Download Cohort and Case Control Studies

Clinical Investigation and
Outcomes Research
Clinical Research in
Drug Development
Marcia A. Testa, MPH, PhD
Department of Biostatistics
Harvard School of Public Health
1
Drug Development
• Process of bringing a new drug or device to the market.
It includes drug discovery and product development,
pre-clinical research (microorganisms/animals) and
clinical trials (on humans).
New Chemical Entities
(NCEs), also called New
Molecular Entities
(NMEs), are compounds
which emerge from the
process of drug
discovery.
2
Drug Development
• NCEs/NMEs have promising activity against a particular
biological target thought to be important in disease;
however, at the time of discovery little will be known
about their safety, toxicity, pharmacokinetics and
metabolism in humans.
It is the function of
drug development to
assess all of these
parameters prior to
human clinical trials
during the pre
clinical research
phase.
3
Drug Development
• Many aspects of drug development are
focused on satisfying the regulatory
requirements of drug licensing authorities.
• www.sfda.gov.sa/
– US: Food and Drug Administration (FDA)
• www.fda.gov
– Europe: European Medicines Agency (EMEA)
– Japan: Pharmaceuticals and Medical Devices
Agency (PMDA)
4
Drug Development
• Regulatory Requirements generally
constitute a number of tests designed to
determine the major toxicities of a novel
compound prior to first use in man.
•It is a requirement that an
assessment of major organ toxicity
be performed (effects on the heart
and lungs, brain, kidney, liver and
digestive system), as well as effects
on other parts of the body that might
be affected by the drug (e.g. the skin
if the new drug is to be delivered
through the skin).
5
Drug Development
6
Global Drug Market by Region
7
Leading Drug Therapies
8
Clinical Studies
• Once the preclinical research has been completed, an
Investigational New Drug (IND) application (US), or
equivalent, is made to receive approval for testing in
humans.
• After human testing confirms that the drug is efficacious
and does not have serious adverse effects in at least
1,000 – 3,000 patients, a New Drug Application (NDA – in
US) is filed, reviewed, and a decision for
approval/disapproval for marketing to the public is made.
• There are many opportunities for clinical investigators to
participate at all stages of drug development research,
especially during Phase I – Phase IV Clinical trials.
9
Development Time
• Average time to develop a new drug is 10 – 12 years
• Out of 10,000 – 30,000 potential substances only 1 is
likely to make it to market
Drug Development Research can be broadly
divided into
 Pre-Clinical
 Clinical
10
The IND and NDA
11
Life Cycle of Drug Development
12
Drug Discovery
Typically over 10,000 – 30,000
compounds are screened before finding
one worthy of further preclinical testing
13
Pre-Clinical
14
15
Pre-Clinical Drug Development
• Pre-clinical drug development is a complex,
regulatory-driven process designed primarily
to assess the safety and viability of new
molecular entities.
• Preclinical encompasses toxicology,
pharmacology, metabolism, bioanalysis,
pharmaceutical analysis and biosafety testing
16
Pre-clinical Drug Development
• During preclinical drug development, a
sponsor evaluates the drug’s toxic and
pharmacologic effects through in vitro and in
vivo laboratory animal testing.
• Genotoxicity screening is performed, as well
as investigations on drug absorption and
metabolism, the toxicity of the drug’s
metabolites and the speed with which the
drug and its metabolites are excreted from
the body.
17
Investigational New Drug (IND)
• IND Submission
– Request to the regulatory agency (e.g.,
FDA in US) for permission to begin testing
the product in humans
– Compilation of the following:
• Data obtained during nonclinical investigation
stage and from previous human experience
• Chemistry, manufacturing, and control data
• Protocol
• Detailed description of proposed studies
– Review Period (e.g.,30-day review period by FDA)18
19
Phase I – III Clinical Studies
• Clinical Studies
– Conducted in healthy volunteers or in
patients
– Three Phases (I-III) during this stage of
development and one phase (4) following
marketing approval
– Takes an average of 6 years to complete
the first three stages
20
Phase I Clinical Studies
• The first testing of a new compound in human
subjects
• For the purpose of establishing the tolerance of
healthy human subjects at different doses
• Defining its pharmacological effects at
anticipated therapeutic levels,
• And studying its absorption, distribution,
metabolism, and excretion patterns in humans
21
Phase I Clinical Studies
• Phase I studies also evaluate drug metabolism,
structure-activity relationships, and the
mechanism of action in humans.
