Health experts argue for swifter trial designs of experimental Ebola treatment

In an open letter to The Lancet, health experts argued that alternative trial designs should be explored when combating the current Ebola outbreak.

“We accept that [randomized controlled trials] can generate strong evidence in ordinary circumstances; not, however, in the midst of the worst Ebola epidemic in history,” the experts wrote. “The urgent need is to establish whether new investigational drugs offer survival benefits, and thus which, if any, should be recommended by WHO to save lives. We have innovative but proven trial designs for doing exactly that. We should be using them, rather than doggedly insisting on gold standards that were developed for different settings and purposes.”

The 17 signatories, made up of senior health professionals and ethicists from Africa, Europe and the United States, wrote that the outbreak’s severity has only increased since WHO’s initial declaration that experimental drug use was ethical in such a situation. They wrote that under these circumstances, the advantages of randomized controlled trials paled in comparison to those of alternative designs.

“The priority must be to generate data about effectiveness and safety as swiftly as possible, so that the most useful new treatments can be identified for rapid deployment,” the experts wrote. “Alternative trial designs have the potential to do this more quickly, and with greatest social and ethical acceptability.”

The experts offered potential models for distributing and observing treatment efficacy that would be subject to adjustment depending on observed outcomes, noting that such models have been used in other areas such as cancer treatment.

“There is no need for rules to be bent or corners to be cut; the necessary procedures already exist, and are used,” they wrote.

Aside from addressing the logistics of alternative designs, they also argued that streamlining treatment was necessary when considering the lives of those at risk.

“No-one insisted that western medical workers offered zMapp and other investigational products were randomized to receive the drug or conventional care plus a placebo,” the experts wrote. “None of us would consent to be randomized in such circumstances.

“When conventional care means such a high probability of death, it is problematic to insist on randomizing patients to it when the intervention arm holds out at least the possibility of benefit. Ethical arguments are not the same for all levels of risk,” they wrote.

The letter’s 17 signatories are: Clement Adebamowo, Oumou Bah-Sow, Fred Binka, Roberto Bruzzone, Arthur Caplan, Jean-François Delfraissy, Dave Heymann, Peter Horby, Pontiano Kaleebu, Jean-Jacques Muyembe Tamfum, Piero Olliaro, Peter Piot, Abdul Tejan-Cole, Oyewale Tomori, Aissatou Toure, Els Torreele and John Whitehead.

Disclosure: The authors reported no relevant financial disclosures.

In an open letter to The Lancet, health experts argued that alternative trial designs should be explored when combating the current Ebola outbreak.

“We accept that [randomized controlled trials] can generate strong evidence in ordinary circumstances; not, however, in the midst of the worst Ebola epidemic in history,” the experts wrote. “The urgent need is to establish whether new investigational drugs offer survival benefits, and thus which, if any, should be recommended by WHO to save lives. We have innovative but proven trial designs for doing exactly that. We should be using them, rather than doggedly insisting on gold standards that were developed for different settings and purposes.”

The 17 signatories, made up of senior health professionals and ethicists from Africa, Europe and the United States, wrote that the outbreak’s severity has only increased since WHO’s initial declaration that experimental drug use was ethical in such a situation. They wrote that under these circumstances, the advantages of randomized controlled trials paled in comparison to those of alternative designs.

“The priority must be to generate data about effectiveness and safety as swiftly as possible, so that the most useful new treatments can be identified for rapid deployment,” the experts wrote. “Alternative trial designs have the potential to do this more quickly, and with greatest social and ethical acceptability.”

The experts offered potential models for distributing and observing treatment efficacy that would be subject to adjustment depending on observed outcomes, noting that such models have been used in other areas such as cancer treatment.

“There is no need for rules to be bent or corners to be cut; the necessary procedures already exist, and are used,” they wrote.

Aside from addressing the logistics of alternative designs, they also argued that streamlining treatment was necessary when considering the lives of those at risk.

“No-one insisted that western medical workers offered zMapp and other investigational products were randomized to receive the drug or conventional care plus a placebo,” the experts wrote. “None of us would consent to be randomized in such circumstances.

“When conventional care means such a high probability of death, it is problematic to insist on randomizing patients to it when the intervention arm holds out at least the possibility of benefit. Ethical arguments are not the same for all levels of risk,” they wrote.

The letter’s 17 signatories are: Clement Adebamowo, Oumou Bah-Sow, Fred Binka, Roberto Bruzzone, Arthur Caplan, Jean-François Delfraissy, Dave Heymann, Peter Horby, Pontiano Kaleebu, Jean-Jacques Muyembe Tamfum, Piero Olliaro, Peter Piot, Abdul Tejan-Cole, Oyewale Tomori, Aissatou Toure, Els Torreele and John Whitehead.

Disclosure: The authors reported no relevant financial disclosures.

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