Epi in the News

Hello everybody..

1) The main advantage of an RCT (over observational studies) is the higher internal validity. Randomization balances the comparison groups, and therefore the groups only differ in the intervention under study, hence minimizing confounding.

2) So, nowadays people are refraining from using the terms "single blind" "double blind" because at time these terms dont reflect the reality. Traditionally, if the patients and the healthcare providers were blinded to the group interventions this was referred to as double blind. However, many studies tend to use the word double blind when in reality other groups of people in the study like outcome adjudicators or data analysts are the ones blinded. So, the recommendation nowadays is to clearly state who all are blinding in the study, rather than using terms like single, double or triple blinded. The people blinded could be patients, health care providers, outcome adjudicators, data collectors, and data analysts.

3) Truvada is the established prophylaxis to prevent contracting HIV. In the presence of an effective established option, it would be unethical to expose the control group to placebo as this would mean putting them at a risk of contracting HIV. Second of all, its required to show that the efficacy of the new injectable is better than or at least equal to the existing standard medication.

4) Based on the statement given, the RR would be 1.89 (interpreted as 89 percent more effective)

5) The trial was stopped early because the test medication proved to be highly effective. In a previous trial this drug proved to be 66% more effective than the control (although in a different population). In comparison, 89% more effectiveness must have prompted the DSMB to stop the trial early, as equipoise no longer exists.

6) Despite the results of the previous trial, a new trial was needed because there is a lack of studies in cisgender women. These women usually are on contraceptive and in the childbearing age-group. Its therefore important to study these medications in this cohort and who make quite a significant proportion of cases.

7) Assuming the cost is not an issue, I would definitely recommend the injectable medication. It would be less problematic than a daily pill intake. Logistic issues would be issue- the patients would need to be traced and reminded to not miss injections, so as to prevent resistance.

8) Efficacy is the performance of the drug in an ideal environment. So, most likely the drug will behave in a similar manner if an RCT is conducted in a different population. The effectiveness if the performance of the drug in real life- and this will need to be seen in the future once the drug has been approved for use, and is used on a large scale.

Looking forward to hearing all your thoughts..

Fathima

1. What is the primary advantage of an RCT over observational epi study designs?

In RCT, Causality can be ascertained because we can establish a temporal association. However, in Observational studies, since exposure and outcome studied at the same time causality cannot be ascertained.
Another advantage of an RCT is, both known as well as unknown confounder get randomly allocated into both the group equally.

2. What does "double-blind" mean? (ok, this is a trick question - read the CONSORT checklist guidelines to learn more)

“Double-blind” is one of the methods of Masking, where information regarding the treatment is withheld from people involved in the research. In Double-blind, both participants and researchers will not know about what treatment they are receiving or what treatment they are providing to a particular individual.

3. Why was Truvada allocated in the control arm, and not a placebo?

As a good clinical practice, in an RCT, instead of placebo, the routine standard of care should be followed in the control arm. Since Truvada is commonly given to women to prevent HIV infection, it was used in the control group instead of a placebo.

4. What is the RR for this study?

RR= IE/IUE = Cannot be measured due to the non-availability of data. A total number of participants were given as 3223, but they did not mention how many women were there in both the arm.

Or

RR could be 1.89 because, in the journal, it has been mentioned that long-acting drug was 89% more effective than Truvada.

5. Why was the trial stopped early?

According to the authors, the incidence of HIV infection is very less in long-lasting injection group, and benefits overweigh the risk in using the injectable drug; hence the trial was stopped early.

6. Given the evidence of effectiveness from the previous trial, why was a new trial conducted with cisgender women?
Drug effectiveness was not studied among cisgender female in the previous trial. Hence this trial was done among cisgender females so that it can be generalised to both men and women.

7. Assuming an affordable price, would you recommend cabotegravir for routine use among high-risk individuals in your country?

Yes, I would recommend it. Community acceptance would be better for an injection (once in two months when compared to a daily dosage of Truvada).

8. Will, the efficacy of cabotegravir, be the same in another population of cisgender women? What about the effectiveness?

Efficacy will not be the same in another population. If the participants were not complaint to the drug, the efficacy of the drug would come down. Effectiveness also would come down because effectiveness is measured in the normal clinical setting. For example, if the population is already affected by HIV infection, the effectiveness of the long-lasting drug would come down.

1. What is the primary advantage of an RCT over observational epi study designs?

You can eliminate confounders more easily.

2. What does "double-blind" mean? (ok, this is a trick question - read the CONSORT checklist guidelines to learn more)

This is the definition from the CONSORT website:

Blinding (masking) - The practice of keeping the trial participants, care providers, those collecting data, and sometimes even those analyzing data unaware of which intervention is being administered to which participant. Blinding is intended to prevent bias on the part of study personnel. The most common application is "double-blinding", in which participants, caregivers and those assessing outcome are blinded to intervention assignment. The term "masking" may be used instead of blinding. (Consort website: http://www.consort-statement.org/resources/glossary#B)

3. Why was Truvada allocated in the control arm, and not a placebo?
"After an interim analysis showed that the long-acting injection was 89 percent more effective than Truvada, an independent data safety monitoring board recommended that the trial be stopped early."

Researchers were looking for a drug that would be an improvement on the existing treatment options for women. Therefore it makes sense to assess the new drug against the existing option.

4. What is the RR for this study?

We do not know how many of the 3,223 participants were taking Truvada versus cabotegravir, therefore lacking information to make this assessment.

5. Why was the trial stopped early?

The trial was stopped early as the independent data safety monitoring board recommended that it was stopped given the conclusive results. Was this because it was no longer ethical to offer a less effective drug to the control group?

"A previous trial tested the drug in nearly 4,600 cisgender men and transgender women who have sex with men and found it to be 66 percent more effective than Truvada in that population."
6. Given evidence of effectivness from the previous trial, why was a new trial conducted with cisgender women?

The previous trial had not included cisgender women (!).

7. Assuming an affordable price, would you recommend cabotegravir for routine use among high-risk individuals in your country?

Yes, I would since the side effects are not significant. The article also mentions that the injection could be bundled with women’s birth control injection - as there is already a level of comfort among women in Britain to receive an injection for birth control, I think it would be accepted among women, and the concept may also be familiar to men because of this.

8. Will the efficacy of cabotegravir be the same in another population of cisgender women? What about the effectiveness?

This trial was run across 20 different sites and 7 different countries in sub-Saharan Africa, so it is fair to say that it has been tested across different contexts already to some degree. I think it would have similar levels of efficacy in another RCT in another population of cisgender women.

Understanding efficacy to be about how well the intervention performs in a trial and effectiveness to be about real world usage, I would make the following comments:
• In terms of effectiveness, perhaps there would be less interest in the treatment in vaccine-hesitant contexts?
• Some groups of high-risk men and women may be injecting drug users in other contexts– would further testing be needed to see if the drug worked with this group?
• Outside of an RCT, this drug will require strong community-based health systems to ensure that people attend their appointments every 8 weeks to continue to get the vaccine

Thank you for your answers Fathima, Sam and Katherine. I agree with you.

I’m just reading up about the difference between efficacy - the benefit under ideal conditions and effectiveness- the benefit under usual circumstances. This is a new distinction to me.

Judith