Clinical Trial Design Considerations

SMA Type I Clinical Trial Design Considerations
Outcome measure for non ambulant patients
by: Eugenio Mercuri
Catholic University, Rome

Comments on the non ambulant phenotype
o Patients with type II SMA or type III who are not able to walk 10 M independently
o Wide variability
o Standards of care available
o Relatively stable condition within 12-18 months
o No consistent endpoint or life altering event
o Need for defining clinically meaningful changes over time in possible trials

Which outcome measures?
* most measures (timed items, 6 minute walk) not applicable to non ambulant patients with neuromuscular disorders
* muscle strength measurements have been used but are not adequate for very weak children
* Recent studies (after 2005) mainly used functional scales
Why functional scales?
* measures of function more sensitive than strength measurements in weak patients
* More clinically meaningful: patients, families and doctor do have difficulties in identifying generic increase in muscle strength if disjointed from measurements of daily life activity that “mean” something.

* Unlike other measures such as myometry or pulmonary function, functional scales can be reliably used in young children from 30 months

Which functional scales?

* There are a number of functional scales available for non ambulant patients with SMA
* In the last few years TREAT NMD and ICC have promoted a series of workshops in Europe and in the US to find a consensus on outcome measures among all the experts on outcome measures and on trials in SMA

Combined TREAT NMD/ICC
* TREAT NMD consensus further discussed with ICC representatives for outcome measures
* In a recent combined meeting in Boston (June 2008) involving both TREAT NMD and ICC representatives a more general consensus was reached for all three forms of SMA, identifying the Hammersmith Motor Functional scale as the most appropriate and specific scale for type II and more generally, for non ambulant patients

Why the Hammersmith scale?
* Disease specific (developed for and validated in non ambulant SMA children)
* Easy, little equipment,
* Short
* Not stressful for children
* Easily used in routine practice

Evidence from literature: ICC review of the literature
AMBULATORY PROBABILITIES
HAMMERSMITH FUNCTIONAL MOTOR SCALE
UPPER EXTREMITY GRADE
SMA FUNCTION RATING SCALE (SMAFRS)
SCOTT SCALE
JEBSEN TEST OF HAND FUNCTION
STANDARDIZED PROTOCOL
FUNCTIONAL MOTOR SCALE
GROSS MOTOR FUNCTION MEASURE (GMFM)
MOTOR FUNCTION MEASURE SCALE (MFM)
EXPANDED HAMMERSMITH FUNCTIONAL MOTOR SCALE
EK SCALE
Method Studies* (Cross-Sectional)
Natural History (Cross-Sectional)
Natural History (Longitudinal)
Clinical Trials
Outcome Measures
Validation studies available
Validation in
* UK (Main et al, 2003)
* Italy (Mercuri et al, 2007)
* US (PNCR data, PC SMA)
* Excellent interobserver reliability
* Very simple instructions, manual available, ideal for multicentric studies

Widely used across the world
* ICC survey on outcome measures (2008)
* ICC Survey Parameters
* Sent to International SMA Community (ICC and TREAT-NMD lists) in February, 2008
* 35 Sites responded
* 22 Countries were represented
* 858 patient exposures (estimated)
* 27 sites
o Ljubljana, Slovenia
o Ankara, TR
o Messina, IT
o Birmingham, UK
o Oswestry, UK
o Rome, Italy
o Bristol, UK
o Warsaw, Poland
o Freiburg, Germany
o Kharkiv, Ukraine
o Rio de Janeiro, Brazil
o Philadelphia, PA USA
o Boston, MA USA
o New York, NY USA
o Chicago, IL USA
o Salt Lake City, Utah USA
o Philadelphia, PA USA
o Salt Lake City, Utah USA
o Chicago, IL USA
o Sydney, Australia

Natural history data available
* 3 and 6-month data available in 110 non ambulant Italian children age 30 months 12 years
* 6, 12 and 18 month data available in 17 patients (Pediatric Neuromuscular Clinical Research Network (PNCR) .
* Similar data collected by the Project Cure SMA network
* No significant changes between baseline and any of the 6,12, 18 months assessment
* According to these data the diseases is relatively stable over 3, 6, 12 and 18 months periods with minimal changes
* Non ambulant patients generally do not have obvious increases in their scores
* Less than 10% has an increase > 2 points

