Integrating Clinical Research into Epidemic Response The Ebola Experience (2017) / Chapter Skim
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3 Assessment of Therapeutic Trials
3 Assessment of Therapeutic Trials
Pages 83-112
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From page 83... ...
. Ultimately, formal clinical trials were conducted on five investigational therapeutic agents in the three countries most affected by the epidemic.
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funded a study of favipiravir (MSF, 2015) , a repurposed medicinal product that was originally developed for pandemic influenza virus infection (Furuta et al., 2013)
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January 2015 TKM-Ebola September 2014– March 2015 June 2015 14 patients Sierra Leone (TKM-130803) January 2015 Ebola Tx November 2014– February 2015 August 2015 99 patients Guinea (Convalescent plasma)
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From page 86... ...
Advantages and Disadvantages The multicenter approach allowed for a large number of participants -- in fact, this was the largest Ebola treatment trial and the first to be conducted during the epidemic. Assessment of viral load permitted stratification of patients into risk groups.
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From page 87... ...
2 was predictive of patient outcome and served as an effective surrogate of viral load; they suggested that future drug trials should systematically stratify analyses by viral load at baseline Ct value in a semiquantitative Ebola virus reverse transcription (a method the PREVAIL II trial team also used [PREVAIL II Writing Group, 2016]
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From page 88... ...
Drug Type Preclinical Evidence Known Safety Issues November 2014) Favipiravir Small molecule antiviral In vitro inhibition IC50 64 Clinical use in healthy 200 mg tablets; dosing at JIKI with activity against µM; higher than that needed volunteers up to 3.6 g on 6 g/first day requires 30 (Fuji/Toyama, Japan)
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From page 89... ...
and provides a summary of the available Ebola treatments that were under evaluation in formal clinical trials in West Africa as of October 2015. The WHO R&D Landscape (WHO, 2015b)
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From page 90... ...
However, based on the available evidence at this time, there is no conclusive evidence that the drug had a beneficial effect, and therefore favipiravir will still require further evaluation in a randomized controlled trial (RCT) during a future outbreak to resolve the question of efficacy.
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From page 91... ...
These additional stages provided some protection against both false positive and false negative results; in reality, however, it may have been difficult to do a controlled study of a drug yielding a promising result in Stage 1 as there likely would have been pressure to provide such a drug to everyone if it was not in limited supply. This design was similar to the common approach to drug development for solid tumors, in which a small single-arm Phase 2 trial that sees a response rate greater than a prespecified threshold is followed by a larger randomized Phase 3 trial with a standard treatment comparator (Horby, 2015)
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From page 92... ...
In addition, given changes in supportive care over time, these historical controls may not have been a relevant comparator. Ebola-Tx: Convalescent Plasma The European Union funded the Ebola-Tx project to investigate the safety and efficacy of convalescent plasma (CP)
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From page 93... ...
. The trial team made the decision not to randomize patients because they believed it would not be acceptable to patients or health care workers, given the volatile epidemic and high mortality rate, and because it would mean withholding a potentially lifesaving treatment from patients (Adebamowo et al., 2014)
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The serious consequence of this study design is that the inability of the trial to identify a significant but moderate efficacy may result in a rejection of CP as a treatment, despite the possibility that plasma, especially with a sufficiently high antibody level, may be effective. The most important findings that can be drawn from the study are that treatment with convalescent plasma appears to be safe and that the treatment appeared to have a high level of feasibility and acceptability in the midst of an outbreak.
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3 days apart, and optimized standard of care included the provision of intravenous fluids, balancing electrolytes, maintaining oxygen status and blood pressure, and treating concurrent infections. If an investigational treatment were proven to be superior to optimized standard of care alone with respect to survival, it would then become the basis of the new standard of care against which additional investigational Ebola interventions could be tested and compared.
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From page 96... ...
Due to the problem with sample size, none of the therapeutic trials were able to reach definitive conclusions about treatment efficacy. However, even if the trials had been able to enroll to completion, it is highly unlikely that the singlearm studies would have provided conclusive evidence on the effectiveness of the agents in the absence of concurrent controls.
