Cancer Clinical Trials: The Basics

Cancer Clinical Trials: The Basics

What Are Cancer Clinical Trials?

* Research studies involving people
* Try to answer scientific questions and find better ways to prevent, diagnose, or treat cancer

Why Are Cancer Clinical Trials Important?

* Cancer affects all of us
* Each year in the U.S.A:
o More than half a million people are expected to die of cancer — more than 1,500 people a day
o 1 of 4 deaths is from cancer
o More than 1 million new cancer cases are expected to be diagnosed

Why Are Cancer Clinical Trials Important?
* Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat cancer

* The more people that take part, the faster we can:
o Answer critical research questions
o Find better treatments and ways to prevent cancer

Do Many People Participate in Cancer Clinical Trials?
* Only 3 percent of U.S. adults with cancer participate in clinical trials

Types of Cancer Clinical Trials
* Treatment trials
* Prevention trials
* Early-detection trials/screening trials
* Diagnostic trials
* Quality-of-life studies/supportive care studies

Clinical Trial Phases
Phase 1 trials
* How does the agent affect the human body?
* What dosage is safe?

Phase 2 trials
* Does the agent or intervention have an effect on the cancer?

Phase 3 trials
* Is the new agent or intervention (or new use of a treatment) better than the standard?
* Participants have an equal chance to be assigned to one of two or more groups

Randomized Trials
Participants have an equal chance to be assigned to one of two or more groups:
o One gets the most widely accepted treatment (standard treatment)
o The other gets the new treatment being tested, which researchers hope and have reason to believe will be better than standard treatment

Randomization
Why Is Randomization Important?
* So all groups are as alike as possible
* Provides the best way to prove the effectiveness of a new agent or intervention

Cancer Treatment Trials
* What new treatments can help people who have cancer?
* What is the most effective treatment for people who have cancer?
Placebos are almost never used:
* Placebos are used only when no standard treatment exists
* Patients are told of this possibility before deciding to take part

Cancer Prevention Trials
* Evaluate the effectiveness of ways to reduce the risk of cancer
* Enroll healthy people at high risk for developing cancer

Cancer Prevention Trials
* Action studies
* Agent studies
(“taking something”)—also called “chemoprevention studies”

Chemoprevention Trials
* Phase 3 chemoprevention trials compare a promising new agent with either a:
o Standard agent
o Placebo

Clinical Trial Protocol
* A recipe or blueprint
* Strict scientific guidelines:
o Purpose of study
o How many people will participate
o Who is eligible to participate
o How the study will be carried out
o What information will be gathered about participants
o Endpoints

Benefits of Participation
Possible benefits:
o Patients will receive, at a minimum, the best standard treatment
o If the new treatment or intervention is proven to work, patients may be among the first to benefit
o Patients have a chance to help others and improve cancer care
Risks of Participation
Possible risks:
o New treatments or interventions under study are not always better than, or even as good as, standard care
o Even if a new treatment has benefits, it may not work for every patient
o Health insurance and managed care providers do not always cover clinical trials

Patient Protection
* There have, unfortunately,
been past abuses in patient
protection
* Federal regulations ensure
that people are told about the benefits, risks, and purpose of research before they agree to participate

How Are Patients’ Rights Protected?
* Informed consent
* Scientific review
* Institutional review boards (IRBs)
* Data safety and monitoring boards

Informed consent:
* Purpose
* Procedures
* Risks and potential benefits
* Individual rights
* Scientific review
* Institutional review boards (IRBs) are required by Federal law for trials that are:
o Federally funded
o Subject to FDA regulation

Data and safety monitoring boards:
* Ensure that risks are minimized
* Ensure data integrity
* Stop a trial if safety concerns arise or objectives have been met

Sometimes patients:
* Don’t know about clinical trials
* Don’t have access to trials
* May be afraid or suspicious of research
* Can’t afford to participate
* May not want to go against physician’s wishes

Why Do So Few Cancer Patients Participate in Clinical Trials?
Doctors might:
* Lack awareness of appropriate clinical trials
* Be unwilling to “lose control” of a person’s care
* Believe that standard therapy is best
* Be concerned that clinical trials add administrative burdens

NCI Information Resources

Cancer Clinical Trials: The Basics.ppt

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The Randomized Controlled Trial

