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Dapagliflozin FARXIGA®
FDA DOSSIER
MASTER AREIPS – MARCH 2016
G. BARRE ; A. CAILLE ; M. CAPPADORO ; O. CHANU ; S. DANIEL ; P. DESBORDES ;
L. DIRSON ; C. GANDOIN ; E. GIL ; A. KAIKMAXOGLOU ; H. MHAOUCH ;
M. PERNELLE ; L. PERRIAT ; C. PICARD ; M. PLEURMEAU ; S. STIRN
Content
Introduction
Name review
Pharmacology
CMC
Non clinical trials
Clinical trials
Post-marketing
Conclusion
2
Introduction
3
Physiopathology of T2DM
4
Statistics on diabetes type 2
29.1 million people or 9.3% of the U.S. population
have diabetes:
-Diagnosed =21.0 million people
-UnDiagnosed =8.1 million people
Cost of diabetes :
-Direct medical costs : $174 billion
-Indirect medical costs (disability, wor loss,
premature mortality ): $58 billion
5
Diabetes itself is a cardiovascular risk
6
Current therapies
LIMITATIONS
Hypoglycemia
Weight gain
GI side effects
Injected
No long-acting
7
Glycemic goal for T2DM
ADA
IDF
AACE/ACE
HbA1c (%)
< 7,0
< 6,5
< 6,5
FPG (mg/dl)
< 130
< 110
< 110
2 Hr PG (mg/dl)
< 180
< 140
< 140
8
Unmet medical needs
62% of patients on oral therapy are not at ADA goal of HbA1c < 7%
9
SO WE NEED
A NEW THERAPEUTIC OPTION!
10
Dapagliflozin
MECHANISM OF ACTION (MOA)
TARGETED ORGANS
11
Phlorizin
Derived from apple tree bark (first isolated in 1835)
Antidiabetic effect discovered (1987)
But…
◦ Very poor oral bioavailability
◦ Non-selective inhibitor of both SGLT-1 and SGLT-2
◦ Serious adverse events (diarrhea, dehydration)
 C-glucoside discovered = Dapagliflozin
• Indications
• Type 2 diabetes in adults
• As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
12
A novel insulin-independent approach to
remove excess glucose
SGLT2 inhibitors
Inhibition of
SGLT2 at PCT
Prevention of
reabsorption of
glucose
Excretion of
glucose in urine
(glycosuria)
Reduction of
blood glucose
level
13
SGLT2
Sodium-Glucose Linked Transporter 2 = Sodium-dependent
glucose co-transporters
Two kinds of SGLTs
◦ SGLT1
◦ SGLT2
SGLT2 inhibitors
SGLT2
inhibitors
Glycosuria
Glycosuria
Net calorie loss of
approximately
200-300
kilocalories per day
Glucose acts
as osmotic
diuretic
Dehydratation
Weight loss
Blood
pressure
reduction
14
Targeted organs
15
Targeted organs
Hypotension
Genital mycotic infections
Hypoglycemia
Ketoacidosis
16
But what about the history?
17
First review cycle
To be submitted : additional data from studies 18 & 19 ; updated analyses
for CV safety, malignancy and hepatic safety
July 2012 :
Applicant files a
formal dispute
resolution
request (FDRR)
Nov 2011 :
major
amendment is
submitted
Dec 2010 : NDA
submitted
July 2011 :
EMDAC vote
2008 : new
guidance
+ rosiglitazone
(2010) : CV risk
Jan 2012 : FDA
issues a
complete
response letter
Sept 2012 :
dispute appeal is
denied
Emdac voted not to support approval of dapa based on current data
Do the efficacy
andthe
safety
providecancers
substantial
evidence to support approval to
 more data are needed
regarding
risksdata
of bladder
and liver
improve glycemic control
injury
6 Yes
9 No
18
First review cycle
July 2012 :
Applicant files a
formal dispute
resolution
request (FDRR)
Nov 2011 :
major
amendment is
submitted
Dec 2010 :
application
submitted
July 2011 : dapa
application
presente to
EMDAC
Jan 2012 : FDA
issues a
complete
response letter
Sept 2012 :
dispute appeal is
denied
Discordance between CV safety data from initial studies vs 18-19 studies
K bladder and hepatic toxicity
Path forward : additional clinical trial data + analysis on K events ; hepatic
safety and CV meta-analysis
19
Second review cycle
Jan 2014 :
July 2013 : NDA resubmission
APPROVAL
Dec 2013 : FDA Advisory
Committee recommends the
investigational SGLT2 inhibitor
dapa for treatment of type 2
diabetes in adults
Are data sufficient to prove an acceptable CV risk profile ?
