Randomisation is essential in Ebola drug trials In their Correspondence (Oct 18, p 1423),1 Clement Adebamowo and colleagues suggest that new Ebola drugs should not be assessed with clinical trials that use randomisation.1 There are at least four reasons to think they are mistaken. First, they argue that “the priority must be to generate data about effectiveness and safety as swiftly as possible” to enable treatments to be developed. This is entirely correct, but the best way to generate such data is in a randomised controlled trial. Failure to randomise patients amounts to research without a control group and would weaken the evidence base,2 which is also disrespectful to research participants. Second, Adebamowo and colleagues1 argue that the high mortality among Ebola patients receiving normal medical treatment means that “it is problematic to insist on randomising patients to it when the intervention arm holds out at least the possibility of benefit”. In many cancer trials, randomisation takes place despite similar mortality risk and little prospect of benefit. The authors seem to be assuming that new drugs will be effective, but until there is strong evidence, there is equally good reason to believe that they will harm patients infected with Ebola. Third, Adebamowo and coworkers1 contend that terrified populations “cannot be expected to offer informed consent to such randomised trials”. This claim might be true, but how can they then give informed consent to receiving an untested drug in what is essentially a non-randomised phase 1 trial? Inability to give consent does not mean that randomisation should not take place, as shown by several important trials in emergency medicine.3 Furthermore, to abandon usual trial protocols and www.thelancet.com Vol 384 November 8, 2014
give all participants a new drug that turns out to be harmful could also weaken trust. Finally, the authors overlook the fact that supplies of ZMapp and other Ebola treatments are very scarce. A randomised controlled trial is the best way to generate strong evidence with these small supplies, and randomisation also means that trials will be twice as large because only 50% of participants will receive the new treatment. Ebola raises many practical problems, but they actually mean that randomisation is vital, not optional. I declare no competing interests.
David Shaw [email protected] Institute for Biomedical Ethics, University of Basel, 4056 Basel, Switzerland 1
2
3
Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014; 384: 1423–24. Rid A, Emanuel E. Ethical considerations of experimental interventions in the Ebola outbreak. Lancet 2014; published online Aug 21. http://dx.doi.org/10.1016/S01406736(14)61315-5. Shaw D. HEAT-PPCI sheds light on consent in pragmatic trials. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S01406736(14)61040-0.
Delayed cord clamping With great interest, I read Nestor Vain and colleagues’ study (July 19, p 235)1 on the influence of gravity on placental transfusion. The study results should help to cease the dangerous practice of clamping and cutting the umbilical cord prematurely. However, I have a few questions about the study design and results that should be considered. Although the authors address some drawbacks, there is no mention of oxytocin use during labour (likely in women who have epidurals), which might have an effect on uterine activity after birth and fetoplacental transfusion. Almost all of the women included in the study gave birth in bed, with most of them lying down (none were reported to be in an
upright position), which might have an effect on perfusion of the vena cava inferior and possibly on blood volumes within the fetoplacental unit. Of the 546 low-risk, full-term, eligible parturients included, 83 (15·2%) were excluded for operative procedures, which seems high for a low-risk population. 17 (3%) of the remaining healthy, full-term, singleton, vaginally delivered newborns needed resuscitation. This rate seems very high. These atypical results in a healthy population point to a general problem with research on normal labour in hospital settings, with routine interventions that might alter the birth process. This makes interpretation of research results in this specialty challenging, as long as routine interventions are common in the clinical (study) setting.
James Akena/Reuters/Corbis
Correspondence
Published Online October 24, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61735-9
I declare no competing interests.
Christiane Schwarz [email protected] Midwifery Research and Education Unit, Hannover Medical School, Hannover 30625, Germany. 1
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40.
Nestor Vain and colleagues’ study1 shows that babies can receive substantially more blood from their placenta while lying in their mother’s arms. The only problem they mention is a slight increase in the frequency of jaundice, which can be easily handled in resource-rich settings. It is important to make sure that late cord clamping (ie, while the thin barrier between the circulations is distorted, perhaps disrupted, for some time) does not lead to other complications, for example, in situations where (undiagnosed) HIV, hepatitis, malaria, or spirochete infections are prevalent or Rhesus screening and anti-RhD prophylaxis are not perfectly organised. Additionally, any unexplained fever before delivery (perhaps as a result of septicaemia, measles, toxoplasmosis,
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1667
give all participants a new drug that turns out to be harmful could also weaken trust. Finally, the authors overlook the fact that supplies of ZMapp and other Ebola treatments are very scarce. A randomised controlled trial is the best way to generate strong evidence with these small supplies, and randomisation also means that trials will be twice as large because only 50% of participants will receive the new treatment. Ebola raises many practical problems, but they actually mean that randomisation is vital, not optional. I declare no competing interests.
David Shaw [email protected] Institute for Biomedical Ethics, University of Basel, 4056 Basel, Switzerland 1
2
3
Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014; 384: 1423–24. Rid A, Emanuel E. Ethical considerations of experimental interventions in the Ebola outbreak. Lancet 2014; published online Aug 21. http://dx.doi.org/10.1016/S01406736(14)61315-5. Shaw D. HEAT-PPCI sheds light on consent in pragmatic trials. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S01406736(14)61040-0.
Delayed cord clamping With great interest, I read Nestor Vain and colleagues’ study (July 19, p 235)1 on the influence of gravity on placental transfusion. The study results should help to cease the dangerous practice of clamping and cutting the umbilical cord prematurely. However, I have a few questions about the study design and results that should be considered. Although the authors address some drawbacks, there is no mention of oxytocin use during labour (likely in women who have epidurals), which might have an effect on uterine activity after birth and fetoplacental transfusion. Almost all of the women included in the study gave birth in bed, with most of them lying down (none were reported to be in an
upright position), which might have an effect on perfusion of the vena cava inferior and possibly on blood volumes within the fetoplacental unit. Of the 546 low-risk, full-term, eligible parturients included, 83 (15·2%) were excluded for operative procedures, which seems high for a low-risk population. 17 (3%) of the remaining healthy, full-term, singleton, vaginally delivered newborns needed resuscitation. This rate seems very high. These atypical results in a healthy population point to a general problem with research on normal labour in hospital settings, with routine interventions that might alter the birth process. This makes interpretation of research results in this specialty challenging, as long as routine interventions are common in the clinical (study) setting.
James Akena/Reuters/Corbis
Correspondence
Published Online October 24, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61735-9
I declare no competing interests.
Christiane Schwarz [email protected] Midwifery Research and Education Unit, Hannover Medical School, Hannover 30625, Germany. 1
Vain NE, Satragno DS, Gorenstein AN, et al. Effect of gravity on volume of placental transfusion: a multicentre, randomised, non-inferiority trial. Lancet 2014; 384: 235–40.
Nestor Vain and colleagues’ study1 shows that babies can receive substantially more blood from their placenta while lying in their mother’s arms. The only problem they mention is a slight increase in the frequency of jaundice, which can be easily handled in resource-rich settings. It is important to make sure that late cord clamping (ie, while the thin barrier between the circulations is distorted, perhaps disrupted, for some time) does not lead to other complications, for example, in situations where (undiagnosed) HIV, hepatitis, malaria, or spirochete infections are prevalent or Rhesus screening and anti-RhD prophylaxis are not perfectly organised. Additionally, any unexplained fever before delivery (perhaps as a result of septicaemia, measles, toxoplasmosis,
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1667