The Randomized Controlled Trial
By: Rakhi Naik, MD

Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C

STUDY OUTLINE
* Hypothesis: Eltrombopag can increase platelet counts in patient with hepatitis C cirrhosis.
* Design: Randomized controlled trial
* Setting: Multicenter trial in US & Europe
* Participants: 74 patients w/Hepatitis C cirrhosis
* Data Collection: Measurement of platelet counts before and after eltrombopag administration for 4 weeks; measurement of platelet counts after standard hepatitis C treatment with peg-interferon/ribavirin
* Outcome: Platelet counts, safety

BACKGROUND
* Chronic liver disease secondary to hepatitis C cirrhosis is often associated with significant thrombocytopenia.
* Thrombocytopenia in chronic hepatitis C infection is multifactorial in origin & is thought to be caused by:
o splenic sequestration (2/2 portal hypertension/hypersplenism)
o decreased thrombopoetin production (2/2 impaired hepatic synthetic function)
o bone marrow suppression (2/2 direct toxic effect of the hepatitis virus itself).

* Platelet counts below 75,000 are often not eligible for treatment with pegylated interferon & ribavirin because treatment itself leads to cytopenias in almost 100% of cases.

BACKGROUND
* Eltrombopag is an oral thrombopoetin receptor agonist that increases megakaryocyte proliferation and differentiation in animal models.

* Research questions:
o Can eltrombopag increase platelet levels in patients with untreated chronic hepatitis C cirrhosis?
o Can continued use of eltrombopag during hepatitis C treatment reduce treatment-related thrombocytopenia?
o What dose of eltrombopag is most effective for achieving these goals?

METHODS

* 22 centers in the United States & Europe were involved in recruitment.
* Inclusion criteria:
o 18 years of age or older
o Presence of serum HCV antibody levels
o Detectable serum HCV RNA levels
o Compensated liver disease (which is not defined explicitly)
o Thrombocytopenia with platelet levels between 20,000-70,000.
o Evidence of cirrhosis defined as: liver biopsy c/w cirrhosis, radiographic evidence of cirrhosis, or endoscopic evidence of varices

* Exclusion criteria:
o Pregnancy
o History of thrombosis
o HIV co-infection
o Hepatitis B co-infection

METHODS
Patients randomly assigned to placebo or eltrombopag (30mg, 50mg, 75mg daily) x 4 weeks
Any patient with plt count >70k or >100k was eligible for treatment with peg-interferon α-2a or peg-interferon α-2b, respectively. The decision to treat was left to the physician & patient.
Patients continued with their previous dose of eltrombopag during treatment.
Study designed by GlaxoSmithKline & academic principal investigator.
Daily eltrombopag doses were held if platelet count rose >200,000 and would be resumed when counts dropped to around 100,000

RESULTS
Approximate bilirubin (converted) 1.5+/- 1mg/dL. INR and creatinine not reported.
5 of total 74 patient listed here were excluded for baseline plt counts >75k but were ultimately eligible for the treatment phase.
Uneven number of patients in each arm because this was a mulicenter trial & not all sites contributed to all 4 arms.

RESULTS
Only 18 patients completed treatment. Only 1 placebo patient completed tx even though 7 were eligible.
Median platelet values prior to inferon treatment and % responders had significant p values compared to placebo

RESULTS
Pre-treatment platelet values, especially in the 50mg and 75mg eltrombopag arms, were statistically significant.
Platelet levels decreased with hep C treatment in all arms. P values for the eltrombopag groups vs. placebo were not statistically significant.
More patients in the eltrombopag arms completed treatment.

CONCLUSIONS/ IMPLICATIONS
* Eltrombopag increases platelet counts in a dose-dependent manner in patients with untreated chronic hepatitis C cirrhosis.
* Eltrombopag can be used to boost platelet counts in patients being considered for peg-interferon & ribavirin treatment.

STRENGTHS
* Clinical relevance: Thrombocytopenia is a very common complication of hepatitis C infection and ineligibility for treatment is a significant public health concern.
* Efficacy: Eltrombopag is extremely effective in increasing pre-interferon platelet counts (i.e. the study was able to demonstrate efficacy even though the sample size was low).
* Ease of use: Eltrombopag can be taken orally and has an easy daily dosing schedule.
* Safety: Eltrombopag has minimal side effects, which do not seem to be dose-dependent, and are not associated with significant morbidity.

