: a formal protocol and prior consent regarding the experimental nature of the procedure. Suggestions regarding oversight for significant innovations that are not formal research include clearance with the chief of surgery or a hospital committee, registries, tracker trials, and review by experts in a particular field.

Strasberg and Ludbrook (2003) analyzed experience with the introduction of laparoscopic cholecystectomy, live donor liver hemitransplantation, radiofrequency tumor ablation, and coronary artery angioplasty. They emphasized the value of registries of early experience for detecting new or unexpected problems that were not discovered in randomized trials of the same procedures. Hazelrigg et al. (1993) reported a registry of early experience with 1820 video-assisted thoracic surgical procedures. The early publication of this collective experience helped to identify the problems encountered during the learning phase, and to establish safe limits to the application of this innovative technology.

At the time of writing, the Children’s Hospital in Boston (Kornetsky, 2001) and the Massachusetts General Hospital had similar effective policies that emphasized expert collegial review, and consultation with the REB/IRB when appropriate. The Hospital for Sick Children and the University Health Network in Toronto have both adopted a

somewhat similar model, as described in the policy section of this chapter.

How should I approach innovation in practice?

Innovation should be encouraged and facilitated in a supportive setting that includes collegial oversight, full patient consent that is explicit about the fact that the consent is for an innovative procedure, attention to effects on institutional personnel and resources, and responsible reporting of outcomes. Innovators should participate in registries of early experience to teach and learn from colleagues about the effects, side effects, useful modifications, and complications of the new procedures or devices. Where doubt exists as to whether an innovation should be the subject of an REB/IRB review, consultation should be pursued.

Innovations should improve healthcare because of greater convenience, less disability or pain, reduced cost, improved accuracy and safety, or better treatment outcomes. Claims to these advantages should be validated before the innovations are widely accepted. Expensive innovations should be held to a high standard of validation before they alter the allocation of institutional resources, and healthcare budgets should include an allocation for innovations to protect standard services from destabilization. While collaboration with industry can accelerate progress toward technological solutions, clinicians should give highest priority to their fiduciary obligation to their patients.

The cases

C’s parents should be informed of the novelty of the STEP procedure, the rationale and experience at other centers, and the fact that C will be the first patient in your hospital to be treated using this

innovative technique. Collegial review and support should be sought from a well-informed pediatric surgeon and the surgeon-in-chief, who should ensure that responsible members of the healthcare team who will be involved in C’s care have the appropriate skills and endorse the treatment plan. A specific pre-agreed number of the serial tapering enteroplasties should then be evaluated, including their cost, outcome, and impact on the institution. Information on the experience with C should be shared with the registry (T. Jaksic, personal communication, 2006). A formal research protocol to establish the scientific validity of the procedure should then be developed in collaboration with the REB/IRB and other clinical scientists. This might include a formal protocol to measure the absorptive capacity of the newly formed intestine and the quality of life of the patient before and after the innovative procedure.

Emergency approval to use the innovative lung assist device (ILA) should be sought from the authorities responsible for evaluating medical devices in human patients. The surgeon-in-chief should be provided with a summary of the evidence supporting the use of the ILA in this young soldier, a summary of the potential risks and benefits, and the endorsement of the planned procedure signed by an informed colleague. All relevant team members should have the necessary skill or training to perform the procedure. The consent process should clearly disclose the innovative nature of the procedure. The experience gained should be carefully evaluated and reported in a registry of ILA applications. This experience and the advice of the innovating team should be shared with the manufacturer to help to improve the effectiveness and safety of the innovative device to enable their research. When the technical and procedural details of the treatment and the most appropriate patients have been identified, a formal research study should be developed working with the REB/IRB to validate the innovation.

REF EREN CES

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Kim, H. B., Fauza, D., Garza, J., et al. (2003). Serial transverse enteroplasty (STEP): a novel bowel lengthening procedure. J Pediatr Surg 38: 425–9.

Kornetsky, S. (2001). Guidelines, Concepts and Procedures for Differentiating Between Research and Innovative Therapy. Boston, MA: Children’s Hospital Committee on Clinical Investigation.

