MMS Holdings Expert Insights Webinar

1. The Blueprint for Success for Effective and Efficient
Clinical Protocols
© MMS Holdings 2021

2. Our Presenters
Aaron Burr
Senior Medical
Writer, Regulatory &
Medical Writing
Tasnim Hoda
Manager, Regulatory
& Medical Writing
2
Hung Lam
Principal Biostatistician
Biometrics
Victoria Murray
Technical Manager
Regulatory &
Medical Writing

3. Agenda
• Introduction to clinical trials and
study designs
• New efficiencies in clinical trial
design
– Statistical methods for
interpreting analysis
• Master protocols/subprotocols

4. 4
Introduction to Clinical Trial Design
• The clinical development industry is an ever-changing field
– Important to stay ahead of industry changes and ensure compliance to
the needs of health authorities
• Close working relationship between the study team and writer helps
collaboratively design research questions, select study populations, develop
objectives/endpoints
• Understanding the purpose of the trial allows the writer to work closely with
the study team to suggest efficiencies that may impact the study design or
long-term success of the clinical study

5. 5
Types of Study Design
Study Design
(Did the investigator
assign exposures?)
Observational
(Records observations of
what occurs to subjects, but
does not intervene)
Experimental
(Intervened research, then
record observations)

6. 6
Types of Observational Study Design
Observational
Study
(Is there a comparison
group?)
Descriptive
(eg, case reports)
Cross-sectional Surveys
(snapshot)
Cohort Studies
(prospective)
Case-control Studies
(retrospective)
Analytical
(hypothesis testing)

7. 7
Types of Experimental Study Design
Experimental
Study
(Randomized?)
Randomized
Controlled Trial
Non-randomized
Controlled Trial

8. 8
Phase I Clinical Studies
• Phase I of Clinical Drug Development
– First in human
– Small number of subjects (20-80) – typically healthy volunteers, but there are exceptions
(eg, cancer)
– Weeks to months to complete
• Purpose of Phase I trials:
– Determine dosing
– Document how a drug is metabolized and excreted - clinical pharmacology (ADME)
– Identify acute side effects – safety
• Pharmacokinetic (PK) and Pharmacodynamics (PD)
• Other Supportive/Critical Path Studies
• 70% of pharmaceuticals move to the next phase

9. 9
Phase II Clinical Studies
• Phase II of Drug Development
– If Phase I studies show drug to be safe and well tolerated
– ~100-300 patients with the disease condition
– Can take several months to year(s) to complete
• Study Design
– Controlled (placebo or active)
– Randomized
– Blinded (single or double)
– Parallel group or crossover
• Purpose of Phase II trials:
– Gather further safety data
– Gather preliminary evidence of the drug's beneficial effects (efficacy)
– Help to develop and refine research methods for future trials with this drug
• 33% of pharmaceuticals move to the next phase

10. Phase III Clinical Studies
• Phase III Clinical Drug Development
– Significantly larger patient population with the
disease (moderate form)
– 300-3,000 patients with the disease or
condition
– Can take several years to complete
• Study Design
– Placebo or Active Comparator
– Blinded, randomized, and of adequate size
• Purpose of Phase III Trials:
– Test the product's effectiveness
– Monitor side effects
– Compare the product's effects to a standard
treatment (in some cases)
– Support marketing approval
• Accelerated Drug Development Program
– Phase II and III combined
– Severely debilitating/life-threatening diseases
• 25-30% of pharmaceuticals move to the next
phase
• PHASE IIIb Trials
– Conducted after regulatory submission, but
before approval
– May be used to supplement earlier trials,
complete earlier trials, or may be directed
toward new types of trials (e.g., quality of life,
marketing)
10

11. 11
Phase IV Clinical Studies
• Phase IV Clinical Drug Development
– Studies are done after the drug or treatment has been approved
• Purpose of Phase IV Trials:
– Gather information on the drug's effect in various populations
– Monitor safety
– Identify any side effects associated with long-term use

12. Efficiencies in Trial Design

13. 13
Efficiencies in Trial Design
Phase 1
Trial Designs
Adaptive
Designs
Master
Protocols

14. Phase I Trial Design
14

15. 15
Efficiencies in Phase I Trial Design
Goal of Phase I: determine dose &
schedule of an IP/initial safety profile
Traditionally, 3+3 design utilized:
• Simple, transparent, and costless
implementation
• Utilizes dose escalation targeting
toxicity rate < 33%
Tourneau et al. J Natl Cancer Inst 1009;101:708-720.