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Single-arm trials may have missed moderate and clearly worthwhile effects and thus discounted a potentially beneficial product for future study. Trials that released preliminary results suggesting the experimental intervention was effective may have contributed to perceptions that overestimated the potential benefits, thereby compromising the ability to perform future controlled trials of these products.
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. Public Webinar of the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak, May 19, 2016.
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During the Ebola outbreak, both TKM-Ebola and ZMapp were given fast track review. Additionally, regulators may aid in selecting products for investigation if the available preclinical evidence is based on animal models.
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Design Considerations - Determined that the randomization of patients was locally unacceptable in the volatile setting of the Ebola outbreak (Adebamowo et al., 2014) Favipiravir Institut national Guinea Trial Design December 2014– Efficacy and tolerance de la santé et - Multicenter proof-of-concept noncomparative June 2015 inconclusive.
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5) • Highly transmissible disease • There was the fear that a randomized research design might lead the community to become even more distrustful, and patients more reluctant to seek care continued 101
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If - the treatment is either effective or promising, the treatment is subjected to further evaluation, i.e., a confirmatory single-arm study if initially effective or a RCT if only promising Design Considerations: - desire to quickly identify highly effective or A clearly ineffective treatments - desire to avoid randomization unless A necessary to establish the effectiveness of a treatment, perhaps because of a perception that randomization would not be acceptable or would be infeasible in the trial setting
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- The statistician's extensive work on sequential trial designs based on boundaries similar to those used in the trial (e.g., the triangular test of Whitehead) , likely facilitating the design and simulation work Ongoing humanitarian crisis + trial involves risks - Need to identify useful therapeutic quickly - Need to discard useless agents quickly High death rate + volatile conditions - Unclear if randomization to standard of care would be acceptable A common approach to developing drugs for patients with solid tumors is a small single-arm phase 2 trial, followed, if promising, by a larger randomized phase 3 comparison with a standard control treatment continued 103
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From page 104... ...
n = 140 if the survival proportion is 0.50) If - the treatment is either effective or promising, the treatment is subjected to further evaluation, i.e., a confirmatory single-arm study if initially effective or a RCT if only promising Design Considerations: - desire to quickly identify highly effective or A clearly ineffective treatments - desire to avoid randomization unless A necessary to establish the effectiveness of a treatment, perhaps because of a perception that randomization would not be acceptable or would be infeasible in the trial setting
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From page 105... ...
- The statistician's extensive work on sequential trial designs based on boundaries similar to those used in the trial (e.g., the triangular test of Whitehead) , likely facilitating the design and simulation work Ongoing humanitarian crisis + trial involves risks - Need to identify useful therapeutic quickly - Need to discard useless agents quickly High death rate + volatile conditions - Unclear if randomization to standard of care would be acceptable A common approach to developing drugs for patients with solid tumors is a small single-arm Phase 2 trial, followed, if promising, by a larger randomized Phase 3 comparison with a standard control treatment continued 105
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who received (54 patients) , § Lower CT value = higher viral load the current standard and the United § Higher CT value = lower viral load of care plus ZMapp.
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From page 107... ...
, it would then become of both mortality the basis of the new SOC against which and duration of additional investigational Ebola interventions hospitalization in all could be tested and compared age groups. - Frequent interim monitoring by an independent data and safety monitoring ZMapp showed board to facilitate early elimination of promise as a possible poorly performing treatments as well as the effective treatment introduction of new candidate therapies was agent for Ebola but incorporated in the trial there were insufficient - The plan was for each experimental therapy data to determine to be examined in up to 100 participants per definitively whether it arm.
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From page 108... ...
2016. Design of a randomized controlled trial for Ebola virus disease medical countermeasures: PREVAIL II, the Ebola MCM study.
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2015. Addressing therapeutic options for Ebola virus infection in current and future outbreaks.
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2016a. Evaluation of convalescent plasma for Ebola virus disease in Guinea.
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2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the women's health initiative randomized controlled trial.
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