WEAKNESSES
* Small sample size, especially in interferon treatment group (underpowered)
* Failed to standardize the protocol for initiation and cessation of interferon treatment phase.

* Lack of generalizability
o The investigators may have referred only patients with cirrhosis without portal hypertension to the study in order to select for a group who was more likely to benefit from treatment.
o Similarly, HCV viral loads were not taken into account.
* ? Clinical utility
o Could not ultimately answer question of whether pre-treatment with eltrombopag resulted in successful clearance of hepatitis C with treatment (i.e. whether the fact that more patients can receive interferon treatment actually leads to more patients who benefit from treatment).

The Randomized Controlled Trial.ppt

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Clinical outcome Measures, Trials

Clinical outcome Measures, Trials
By:Professor and Acting Chair of Neurology
Director, MS Comprehensive Care Center
SUNY at Stony Brook, New York


MS: Diagnostic Issues
* Diagnostic principles
* Misdiagnosis clues
* Differential diagnosis
* Case presentations

Diagnosis Of MS
Diagnosis Based On Schumacher Criteria
* Appropriate age (10-50 years)
* CNS white matter disease
* Lesions disseminated in time and space
* Objective abnormalities
* Consistent time course
* No better explanation
* Diagnosis by a competent clinician
(preferably neurologist)

MRI Dissemination In Space
MRI Dissemination In Time
Diagnostic Criteria
Diagnostic Criteria For Primary Progressive MS
Diagnosis Of MS: MRI
MRI Features Suggestive of MS
Diagnosis Of MS: CSF
Diagnosis Of MS: Blood And Ancillary Tests
Diagnosis Of MS: Evoked Potentials
Misdiagnosis of MS
* Clinical
* Neuroimaging
* Cerebrospinal fluid (CSF)

Clinical Clues
* Normal examination
* No dissemination over time and
space
* Onset before age 10 or after age 55
* Genetic "red flag”
+ positive family history
+ early age onset
+ unexplained non CNS disease
* Progressive course starting before age 35
* Localized disease
* Atypical features
+ prominent fever
+ prominent headache
+ abrupt hemiparesis
+ abrupt hearing loss
+ prominent pain (except trigeminal
neuralgia)
+ no optic nerve or ocular motility
disturbance
+ normal sensory and bladder function
+ progressive myelopathy without
bladder /bowel involvement
+ impaired level of consciousness
+ prominent uveitis
+ peripheral neuropathy
+ nonscotomatous field defects
+ gray matter features (prominent
early dementia, seizures, aphasia,
fasciculations, extrapyramidal
features)

Neuroimaging Clues
Brain
* Normal brain MRI
* Small lesions (< 3mm)
* Subcortical lesions (internal
capsule)
* Predominant infratentorial
involvement
* Prominent GM involvement (basal
ganglia)
Neuroimaging Clues
Brain
* Symmetric, confluent hemispheric
WM involvement
* Significant mass effect
* Hydrocephalus
* Severe cerebellar/ brainstem atrophy
* Absence of callosal or periventricular
lesions

Neuroimaging Clues
Spinal cord
* Lesion > 2 vertebral segments
* Severe swelling
* Full thickness lesions
CSF Clues
* Normal CSF
* Disappearance of oligoclonal bands;
normalization of intrathecal IgG production
* Cell count > 50 WBC /mm3
* Protein > 100 mg/dl

Differential Diagnosis of MS
* Genetic
* Infectious
* Inflammatory
* Metabolic
* Miscellaneous
* Neoplastic
* Psychiatric
* Structural
* Toxic
* Vascular
* Variants