10 Yes ; 4 No
Does the benefits of dapa outweigh the identified risks (K bladder ; infection ; CV
event) to control glycemic in DBT2
13 Yes ; 1 No
Consensus : post-marketing studies
20
Name review
21
Name Approval Players
Office of
Prescription Drug
Promotion
CDER
Division of
Medication Error
Prevention and
Analysis (DMEPA)
1. Promotional
Assessment
2. Safety Assessment
Evaluate the proposed proprietary name (PPN) from a safety and promotional perspective
22
Name Review
• Submission of the PPN (Proposed Proprietary Name) : FORXIGA®
Sept 2011
• ACCEPTANCE OF FORXIGA® by OPDP and DMEPA
Dec 2011
• Resubmission of PPN
July 2013
• Re-review of PPN by FDA  « fo » is reserved for phosphoro-derivatives  not acceptable
• Proposition of FARXIGA® by the DMEPA
August 2013 • review by OPDP for promotional assessment  ACCEPTANCE
FARXIGA®
23
Pharmacology
P HA R MACOKI NETICS
P HA R MACODYNAM ICS
I N T RINSIC/ EXTRINSIC FAC TORS
24
Pharmacokinetics
Absorption
◦ Tmax : 1 hour (PO, 10 mg)
◦ F% : 77,8
Distribution
◦ Protein Binding : 91%  High fixation
Metabolism
◦ Primary metabolite in human = dapagliflozin 3-O-glucuronide
◦ UGT1A9 is the major enzyme
◦ T1/2 : 12,9 hour
Excretion
◦ 96% of the administered dose recovered in the urine (75%) and feces (21%)
◦ In urine  61% of primary metabolite
◦ 1,2% of dose as parent drug
Dose-proportionality
25
Pharmacodynamics
Healthy subjects
◦ Wide dose range (2,5 mg to 500 mg) in single dose (120 h)
◦ Wide dose range (2,5 mg to 100 mg) in multiple dose (14 days)
T2DM
◦ 25 mg or 100 mg for Day 1 and Day 14
T2DM = Type 2
Diabetes Mellitus
Dose-response relationship for effectiveness supports the proposed dose of 10 mg QD
For doses > 10 mg, increased incidence of genitourinary infection, hyperphosphatemia and
increases in haematocrit
26
Intrinsic factors
Renal impairment
◦
◦
◦
◦
◦
Healthy subjects with normal renal function
Subjects with T2DM and normal renal function
Subjects with T2DM and mild renal impairment
Subjects with T2DM and moderate renal impairment
Subjects with T2DM and severe renal impairment
27
Intrinsic factors
• Hepatic impairment
• Age
• Weight
• Gender
• Race/Ethnicity
• Paediatric patients
No dose adjustment based on intrinsic factors
28
Extrinsic factors
Co-administered drugs
Diet
◦ In presence of high fat meal  no change in AUC
Not evaluated :
◦ Herbal products
◦ Smoking
◦ Alcohol use
No dose adjustment based on extrinsic factors
29
Chemistry, Manufacturing & Control
CMC
30
Active Pharmaceutical Ingredient (API)
Dapagliflozin propanediol monohydrate
Formule
C21H25ClO6 . C3H8O2 . H2O
Chemical name
(2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,(2S)propane-1,2-diol (1:1) monohydrate
Molecular weight
Dapagliflozin propanediol monohydrate: 502,98 g/mol :
Dapagliflozin: 408,87 g/mol
Biopharmaceutics
Classification System (BCS)
Class 3 (low permeability, high solubility)
31
Active Pharmaceutical Ingredient (API)
Dapagliflozin propanediol monohydrate
The development of the
manufacturing process
Stability
On 30 batches
Quality by Design (QbD)
- Long-term conditions 25°C/60% RH
- Intermediate conditions 30°C/65% RH
- Accelerated conditions (40°C/75% RH)
→during 6months
- Diverse stress conditions
Manufacturer:
BMS Facility in Swords,
Ireland
32
API specifications at release
Characters:
◦ Appearance
◦ Color
Identification:
◦ IR or Raman, and HPLC
Assay:
◦ Dapaglifozin content by HPLC
These specifications were identified
by the applicant as critical quality
attributes established for the drug
substance linked to patient safety.
