February 9, 2018 In the past several years, the United States has struggled to respond to viral outbreaks, such as Ebola and Zika. There is now an awareness of the need to rapidly develop vaccines and treatments for epidemics that can quickly spread from country to country. But questions remain as how to best conduct clinical trials and development of vaccines in the context of an epidemic or outbreak. At this panel discussion, two health policy experts examined the appropriate conduct of clinical trials during public health emergencies. Learn more at: http://petrieflom.law.harvard.edu/events/details/clinical-trials-during-public-health-emergencies

1. EVALUATING TREATMENTS IN
SETTINGS DEMANDING
URGENCY: LESSONS FROM THE
2014-15 EBOLA EPIDEMIC
Susan S. Ellenberg, Ph.D.
Division of Biostatistics, Epidemiology and
Informatics, University of Pennsylvania
Harvard Law School Petrie-Flom Center
February 9, 2018

2. 2
EBOLA VIRUS DISEASE
OUTBREAK IN WEST AFRICA
Appears to have emerged in small town in southern Guinea, Guéckédou,
near the border of Sierra Leone and Liberia, in December 2013,
N Engl J Med 2014; 371:1418-1425.
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3. 3
EBOLA EPIDEMIC 2014-15
 Largest Ebola outbreak ever
― > 28,000 infected
― > 11.000 deaths
 No known effective drug treatments or vaccines
 Highly infectious
 High fatality rate
 Very limited health care facilities in areas of
outbreaks

4. 4

5. 5
WHO MEETING NOVEMBER 2014
Debate about the feasibility and the ethics
of conducting randomized trials of potential
treatments
―Research organizations and regulators supported
initiation of randomized trials
―Humanitarian organizations argued against RCTs
 Randomization would be unethical; whatever could be
made available should be provided to everyone, as those
infected had nothing to lose by trying an untested
treatment
 Randomization would be infeasible; communities would
not accept it
 Randomization would be impractical; focus needed to be
on providing treatment, not doing research

6. 6
MUCH DEBATE ABOUT RESEARCH
DURING OUTBREAK
 Some trials, randomized and nonrandomized,
were implemented
 Limited coordination of effort
 Trials did not start until the epidemic was
waning; enrollment too limited in RCTs to yield
definitive results

7. 7
TIMELINE

8. 8
A STEP BACK IN TIME

9. 9
CLINICAL TRIALS TIMELINE
 1948: First randomized clinical trials of modern era
 1962: Amendments to Food, Drug and Cosmetic Act
requiring demonstration of efficacy as well as safety
 1964: First version of Declaration of Helsinki
 1966: Beecher, NEJM: Ethics in Clinical Research
 1976: Medical Device Amendments
 1979: Belmont Report
 1991: Accelerated Approval
 1996: Good Clinical Practice
 2013: Current version of Declaration of Helsinki

10. 10
RANDOMIZATION IN CLINICAL
RESEARCH
Austin Bradford Hill:
“…having used a random allocation, the sternest critic is
unlikely to say when we eventually dash into print that
quite probably the groups were differentially biased
through our predilections or through our stupidity.”
New England Journal of Medicine, 1952

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PUSHBACK
 Substantial resistance among oncologists in
particular on ethical grounds
― Gehan and Freirich, NEJM 1974: “If preliminary clinical
studies suggest that a new treatment is significantly more
effective than a standard…the physician would not be
fulfilling his ethical responsibility if he planned a
randomized comparative trial…”
 Others argued for alternative, more efficient
approaches
― Weinstein, NEJM 1974: …to control for variables that can
be identified…as interfering factors, matching, blocking or
adjusting may be far more efficient…than purely
randomizing.”
― Hellman and Hellman, NEJM 1991: “It is fallacious to
suggest that only the randomized clinical trial can provide
valid information or that all information acquired by this
technique is valid.”