16. 16
Efficiencies in Phase I Trial Design
• 3+3 design has been successful for cytotoxic agents, may not be the
most optimal design for molecularly targeted agents
• Need for phase 1 efficiencies
– Accelerated titration designs (ATDs)
– Modified Toxicity Probability Intervals (mTPI)
– Continual Reassessment Method (CRM)
– Phase 0 designs

17. 17
Accelerated Titration Designs
• Benefits of ATDs
– Rapid initial escalation phase
– Intrapatient dose escalation
– Analyze trial results using dose-toxicity model
• Examples of ATDs:
– Design 4
– Continual Reassessment Method (CRM)

18. 18
Accelerated Titration Designs: Design 4
Characteristics
• Single patient cohorts; double dose steps
per dose level
• After 1st DLT or 2nd moderate toxicity 
expand to 3 patients and revert to 3+3
design
• Analyze trial results using a dose-toxicity
model
Benefits
• Allows intrapatient dose escalation if no
toxicity at current dose
• Reduce the number of patients potentially
undertreated
Tourneau et al. J Natl Cancer Inst 1009;101:708-720.

19. 19
Accelerated Titration Designs: Design 4
Analysis
Data from all patients, cumulative
toxicity, and interpatient variability can
be fit to a dose-toxicity model to
estimate the relationship between dose
and DLT risk.
DLT = Dose-limiting toxicity, MTD = Maximum tolerated dose, TTL = Target toxicity level
Wheeler et al. BCM Medical Research Methodology. 2019;19(1):18

20. 20
Accelerated Titration Designs: Continual Reassessment Method
Characteristics
• Bayesian adaptive design (based on binary toxicity
outcome)
• Dose of next patient based on outcomes of ALL
patients previously treated
• Over time, numerous modifications have been made
to increase flexibility and add safety constraints
Approach
• Determine target level of toxicity (20-33%)
• ‘n’ for each cohort selected (originally 1, recently
2-3/cohort)
• Mathematical model for dose/toxicity relationship is
specified
• Stopping rules must be determined DLT = Dose-limiting toxicity
Tourneau et al. J Natl Cancer Inst 1009;101:708-720.

21. 21
Accelerated Titration Designs: Continual Reassessment Method
Implementation of the method
• The dose for the initial cohort is based on
the prior dose toxicity curve assuming the
desired level of toxicity is 0.25, patient 1
would receive dose level 4
• The dashed line shows the estimated DTC
after observing the first patient
experienced a DLT, patient 2 would
receive dose level 3
• The dotted line shows the estimated DTC
after observing the first patient did not
experience a DLT, patient 2 would receive
dose level 5
DTC = Dose toxicity curve
Ivy et al. Clin Cancer Res. 2010;16(6):1726-1736.

22. 22
Accelerated Titration Designs
• Despite excitement in statistical community, not often implemented in trial
designs
– Challenging for non-statisticians to understand
– Often require considerable logistic burden and complexity to implement
– PRCs, IRBs/IECs, HAs have been hesitant to accept these designs
• Modifications of these designs can/have been made to increase acceptance:
– Eg, use 3+3 design (with predefined doses) until 1st DLT, then switch to
CRM to make further updates to dose

23. 23
Modified Toxicity Probability Interval (mTPI)
• Compared with 3+3 design, equally as simple, transparent, and costless to implement
• mTPI design uses a Bayesian statistical framework and a beta/binomial hierarchical model to
compute the posterior probabilities of three intervals that reflect the relative distance between the
toxicity rate of each dose level to the target probability, pT.
• The mTPI design replaces the 3+3 rules with a model-based inference on the toxicity probability
intervals
If toxicity rate is within
overdosing interval,
mTPI design
recommends
de-escalating the
dose level
If toxicity rate is within proper dosing
interval, mTPI design recommends
continuing at the current dose level
If toxicity rate is within
underdosing interval, mTPI
design recommends
escalating the dose level
Ji et at. JCO 2013, 31:1785-1791

24. 24
Modified Toxicity Probability Interval (mTPI)
Benefits
• Automatically and appropriately tailors
dose-escalation decisions for different
trials with different toxicity parameters
• All dose-escalation decisions can be
precalculated and presented in a 2-way
table
Simulations have shown that 3+3 design is
more likely to treat patients at toxic doses
above the MTD and less likely to identify the
true MTD than the mTPI design
Ji et at. JCO 2013, 31:1785-1791
Ji et at. JCO 2013, 31:1785-1791

25. 25
Phase 0 Designs
• FDA released an exploratory
Investigational New Drug (IND)
guidance in 2006 to support clinical
evaluation before the dose escalation,
safety, and tolerance studies associated
with a traditional IND
• Phase 0 trials have no therapeutic intent
• Data obtained from such pilot trials
involving small number of patients can
guide decisions regarding further
clinical development and better inform
the design of subsequent trials
Murgo et al. Clin Cancer Res. 2008;14(2):3675-3682.