Test:
◦ Water content
◦ Residual solvents
◦ Purity
◦ …
33
Finished Product
Farxiga®, Tablets for immediate release
Strengths
- 5 mg
- 10 mg
Rx/OTC Dispensed
Rx
Container closure systems
-
HDPE bottles, 95-cc (30-count) and 200-cc (90-count)
Blister
-
Active ingredient:Dapagliflozin
-
Excipients: Anhydrous lactose, microcristalline cellulose, silicon
dioxide, crospovidone, magnesium stearate
Composition
34
Finished Product
Farxiga®, Tablets for immediate release
The development of the
manufacturing process
Quality by Design (QbD)
- Long-term conditions 25°C/60% RH On-going (available results at 24
Stability
On 6 batches (3 for 5mg and 3 for
10mg)
months)
- Intermediate conditions 30°C/65% RH
- Accelerated conditions 40°C/75% RH during 6 months
→ The stability protocol includes matrix testing design.
Shelf-life and Storage
condition
- 24 months
- Store at 25°C, excursions permitted 15°C to 30°C into HDPE
bottles or into blisters
Manufacturers:
- BMS manufacturing
company in Humacao, US
- BMS manufacturing
company in Mount
Vernon, US
35
FP specifications at release and at shelf-life
Specifications at release
Specifications at shelf-life
Characters:
◦ Appearance (visual examination)
Identification:
Idem
+ Impurities
◦ IR
◦ HPLC
Assay:
◦ Dapaglifozin content by HPLC
Other tests:
◦ Disintegration (surrogate of dissolution)
◦ Content uniformity
These specifications were based on
the drug product critical attributes
indentified by risk assessment and
developmental studies.
36
Excipient specifications
According to the US pharmacopoeia
37
Recommendations
Recommendation and Conclusion on Approvability
◦ From CMC point of view this application is recommended for Approval.
◦ The recommendation for the acceptability of the manufacturing sites is still outstanding.
◦ The CMC recommendation does not incorporate any potential facility inspection issues.
Recommendation on Phase 4 (Post-Marketing) Commitments and Risk Management Steps
◦ None
38
Non clinical trials
39
MRHD - Maximum Recommended Human Dose
Selectivity – in vitro studies
436 fold
207 fold
130 fold
In vivo testing
with X MRHD
40
Toxicology
MRHD
Mecanism
related
( x dose)
Non mecanism
related
High dose
(mortality)
Toxicity
41
Distribution
Steady state volume of distribution > total body water
→ Extravascular distribution
Concentration : 1% at 48 hours in tissues
→ no drug accumulating
42
Excretion
Mean Concentration of Radioactivity in rat Blood, Plasma and Milk Following a
Single Oral Administration of [14C]Dapagliflozin at 5 mg/kg
Dapagliflozin not recommended for nursing women
43
General toxicology
Single-Dose Oral Toxicity Study
•Multilple mortality at HD
Rats
6 months
DAPA 85-3097x MRHD
• Major target organs : kidneys, heard, bones, liver
•
Dose-dependent :
DAPA 128-3269x MRHD
↗ weights :kidneys, adrenal, liver
Dogs
12 months
↗ urinary volume
↗glucose,
↗ calcium, phosphorus, protein
•Urothelial hyperplasia of the bladder and/or
lining of the renal pelvis
In addition, a 3 month toxicity study was conducted in mice
44
Reproductive toxicity
FERTILITY
EARLY EMBRYONIC DEVELOPMENT
PRE & POST-NATAL DEVELOPMENT
JUVENIL ANIMALS
Recommended against the use during the second and third trimesters of
pregnancy and during nursing
45
Carcinogenicity
• Exploring whether dapagliflozin had activity that may contribute to bladder
cancer development  Tumor Promotion Investigations
 in vitro studies
 study of a bladder tumor xenograft implanted in the flank of
immunodeficient mice
Dapagliflozin did not increase the incidence of any tumor in rats and
mice at drug exposures reaching 131x and 72x the clinical dose
Dapagliflozin had not been found to be a direct carcinogen/tumor
promoter, after review of the applicant’s standard 2-year rodent
carcinogenicity study
46
Genetic toxicity
in vitro and in vivo
AMES assay
Micronucleus
→ Dapagliflozin was not mutagenic or
clastogenic
→ Dapagliflozin and its identified metabolites
are unlikely to be clastogenic in human
subjects
Chromosomal aberation assay
47
Conclusion
.
