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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

Novel therapies may be necessary both in the interests of the individual animal and in the advancement of veterinary science. However, special consideration is necessary to safeguard the welfare of the animals, ensure fully informed consent from the owner, determine the procedure's value in other cases and appropriately disseminate results. This article reviews ethical and evidential considerations raised when novel therapies are undertaken in veterinary practice, based on a series of committee meetings and intervening discussions held between members of the British Small Animal Veterinary Association Scientific Committee and Officers (2010–2011). The aim of this article is to encourage the advancement of novel veterinary therapies while safeguarding the welfare of animals.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

The possible use of novel treatments can create dilemmas for owners, practitioners, researchers, governance bodies, courts and insurance companies. The role of the British Small Animal Veterinary Association (BSAVA) Scientific Committee includes providing advice on topical issues and it has produced this review in order to give information and a considered opinion on the overarching issues regarding novel therapies and provide general guidance for individual practitioners’ decision-making when considering undertaking novel therapies in their practice (without giving overly prescriptive clinical or legal advice).

Novel Therapies And Accepted Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

Significant developments in veterinary practice have been achieved through the design and trial of novel therapies. In at least some cases, the introduction of novel therapies is driven by the recognition that the existing therapies for a condition are unsatisfactory or imperfect. This may motivate practitioners to design and apply novel therapies, which may include surgical procedures, medical treatments or behavioural interventions (and other developments may introduce novel diagnostic methods).

This article differentiates “novel” and “accepted” procedures, as two complementary concepts. A therapy may be novel if it fulfils any of the criteria listed in Table 1. A therapy may be considered to be accepted when it is either in widespread use or when it has been sufficiently employed, investigated and reported (Table 1). A practical threshold might be the publication of evidence of both effectiveness and lack of a wide range of adverse events in the peer-reviewed scientific literature. A treatment can also be considered as an accepted practice when the performance of that treatment is widespread amongst a “reasonable body” of veterinary surgeons, without necessarily having been investigated in clinical trials.

Table 1. Sufficient criteria for a therapy to be classified as novel or accepted
Criteria for novel therapiesCriteria for accepted therapies
The therapy is completely original, i.e. it has never before been performed for a particular condition affecting this speciesThe treatment is established for this species for this condition amongst a “reasonable body” of veterinary surgeons
The therapy has been performed by a limited number of veterinary surgeons on animals of this species affected by a specific disease 
The therapy has been performed in a limited number of cases of this disease affecting this speciesThe treatment is accepted by the publication of sufficient peer-reviewed evidence for this species that:

• Demonstrates efficacy(“proof of principle”)

• Screens for unexpected side effects

• Assesses long-term effects

The therapy involves a novel combination of previously accepted therapies (e.g. a new protocol) 
The therapy involves significant modifications to accepted treatments 
The therapy involves the application of an accepted therapy to a condition for which it is not accepted as a treatment in this species 

Until sufficient evidence has been accumulated regarding the safety and efficacy of a novel therapy, there are likely to be issues in the discussion of treatment options and ensuring that the owner is in a position to give informed consent. Special procedures may also need to be in place to ensure appropriate animal welfare. However, novel therapies are not necessarily or uniquely “extreme”. Many accepted therapies are significantly invasive; can involve significant disruptions to major body parts or systems; can cause substantial pain, discomfort, distress and fear; and may have high mortality rates. Veterinary surgeons considering the use of novel treatments should ensure that they are fully aware of previously and currently used therapies and their limitations as well as evidence relating to the novel therapy, even if this is extrapolated from another species or from pathophysiological reasoning. The veterinary surgeon should also ensure that they have the relevant knowledge, skills and facilities to carry out the procedure as well as any emergency, palliative or salvage procedures that may be required.

Novel Therapies And Clinical Values

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

Veterinary decisions should be based primarily on the welfare of the animals directly affected (Rollin 2006a,2006b) and only harms that are necessary to obtain a realistic long-term benefit should be permitted. This means first that suffering should be controlled to the highest extent possible for any intervention. Practitioners should consider all the possible types of suffering (e.g. pain, frustration, illness, distress and fear) and the whole range of possible sources (e.g. injury, disease, confinement, behavioural restriction and threats). Each cause should be minimised or each effect mitigated, except where doing so creates greater risks of suffering. Secondly, this means that treatments are not permissible where the benefits do not outweigh the harms. No treatment should be given that is not expected to be in the patient's interest compared with other available options, including euthanasia (Yeates 2010a).

