The document discusses Phase 2 and Phase 3 clinical trials, outlining their respective study designs, participant numbers, and purposes. It highlights challenges faced during the COVID-19 pandemic, including resource allocation and ethical considerations, while providing statistics on trials currently registered in Malaysia. Additionally, it emphasizes the importance of designing research that is scientifically valid and ethically sound, especially under public pressure.

1. Introduction to Phase 2 & 3
Clinical Trials
Dato’ Dr Chang Kian Meng, FRCP
SREC Sunway Medical Centre

2. Disclaimer
• This slide was prepared for the Webinar Series Demystifying
Clinical Trials and challenges during the COVID-19 pandemic
session on 28 July 2021, by Dato Dr Chang Kian Meng,
Haematologist from Sunway Medical Centre
• This is intended to share within healthcare professionals, not
for public
• Kindly acknowledge “Clinical Updates in COVID-19
http://www.nih.gov.my/covid-19” should you plan to share the
information obtained from this slide with your colleagues.

3. Outline
Drug Discovery and
Development
Phase 2 & 3 Clinical Trial
Challenges related to clinical trial
research during the COVID-19
pandemic

4. Stages of Drug Development
To develop ONE
successful
medicine, it can
take:
•Testing of 10k drug
candidates
•Over a decade
•Over 1 billion
dollars

5. 5
Critical to the health of a population is the
development of safe and effective diagnostic,
therapeutic, and vaccine products, processes
that depend upon clinical trials …
Bierer et al. Journal of Bioethical Inquiry 2020

6. Phase 2 Clinical Trial
• Study Participants: Up to several hundred
patients.
• Length of Study: Approx. several months to 2
years

7. Phase 2 Clinical Trial
• often referred to as “therapeutic exploratory”
• involve small numbers of patients with the disease of interest
• primarily to test safety, pharmacodynamics and pharmacokinetics
• may help to determine dose, dose frequencies, administration
routes for phase III trials
• these studies are not large enough to show whether the drug will
be beneficial or efficacious
• Drug sponsors or sponsor investigators then use these data to
refine research questions, develop research methods, and design
new Phase 3 research protocols.

8. Phase 2
Clinical Trial

9. Phase 3 Clinical Trial
• Study Participants: 1,000 to 30,000 volunteers who
have the disease or condition
• Length of Study: 1 to 4 years

10. Phase 3 Clinical Trial
• “therapeutic confirmatory” or pivotal trial
• these studies involve a larger and more diverse target population,
1,000 to 30,000 participants.
• confirm efficacy and to estimate incidence of common adverse
reactions
• however less common adverse reactions may need a larger
population, hence Phase IV trials are needed
• Vaccine trials

11. Phase 3
Clinical Trial

12. Phase 2/3 Clinical Trials in Malaysia
817 registered
Phase clinical trial
2, 2/3 and 3 in
clinicaltrials.gov
• 496 completed
• 116 recruiting
Sources:
www.clinicaltrials.gov

13. Phase 2/3 Clinical Trials in Malaysia
• 86.8% Drugs
• 8.7%
Biological
• 1.4% Device
• 1.1% Dietary
• 0.5% Procedure
• 0.2% Combination
• 0.1% Radiation
• 1.2% Others
Sources:
www.clinicaltrials.gov

14. Phase 3 Clinical Trial Design
• Single arm
• Randomized Controlled trial
• Placebo-controlled
• Active-controlled
• Adaptive trial

15. Phase 3 Clinical Trial Design
Single arm
• Less popular due to lack of controlled group
• Used when therapeutic effect is expected to be very
huge and obvious (ie. Hepatitis C treatment with
SVR12 of above 90%)
Follow up
Intervention
Screening
Outcome
Study
population

16. Phase 3 Clinical Trial Design
Randomized Controlled trial
• Placebo-controlled
• To maintain blinding, and comparison with standard of care
(SOC)
• Active-controlled
• To compare with gold standard treatment
• Randomization to ensure every patient has equal
chance to receive any treatment in the study
• Control biases and confounders

17. Phase 3 Clinical Trial Design
Follow up
Randomization
Screening
Outcome
Study
population
Outcome
Study drug
Placebo / Active treatment
/ SOC
Randomized Controlled Trial Design

18. Phase 3 Clinical Trial Design
Adaptive trial design
• Utilize the accumulated data to decide any modification in
accordance with prespecified rules without affecting the
trial integrity and validity
• often more efficient, informative and ethical than fixed
design, may make better use of resources, time and
money and fewer participants

19. Phase 3 Clinical Trial Design
Adaptive trial design
• Types of modification may include:
• Sample size changes
• Early termination due to futility or efficacy endpoint achieved
• Addition or removal of intervention arms
• Study population eligibility criteria, new subgroup
• Hypothesis (ie. superiority and non-inferiority)
• Randomization ratio

20. Adaptive Trial Design
Follow up
New
subgroup
Screening
Outcome
Study
population Outcome
Study drug
Placebo / Active treatment
/ SOC
Outcome
New study drug
Subgroup
↑ sample size
Superiority vs
non-inferiority

21. Challenges to clinical research
during the COVID-19 pandemic
• COVID-19 first reported in Dec 2019, Wuhan, China
• WHO declared COVID-19 a Public Health Emergency of
International Concern Jan 30, 2020
• WHO declared pandemic on Mar 11, 2020
• As of July 1, 2021, 182 mil Covid-19 cases and 3.9 mil
deaths
• Global disruption to healthcare, supply chain, economy
and social interaction
Ethical Challenges in Clinical Research During the COVID-19 pandemic. Bierer et al. Journal of Bioethical Inquiry 2020

22. Challenges to clinical research
during the COVID-19 pandemic
• Shift of resources and focus on COVID-19 patient
management and research
• need to triage non-Covid clinical trials
• trial location and resources
• indication for trial
• urgency for continuation
• safety of participants and healthcare workers
• risks to trial integrity
Ethical Challenges in Clinical Research During the COVID-19 pandemic. Bierer et al. Journal of Bioethical Inquiry 2020

23. 23
Summary of clinical trials registered on
ClinicalTrials.gov as of October 31,2020
Hashem et al. Frontiers in Medicine
● 2,145 interventional studies for
COVID-19 covering a spectrum of
potential therapeutics
● Designing research with scientific and
social value is still paramount even
with public pressure and demand
● Drug Repurposing
● Evidence vs Emotional based medicine
● Avoid therapeutic misconception
○ Hydroxychloroquine
○ Ivermectin

24. COVID-19 Vaccine Trial Updates
24
https://covid19.trackvaccines.org/vaccines/#phase-3

25. Vaccine candidates in Phase 3 Clinical Trial
25
https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines

26. Pandemic Response to the Evolving
Knowledge on Treatment for COVID-19
• Large volume of data and publications from RCT,
observational cohorts, case series at rapid pace, some peer
reviewed, some not yet peer-reviewed and others, press
releases
• The panel continuously review all data and assess scientific
rigor and validity and make recommendations
• Whenever possible, promising, unapproved or unlicensed
Rx be studied in well-designed, controlled clinical trials incl
drugs approved for other indications
26
NIH COVID-19 Treatment Guidelines

27. Pandemic Response to the Evolving
Knowledge on Treatment for COVID-19
• However the panel also realize many patients and
providers cannot access these potential treatment
via clinical trials and need guidance
• Finally, it is important to stress the recommended
treatments are not mandates. The choice of what
to do for an individual patient is ultimately decided
by the patient and his provider
27
NIH COVID-19 Treatment Guidelines