Data from additional animal studies is not likely to
supplant conclusions about the risk of bladder cancer
derived from human clinical trial and postmarketing data
48
Clinical trials
49
Overview of Clinical Studies
50
Choice of Primary end-points :
-
Change from baseline to week 24 in HbA1c (%)
Why ?
-
Surrogate measure of glycemia that correlates blood glucose over the
preceding 3 months
Standardized methodology reduce inter-laboratory measures
Reliable & predictive
Reduce microvascular complications (and may lower macrovascular
complications)
→ Decrease 1% of Hb1Ac => Decrease 21% complications
51
EFFICACY
52
Overview of Efficacy
●
Placebo-controlled studies
- Glycemic efficacy
- Weight
- Blood pressure
●
Active-controlled studies
- Vs Metformin
- Vs Glipizide
●
Long-term extension data - 52 weeks
53
Glycemic Efficacy
 Significant HbA1c
Reduction across
studies at week 24
54
Overview of Efficacy
●
Placebo-controlled studies, double-blind
- Glycemic efficacy
- Weight
- Blood pressure
●
Active-controlled studies, double-blind
- Vs Metformin
- Vs Glipizide
●
Long-term extension data - 52 weeks
55
Effects on weight and SPB
 Body Weight
Reduction vs
Placebo observed
across studies at
Week 24
LDL (mg/dL)
 Significant systolic
blood pressure
reduction at Week
12
56
Overview of Efficacy
●
Placebo-controlled studies
- Glycemic efficacy
- Weight
- Blood pressure
●
Active-controlled studies
- Vs Metformin
- Vs Glipizide
●
Long-term extension data - 52 weeks
57
Results : Dapagliflozin vs Metformin
 Combination therapy was
superior to both dapa and
metformin monotherapy
treatment arms the both the
dapa 5mg and 10mg dose
groups.
 Dapa + Metformin superior
to individual monotherapies
58
Overview of Efficacy
●
Placebo-controlled studies, double-blind
- Glycemic efficacy
- Weight
- Blood pressure
●
Active-controlled studies, double-blind
- Vs Metformin
- Vs Glipizide
●
Long-term extension data - 52 weeks
59
Results : Dapagliflozin vs Glipizide
 HbA1c reductions with
Dapa equivalent to
Glipizide at Week 52
60
Overview of Efficacy
●
Placebo-controlled studies
- Glycemic efficacy
- Weight
- Blood pressure
●
Active-controlled studies
-
●
Vs Metformin
Vs Glipizide
Long-term extension data - 52 weeks
61
Results : Dapagliflozin + Metformine VS. Metformine + Glipizide
62
Dapagliflozin Efficacy Conclusion
● Glycemic Efficacy
– HbA1c lowering with 10mg equivalent to Metformin and to Glipizide
– Demonstrated in a broad range of patients with T2DM
– Sustained over 2 years
● Consistent reductions in body weight
● Reductions in SBP in hypertensive patients with T2DM
63
SAFETY
64
Overview of Safety
●
●
General Safety
- Hypoglycemia
-
Weight
-
Renal function / Urinary tract infections
Safety topic of interests
-
Hepatic safety
-
Malignancy assessment
-
CV safety
65
AEs reported & deaths
66
Summary of Adverse Events
★ Significant adverse events:
★ Specific Primary Safety Concerns:
-
-
-
Bladder cancer
Malignant or unspecified tumors
(including Breast Cancer)
Hepatic safety
CV Safety → Major Adverse Cardiac
Events (MACE)
-
Hypoglycemia
Genital infections
Urinary tract infections
Renal impairment and volume depletion
events
Bone safety
focused primarily on, which were
identified as significant safety
concerns during the first review.