Balancing a patient's welfare requires the consideration of both predicted benefits and foreseen harms and of both short- and long-term effects, with the clinician taking into account the intensity, incidence, duration and probability of all possible good and bad effects. Lengthening a patient's life is beneficial when its welfare will be good; whereas animals’ lives should not be perpetuated when their quality of life is poor (Yeates 2009b, 2010b). Usually the balance focuses on the short-term harms and long-term benefits. For example, the acute pain of surgery may be offset by improved functionality or decreased chronic pain. However, in some cases interventions may appear to have short-term benefits but have longer term implications for welfare. For example, the use of coercive techniques in animals showing undesired behaviours where the intervention may appear to interrupt an undesired response but can cause increased anxiety in the patient in the longer term.

Novel therapies should ideally lead to improved animal welfare. They can be more beneficial than accepted therapies if they treat conditions more effectively, including treating conditions that would otherwise not be treatable, or if they are more cost effective allowing more animals to receive appropriate treatment. They can be less harmful than accepted therapies if they involve less pain, restraint, etc.; have fewer or lesser adverse effects; or have fewer complications. However, novel therapies may also be less effective, cause worse direct adverse effects (e.g. pain or nausea), perpetuate suffering or have more significant unexpected adverse effects than a previously accepted therapy. The concern about novel therapies is therefore not that they are more harmful, but that practitioners cannot know whether a novel treatment will be better or worse than accepted practices.

In addition, a novel therapy is likely to be performed first by one individual or a small group of individuals, who will have considered it beneficial insofar as they decided to provide it. In some cases, there may also be commercial interests in promoting a novel therapy. These factors suggests that the pioneer is unlikely to be the best impartial judge of evidence of the effectiveness and adverse effects of the therapy, since they have already demonstrated a bias towards the therapy, and this raises a possible suspicion over pioneers’ reports, unless those reports are carefully peer-reviewed. A similar consideration may apply to novel therapies based on therapeutic products developed by institutions, where commercial and legal pressures may create a publication bias towards reporting data that support the use of the novel therapy.

Veterinary surgeons should not choose treatments solely for the technical or intellectual challenge, for the romantic appeal of appearing heroic, for profit or for academic achievement. Nor should veterinary surgeons provide treatments simply because owners request them. Some owners may be desperate to keep their animal alive, believe heroic treatments to be a way of showing concern for their beloved pet or feel guilty for funding only cheaper accepted therapies. However, while owners’ wishes can prohibit the provision of novel treatments where they refuse consent, they cannot mandate clinicians to provide novel treatments.

Novel Therapies And Evidence

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

Decision-making should be based on predictions of beneficial and harmful effects. Predicting the effects of any treatment should be based on evidence and as a general rule clinicians should tend to avoid treatments where there is more evidence of greater adverse effects or to select treatments with more evidence of greater efficacy, and be cautious of treatments where evidence is absent or weaker (in the specific species and/or in comparable species). Evidence is also important when advising owners’ of the options available to enable them to give informed consent.

Evidence should ideally be in the form of published peer-reviewed scientific reports, as the peer-reviewed process provides confidence that reports are objective and methodologically appropriate. Peer-review places the burden of proof on a study's authors, who need to convince the reviewers and editors that the report adds robust evidence to the existing clinical knowledge base. This process also places a responsibility on the reviewers of the manuscript and the editor of the publishing journal to ensure that reports reach a required standard of methodology, writing and relevance. It is worth remembering that a large amount of research is funded by bodies with commercial interests in the results. This can lead to cases where the treatments are “evidenced” by relatively un-robust studies, as recently suggested to be the case for pheromonal behavioural modifications (Frank et al. 2010). Clinicians also have a responsibility to critically appraise scientific literature, although many practitioners’ ability to critically evaluate scientific literature may be limited if they have received little or no training in such evaluation.

There is a hierarchy of evidence that describes the persuasiveness of information from different sources from in vitro studies, through single case studies and case series, through to meta-analyses and systematic reviews (Cockcroft & Holmes 2003, CEBM 2001, Innes 2007). However, it should be noted that there may be particular problems in veterinary medicine where many accepted therapies are not supported by high quality peer-reviewed evidence. It should also be noted that the significant proportion of veterinary research funded by commercial companies may lead to research into less commercially viable therapies, or minor species, being overlooked and to the promotion of therapies on the basis of relatively weak evidence.

By definition, decisions about most novel therapies will have to be made without access to high quality peer-reviewed evidence. It is acknowledged that decisions regarding novel therapies may have to rely on extrapolation of evidence from other conditions, from other species or from first principles, but in all cases clinicians face a responsibility to ensure their clinical decisions are based on the best evidence available (Table 2).

