Research Skills for the Modern Surgeon

By P.A. Sutton, N.S. Blencowe and H.M. Mohan

Research Skills for the Modern Surgeon is the third textbook in the ASiT series, accompanying Foundation Skills in Surgery and Core Laparoscopic Skills. This book consists of three sections covering clinical studies, research methodology and research skills. The text will provide a solid grounding in the skills necessary to become an active researcher in modern day surgical practice.

• Language: English
• Publisher: BookBaby
• Release date: Jan 31, 2019
• ISBN: 9780993571756

Book preview

Section 1

Clinical studies

Chapter 1

Principles of good clinical practice and research ethics

Deirdre M Nally

History of ethics and underlying principles

Good clinical research practice demands that all research complies with the highest ethical code. Unfortunately, however, there are multiple examples of human rights abuses and exploitation of vulnerable groups in medical research. These include atrocities committed by Nazi doctors in concentration camps; trials where antibiotics were deliberately withheld from syphilis patients to facilitate observational studies, and experiments on American prison inmates recruited via coercion. Modern medical ethics evolved in response to such events. It originates from the Nuremberg Code: ten doctrines issued by the jurists involved in the Doctors Trial at Nuremberg. These principles advocate for the autonomy of participants and informed consent. The field of ethics has progressed from this time with the publication and subsequent revision of landmark guidelines including the Helsinki Declaration, the Belmont report and the Georgetown mantra. The overarching principles of ethical research include respect for autonomy, beneficence, non-maleficence and justice.

The Declaration of Helsinki states that research must be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. The current norm is that all research involving patients, service users or volunteers (or their organs or tissues) is subject to independent review to ensure it meets a minimum ethical standard. Gaining approval from the relevant research ethics committee is a crucial step in conducting research and it is now a ubiquitous requirement for publication. However, this is not a one-off process and good practice demands ongoing respect for ethics in completing the project and disseminating the results.

The following seven principles have been proposed as requirements for ethical research:

1.Value

The proposed project must be of value to society by enhancing the knowledge base regarding a specific disease or treatment, and hence contribute to an overall improvement in health. This ensures that finite research resources are maximized for social or scientific benefit.

2.Scientific validity

The study design proposed must be feasible and scientifically robust to answer the specific research question and hence generate meaningful new information. To produce reliable and valid data, the methodology proposed must be appropriate with logical statistical techniques, including an adequate sample size. Those involved must have adequate experience to complete the project, including interpretation and dissemination of the results.

3.Fair subject selection

The purpose of inclusion/exclusion criteria is to meet the scientific goals of the study. However, these steps must also ensure that participation balances the risks and benefits of the study among different groups. Special consideration must be given to protect vulnerable groups including their capacity to provide informed consent.

4.Favourable risk-benefit ratio

For research to be considered ethical, benefits must be maximized while simultaneously minimizing any risks or harms. Overall, potential benefits must outweigh any risks including non-health risks.

5.Independent review

Independent review via a Research Ethics Committee minimises the impact of any potential conflicts of interests those involved in the project may hold and provides social accountability.

6.Informed consent

Informed consent is pivotal in respecting the personal autonomy of participants. To provide valid informed consent potential participants must be provided with - and understand - information about the purpose, risks, benefits and alternatives to participation. They must be enabled to make a voluntary personal decision, free from any coercion. To this end, Participant Information Sheets discussing these issues should be provided, written in clear language, with opportunities to discuss and ask questions. Time between requesting participation and signing consent facilitates due consideration and prevents undue pressure.

7.Respect for potential and enrolled subjects

While a study is in progress, ongoing respect for subjects involves informing them of their right to withdraw consent, at any time, without reason. Safeguarding privacy and maintaining the welfare of participants must remain priorities, with contingency planning if required.

Good Clinical Practice (GCP)

The quality and value of scientific, clinical and medical education research is critically dependent on the integrity and rigor of with which is conducted. The National Institute of Health Research (NIHR) defines good clinical practice as the international ethical, scientific and practical standard to which all clinical research is conducted, recorded and reported. Thus, good clinical research practice extends beyond ethics to encompass honesty, accountability, professional fairness and good stewardship or governance. GCP sets out the responsibilities of those parties involved in research including investigators, sponsors, monitors and institutional review boards. The Research Governance Framework for Health and Social Care requires that everyone involved in the conduct of clinical research must be competent to perform their tasks, qualified by education, training and experience. In most surgical specialties, GCP training in Research Governance is now a Joint Committee Surgical Training (JCST) requirement for certification for completion of training (CCT).