67
★ Common Adverse Events (>1%)
68
Overview of Safety
●
●
General Safety
- Hypoglycemia
-
Weight
-
Renal function / Urinary tract infections
Safety topic of interests
- Hepatic safety
- Malignancy assessment
- CV safety
69
Overview of Safety
●
●
General Safety
- Hypoglycemia
-
Weight
-
Renal function / Urinary tract infections
Safety topic of interests
- Hepatic safety
- Malignancy assessment
- CV safety
70
Overview of Safety
●
●
General Safety
- Hypoglycemia
-
Weight
-
Renal function / Urinary tract infections
Safety topic of interests
- Hepatic safety
- Malignancy assessment
- CV safety
71
Impact on renal function
72
November 2011 Major Amendment
• FDA asks for updated analyses to
– Determine impact of additional exposure on liver safety signal
– Determine impact of additional exposure on malignancy signal
– Assess the estimate of CV-risk with additional data
• Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type
2 Diabetes’, issued December 2008, “FDA’s guidance documents, including
this guidance, do not establish legally enforceable responsibilities.”
73
Overview of Safety
●
●
General Safety
- Hypoglycemia
-
Weight
-
Renal function / Urinary tract infections
Safety topic of interests
- Hepatic safety
- Malignancy assessment
- CV safety
74




No Signal for Drug Induced Liver Injury
No preclinical liver signal
No increases in liver test abnormalities
All cases of combined elevations of aminotransferase (>3X ULN) and bilirubin (>2X ULN) have alternative
diagnoses
75
Overview of Safety
●
●
General Safety
- Hypoglycemia
-
Weight
-
Renal function / Urinary tract infections
Safety topic of interests
- Hepatic safety
- Malignancy assessment
- CV safety
76
Bladder cancer concerns
2011 : No bladder cancer in vitro (animal data)
2011 : 10 (+1 with placebo) cases of bladder cancers in vivo (humain data)
2013 : No bladder cancer in vitro (animal data)
2013 : FDA asked for updated information – Results :
Dapagliflozin
Comparator
9/1626 (0,15%)
1/1150 (0,03%)
Populations :
IRR = 5,428 (IC 95% - 0,712 ; 245,10)
• Risk factors : 60% used tabacoo and history of using tabacoo, some of them were taking
pioglitazon
• 5/9 patients on dapagliflozin had bladder cancer within 1-2 years compared to none in
placebo group
• 4/9 patients on dapagliflozin had bladder cancer within 6 months compated to one in
placebo group
77
Bladder cancer explanations
FDA concluded no link between bladder cancer and dapagliflozine due to :
 No statistically significant data over 9 cases (4 30 months)
 Patients may had cancer previously and were not diagnosed + long-time evolution
 More frequent monitoring due to higher rates of urogenital AEs among dapagliflozin patients
 Event rates for males observed in the active treatment arms significantly exceeded the rates expected
in an age-matched reference diabetic population.
 “Dr. Hampp points out that the limitations of these analyses preclude a conclusion of an association
between dapagliflozin treatment and bladder cancer risk, but states the rate ratios unfavorable to
dapagliflozin cannot be ignored, must be taken into account for a thorough assessment of the risks
and benefits regarding a regulatory action and, if approved, must continue to be evaluated
postmarketing.”
78
Overview of Safety
●
●
General Safety
- Hypoglycemia
-
Weight
-
Renal function / Urinary tract infections
Safety topic of interests
- Hepatic safety
- Malignancy assessment
- CV safety
79
Study CV: original NDA Submission
→ conducted to compare the effect of standard treatment (target LDL-C level: <120 mg/dL (JASGL 2007 target level)) and intensive
treatment (target LDL-C level: <70 mg/dL) in the prevention of major adverse cardiac events (MACE) in hypercholesterolemia patients
with concomitant type 2 diabetes and hypertension.