Table 2. Bases for considering the use of a novel therapy
Type of basisSpecific basesExamples
Extrapolation of procedures recognised elsewhereAccepted treatments for other animal speciesAdaptation of neutering procedures from domestic to exotic species
 Accepted medical practice for humansUse of human antimicrobials
Extrapolation of previous evidenceEvidence from preclinical scientific experimentationExtrapolation from in vitro studies
 Evidence from serendipitous eventsGood welfare outcome following accidental overdose
Common senseSuggested by basic biological understandingKnowledge of species physiology, anatomy, pharmacology, etc.
 Expected equivalence of effects but significant increase in utilisationNovel administration protocol or formulation to increase compliance
  More cost effective making the treatment available to more animals
InnovationRecognition that current therapies have significant drawbacksBehavioural modification techniques

It is also imperative that the veterinary surgeon makes clear to the owner the nature of the novel therapy, the evidence that is and is not available regarding the treatment options and that the owner understands that the treatment is “novel”, in order to obtain informed consent.

The lack of published evidence on novel treatments should provide a motivation to generate and report information about such treatments. This can help to inform future clinical decisions. In some cases, the retail and marketing of novel therapeutic products by commercial companies may legally require evidence of quality, safety and efficacy (e.g. for registration or licensing). The generation of such data is a valuable process that can lead to significant animal welfare improvements for other animals. Funding of research from non-commercial sources is also important to accrue evidence for therapies and techniques which may have welfare benefits for animals but which are not necessarily commercially viable.

However, patients should not be provided with treatment solely to provide wider benefits through advancing medical or veterinary science. Practitioners have a responsibility to their patients that mandates a concern for those animals’ welfare, and it is illegitimate to sacrifice their welfare for other animals (Yeates 2009a). These wider scientific aims should instead be achieved under legal regulations for animal experimentation. Many countries have developed protocols and safeguards for scientific procedures using animals [e.g. the UK's Animals (Scientific Procedures) Act 1986 and the EU Directives 86/609/EEC and 2010/63/EU], which provide strict safeguards to the experimental subjects’ welfare. In contrast, novel therapies of individual patients may be regarded as part of accepted veterinary practice and are not normally subject to the provisions of the Animals (Scientific Procedures) Act 1986. Veterinary treatment should be limited to “procedures and techniques performed on animals by veterinary surgeons in the course of their professional duties, which ensure the health and welfare of animals committed to their care”, as defined by the RCVS as “recognised veterinary practice” (RCVS 2012).

Recommendations For Patient Treatment Choices

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

Novel therapies may be legitimate, and even desirable, in some cases. Accepted treatment options may be unsatisfactory for good reason. Indeed, in many areas of veterinary medicine, existing or conventional practices are based on limited evidence. A novel treatment, with no evidence of benefit or harm, may be preferred over an accepted treatment for which there is good evidence of significant harms. Alternatively, accepted options may be contra indicated for particular patients by concomitant conditions, or owners’ financial limitations. So the use of novel treatments should not be prohibited per se.

However, novel treatments should be provided only under special arrangements, such as the conditions listed in Table 3. Most importantly, all novel therapies should be expected to be in the interests of the patient, insofar as there is a sufficiently high likelihood of benefit and a sufficiently low likelihood of harm, with the combination better than accepted therapies. This interests-based assessment requires that there are some grounds on which to suggest that the novel therapy will be beneficial (Table 2).

Table 3. Necessary conditions under which novel treatments may be performed
ConcernSpecific conditions
OwnerInformed consent – the owner understands:

• the subjective assessment of the risks and benefitsof the novel therapy

• all relevant information regarding the risks andbenefits of accepted treatments

• that the novel treatment is unproven and notestablished

 Owner not pressured into the decision
PatientThe clinician genuinely and reasonably believes the treatment is in the patient's interests relative to other options, including

• euthanasia

• no treatment

• other accepted treatments

 The clinical team has the skill and facilities to administer the treatment
 The patient is given adequate analgesia or other necessary drugs such as anti-emetics to minimise welfare harms
Contingency planningThe patient is carefully and expertly monitored for detrimental welfare effects
 The case is regularly or constantly reviewed by owner, clinician and an independent clinician
 The clinical team has the skill and facilities to deal with all plausible side effects
 There is adequate preparation of equipment and medication for emergency or salvage procedures, including

• palliation

• euthanasia

 There is adequate advance consent for emergency procedures, including euthanasia
LegalAny legal and professional requirements are followed (e.g. in the UK the Veterinary Medicines Directorate's prescription “cascade”; rules in the RCVS Code of Professional Conduct)
GovernanceAll cases are specifically subjected to clinical audit and governance processes
 Each individual case is reviewed by clinical and research ethical review bodies where available
PublicationIf the first case: is submitted for peer-reviewed publication as a case study
 If the second case onwards: is included as part of a clinical trial to be submitted for peer-reviewed publication (whether or not results are positive)

Novel therapies provide a special need for contingency planning. Wherever possible, novel therapies should be performed in establishments with appropriate emergency and critical care facilities and by practitioners with relevant skills, knowledge and facilities. Usually these may be best provided by specialists in the relevant area of practice (e.g. surgery or behavioural medicine), but it may be appropriate to pioneer novel therapies in primary practice, for example where the reason for developing the novel therapy is to avoid realistic financial constraints. There should be pre-specified humane end-points and “exit plans” (including euthanasia), discussed and agreed by clinician and owner before any novel therapy is performed.