Acute Leukoencephalopathy
Feature Disorders
Cranial neuropathies - Lyme disease, Sarcoidosis
Cortical blindness - multiple infarcts, PML,
Hearing loss - Cogan’s, Susac
Intracranial - hemorrhagic infarction, tumor,
hemorrhage venous infarction
Acute Leukoencephalopathy
Feature Disorders
Lockedin syndrome - CPM, infarction
Migraine - antiphospholipid syndrome,CADASIL, mitochondrial encephalopathy
Muscular rigidity - paraneoplastic brainstem encephalitis
Myoclonus - antiamphiphysin paraneoplastic syndrome, hashimoto’s
Papilledema - Gliomatosis, venous sinus thrombosis
Differential Diagnosis:
Variants
* Balo's concentric sclerosis
* Disseminated subpial demyelination
* Neuromyelitis optica (Devic's disease)
* Marburg variant
* Tumefactive MS
* Myelinoclastic diffuse sclerosis
(Schilder disease)
* Postinfectious encephalomyelitis
* Clinically isolated syndromes

CIS Issues
CIS Controversies
* What features define first attack MS
* What features predict subsequent course
* Who should be offered MS DMT

CIS Considerations
* Appropriate age
o excludes too young and too old
* Characteristic syndrome
* Other causes excluded
* Abnormal brain MRI
o with suggestive features
MS CIS Syndromes
* typically unilateral
* retrobulbar
* typically painful
* some recovery expected
* no retinal exudates or

Optic neuritis
MS CIS Syndromes
Myelitis
MS CIS Syndromes
MRI Dissemination in Space*
MRI Dissemination In Time
Diagnostic Criteria
CIS and MRI Predictors*
Role Of MRI In Suspected MS*
MS Differential Diagnosis
* Migraine
* Sarcoid
* Sjögren syndrome
* Stroke and ischemic
* Unidentified bright objects on MRI
* Vascular malformations
* Vasculitis (primary CNS or other)
* Vitamin deficiency (B12, E)
* Number and volume of brain MRI
CIS and Therapy
CIS: Conclusions
Cognitive Impairment In Minimal Disability MS*
Diagnostic Criteria For Primary Progressive MS
Neuromyelitis Optica (NMO)
NMO Differential
NMO: Clinical Features
Recent Pediatric Series ..........

Clinical outcome Measures, Trials.ppt

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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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Clinical Protocol Development

CLINICAL PROTOCOL DEVELOPMENT

What’s The Question?
What is the study hypothesis?

What’s The Question?
* What’s the outcome?
* What’s the intervention?
* When and for how long?
* For whom?
* How many participants are needed?
* How can we optimize potential benefit (and what we learn) while minimizing potential harm?

Answering the Question
* Response variable selection and measurement
* Defining the intervention
* Study design
* Eligibility criteria
* Sample size estimate
* Patient management procedures
* Monitoring for safety and benefit
* Data analysis approaches
Response Variable Selection
* “Dose ranging”
* Biologic activity
* Biomarker
o Understand mechanism
o Surrogate outcome
* Toxicity
* Condition/vector/gene interaction
* Feasibility for larger study
* Clinical outcome

Response Variable Criteria
* Well defined
* Stable
* Reproducible
* Unbiased
* Ascertainable in all participants
* Adequately address study hypothesis

Defining the Intervention
* Dose/dosing schedule
* Vector
* Route of delivery
* Method of preparation

Study Design
* Uncontrolled
* Controlled
o Before/after
o Historical
o Concurrent, not randomized
o Randomized

Comparing Treatments
* Fundamental principle
o Groups must be alike in all important aspects and only differ in the intervention each group receives
o In practical terms, “comparable treatment groups” means
“alike on the average”
* Randomization
o Each participant has the same chance of receiving any of the
interventions under study
o Allocation is carried out using a chance mechanism so that neither the participant nor the investigator will know in advance which will be assigned
* Blinding
o Avoidance of conscious or subconscious influence
o Fair evaluation of outcomes

Non-randomized Trials May Be Appropriate
* Early studies of new and untried therapies
* Uncontrolled early phase studies where the standard is relatively ineffective
* Investigations which cannot be done within the current climate of controversy (no “clinical equipoise”)
* Truly dramatic response

Advantages of Randomized Control Clinical Trial
1. Randomization "tends" to produce comparable groups
2. Randomization produces valid statistical tests

Disadvantages of Randomized Control Clinical Trial

1. Generalizable Results?
o Participants studied may not represent general study population.
2. Recruitment
o Hard
3. Acceptability of Randomization Process
o Some physicians will refuse
o Some participants will refuse
4. Administrative Complexity
Study Population
Subset of the general population determined by the eligibility criteria
General population
Eligibility criteria
Enrollment
Study sample
Eligibility Criteria
* State in advance
* Consider
o Potential for effect of intervention
o Ability to detect that effect
o Safety
o Ability for true informed consent