26. Adaptive Design

27. 27
Adaptive Designs (ADs)
Traditional designs are inflexible and don’t allow for changes that may
become desirable or necessary over the course of the trial – ADs
provide an alternative
Pallmann et al. BCM Medicine 2018; 16:29

28. 28
Adaptive Designs (ADs) - Examples
Design Idea
Continual reassessment method Model-based dose escalation to estimate the maximum tolerated dose
Group sequential Include options to stop the trial early for safety, futility or efficacy
Sample size re-estimation Adjust sample size to ensure the desire power
Multi-arm multi-stage
Explore multiple treatments, doses, duration or combinations with options to ‘drop
losers’ or ‘select winners’ early
Population enrichment
Narrow down recruitment to patients more likely to benefit (most) from the
treatment
Biomarker adaptive Incorporate information from or adapt on biomarkers
Adaptive randomisation Shift allocation ratio towards more promising or information treatment(s)
Adaptive dose-ranging Shift allocation ratio towards more promising or informative dose(s)
Seamless phase I/II Combine safety and activity assessment into one trial
Seamless phase II/III Combine selection and confirmatory stages into one trial
Pallmann et al. BCM Medicine 2018; 16:29

29. 29
Adaptive Designs (ADs) - Benefits
Gateway to more efficient trials
• Recruitment to futile treatment arms may stop early
• Patient population most likely to benefit from treatment may be identified
• Underpowered trial may be prevented
• Treatment effects may be estimated with greater precision
• Fewer patients may be required overall to get same results as traditional
designs
• Definitive conclusions may be reached earlier
• Seamless designs allow for rapid transitions
• Better understanding of dose-response or dose-toxicity relationship

30. 30
Adaptive Designs (ADs) - Implementation
Given many benefits, ADs still
not widely used
• Lack of expertise/experience
• Worry if IRBs/IECs or HAs will
accept design
• Statistical challenges

31. 31
Considerations for Adaptive Design (AD)
• A clear rationale for choosing an AD instead of
a more traditional design
• Who has access to interim data or performed
interim analyses
• How the results are shared and confidentiality
maintained
• What the role of the sponsor is in the
decision-making process
Non-Statistical Issues
• Describe approach to control the Type I error
rate in AD, the total probability of rejecting the
null hypothesis
• Estimated treatment effect using naïve methods
can be biased, with an incorrect mean value
• P-value: Calculated in the traditional way may
not be well-calibrated
• Computed confidence interval without taking
into account of the AD can lead to incorrect
coverage
Statistical Issues

32. Benefits of Master/Subprotocols

33. 33
Master Protocols - Advantages
Time Saving
• Common Screening Procedures
– No need to repeat data collection and screening for multiple separate studies
– This screening platform can identify all trials for which a patient is eligible: more efficient for
patients and sites
• Shared Governance Bodies
– Single governing bodies (example: Institutional Review Boards, Data Monitoring Committee)
assigned to oversee all substudies within a master protocol
– Enables informed decisions about various aspects across all trials
• Study Sites
– As master protocol expands to include additional therapies or therapeutic areas, sites have
shorter start-up time compared to multiple, separate trials

34. 34
Master Protocols - Advantages
Cost Saving
• Site start-up and recruitment
• Site monitoring
Continuous Learning
• Requires collaboration between leading research and clinical experts
• Allows for sharing of latest data and real-world evidence
Patient Benefit
• For biomarker driven studies, master protocols offer more personalized
treatment based on genetic makeup

35. 35
Master Protocols
• In contrast to traditional trial designs, where a single drug is tested in a
single disease population in one clinical trial
• Master protocols use a single infrastructure, trial design, and protocol to
simultaneously evaluate multiple drugs and/or disease populations in
multiple substudies, allowing for efficient and accelerated drug
development.
• Often categorized as:
Basket Trials Umbrella Trials Platform Trials