The International Conference on Harmonization (ICH) has standardized GCP recommendations between Europe, the U.S. and Japan, which is particularly advantageous for international research collaborations and in industry. However, GCP has been criticized due to over emphasis on monitoring and reporting and the significant economic implications of ensuring compliance, which may not improve research quality. Before you undertake any form of clinical research, or contribute to clinical trials, you must undertake formal training in Good Clinical Practice. This is available online or through a half day face to face training session.

Data protection

GCP requires that research data are recorded, handled, and stored in a way that allows accurate reporting, interpretation and verification while respecting the confidentiality of participants. Data protection legislation governs the use of data generated through research and stipulates when and how it can be collected, stored, used, transferred and disposed. The requirements and technical processes for data management, retention and preservation are determined by the type of study being conducted. New General Data Protection Regulations (GDPR) were introduced in May 2018.

Conflicts of interest

One of the principles of GCP is transparency of conduct. Legitimate conflicts of interest (e.g. academic, clinical and personal) can occur during a project and should be identified, declared and addressed if necessary, to maintain transparency.

Research misconduct

The emphasis and esteem placed on published research for career advancement predisposes to improprieties in the execution and reporting of research both in science in general and in academic or clinical surgery. The US office of Science and Technology Policy defines research misconduct as fabrication, falsification, or plagiarism in proposing, performing or reviewing research. Quantifying the forms and frequency of impropriety is, however, difficult. A meta-analysis of survey data of scientific misconduct found that 2% of scientists across all disciplines admitted to fabrication or modification of data at least once and up to 34% admitted to other questionable practices¹. There is evidence that research fraud is increasing. As a proxy marker, the number of articles retracted has increased 19 fold from 2001 to 2010². A high-profile example of research fraud in a surgical setting is that of Paolo Macchiarini, a former thoracic surgeon and regenerative medicine researcher, who fabricated academic positions and qualifications. He also performed experimental surgeries using donor or synthetic trachea models enveloped in patient stem cells to minimize rejection. Although seven out of eight patients receiving such grafts died, misleading reports of treatment success were published, some of which have subsequently been retracted.

Not all misconduct is as dramatic. The Lancet retracted a trial on stem cell research on urinary incontinence because those involved failed to get valid ethical approval and, during the consent process, patients were not informed as to the experimental nature of the procedure. Furthermore, the head of the relevant Urology department denied involvement, despite having signed documentation stating he contributed to the trial³.

At the most extreme, research fraud causes harm to patients and reduces public confidence in science and medicine. Even minor transgressions can misrepresent the evidence base and waste resources. Researchers should report any concerns or suspected misconduct through the appropriate channels.

Additional resources

There are a number of websites which cover aspects of research ethics and good medical practice in more detail. Some of these are:

1.MRC good research practice principles and guidelines. Available at: https://mrc.ukri.org/publications/browse/good-research-practice-principles-and-guidelines/

2.UKRIO: an independent charity providing advice and support to the public, researchers and organizations to further good practice in academic, scientific and medical research. Available at: http://ukrio.org/

3.International Committee of Medical Journal Editors (ICMJE) recommendations for the conduct, reporting editing, publication of scholarly work in medical journals. Available at: http://www.icmje.org/

4.NIHR Learn: Good Clinical Practice for Secondary Care. Available at: https://learn.nihr.ac.uk/

Summary

The quality and value of research depends on the integrity with which it is conducted. Adopting and applying the principles of good clinical research practice will maximise the potential benefit of research. Research fraud can have serious consequences and should be reported through appropriate channels. Ethical research is that which respects the principles of autonomy, beneficence, non-maleficence and justice for the entire duration of the project.

Review questions

1. What is Good Clinical Practice?

2. What is research misconduct?

3. What are the four principles of ethical research?

References

Fanelli D. How Many Scientists Fabricate and Falsify Research? A Systematic Review and Meta-Analysis of Survey Data. PLoS ONE. 2009;4(5):e5738.

Grieneisen ML, Zhang M. A comprehensive survey of retracted articles from the scholarly literature. PLoS One. 2012;7(10):e44118.

Dyer C. Lancet withdraws research paper and warns authors about rules of gift authorship. BMJ. 2008;337.