12. 12
PROBLEMS WITH HISTORICAL
CONTROLS
 Basic problem: historical cases may be different
from cases given new treatment; CANNOT assume
that prognosis is equal in comparison groups
― New diagnostic techniques permitting identification of
cases at earlier disease stage; current cases may on
average be earlier stage than historical cases
― Improved supportive care
― Selection of those presenting for care (e.g., exclusion of
those with very limited life expectancy)
 Historical data often poorly estimate treatment
effect in later trials

13. 13
EXAMPLE: ECMO (1989)
 Extracorporeal membrane oxygenation (ECMO)
introduced for treatment of premature infants with
persistent pulmonary hypertension
 Expected mortality in such infants with then-current
standard of care: 80%
 Great concern about performing randomized trials
 First comparative trial showed mortality of 40% with
standard of care
 A new treatment showing showing mortality of 40-
50% in a single-arm trial would have been hailed as a
great advance

14. 14
CAN WE SOLVE THIS PROBLEM WITH
STATISTICAL MODELING?
Well…maybe
The problem is that you never know what you
don’t know
If there are important but unknown and/or
unmeasured prognostic factors our models
may not be adequate
Clinical trialists worry about this a lot

15. 15
EBOLA MORTALITY
 Schieffelin et al (NEJM, 2014) reported on 106
patients treated in Sierra Leone
― Overall mortality: 74%
― Mortality increased with age (57% in youngest group,
94% in oldest group)
 Ansumana et al (NEJM, 2015) reported on 581
patients treated in Freetown, Sierra Leone
― Overall mortality: 31%
― Mortality over time decreased from 48% to 23%, just in
the few months from 9/14 to 12/14
 Reported mortality statistics varied widely by
country, age, time
 Overall death rate in 2014: 37% (Kalra et al, J Glob
Infect Dis, 2014)

16. 16
IMPLICATIONS
 Diminishing mortality was very likely due largely to
introduction of improved supportive care measures—
fluid replacement and electrolytes
 As experience gained, would be expected that
mortality would continue to decrease
 Variability in mortality by age (and undoubtedly
other factors, some unmeasured) would complicate
historical comparisons
 With such variable mortality rates a historically
controlled trial could not yield convincing results
unless the treatment effect was VERY large
 Clear that those infected did have “something to
lose” by exposure to potentially harmful product

17. 17

18. 18
CHALLENGES DURING EARLY AIDS ERA
 Apparently uniformly fatal illness + no treatments +
young (already stigmatized) population = desperation
 Many with HIV sought treatment with unproven
remedies
 Treatments like AL-271, peptide T, ampligen, low
dose oral alpha interferon, etc, promised benefit
without toxicity of proven drugs like AZT
 Tensions about randomized trials (particularly about
use of placebo controls)

19. 19

20. 20
ACT UP DID NOT ARGUE AGAINST RCTs
 Concerns related to other aspects of trials
― Overly restrictive entry criteria
― Choice of endpoints
― Restrictions on concomitant medications
― Coverage of costs for trial participants
― Efficiency of trials networks
 Statisticians engaged in discussions with AIDS
activists about optimal approaches to studying new
treatments
 Activists became the strongest advocates for
rigorous research
 Availability of many treatments when you don’t know which
ones work is useless

21. 21
PROPOSED CRITERIA FOR HISTORICALLY
CONTROLLED TRIAL
 No treatment to serve as appropriate control
 Sufficient experience to show that untreated
patients have uniformly poor prognosis
 Therapy not expected to have substantial side
effects that could compromise potential benefit
 Justifiable expectation of sufficiently large benefit
to make results interpretable
 Strong scientific rationale for treatment to support
wide acceptance of positive findings
Byar et al, 1990: Design considerations for AIDS trials, NEJM
323:1343-8

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PROPOSED CRITERIA FOR HISTORICALLY
CONTROLLED TRIAL
 No treatment to serve as appropriate control 
 Sufficient experience to show that untreated
patients have uniformly poor prognosis
 Therapy not expected to have substantial side
effects that could compromise potential benefit
 Justifiable expectation of sufficiently large benefit
to make results interpretable
 Strong scientific rationale for treatment to support
wide acceptance of positive findings
Byar et al, 1990: Design considerations for AIDS trials, NEJM
323:1343-8

23. 23
PROPOSED CRITERIA FOR HISTORICALLY
CONTROLLED TRIAL
 No treatment to serve as appropriate control 
 Sufficient experience to show that untreated
patients have uniformly poor prognosis X
 Therapy not expected to have substantial side
effects that could compromise potential benefit
 Justifiable expectation of sufficiently large benefit
to make results interpretable
 Strong scientific rationale for treatment to support
wide acceptance of positive findings
Byar et al, 1990: Design considerations for AIDS trials, NEJM
323:1343-8