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Dr. D, a clinical investigator, is conducting a clinical trial on a recently developed therapy for the treatment of a progressive neurodegenerative disorder. While initial results in a previous study generally appeared promising, the therapy has been associated with fatal bone marrow suppression in approximately 1% of patients. A colleague pediatrician, who has a patient with this neurodegenerative disorder, asks Dr. D if the child can be enrolled in the clinical trial. There are no data in the literature about this therapy having ever been used or tested in children with this condition, and Dr. D wonders whether the child should be included in the trial.

What are clinical trials?

Clinical trials are scientific evaluations of medical interventions for the treatment of somatic or psychological conditions that provide an analysis of the quality, safety, and efficacy of particular products, or a method of evaluating two products for their comparative value. While clinical trials are most often used to test therapeutic pharmaceutical products, they can also be utilized to evaluate medical devices or surgical procedures, plus other preventive, screening, detection, and non-pharmacological therapeutic products/methods.

Clinical trials influence clinical practice by providing vital information to clinicians and patients to use in assessing appropriate treatment options. Clinical trials allow for the generation of sound empirical evidence that individuals can use to address important questions concerning the benefits

and harms of particular therapies in a scientifically rigorous and ethical way.

At the planning stage of a clinical trial, investigators produce a research protocol that specifies the procedures and methods to be performed throughout the course of the trial. An appropriately constituted research ethics committee – be it an institutional research ethics board or a multicenter research ethics board – must approve this protocol for scientific thoroughness and ethical appropriateness. This may include, amongst other considerations, ensuring that the experimental design is sound, the number of research subjects will accurately represent an adequate statistical sample, there is a suitable informed consent process, if there is compensation being provided it is not unduly coercive, and that the proposed research is in accordance with current scientific practices and ethical/legal regulations (Chow and Liu, 2003).

Clinical trials can be randomized (RCT) and nonrandomized. An RCT comprises two (or possibly more) experimental or treatment groups/arms in which trial subjects are randomly assigned into different groups to ensure internal validity. If there are two groups, one group receives the product being studied and the other group receives the standard therapy/product, or a placebo. Where possible, the highest standards for RCTs include blinding, where the trial subjects (single-blind trial) or the trial subjects and investigators (double-blind trial) do not know which product is being tested. Non-randomized trials are sometimes conducted where randomization is impossible for ethical or

pragmatic reasons. They face greater problems of bias, although these can sometimes be limited by careful design (Reeves et al., 2001).

When new therapies are tested in humans, especially in the case of pharmaceutical therapies, RCTs generally comprise four progressive phases. The successful completion of each phase provides further evidence that the product may demonstrate to be safe and efficacious. Not all therapies will complete all four phases; for instance, RCTs may be stopped prematurely if the results show great potential, or if there are safety concerns for trial subjects. At any time during the course of the trial if adverse results arise that suggest possible risk or harm to trial subjects, these findings should be reported to current trial subjects, potential future subjects, other clinicians involved in the subjects’ medical care, institutional research ethics board, study sponsor(s), and possibly national bodies responsible for research regulation and licensing (Piantadosi, 1997; Levine, 1998). The different types of clinical trials are as follows (with phase III trials usually being RCTs).

Phase I. In this phase, products are tested on a small number of subjects to collect data on considerations such as toxicity and best method of administration. These subjects may be healthy volunteers or patients with specific conditions, depending on the type and nature of the product. Testing in this stage seeks to collect data on the pharmacokinetic action of products in humans, possible risks or side effects associated with products at different dosages, amongst other consideration. The number of subjects participating in this phase is usually under 100. If sufficient and appropriate data are collected in this preliminary phase, it is used to design phase II studies.

Phase II. In this phase, products continue to be tested on a larger number of subjects to collect further data on pharmacological and pharmacokinetic activity, particularly in patients with the condition the product is proposed to treat. It is also at this stage that the new product is measured against the standard treatment or

placebo for its comparative efficacy. The number of subjects participating in this phase is usually no more than several hundred. If sufficient and appropriate data are collected in this secondary phase, it is used to design phase III studies.

Phase III. In this phase, the product is tested on an even larger number of subjects in a continued effort to evaluate the product’s safety and efficacy, especially in relation to standard treatments or placebos. At this stage, the product is generally dispensed as it would when it is to be marketed, and it is evaluated for its overall risk–benefit relationship and clinical labeling profile. The number of subjects participating in this phase is usually several hundred to several thousand. When this stage is complete, the study sponsors usually make an application to the appropriate national regulatory and licensing bodies for approval to market the product as safe and efficacious.

