Use of Placebo in Surgical Clinical Trials

Back in the 1950s, bilateral ligation of internal mammary arteries was treatment of choice for patients with angina pectoris. Doctor Cobb was skeptical about the effectiveness of this procedure hence, decided to compare a group of patients who underwent this surgery with another group of participants whom he performed all other procedures except ligating internal mammary arteries. Despite being ethically questionable, this study is considered to be the first documented placebo-controlled randomized double blinded clinical trial in surgery. Interestingly, it was later found that there was no significant improvement in patients due to this surgery compared to placebo. 

Comparing an intervention (medicine or surgical procedure) with a fake counterpart in order to check the superiority of intervention is the concept behind Placebo controlled studies. For any placebo controlled surgical trials, the procedure we perform should meet these two criteria: definition of surgery and the definition of placebo. Any medical intervention that involves changes in anatomy and requires skin incision or use of endoscopic procedures is surgical intervention. In order to fit with the definition of placebo, these surgeries should have been performed following all procedural aspects excluding actual penetration of intended anatomical structure. 

Surgical randomized trials are less commonly practiced in the research community. 

Steps of Performing Placebo Controlled Surgical Trials 

• Participants screening, selection of potential candidate and consenting are performed as per the standard practice of clinical trials. 

• like other drug / vaccine trials, participants will be randomized, allocated into different treatment arms  and pre surgical procedures will be performed for both placebo as well as control groups. Blinding of surgeons who are making an intervention is not possible in most of the surgeries, hence such trials are single blinded. 

• Relevant anesthesia is administered based upon the nature of surgery. But in case of surgical procedures where the patient is either on general anesthesia or heavy sedation, patient factor is easily controllable.

• Making skin incision or insertion of scope is mandatory following aseptic precautions. Wounds should be later identifiable by participants. 

• If the participant is under regional / topical anesthesia, surgical staff should pretend as if they are doing the actual surgery. Surgical set-up, auditory, visual and physical activities are mimicked. Duration of surgery should be exactly similar for both placebo as well as intervention group. 

• If Implants are to be administered, manufacturers themselves develop different tools without actual implants. In such cases, even blinding of the surgeon is possible - refereed as double blind trials. 

• All the pre surgical, on table and post operative measures are mimicked even in placebo groups but any changes in the intended anatomical structure is omitted throughout the process. 

• Examples of major surgical trials

• In one cardiovascular surgical trial, patients enrolled for Percutaneous Transluminal coronary angioplasty (PTCA) underwent a surgical process followed by medical therapy but actual revascularization was performed only on the controlled arm.
  
  
  

• In a trial with Internal mammary artery ligation, all patients underwent surgery to expose internal mammary artery, but ligation was not performed in the placebo group. 

• In transplantation surgery of dopaminergic neurons in patients with Parkinson's disease, patients under placebo group underwent skull hole but dura mater was left unpenetrated. 

• Endoscopy or Bronchoscopy without radiofrequency

• Knee surgeons have practiced placebo during surgical corrections of osteoarthritic knee and  meniscus repair surgery. 

Ethical Aspects of Placebo in trial

• Intention behind the use of placebo in clinical trials is to benefit a large population by putting a few people at mitigated risk. This concept is descried as the utilitarian ethics to maximize the benefits. Surgery being a more objective and risk bearing interventional aspect of healthcare, it carries a concern on patient-physician relationship.
• As per the concept of risk - benefit analysis, minor risk imposed on a few patients because of placebo controlled exposure could be considered as less important than the anticipated outcome of the trial. The difference between pharmaceutical products trials and sham surgery is that after a positive outcome of the study, a new drug can be re-administered to people of a controlled group once trial ends but it would be unfortunate to suffer with two major surgeries in the name of research.
• Participant enrollment and retention might be quite challenging if they are aware that surgery they going through might not result in any significant improvement on them. This might affect data quality and integrity of the overall study.

Lastly,

Because it is challenging to conduct placebo controlled blinded clinical trials ethically as  procedurally also there is no compelling evidence of utilitarianism ethics for putting participants at risk by blinding, such clinical trials are barely recommended and quite few in numbers. All those studies which are currently in the recruiting phase, should have been more vigorously monitored by sponsors as well as ethics committee.

Thank You !!!

References;

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717470/

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717470/

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995345/

4. https://pubmed.ncbi.nlm.nih.gov/30824993/

5. https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0317167100005540

6. https://pubmed.ncbi.nlm.nih.gov/12626957/

7. https://clinicaltrials.gov/ct2/results?cond=blinded+surgical+trial&term=&cntry=&state=&city=&dist=