The presentation is a brief overview of issues Clinical Pharmacologists and team come across during various processes involved in conduct of clinical trial of infectious diseases. It also discusses off-track topics but related topics like Antimicrobial Stewardship and ends with measures suggested to overcome some of the challenges.

1. Special Issues in Conduct of
Clinical Trials in Infectious
Diseases
Dr. Shakeeb Dhorajiwala,
First year resident,
DM Clinical Pharmacology

2. Outline
Ways to deal with issues
Good Anti-biotic Prescribing Practices & Antimicrobial Stewardship
Current Challenges during ongoing pandemic
Selective issues with certain aspects of CT
What numbers say
Historical aspect
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3. History
Random allocation- 1946- Trial testing efficacy of
immunization against whooping cough
Modern era of randomised trials- began with evaluation
of streptomycin for treating severe TB- UK,1948.
Schwartz and Lellouch – Pragmatic & Explanatory
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5. Facts & Figures
55.9 million people died in 2017 of preventable causes.
If we sum up all life years lost due to premature death
Σ(life expectancy - age of death)
we find that the world population lost 1.65 billion years
of potential life due to premature death in that year
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https://ourworldindata.org/burden-of-disease

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Goswami ND et al. The State of Infectious Diseases Clinical Trials: A Systematic Review of ClinicalTrials.gov. PlosOne. October 2013 : 8(10); 5

9. Why the hesitancy
Process of developing new antibiotic is
• expensive
• takes lot of time and effort
• requires intensive scientific knowledge
• huge number of failures vs few successes.
Single new antibiotic incurs costs of > billion USD & time
period of well >decade
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10. Why doesn’t it interest Pharma Industry ?
• Treatment of acute infections short course
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11. CT of Infectious
Disease
Therapeutics
Prophylactics-
vaccine
Diagnostics
Medical devices eg
simple syringe and
complex robotics
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e.g. Smaller, shorter trials for conditions showing dramatic improvement

12. Epidemiological
In case of multi-
centric trials
variability in strains
Affects severity of
disease
Skewed results
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13. Challenges in Trial Design
NI is not transitive. A being noninferior to B, and B being noninferior to C, does
not imply that A is noninferior to C
risk that newest antimicrobial put into clinical use after being proved non-
inferior, but is truly inferior to prototype antibiotic (a process known as
biocreep).
Pragmatic trials yield reliable results (e.g., will the antibiotic work in clinical
practice
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14. Selection Criteria
Criteria should:
• maximize likelihood that patients
have type of infection under study
• minimize enrolment of patients likely
to resolve rapidly without therapy
• should demonstrate protocol-defined
min. no. of S&S associated with an
ongoing acute infectious process
Special attention:
• groups (e.g. diabetics)
• recent use of antipyretic agents
• hypothermia and/or a low WBC 
very severe infections
• rapidly advancing bilateral pulmonary
tuberculosis rare e.g. where all
patients died in the timeframe of the
study
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ema
Soln : Time to death  Primary outcome measure

15. Issues with Allocation
1:1 allocation for all practical purposes is statistically most
efficient. However not always possible
patient pool-limited- To obtain more information within the
trial from
the test treatment rather than the well-known standard- ratio
set at 2:1/3:1 etc. in favor of test loss of statistical power
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16. Challenges in Special Population
Neonatal deaths now represent 44 percent of all deaths in children under the age of five2. And of great
concern, is the estimated 214,000 deaths in newborns attributable to drug-resistant infections3
Children are not small adults and require treatments that are adapted in terms of regimen, dose and
formulation- Need more dedicated trials
AMR can affect anyone, of any age, in any country, it is disproportionately impacting children still a
challenge
Soln: develop and implement pediatric investigation plans of new and important old antibiotics in
partnerships with companies
Special care to be taken in cases elderly:of fever and/or an elevated white blood cell (WBC) counts
may be absent in the evidence of ongoing bacterial infection
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17. Interventions
Test drug
compared
with:
SOC
Placebo
As add-
on
As FDC
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18. Treatment Compliance
System generated
automatic
reminders
Counselling
Limited by level of
intellect
Diary
DOTS: For TB
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19. Indicators of Treatment failure
persistent fever >72 h after initiation of the antibiotic therapy,
clinical deterioration (transfer to the intensive care unit, intubation, use of
vasoactive drugs),
change of antibiotic regimen during the treatment, independent of the cause
(e.g. premature withdrawal of the study medication because of a side-effect),
isolation of a resistant pathogen with worsening of infection symptoms, death,
or discontinuation of therapy for personal reasons
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20. End-point selection
E.g. Trial on sepsis:
Most safe: use overall survival
Increasing overall survival but at the cost of increased hospital expenditure
better endpoint shortening of hospital stay
mortality end points forces the study design to include only those patients with
a high likelihood of mortality
failure to reach mortality end points leads to rejection of specific agents that
are clinically useful but marginally effective as single agents
PRO- attractive option-challenging to specify a margin for such endpoints
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21. Challenges in Consenting Process(1/2)
Language barrier
Overcome : ICD in local language
Consenting in special population
relinquish autonomy and depend on the health workers decisions health workers are competent in
what they do
Communal decision making- (leaders deciding for individuals)
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22. Consent (2/2)
Consenting severely ill patients especially when the designated next
of kin not available
active effort to locate the next of kin if not possible Do not enrol
After consenting refusal to receive test treatment ITT analysis
• Limitation: conservative-dilute the estimate of true difference between test and
comparator
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23. QTc Prolongation
Special emphasis on this feature
Study to be done in P1
Comparator- Moxifloxacin(mostly)
Waiver applied if no pre-clinical signal detected
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24. Financial Issues
most frequent reason for stopping clinical
development low return on investment
Economics of antimicrobial R&D not favorable today
 one of the main reasons for desertion of this
therapeutic area by companies since the 1990s
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25. Which test to use: Sensitive vs specific
sensitive tests will enroll more patients with low bacterial loads
Too much emphasis on sensitivity compromises generalizability
specific tests higher rates of patient eligibility for microbiological
intent to treat population and the microbiologically evaluable
population than sites using less specific tests
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26. Clinical Data Management
Key feature of any scientific study is the implication that the data generated are of high quality
CRFs- vital component to the eventual success of any clinical trial protocol
Errors are liable to happen in the recording of data in the CRFs, as well as in the transfer of data to
the computer
Regulatory Agencies rightly demand a guarantee of high quality data in any submission made to
them for product registration
Regular monitoring of trial progress, especially during the early stages, is advisable, and prompt
attention to data errors, inconsistencies or missing items on the CRFs
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27. Data Protection
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Challenge: multiple sites, many users accessing same network, possibly performing
different tasks, for example:
• database design,
• entry and resolution by data managers,
• data retrieval, query and analysis by statisticians,
security of the system is of primary concern
clinical trial system should allow network-wide security standards to be enforced by
enabling system administrators to assign, monitor and control access to sensitive
clinical data records