24. 24
PROPOSED CRITERIA FOR HISTORICALLY
CONTROLLED TRIAL
 No treatment to serve as appropriate control 
 Sufficient experience to show that untreated
patients have uniformly poor prognosis X
 Therapy not expected to have substantial side
effects that could compromise potential benefit 
 Justifiable expectation of sufficiently large benefit
to make results interpretable
 Strong scientific rationale for treatment to support
wide acceptance of positive findings
Byar et al, 1990: Design considerations for AIDS trials, NEJM
323:1343-8

25. 25
PROPOSED CRITERIA FOR HISTORICALLY
CONTROLLED TRIAL
 No treatment to serve as appropriate control 
 Sufficient experience to show that untreated
patients have uniformly poor prognosis X
 Therapy not expected to have substantial side
effects that could compromise potential benefit 
 Justifiable expectation of sufficiently large benefit
to make results interpretable X
 Strong scientific rationale for treatment to support
wide acceptance of positive findings
Byar et al, 1990: Design considerations for AIDS trials, NEJM
323:1343-8

26. 26
PROPOSED CRITERIA FOR HISTORICALLY
CONTROLLED TRIAL
 No treatment to serve as appropriate control 
 Sufficient experience to show that untreated
patients have uniformly poor prognosis X
 Therapy not expected to have substantial side
effects that could compromise potential benefit 
 Justifiable expectation of sufficiently large benefit
to make results interpretable X
 Strong scientific rationale for treatment to support
wide acceptance of positive findings X
Byar et al, 1990: Design considerations for AIDS trials, NEJM
323:1343-8

27. 27
ETHICS AND SCIENCE: 2 SIDES
A well designed, scientifically valid study can be
unethical
A poorly designed study that is unlikely to yield
reliable information raises ethical concerns

28. 28
28
Trial Name
(investigational
agent)
Country Number
Enrolled
Trial Design Results
JIKI
(Favipiravir)
Guinea 126 non-random, historical controls Inconclusive
RAPIDE-BCV
(Brincidofovir)
Liberia 4 non-random, historical controls Inconclusive
RAPID-TKM
(TKM-100802)
Sierra Leone 14 non-random, historical controls Inconclusive
Ebola Tx
(Convalescent
plasma)
Guinea 99 non-random, historical controls Inconclusive
PREVAIL II
(Z-Mapp)
Guinea, Liberia,
Sierra Leone,
United States
72 Randomized, controlled
(optimized standard of care)
Suggested
possible benefit
ASSESSMENT OF THERAPEUTIC TRIALS
“Thin Scientific Harvest”1
1 Cohen & Enserink Science 351: 12-13, 2016
• No trials reached conclusive results
• One RCT was implemented, demonstrating feasibility–results
suggest some benefit but further study is needed
• Single arm trials: a gamble (usually a losing gamble)

29. 29
28-DAY MORTALITY: PREVAIL
Variable OSC ZMapp+OS
C
Total
Total
randomized
36 36 72
Total
evaluable
35 36 71
Deaths 13 (37%) 8 (22%) 21 (30%)

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CONCLUDING COMMENTS
 Conducting research in situations of extreme urgency
is challenging—but possible
 Experience in early days of AIDS epidemic was
challenging (very different from Ebola epidemic), but
showed that randomized trials could be done, and
done well in a setting of extreme urgency and tension
 Ongoing discussions now to plan approaches in next
infectious disease outbreak, and to identify
resources for building capacity
― World Health Organization
― Center for Strategic and International Studies
― Center for Global Development
― World Bank

31. 31

32. 32
RESPONSE-ADAPTIVE RANDOMIZATION
In most trials, allocation ratio (usually but not
always 1:1) is consistent throughout the trial
Some advocate a “response-adaptive” approach
to randomization as a more ethical approach
―Change the allocation ratio as trial progresses to
favor the treatment that is looking better
―Goal: end up with more participants receiving the
superior treatment
―Several such approaches have been proposed
 “Play the Winner”
 Adaptive biased coin designs
 Urn designs

33. 33
ISSUES WITH RESPONSE-ADAPTIVE
RANDOMIZATION
 Patient characteristics may change over time; may end up
with imbalances
 Supportive care may change over time; effects of
supportive care will be confounded with treatment
effects
 Imbalanced allocation is less efficient; will need a larger
trial, offsetting reduction in actual number getting
inferior treatment
― Could have a smaller proportion but a larger number getting
inferior treatment
 A trial with a fixed ratio allocation but with a sequential
design allowing early termination and with frequent
interim reviews may be most efficient approach