No pressure should be placed on either clinician or owner to provide novel treatment options, and veterinary surgeons should take steps to avoid and counter any inadvertent pressure (Yeates & Main 2010). In some cases, owners might be legitimately encouraged to choose conventional options with proven welfare benefits (Main 2006, Yeates & Main 2011), but this argument cannot apply to novel therapies, since their novelty means they are unproven. The available evidence for the effectiveness of a therapy may also be a factor that insurance companies and civil courts may consider when determining what funding or compensation is provided, perhaps restricting the finances available for novel treatments.

Preparation should include prospective ethical review by both in-practice clinical governance processes and (where appropriate) institutional clinical research ethical review processes (e.g. a university or independent research institute with established ethical review procedures and committees). Retrospective evaluation should also be conducted on all cases. When formal clinical ethical review bodies or processes are not indicated or impractical for reasons of urgency of intervention for the benefit of the patient, clinicians should discuss the case with in-practice colleagues and/or the referring practitioner (Mullan & Main 2001). These discussions can be made more useful if all parties have a level of understanding of ethical, welfare and scientific concepts. If it is anticipated that numerous cases will be treated consideration should be given to setting up a clinical trial, although it should be noted that this will probably fall outside the remit of accepted veterinary practice and may require a licence under the Animals (Scientific Procedures) Act 1986.

As an additional concern, the provision of a novel therapy should always be done as part of an effort to demonstrate its effects through peer-reviewed publication. Cases should involve special arrangements for clinical audit and research, and should be submitted for publication as case reports wherever possible. Where multiple cases are expected, then a clinical trial (or regulated experiment) should be set-up, using established long-term outcome-based measures (e.g. pain, function or quality of life scoring systems) to facilitate comparison with accepted therapies. This process should avoid any publication bias, and follow other rules for ethical reportage. It is also important that novel therapies are reported even when they have limited effectiveness or significant side effects. Novel therapies should not be reported in non-peer-reviewed publications until they are subject to a successful clinical review, and especially not in public media. Most importantly, publication of results should be a “spin-off” to beneficial treatment; novel treatments should not be provided in order to obtain publications (outside of primary scientific research within regulated projects).

Regulatory bodies should have rules requiring that treatments are provided only when they are reasonably expected to be in patients’ interests, compared to other available treatments, that novel therapies should be reported, whether they produce positive or negative results, and that practitioners should not publicly promote therapies before they have undergone suitable evaluation, including peer-review of clinical trials. Disciplinary procedures should investigate reports of cases where these rules are not followed. Regulatory bodies should provide generic guidelines on treatment decision-making and reportage concerning novel therapies, in order to inform decision-makers and disciplinary procedures. Regulatory bodies could also provide guidance or facilitate ethical review of proposed (non-emergency) cases, for example via an independent committee that reviews clinical cases, based on scientific, practical, legal and ethical knowledge and principles.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

The present analysis suggests that novel procedures in veterinary practice should be subject to ethical considerations. These are similar, but not identical, considerations to those commonly applied to scientific procedures. Like scientific procedures, novel therapies should be designed to cause the minimum amount of pain and suffering, for example through welfare assessment, administration of analgesia, use of clinical skills and humane exit plans. Like scientific procedures, novel therapies should be provided only when there are sufficient expected benefits. Unlike scientific procedures, the only benefit relevant in veterinary practice is to the patient's welfare, relative to accepted treatment options, including euthanasia. A scientific approach to novel therapies is also important in reportage and publicity. Cases should form part of peer-reviewed publication and widespread use of a novel therapy should not be promulgated until it has become accepted.

This article is not intended to provide specific clinical or legal advice, and practitioners must continue to use their own clinical judgement in individual cases. The present analysis may provide guidance for practitioners, academics and regulatory bodies. It is also hoped that it will lead to further debate and applications to particular clinical decisions – and that these debates and applications are themselves published in peer-reviewed journals.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

The authors thank other members of the BSAVA Scientific Committee, staff and Officers. At the time of writing, Professor Day was BSAVA Junior Vice President, Dr Everitt was BSAVA Scientific Policy Officer, Professor Innes was Chair of BSAVA Scientific Committee and Dr Yeates was a member of BSAVA Scientific Committee.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References

None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Novel Therapies And Accepted Procedures
  5. Novel Therapies And Clinical Values
  6. Novel Therapies And Evidence
  7. Recommendations For Patient Treatment Choices
  8. Discussion
  9. Acknowledgements
  10. Conflict of interest
  11. References