• The total number of subjects included in Phase
I studies varies with the drug, but generally
requires a minimum total in the range 20 to
100.
• Final objective of Phase I studies is to have
determined the maximum-tolerated dose with
potential toxicities well-defined
22
Phase I - Multiple Sclerosis
• In human trials, CTLA4Ig was shown to be effective
in improving the signs and symptoms of rheumatoid
arthritis (RA) and has been approved by the US Food
and Drug Administration (FDA) for the treatment of
RA.
• CTLA4Ig was also tested in patients with psoriasis, a
T cell–mediated skin disorder, in a Phase I, open
label, dose-escalation trial showing clinical
improvement that correlated with decreased T-cell
infiltrates and diminished epidermal proliferation.
• It was the tested in individuals with multiple sclerosis
(MS)
23
Phase I - Multiple Sclerosis
• Disease: multiple sclerosis (MS).
• Drug Mechanism: infusions of CTLA4Ig to block the
CD28/B7 T-cell costimulatory pathway.
• Design: Phase I dose-escalation study
– 16 patients with relapsing–remitting MS received a single
CTLA4Ig infusion and were monitored for up to 3 months
after treatment.
– assigned to one of four dose cohorts (2, 10.0, 20.0, or 35.0
mg/kg), each one consisting of 4 subjects.
– Patients were enrolled starting with the lowest dose (2.0
mg/kg) and proceeding to the next dose group after a 1month safety evaluation was completed.
24
Phase I - Multiple Sclerosis
• Results: CTLA4Ig was well tolerated in
patients with MS, and most adverse events
were rated as mild.
• Immunologic assessment of the patients
showed a reduction in myelin basic protein
(MBP) proliferation within 2 months of
infusion and decreased interferon- production
by MBP-specific lines.
• Viglietta V et al. CTLA4Ig treatment in patients with multiple
sclerosis: an open-label, phase 1 clinical trial. Neurology. 2008
Sep 16;71(12):917-24
25
Phase I Clinical Studies
There are
several separate
Phase 1 Studies
conducted to
yield 100 total
patients
Adverse events at different doses
26
Phase II Clinical Studies
• Phase II includes the early controlled clinical studies
conducted to obtain some preliminary data on the
effectiveness of the drug for a particular indication or
indications in patients with the disease or condition.
• This phase of testing also helps determine the
common short-term side effects and risks associated
with the drug.
• Phase II studies are typically well-controlled, closely
monitored, and conducted in a relatively small
number of patients per study with the total number in
the Phase II studies usually involving several
hundred people.
27
Phase II Clinical Studies
• Initial assessment of efficacy (proof-of-concept) and
further assessment of safety
• Involve patients who have the indicated disease or
condition
• Small patient population (100 - 300 in total for all
Phase II studies)
• Usually last 2 years (37% of drugs fail Phase II
testing)
• Final objective of Phase II Studies is to have
rigorously defined the dose regimen of the drug that
elicits the desired therapeutic benefit and that
outweighs the observed clinical risks
28
Phase II Study – Dry Eye
keratoconjunctivitis sicca
• Objective: To explore the safety and efficacy of
CF101, an A3 adenosine receptor agonist, in patients
with moderate to severe dry eye syndrome.
• Design: Phase II, multicenter, randomized, doublemasked, placebo-controlled, parallel-group study.
• Participants: Sixty-eight patients completed the
study, 35 patients in the placebo group and 33
patients in the CF101 group.
• Intervention: Patients were treated orally with either
1 mg CF101 pills or matching vehicle-filled placebo
pills, given twice daily for 12 weeks, followed by a 2week post treatment observation.
29
Phase II Study – Dry Eye
• Primary Outcome Measures:
• Improvement of more than 25% over baseline
at week 12 in one of the following
parameters:
– (1) tear break-up time;
– (2) superficial punctate keratitis assessed by
fluorescein staining results; and
– (3) Schirmer tear test 1 results
• Laboratory tests, ophthalmic examinations,
intraocular pressure measurements,
electrocardiographic evaluations, vital sign
measurements, and adverse events.