36. 36
Master Protocols – Basket
• Commonly Phase I/II
• Single investigational drug or
combination studied across multiple
cancer populations
• Can establish whether efficacy in
genetic mutation in a particular site
is effective in treating the same
mutation in another site
• Single screening process for
mutation
Cancer 1 Cancer 3
Cancer 2
Biomarker Positive
Biomarker Driven Treatment

37. 37
Master Protocols – Umbrella
• Commonly Phase I/II
• Evaluates multiple investigational drugs in
a single disease population, with
potentially different genetic mutations
• Consists of many small sub-trials to test
multiple drugs simultaneously in one large
trial
• Can include multiple arms, flexible design
so that arms can be added or removed
• Multiple arms allow for improved
screening success rate, rather than relying
on one specific mutation
Biomarker 1 Biomarker 3
Biomarker 2
Single Disease Type
Treatment
Arm 1
Treatment
Arm 3
Treatment
Arm 2

38. 38
Master Protocols - Platform
• Commonly Phase II/III
• Multiple interventions can be
evaluated simultaneously
• Extension of adaptive design
trials
– Multiple interventions
– Multiple interim evaluations
– Flexibility of allowing new
experimental arms
Interim Analysis
And
so
on….
Interim Analysis
Patient
Population
Control
Arm
Intervention
2
Intervention
3
Control
Arm
New Arm
Introduced
X
Intervention
3
Arm
Dropped

39. 39
Master Protocols - Platform
Traditional Design Platform Design
Intervention-focused Disease-focused
“Can this intervention offer benefit over current
standard of care or placebo?”
“What is the best intervention option for a given
disease?”
Multi-arm trials require that all therapies must
be available when trial begins – if a new
therapeutic discovery is made, a new trial is
needed
Allows for rolling design – arms can be added
or removed at any time

40. 40
Master Protocols - Implementation
• Due to dependency on biomarkers, basket/umbrella trials most commonly
used in oncology
• Adaptability of platform trials can benefit many therapeutic areas
• Master Protocols already implemented:
Influenza Ebola Pneumonia
Alzheimer’s
Disease

41. 41
Master Protocols - Implementation
Master Protocols and COVID-19
• FDA introduced COVID-19 Master Protocol Guidance in May 2021
• World Health Organization COVID-19 Platform Trial (SOLIDARITY)
currently ongoing, among others
• Faster drug development
• Can adjust with new information

42. 42
Master Protocols – Keys to Success
Clear and consistent goal
Early engagement with regulatory agencies, with frequent communication
Planning and adapting to changing diseases and therapies
Flexible systems, including study databases, simulation, planning tool to ‘model’ potential
protocol amendments
Open mind – stay flexible and proactive
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43. Further Efficiencies in Clinical Development:
Tech-enabled Templates

44. Design for Submission:
MMS Tech-enabled Suite of Templates Provide Increased Efficiencies
Benefits:
• Reusable content automatically shared within and across
protocols, SAPs, and CSRs
• Innovative solution to content creation by leveraging
technology to reduce effort and increase quality
• Efficient and consistent presentation of reusable content
across products, within programs, and across therapeutic areas,
especially when suite of templates are bundled
• Decrease review times, reviewers focus on newly added
content, not wordsmithing
• Reduced QC burden, applicable text within the body of the
document will be duplicated in the synopsis
44
The tech-enabled
templates provide an
innovative solution to
document content
creation.
MMS has utilized technology
to create a suite of templates
(Protocol, SAP, CSR) for
structured authoring.

45. Structured Authoring: Automated Content Reuse
45
Reusable content
populated during
protocol development
can be reused in
downstream documents
and within the
document
Study
Interventions
Protocol SAP CSR
Reused As Is
Editable Reuse
Editable Reuse
Reused As Is
SAP-specific Content
Study
Title/
Schema
Objectives/
Endpoints
Statistical
Methods
Editable reuse
CSR-
specific
Content

46. Modified content tags
increase the content
that can be reused
across documents
Writers experienced
using the tech-enabled
templates (6 years)
Therapeutic area
libraries to align with
industry standards
Templates can be
adapted to align with
client-specific style
preferences
46
The MMS Difference

47. 47
IN CONCLUSION:
Clinical trials may take years for outcomes to develop,
but the design choice is critical for efficient drug
development

48. Thank you!
Any questions?
email
media@mmsholdings.com
visit
www.mmsholdings.com