Already used in trials
* Salbutamol (published)
* Phenylbutyrate (double blind) (published)
* Valproate (just completed)

Is this clinically meaningful?
* Difficult to define what is clinically meaningful
* No clear life altering events that could be predicted
* Relatively stable condition
* Quite wide variability in functional abilities and in possible improvements
What is clinically meaningful for families
* Questionnaire developed by ICC
* 91 families of children with non ambulant SMA
* Families were asked if they were happy to participate to clinical trials and what would be the reason for participating into a trial
* THE CURE!
* Stabilization of the disease over long periods of time
* Any improvement of functional activities

(short term studies)

* While in the long run stabilization would be acceptable by families, in a short trial (1 year) any improvement would be considered beneficial
Primary endpoint: Hammersmith scale
* Evidence from literature
* Validation studies
* Widely used across Europe and US
* Natural history data available
* Already used in trials on non ambulant SMA patients
Secondary measures
* Electrophysiology measure: CMAP
* QOL measure
* Caregiver assessment questionnaire
* Growth parameters
* Pulmonary Function: excellent outcome measure

Reliable, already used in clinical trials but can only be reliably performed in children above the age of 5
* Strength reliable in most patients but can only be reliably performed in children above the age of 5
Summary

Clinical Trial Design Considerations.ppt

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Clinical Trials Design

Clinical Trials Design
By:Martha A. Feldman, RAC
Drug & Device Development Co., Inc.

Purposes of conducting clinical studies
Types of clinical studies
Ethical considerations
Regulatory requirements
Monitoring
Database management issues
Statistical considerations
Reports for submissions or papers

Purposes of Clinical Studies
Further scientific knowledge
Prove concept
Evaluation of product features, capabilities
Obtain initial safety data
Substantiate claim/indication for use
Establish degree of efficacy or effectiveness
Compare with competitor product; marketing evaluation

Types of Clinical Studies
Prospective or retrospective
Blinded/masked or open label
Randomized or not
Active control or placebo
Normal subjects or patients
Actual or surrogate clinical endpoints
Statistically significant or “anecdotal”

Ethical Considerations
Human Subject Review: IRB, Declaration of Helsinki
Informed consent, community consent, waiver of consent
Use of placebos versus positive control
Use of normal subjects
Use of investigational material in addition to standard care
Vulnerable populations

Regulatory Considerations
Drug/Therapeutic Biologic Studies

Overall investigation Plan
Phase 1 - Normal subjects: usually < 50 subjects, at one facility, safety parameters
Phase 2 - Patients: about 50 - 100 subjects; at two sites; may do some dose-range assessment; safety and some initial efficacy
Phase 3 - Patients: few hundred to several thousand; multiple sites; main support study
Phase 4 - Patients (post-marketing): varies


Phase 1 Clinical Study
Normal subjects; occasionally use patients
See if/how pharmacokinetics data from animal studies extrapolates to human data
Document pharmacodynamic effects
Usually open label with ascending doses; establish dose-range
Build safety profile: monitor adverse effects

Phase 2 Clinical Study
Patients or people with clinical condition
Confirm dose range is similar in such people; if not, re-define range
Blinding, randomization, controls used
Strict entry criteria
Initial efficacy determination

Phase 3 Clinical Study
Few hundred to few thousand patients
Multiple sites
Blinding, randomization, controls, prospective
May have slightly broader entry criteria - age, severity of disease,
Continue developing safety and efficacy profiles

Post-marketing Study
Surveillance or study
Numbers to be negotiated
Parameters determined as a result of Phase 3 study
May involve labeling issues

Device Clinical Studies
“It Depends”
Steps in Investigation Plan
Proof of concept/Feasibility: < 5 subjects or patients; one site, safety and some effectiveness
Pilot study: 20-50 subjects; “test drive” protocol, case report forms, initial effectiveness and safety; two sites
Pivotal study: 50 - 500 subjects; multiple sites; main supporting study for claims

Proof of Concept/Feasibility Study
few patients (<5)
limited to one site
usually investigator-sponsored study
goal: prove concept, check instructions for use; early safety and effectiveness assessments


Pilot Study
More rigorous protocol
May be up to 50, but usually around 20 subjects
One or two sites
Company-sponsored study
“Test drive” protocol, comparison of use at two sites, safety and some effectiveness data; finalize training plan
Adjust final protocol for pivotal trial