Sample Size (1)
* The study is an experiment in people
* Need enough participants to answer the question
* Should not enroll more than needed to answer the question
* Sample size is an estimate, using guidelines and assumptions

Sample Size (2)
* Approaches for early phase studies
o Dose escalation schemes
o Decision that intervention is unlikely to be effective in ?x% of participants
o Decision that intervention could be effective in ?x% of participants
* Standard ways of estimating for phase III
Sample Size (3)
* Assumptions depend on
o Nature of condition
o Desired precision of answer
o Availability of alternative treatments
o Knowledge of intervention being studied
o Availability of participants

Regular Follow-up
* Routine Procedures (report forms)
o Interviews
o Examinations
o Laboratory Tests
* Adverse Event Detection/Reporting
* Quality Assurance
Contingency Plans
* Patient management
* Evaluation and reporting to all relevant persons and groups
* Data monitoring plans
* Protocol amendment or study termination
Data Analysis (1)
* Occurrence of event
* Time to event
* Mean level of response
* Duration of response
Data Analysis (2)
* Intention-to-treat
* Explanatory
* Subgroups
* Adjusted vs. Unadjusted

Data Analysis (3)
* Specify in advance
o Primary
o Secondary
o Other
o Statistical approach
* Exploratory

Clinical Protocol (1)
* Background/Justification
--Where we are in the field
--What the study will add that is important
* Objectives
--Primary hypothesis
--Secondary hypotheses
--Other
Clinical Protocol (2)
* Study Design and Methods
--Type of study, comparison
--Inclusion and exclusion criteria
--Description of intervention (what, how)
--Concomitant therapy
--Examination procedures (baseline, follow-up, outcome assessment)
--Intervention assignment procedure

Clinical Protocol (3)
* Monitoring and Management
--Data and safety monitoring
--Adverse event assessment, reporting
--Contingency procedures
--Withdrawal criteria

Clinical Protocol (4)
* Statistics
--Sample size
--Stopping guidelines
--Analysis plans
* Participant protection issues
Summary
* Protocol lays out who, what, why, when, where, how
* Safeguards participants
* Safeguards study integrity
* Midcourse changes are often appropriate (even necessary)

Clinical Protocol Development.ppt

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Introduction to Clinical Trials

Introduction to Clinical Trials

Issues in Analysis of Randomized Clinical Trials
Sources of Bias
1. Patient selection
2. Treatment assignment
3. Patient Evaluation
4. Data Analysis

Minimize Bias
1. Randomized Controls
2. Double blind (masked)
3. Analyze what is randomized

What Data Should Be Analyzed?
* Basic Intention-to-Treat (ITT) Procedure
o Analyze what is randomized!
* Randomized control trial “gold” standard
o Beware of lookalikes
* Definitions
Exclusions
o Screened but not randomized
o Affects generalizability
o Validity OK
Withdrawals from Analysis
o Randomized, but not included in data analysis
o Possible to introduce bias!

Patient Closeout
* ICH E9 Glossary
o “Intention-to-treat principle - …It has the consequence that subjects allocated to a treatment group should be followed up, assessed, and analyzed as members of that group irrespective of their compliance with the planned course of treatment.”

Patient Withdrawn in Analysis
* Common Practice - 1980s
o Over 3 years, 37/109 trials in New England Journal of Medicine

* Typical Reasons Given
a. Patient ineligible (in retrospect)
b. Noncompliance
c. Competing events
d. Missing data

I. Patient Withdrawn in Analysis
A. Patient INELIGIBLE
o After randomization, discover some patients did not in fact meet entry criteria
o Concern ineligible patients may dilute treatment effect
o Temptation to withdraw ineligibles
o Withdrawl of ineligible patients, post hoc, may introduce bias

Betablocker Heart Attack Trial
* 3837 post MI patients randomized
* 341 patients found by Central Review to be ineligible
* Results

Anturane Reinfarction Trial (1980) NEJM
* Randomized, double blind, placebo controlled
Anturane Reinfarction Trial (1980)
* 1629 patients randomized
o 1631 entered, but two patients randomized twice
o Need to delete 03013, 17008
o Use first randomization!