Chapter 2

Designing and conducting randomised controlled trials in surgery

Narendranath Govindarajah

Introduction

In 1996, Richard Horton, editor of the Lancet, published a disparaging editorial about the quality of surgical research, parodying it as a ‘‘comic opera’’¹. He highlighted that most published research papers were single-surgeon case series and criticised surgeons’ limited insight about the weakness of this study design in establishing causation. Combined with a lack of collaborative working — ‘‘…the personal attributes that make a successful surgeon differ from those needed for…multicentre research’’ — he postulated that specific methodological challenges unique to the evaluation of surgical interventions may explain the lack of randomised controlled trials (RCTs) in this field.

The challenges of designing and conducting RCTs in surgery

Surgical RCTs are notoriously difficult to design and conduct due to numerous methodological challenges (Table 2.1). Many of the methodological challenges relate to the fact that surgical procedures are complex healthcare interventions, meaning that unlike 20 milligram tablets, no two surgical procedures are the same and achieving standardisation of interventions within RCTs is difficult²,³. Challenges for evaluation arise from surgeons’ personal preferences, as well as their skill levels and ability to learn new techniques. Surgical procedures also involve other team members (i.e. anaesthetists, surgical assistants, and nurses) and associated pre-, peri-, and post-operative interventions, all of which may influence the overall outcome of an operation. Moreover, surgery is constantly evolving and it has been said that it is always too early [for rigorous evaluation such as a trial] until, unfortunately, it’s suddenly too late⁴. Other challenges include achieving blinding of surgeons and other caregivers and appropriate outcome selection; there is a tendency for surgeons to put great emphasis upon early technical adverse events and focus less on longer term patient-centred outcomes⁵.

Table 2.1 - Methodological challenges in designing and conducting RCTs in surgery

A number of comparator interventions are available for surgical RCTs, outlined in Table 2.2. This adds further complexity to both the design and delivery.

Table 2.2 - Types of comparator intervention in surgical RCTs

Considerations before embarking on an RCT in surgery

The aim of an RCT is to ask an important question about the effectiveness of a treatment and to provide a reliable answer by assessing whether an observed treatment difference is due to chance. It is crucial that the research question being asked is important and has implications for clinicians, patients and the health service. Research questions are no longer solely generated by the academic community, but increasingly involve patient-led groups as well as clinicians. Research questions generally follow the ‘PICO’ format (population, intervention, comparator, outcomes) and are formulated into a null hypothesis, which can then be tested in the RCT. The null hypothesis is usually that there is no difference between the interventions in each arm.

Next, a thorough review of the published literature needs to be performed to see if the question has already been asked and/or answered previously to avoid repetition, rendering the RCT unnecessary and potentially unethical. The systematic review (see Chapter 10) should be undertaken before embarking on trial design, using PRISMA-P guidelines¹¹. It is also important to check existing registries see if a similar trial has already been performed. Finally, RCTs are a significant undertaking and are usually designed and conducted in the context of a multi-disciplinary team. Examples of team members include methodologists, statisticians, health economists, qualitative researchers, patients, clinicians, trial co-ordinators and administrators. When designing an RCT it is important to align yourself with an experienced trials team to have the best chance of securing funding for your work. The UK has a network of clinical trials units and the Royal College of Surgeons has funded seven trials centres with particular focus on undertaking RCTs in surgery¹².

Writing a protocol for a surgical RCT

The protocol for an RCT plays a key role in study planning, conduct and reporting. It contains information about the background, rationale, objectives, study population, interventions, methods, analyses, ethical considerations, dissemination plans, and administration. Trial protocols should be written before a study begins and, ideally, published, so that readers of the trial report (including journal editors, funding bodies and reviewers) can assess whether the trial team adhered to the protocol. For example, outcome reporting bias (see Chapter 3) can be assessed by comparing the outcomes listed in the protocol with those that were collected and reported during the study, and the statistical analysis plan can be compared with what was actually done. Currently, protocols are often of poor quality, including a lack of description of treatment allocation methods, blinding, sample size calculations and outcomes¹³,¹⁴. This leads to problems with trial conduct, which in turn may lead to (avoidable) protocol amendments, poor reporting of trial results, and compromising the rigor and internal validity of the study.

Guidance for writing trial protocols

The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidance comprises a 33-item checklist for the minimum content of protocols for RCTs¹⁵. SPIRIT is designed to be used in conjunction with CONSORT (CONsolidated Standards Of Reporting Trials), which provides recommendations for writing trial reports¹⁶. It is important to emphasise that the checklist serves to promote transparency and improve reporting of what is planned, rather than to mandate how the RCT should be designed. A poorly designed RCT could fulfil all SPIRIT checklist items simply