30
Phase II Study – Dry Eye
31
Phase II Study – Dry Eye
32
Phase II Study – Dry Eye
• Results: A statistically significant increase in the
proportion of patients who achieved more than 25%
improvement in the corneal staining and in the
clearance of corneal staining was noted between the
CF101- treated group and the placebo group.
• Conclusions: CF101, given orally, induced a
statistically significant improvement in the corneal
staining and an improvement in the BUT and TM in
patients with moderate to severe dry eye syndrome.
The drug was very well tolerated. These data and the
anti-inflammatory characteristic of CF101 support
further study of the drug as a potential treatment for
the signs and symptoms of dry eye syndrome.
33
Phase II Clinical Studies
34
Phase III Clinical Studies
• Phase III studies are expanded controlled and
uncontrolled trials.
• They are performed after preliminary evidence
suggesting effectiveness of the drug has been
obtained in Phase II and are intended to gather the
additional information about effectiveness and safety
that is needed to evaluate the overall benefit-risk
relationship of the drug.
• These are often referred to as “pivotal” – you usually
have to have at least two large “successful” Phase II
studies before receiving drug approval
35
Phase III Clinical Studies
• Large-scale studies aimed at verifying efficacy
establishing safety, and establishing the optimum
dosage
• Involve a larger number of patients (minimum total
studied for all Phase III trials -1,000-3,000). Often, as
many as 6,000 (or more) patients will be studied.
• Usually lasts 3 years (6% fail Phase III testing)
• Objective of Phase III Clinical Studies
– To provide the data sufficient to convince the agency of the
favorable benefit/risk ratio of the drug under investigation
36
Phase III – Renal Carcinoma
• Purpose: Pazopanib is an oral angiogenesis
inhibitor targeting vascular endothelial growth
factor receptor,platelet-derived growth factor
receptor, and c-Kit.
• Design: Randomized, double-blind, placebocontrolled Phase III study evaluated efficacy
and safety of pazopanib monotherapy in
treatment-naive andcytokine-pretreated
patients with advanced renal cell carcinoma
(RCC).
37
Phase III – Renal Carcinoma
• Subjects: Adult patients with measurable,
locally advanced, and/or metastatic RCC
were randomly assigned 2:1 to receive oral
pazopanib or placebo.
• Endpoints:
– primary end point was progression-free survival
(PFS).
– secondary end points included overall survival,
tumor response rate (Response Evaluation
Criteria in Solid Tumors), and safety.
38
Consort (Study Flow) Diagram
39
Survival Results
40
Phase III Clinical Studies
41
New Drug Application (NDA)
• Formal proposal to the regulatory
agency (e.g., Food and Drug
Administration in the US – FDA) to
approve a new drug
• Research evidence provided to agency
– Drug is safe and effective
– Benefits outweigh risk
– Proposed labeling is appropriate
42
Market Launch-Phase IV
Phase IV Clinical Studies Begin
43
Phase IV Clinical Studies
• Also known as Post Marketing
Surveillance Trial
• These are structured clinical trials –
often open labeled, can be randomized
or observational
• Phase IV studies may be required by
regulatory authorities
44
Post Marketing Surveillance
• Also known as Post Marketing
Surveillance Trial
• These are structured clinical trials –
often open labeled, can be randomized
or observational
• Phase IV studies may be required by
regulatory authorities
45
Post Marketing Surveillance
Pharmacovigilance Studies
• Clinical trials are designed to approve
new drug entities and indications.
• Pharmacovigilance is the term used to
describe drug safety surveillance after a
drug is approved.
46
Pharmacovigilance
• “the pharmacological science relating to
the detection, assessment,
understanding and prevention of
adverse effects, particularly long term
and short term side effects of
medicines.”
•
Source: The Importance of Pharmacovigilance, WHO 2002
47
SFDA National
Pharmacovigilence Center
http://www.sfda.gov.sa/En/Drug/Topics/Administrations/PostmarksurvAdmin.htm
• Gathers and evaluates adverse drug
reactions
• Manages tje spontaneous reporting system.