Pivotal Study
The main study to support the submission
Subject number could be from around 100 to several hundred
Multicenter study; each site should enroll sufficient subjects for separate analyses
Should demonstrate device is independent of inventors


IVD Studies
May be done in two parts: collection of samples (may take > 1 year) and use of IVD (may take < 1month); separate protocols
Collection of samples may involve dozens of sites; testing phase may be at minimum of three sites
Study size may range for 100 (for some monitoring studies) to several thousand (for screening indication)
May enrich samples with stored, known, positive samples: special IRB and consent issues

Monitoring
At least one a year on-site
Between visits: by telephone, e-mail, FAX and courier services

Prestudy Activities
Investigator selection and qualification
Site qualification:
additional staff
sufficient number of subjects
laboratories, pharmacies
special needs
Conduct Pre-study site visit

Prestudy Site Visit
Meet investigator, coordinators, other staff
Review protocol, case report forms
Emphasize consent procedure, requirements
Review adverse event procedures
Review investigator documentation
Review Regulatory Notebook
Visit, as needed, labs, pharmacy, etc.
“Build” study team

Routine, Interim Visit
Review regulatory notebook
Verify consent procedures followed
Ensure study eligibility criteria met
Compare data entries on CRFs and source data
Check investigational product accountability
Check for unreported adverse events
Resolve queries

“For Cause” Visit
Possible reasons
too little/too much enrollment
much greater number adverse events
badly completed case report forms
new coordinator/investigator needing training
results “too good”
Monitor has concerns about investigator or coordinator compliance with regulations

Close-Out Visit
Regulatory Notebook is complete
Supplies accountability checks out
All queries resolved
No unreported, unresolved adverse events
All patient follow-up completed
Investigator’s report done
Files prepared for FDA inspections and for storage

Database Management Issues
Programming for the case report entries
Developing a data entry plan; data entry verification plan
Generating queries for the monitors to have coordinators resolve
Entering amended data; database clean-up
Data editing plan
Closing database; data validation plan; send to statistician
Developing tables for the reports, submissions, etc.

Statistical Considerations
Developing hypotheses
Calculating sample size requirements
Developing plan for interim analysis, if needed, and for final analysis (including sub-analyses)
Determining how interim analysis results impact sample size
Perform analysis and data evaluation
Write statistical report

Sponsor Reports - Submissions
Adverse event reports
Use of investigational product without consent
IRB withdrawal of approval
Annual reports
Updating submissions with each advance in the investigational plan (e.g., study completion or termination)

Investigator Reports
Withdrawal of IRB approval
Use of product without consent
Adverse events - to sponsor and IRB
Study status reports; study close-out report
For device studies: malfunction, repair or replacement

Other Reports
Publications, posters, presentations
can review manuscript for proprietary information
cannot stop the publication of negative results
off-label use: company may not promote it, but can distribute articles written by health care practitioners
References

Code of Federal Regulations, Title 21
Part 50 - Informed Consent
Part 56 Institutional Review Boards
Part 312 - Investigational New Drug, antibiotic, Biotechnology-Derived Product regulations
Part 812 - Investigational New Device regulations
FDA Guidance Document on Good Clinical Practices, January 1988
ICH Guidance Document E6 - Good Clinical Practices
More References

Clinical Trials Design.ppt

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Increasing Complexity of Clinical Trials

Increasing Complexity of Clinical Trials

Definitions:
Procedures: include lab & blood work, routine exams, x-rays & imaging, questionnaire & subjective assessments, invasive procedures, heart assessment, etc.

Protocol: the clinical-trial design plan
Enrollment rate: the percentage of volunteers meeting the increasing number of protocol eligibility criteria (percentage screened who were then enrolled)

Retention rates: the percentage of volunteers enrolled who then completed the study; declining retention rates mean that firms must enroll more patients initially and/or recruit more patients during the trial.

Increasing Complexity of Clinical Trials
During the last decade clinical trial designs and procedures have become much more complex, demanding more staff time and effort, and discouraging patient-enrollment and retention

Unique Procedures per Trial Protocol (Median)
Total Procedures per Trial Protocol (Median)
Clinical-Trial Staff Work Burden (Measured in Work-effort Units)
Length of Clinical Trial (Days)
Clinical-Trial-Participant Enrollment Rate
Clinical-Trial-Participant Retention Rate

Increasing Complexity of Clinical Trials.ppt

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