-
Interventionnal study
Randomized
Efficacy study
Open label
Single Group Assignment
80
*in 2011
81
CV Endpoint: original NDA Submission
 NON SIGNIFICANT
82
Study Meta-analysis CV for New application
New application :
2 updated meta-analysis of a pool of fourteen Phase 2b and Phase 3 clinical trials to support CV safety of
dapagliflozin
Primary endpoint :
composite of time-to-first event of CV death myocardial infarction (MI), stroke, and hospitalization for
unstable angina (MACE-plus), with all events adjudicated by an independent endpoints committee, blinded
to treatment assignments
→ HR point estimate of this analysis was 0.67 (98%CI: 0.38-1.18) in favor of dapagliflozin over comparators
83
Study Meta-analysis CV for New application
No unacceptable increase in CV risk
No risk of over mortality proven demonstrated
84
Dapagliflozin Safety Conclusion
FDA concluded :
AEs with significant meaning :
Hepatic failure, tumors (especially bladder cancers), CV failure
 Post-Marketing requirements
85
Post-marketing
requirements
86
RMP (1/4)
Risk Management Plan
December 2010 : RMP submitted by the sponsors on
Two main categories of risks :
1/ Identified risks : genital infections and urinary tract infections
2/ Potential risks : hypoglycemia, volume depletion, clinical consequences of increased hematocrit, renal
impairment/failure, bone fracture and liver injury
+ limited informations in populations as ederly, pregnancy, …
NO REMS
(Risk Evaluation and Mitigation Strategy)
87
RMP (2/4)
Risk Management Plan
• Revised version of the RMP included breast and bladder cancers
August 2011
September
2011
October
2011
• Revised version of the label including a Medication Guide and a redline version of the revised RMP
• FDA meeting is scheduled (discussion of data from ongoing clinical trials, a revised PV plan)
• Risks of breast and bladder cancer
• Medication guide to replace the proposed patient package insert
• Update to the cardiovascular outcome trial synopsis
88
RMP (3/4)
Risk Management Plan
July 2013 : resubmission but without REMS or RMP
Use of the previous RMP
89
RMP (4/4)
Risk Management Plan
Routine pharmacovigilance activities include the following to address all the identified and potential risks
Targeted questionnaires : events of genital infections (serious), UTI (serious), renal impairment/failure and liver
impairment
Supplemental CRF (Case Report Form) : more detailed information and assessment in clinical studies
Evalution/communication of potential risk in product labeling
Cumulative review of events of interest
Describe results of cumulative safety reviews in aggregate reports
Pharmacoepidemiology studies ++
90
DECLARE – TIMI58 (Study D1693C00001) (1/2)
Dapagliflozin Effect on Cardiovascular Events
 CV outcome trial (CVOT) asked by FDA (first review cycle) = morbidity/mortality study
 Designed in accordance with the recommendations of the 2008 FDA Guidance […] Evaluating Cardiovascular
Risk in New Antidiabetic Therapies […]
 Randomized, controlled, double blind, Phase III
 17 150 patients with T2DM : CV disease or at least two CV risk factors
91
DECLARE – TIMI58 (Study D1693C00001) (2/2)
Dapagliflozin Effect on Cardiovascular Events
 Superior study  dapa 10mg oral dose versus placebo
 The primary outcome measure: reduction of Major Adverse CV Event (MACE) = CV death,myocardial
infarction (MI), or ischemic stroke
6 years Study start date : April 2013
92
http://www.timi.org/index.php?page=declare-timi-58
93
Conclusion
94
Conclusion
• Dapagliflozin FARXIGA®
• Indications
• As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
• Approval
• Many challenges for approbation: 2 submissions
• No animal data which show signs of carcinogenesis BUT clinical cases of bladder cancer in
clinical trials
• RMP BUT no REMS
• Study DECLARE
The weight of evidence does not support a causal link
between Dapagliflozin and bladder cancer
95
Sources
 Center for Drug Evaluation and Research – Administrative and correspondence documents
 Center for Drug Evaluation and Research – Chemistry review(s)
 Center for Drug Evaluation and Research – Clinical pharmacology and biopharmaceutics review(s)
 Center for Drug Evaluation and Research – Cross discipline team leader review
 Center for Drug Evaluation and Research – Medical review(s)
 Center for Drug Evaluation and Research – Microbiology/virology review(s)
 Center for Drug Evaluation and Research – Proprietary name review(s)
 Center for Drug Evaluation and Research – Pharmacology review(s)
 Center for Drug Evaluation and Research – Risk assessment and risk mitigation review(s)
 Guidance for Industry – Diabetes Mellitus – Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2
diabetes
96
97