Phase IV. In this phase, which occurs only after the product has been approved and licensed for use, the product is evaluated for potential long-term side effects associated with the drug. This postmarketing surveillance phase could also include studies concerning how different dosages, schedules, or length of administration of the product affect patients, or how different patient populations react to the product.

While clinical trials are valuable for testing safety and efficacy, it is also important that other research methods of validating products are not forgotten (Fried, 1974; Freireich and Gehan, 1979; Reeves et al., 2001).

In addition to the important exchange of information between study investigators, sponsors, and institutional/regulatory bodies, it is essential that the dissemination of results from clinical trials – positive, negative, and inconclusive results – occurs through peer-reviewed conferences and peerreviewed journals; even if the results are unpublished, it is important that they are registered in a clinical trials registry. This ensures that clinicians and patients have access to the best information

possible to make responsible decisions about what medical interventions are worthwhile undertaking (Simes, 1986; Horton and Smith, 1999; Rennie, 2004; International Committee of Medical Journal Editors, 2006).

Why are clinical trials important?

Ethics

The ethical importance of clinical trials is sometimes underestimated. Yet the need to evaluate treatments for their safety and efficacy, so as to minimize harm to patients, reduce clinical uncertainty, and improve the efficiency of resource allocation, is great, as has been recognized since Archie Cochrane’s (1972) lectures on Effectiveness and Efficiency and the rise of the evidence-based medicine movement (Daly, 2005). Much more attention has been paid to the ethics of the conduct of clinical trials. The standard principles of research ethics apply to clinical trials, such that the avoidance of coercion and undue inducement, the properly informed consent of the patient, the proportionality of risk and benefit, and the scientific and clinical competence of the investigators all need to be assured. In recent years, attention has focused on the need to warrant randomization in clinical trials. The principal theory of the ethics of randomization is the ‘‘equipoise’’ theory (Freedman, 1987; Ashcroft, 1999; Miller and Weijer, 2003). On this theory, clinicians discharge their responsibilities to do their best for their patients if, faced with genuine uncertainty as to which one of the available treatments is most effective (or safest) in treatment of a condition, they allocate the patient treatment by randomization, thereby giving the patient an equal chance of receiving the treatment which is actually most effective. On the equipoise theory, clinicians may have a preference for one or other treatment, but where the clinical community is uncertain or divided, clinicians should submit their judgements to that of the clinical community at large, and enter a patient

into a properly conducted clinical trial. At issue is the question of whether the uncertainty is genuine, and whether the patient understands this. Some patients can experience the ‘‘therapeutic misconception,’’ according to which they believe that the treatment they are receiving must be the treatment that is best for them, when this is actually not certain and the treatment is in a broader or narrower sense ‘‘experimental’’ (see Ch. 29). Current best practice is that uncertainty should be underwritten by the conduct of an appropriately rigorous systematic review of the existing clinical evidence before a trial is initiated; and a stronger claim is sometimes advanced, that where uncertainty exists a trial ought to be initiated.

In practice, not all clinical trials exist to resolve clinical uncertainty, since many trials are run in order to establish the safety and licensure credentials of a new treatment, rather than to assess the merits of a new or established treatment in the light of the alternatives. This has provoked some controversy when it came to light in the context of trials run in the developing world. There is a heated controversy about the choice of controls in many such trials (but also in some trials in the developed world). Many commentators argue that use of a placebo control where a proven effective treatment exists is unethical, since trial lists are failing to act in the best interests of their patients. Some would go further and say that such trials exploit poor patients by taking advantage of their inability to purchase or access treatments known to be effective in the developed world. Critics of this position hold that duties of beneficence do not extend to providing treatments to trial participants that would otherwise be unavailable, and further that imposition of this standard as an ethical norm would make much medical research unaffordably expensive, thus limiting possible benefit to future patients in the developed and developing world alike (Schu¨klenk and Ashcroft, 2000). Ethical controversy also exists about the extent to which patients’ preferences should be allowed in what treatment they receive, and about the way to make resource-allocation decisions in order to prioritize