• Performs surveillance of high incidence side
effects.
• Conducts Pharmacoepidemiology studies.
• Provides up to date information to health
professionals regarding safety of
pharmaceutical products.
48
Safety Data Mining Analysis
• Use of computer algorithms to
systematically and objectively analyze
records contained in huge drug safety
databases.
• Goal: to discover hidden interesting
patterns of unexpected adverse drug
occurrences.
49
Safety Data Mining at FDA
• Algorithm: Multi-Item Gamma Poisson
Shrinker (MGPS)
• Database: FDA’s Adverse Event
Reporting System (AERS)
50
Ev e nt Code and Total Re port Count
Clozapine _21939
Se rtraline _16467
Drug and Total Report Count
Insulin_14492
Le v onorge stre l_14236
Ce faclor_13757
Isotre tinoin_13566
Valproate _12842
Intraute rine De v ice _12672
Warfarin_12455
Diatrizoate _12275
Lov astatin_10748
44
28
322
62
42
24
38
19
20
7
31
44
19
10
9
15
9
3
1
1
156
101
71
35
37
27
28
10
31
29
27
9
18
17
8
14
3
1
62
18
12
4
11
11
21
7
9
21
17
4
13
9
13
3
3
3
41
30
20
22
2
5
7
23
4
5
2
1
17
1
50
29
41
13
13
6
14
12
3
4
3
3
4
3
1
222
65
33
56
4
46
13
4
19
15
11
5
8
7
11
6
389
100
80
74
160
28
75
8
31
45
34
55
14
17
11
14
20
19
1
2
91
21
32
28
13
15
15
12
12
4
3
6
6
3
11
5
1
2
1
69
191
1
890
191
Hepatorenal syndrome_846
Cholestasis_1295
Cholecystitis NOS_1371
Hepatic disorder NOS_1824
Hepatic necrosis_1939
Hepatomegaly_2118
Cholelithiasis_2502
Jaundice cholestatic_3401
Hepatocellular damage_3651
Hepatic failure_5052
Hepatic encephalopathy_903
88
Hepatic cirrhosis NOS_1547
116
Hepatic steatosis_2147
161
Blood bilirubin increased_4067
467
Hyperbilirubinaemia_6245
Jaundice NOS_8173
Fluoxe tine _37443
Showing the actual (“observed”) count
AND the RR05 for each drug-event
combination (EB05 >2 are in red
boxes)
Hepatitis NOS_9579
64
32
16
8
4
Hepatic function abnormal_19982
RR05: Value
> 64
> 32 and <=
> 16 and <=
> 8 and <=
> 4 and <=
> 2 and <=
<= 2
RR05: The estimated lower 95% “confidence limit” for the
unadjusted N/E value
Note: you cannot automatically look at the
numbers
or 43
unadjusted
scores
to
determine
53
37
30
32
15
7
23
28
10
6
4
signals!
2
14
3
30
37
49
44
20
18
2
17
39
2
6
51
[email protected] data JUL-2003, page 1 -
Run_96_N1_conc label_____.bin
Spatial Needle In A Haystack RR05-----.dsn
Drug Development Summary
(minimum number subjects)
Phase III
FDA
Approval
3.5
1-2
2-4
4-6
1.5
Total = 12 - 17
Lab
and
Animal
Studies
20 to 100
Healthy
Volunteers
100 – 300
Patient
Volunteers
1,000 to 3,000
Patient
Volunteers
Assess
Safety
and
Biologi
cal
Activity
Determine
Evaluate
Safety and Effectiveness.
Dosage
Look for Side
Effects.
70% of
INDs
30% of INDs
Verify
Effectiveness,
Monitor Adverse
Reactions from
Long-Term Use
27% of INDs
FILE NDA
Phase II
FILE IND
Phase I
% of all
new
drugs
that
pass
Purpose
Test
Population
Years
Pre
Clinical
Testing
Phase IV/Post
Marketing
Safety
Monitoring
Review
Process
Large Scale
Manufacturing
-------------Distribution
-------------Education
20% of
INDs
52
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