* Declared post hoc 71 “ineligible” patients

Analyzable Deaths - Within 7 days of being off drug

1980 Anturane Mortality Results
Total Mortality
Anturane Reinfarction Trial (1980)
Total Mortality
Anturane Sudden Death (SD)
for Total Follow-up
Anturane Analysis
Acceptable Policies For Ineligible Subjects

1. Delay randomization, confirm eligibility and allow no withdrawals (e.g. AMIS) (Chronic Studies)
2. Accept ineligibles, allow no withdrawals
(e.g. BHAT, MILIS) (Acute Studies)
3. Allow withdrawals if:
a. Procedures defined in advance
b. Decision made early (before event)
c. Decision independent and blinded
d. Use baseline covariates only (two subgroups)
e. Analysis done with and without

B. WITHDRAWL FOR NON-COMPLIANCE
References: Sackett & Gent (1979) NEJM, p. 1410

Coronary Drug Project (1980) NEJM, p. 1038
* Two Types of Trials
1. Management
- "Intent to Treat" Principle
- Compare all subjects, regardless of compliance

2. Explanatory
- Estimate optimum effect, understand mechanism
- Analyze subjects who fully comply
WITHDRAWALS FOR NON-COMPLIANCE MAY LEAD TO BIAS!

Breast Cancer Adjuvant Therapy Probability of Disease Free Survival for Years Post Mastectomy (Method I)
Breast Cancer Adjuvant Therapy
Probability of Disease Free Survival for
Years Post Mastectomy (Method II)
Redmond et al (1983) Cancer Treatment Report
Example: Coronary Drug Project 5-Year Mortality
Comments

* Higher % of estrogens patients did not comply
* Beneficial to be randomized to estrogen & not take it
* (6.1% vs. 9.9%)
* Best to be randomized to placebo & comply (4.8%)
Aspirin Myocardial Infarction Study (AMIS)
Summary of Compliance
* No consistent pattern
Example Non-compliance Did Worse
CDP Clofibrate, AMIS Both Treatment & Control
CDP Estrogen Control Only
Beta-blocker, Wilcox Two Treatments, Not Control
* Compliance an outcome, not always independent of treatment
* Withdrawal of non-compliers can lead to bias
* Non-compliers dilute treatment
* Try hard not to randomize non-compliers

II. Competing Events
* Subject may be censored from primary event by some other event (e.g. cancer vs. heart disease)
* Must assume independence
* If cause specific mortality used, should also look at total death
* If non-fatal event is primary, should also look at total death and non-fatal event
* Problem for some response measures

Problem of Definitions
Classification Anturane Placebo P-value
Anturane Reinfarction Trial Sudden Death
Category Source Placebo Anturane P-value

III. "Wrong", Inconsistent, Outlying Data
* "Wrong" or "outlying" data may in fact be real
* Decisions must be made blind of group assignment
* All modifications or withdrawals must be documented
IV. Missing Outcome Data
* Design with zero
o missingness may be associated with treatment
+ for analysis, data are not missing at random
+ even if same number missing, missing may be for different reason in each treatment group
* Implement with minimum possible
* Analyze exploring different approaches
o if all, or most, agree, then more persuasive

“Best” and “Worst” Case Analyses
VI. Poor Clinic Performance in a Multicenter Study

* If randomization was stratified by clinic, then withdrawal of a clinic is theoretically valid
* Withdrawal must be done independent of the outcome at that clinic
VIII. Fishing or Dichotomizing Outcomes
* Common practice to define a response (S,F) from a non-dichotomous variable
* By changing our definition, we can alter results
* Thus, definitions stated in advance
* Definitions should be based on external data

Dichotomizing Outcomes
Example
IX. Time Dependent Covariate Adjustment
* Classic covariate adjustment uses baseline prognostic factors only
o Adjust for Imbalance
o Gain Efficiency

* Adjustment by time dependent variates not recommended in clinical trials (despite Cox time dependent regression model)

* Habit from epidemiology studies
Intent To Treat (ITT) Principle

* Analyze all patients randomized, regardless of compliance to assigned intervention
* Analyze all events in the follow-up, regardless of compliance


Introduction to Clinical Trials.ppt

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