28. Generalizability
Special population including
• pregnant and lactating mothers,
• Children
• elderly (>65 years)
• Pts with co-morbidities
• patients too ill to receive trial antibiotics
generally excluded not representative of everyday medical
practice
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29. Biggest Unprecedented Challenge :
Covid19 Pandemic
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30. Ethical Review
Ethical review critical role in protecting participants’
• Rights
• safety
• well‐being
• ensuring scientific integrity
Expedited review  emergency approvals reviewed and ratified later
Process hampered by lockdown and movement restrictions
Soln: online electronic platform for submission of research applications that ensured safe ongoing
paperless research review
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31. Research Staff and Clinical Care Team Interactions
Reduction in number of workers
Extra workload on existing workers-primary clinical care teams to perform
all study procedures including :
• Consent
• sample collection
• data collection
Soln: Ensure uniform distribution of work and compensate extrawork done.
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32. Patients’ Compensation
potential risk of transmission of
infection through direct cash
payments
Soln:
Mobile/ online payment
Time of discharge after a negative
COVID-19 test was confirmed-
Another challenge arose- complained
of delayed compensation
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33. Consent procedures
Zone
•Non-infected area
•Documents sealed
in biohazard bag
doubly disinfected
Zone
•Pt infected area
•Stationaries left
here
Fomite spread
Uncertainty how to deal with?
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34. Bigger Challenge
emergence of resistance and the re-emergence of the disease
time factor is crucial, as usual. For acute infections treated in hospitals, such as
Septicemia, meningococcal meningitis, etc., the situation could be as
controlled as in a laboratory experiment.
For malaria, TB and the like, the messiness of everyday life will always threaten
to put an end to the controlled situation
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35. Good Anti-biotic Prescribing Practices
Check for 4D’s
Appropriate investigations in all infections
Initiation/ change of anti-biotic only after culture reports
Follow hospital policy in selecting AMA. Document reason for choosing alternatives
Need for AMA reviewed on daily basis. Most infections 7 Days course sufficient
Assess organ functions, D-D-I, Hypersensitivity status
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36. After culture-sensitivity reports- step down to
• narrowest spectrum
• Most efficacious
• Most cost-effective option
Empiric therapy- justified only if waiting time for c-s reports life-
threatening consequences
No substitute for handwashing in preventing HAI
High stds of hospital cleanliness- utmost importance in curbing spread of
resistant organisms
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37. Anti-microbial Stewardship
Set of co-ordinated strategies to improve use of anti-
microbial medications.
Goal:
• Enhance pt health outcome
• Reduce resistance
• Decrease unnecessary cost
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38. Stewardship Team
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39. Techniques
Formulary
restriction
Order sets and
treatment
algorithms
Education
Pharmacodynamic
dose optimization
Computer assisted
decision support
programs
Antibiotic cycling
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40. Challenges in Publication
Most of the trials fail due to limited efficacy but are not published which may lead to trial
duplication
SR & MA fails to show a comprehensive analysis
Recommendation are there but implementation is a challenge. Trials underreported. Duplication of
failed trial.
Possible solution: make registration mandatory and should include prospective plan of
publication to be mandatory
Consent for publishing Photos i/c/o leprosy
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41. Few Ways to deal with issues
Avoid commercial/ independent review boards/ committees
Instructions in language they understand best
Empower people with autonomy to make informed decisions
Awareness program for patients encouraging participation
Develop quality education and training programs for researchers & clinicians
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42. Ensure proper spacing of patients for pts’ safety
Set up data monitoring and safety committee
Organize GCP training courses/ basic research and conduct of CT
CONSORT guidelines
encompasses various initiatives to alleviate the problems arising from inadequate reporting of RCTs
minimum set of recommendations for reporting RCTs
standard way for authors to:
• prepare reports of trial findings
• facilitating their complete and transparent reporting
• critical appraisal and interpretation
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