fda on safety

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Cosponsored by

FDA’s Office of Critical Path Programs (OCPP)and

The Clinical Trials Transformation Initiative (CTTI)

FDA’s Clinical Investigator Course

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Safety in Clinical Trials

Lourdes Villalba, MDNovember 9, 2010

Senior Medical Reviewer, Safety Team

Division of Neurology Products

Center for Drug Evaluation and Research

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Outline

• Scope of clinical safety assessment• Clinical safety evaluations• Limitations of premarket database to assess

safety• Postmarketing safety• Example of drug that was withdrawn from

the market for safety reasons (Vioxx)• Summary

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Outline




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Introduction

• Evaluation of a drug’s safety is an evolving process

– Different from evaluation of efficacy– Does not end at the time of approval

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Sources of Safety Information1

• Clinical studies

• Non-clinical data• Studies of other indications• Clinical Pharmacology studies• Safety profile of other drugs in the class• Medical literature

• Postmarketing experience

1 For products under investigation, the Investigator Brochure (IB) is equivalent to the Package Insert of an approved drug.

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Outline




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Clinical Safety Evaluations

• Exposure• Adverse events

– Big ticket items– Definitions– Reporting requirements– Approach to causality assessment– Coding– Ascertainment– Follow up

• Other safety evaluations• Adequacy of safety evaluations

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Exposure

• The likelihood of observing an AE depends on several factors

- Number of patients evaluated

- Duration of treatment

- True risk of a drug-induced reaction (common vs. rare)

- AE risk over time (hazard)

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HAZARD FUNCTIONS FOR THREE PATTERNSOF DRUG-INDUCED CLINICAL EVENTS

O'Neill RT 1988

MONTHS FROM INITIAL DRUG EXPOSUREMONTHS FROM INITIAL DRUG EXPOSURE

*HA

ZA

RD

*HA

ZA

RD

0 1 2 3 4 5 6 7 8 9 10 11 12

DECREASINGDECREASING

DELAYED (INCREASING)DELAYED (INCREASING)

CONSTANTCONSTANT

*Hazard: risk per unit time

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ICH1 E1A Guidance (1)

• Minimum ICH recommendation

If chronically administered • 1500 people total• 300-600 people for 6 months• 100 people for one year• At clinically relevant doses

1 International Conference on Harmonisation (ICH-E1A).

ICH E1A: Guideline for Industry. The extent of population exposure to assess Clinical Safety. For drugs intended for long-term treatment of non-life-threatening conditions. http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/ucm073083

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ICH-E1A Guidance (2)

• Safety database in a drug development program is not expected to detect rare AEs (e.g., those occurring in < 1 in 1,000 patients)

• It is expected to characterize short-term events (cumulative 3 month about ≥ 1%)

• In some circumstances minimum standards for clinical safety evaluation may not be applicable.

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Pooling Safety Studies

• Pooling may improve power and precision for estimating AE (basis for the Integrated Summary of Safety analyses)─ When pooling, need to consider study design, dose,

duration, population (also need to look by individual study)

Risk number of cases number of persons exposed

Rate number of cases person-time exposed

─ Using person-time allows adjustment for differential dropout (assuming that hazard is constant). Sometimes need to use Kaplan Meier analyses.

=

=

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“Rule of 3”: Capping the risk

• Observing no serious AEs in a database should not be interpreted as “no risk”

- “Rule of 3” estimates the upper 95% CI for the risk of an AE= 3/N

E.g. If no case in a 3000 pt database, the risk of having the AE is < 1/1000.

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Adverse Event – Big Ticket Items

• Deaths*• Serious AE• Discontinuations due to AE*

* Require Case Report Form (CRF) and narrative at the time of NDA submission. CRF and narratives of Serious AE are usually requested by Divisions.

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Adverse Event – Definitions* (1)

• Adverse Event (or Adverse Experience) (AE): Any untoward medical occurrence associated with use of a drug in humans whether or not considered drug related– sign (e.g. abnormal lab finding)– symptom– disease

•21 CFR 312.32. Guidance for Industry and Investigators: Safety reporting requirements for INDs and BA/BE studies (Draft Guidance, September 2010). Definition applies also to biological products. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf

•Effective date for the Final Rule: March 28, 2011.

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Adverse Event – Definitions (2)

• Adverse Reaction

– Any AE caused by a drug

• Suspected Adverse Reaction

– Any adverse event for which there is a reasonable possibility that the drug caused the AE

• Single occurrence of an event that is uncommon and known to be associated with drug exposure

• One or more occurrences of an uncommon event

• An aggregate analysis of specific events observed in a clinical trial indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group

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• Unexpected

– Any AE or suspected adverse reaction that is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed

• E.g. Hepatic necrosis if the IB only listed elevated hepatic enzymes

• It does include events or reactions that are anticipated based on class effects or the pharmacological properties of the drug but are not specifically mentioned with the drug under investigation

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• Serious: AE that results in• Death or a life-threatening event• Inpatient hospitalization or prolongation of – existing hospitalization • Persistent or significant disability/incapacity• Congenital anomaly / birth defect• Or it is an “Important medical event”…may

require medical or surgical intervention to prevent one of the above outcomes, such as allergic bronchospasm, blood dyscrasias, convulsions, drug abuse or dependence

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IND AE Reporting Requirements* for Investigators to the Sponsor

• Immediate

- All serious AEwhether drug related or not, even if listed in the protocol or the IB as anticipated to occur (except study endpoints)

- Study endpoints that are also serious AE if evidence suggests a causal relationship (e.g. fatal anaphylactic reaction)

SAE reports include causality assessment

• Not immediate (according to the protocol)

- Nonserious AE No need for causality

assessment

- Study endpoints that are serious but not suspected to be drug related

All AE need to be collected and recorded in CRF

* 21 CFR 312.64. Guidance for Industry and Investigators. Safety reporting requirements for INDs and BA/BE studies (Draft guidance. September 2010)

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IND AE Expedited Reporting Requirement (for the Sponsor)* (1)

• Potentially serious risks from clinical trials or any other source must be reported to FDA and all participating investigators– No later than 15 calendar days after receiving the safety information

and determining it qualifies for reporting– In an IND safety report (could be electronic) – Unexpected fatal or life-threatening suspected adverse reactions must

be reported to FDA within 7 calendar days (telephone, fax, email)

* 21 CFR 312.32. Guidance for Industry and Investigators. Safety reporting requirements for INDs and BA/BE studies (Draft guidance. September 2010).

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IND AE Expedited Reporting Requirement (for the Sponsor) (2)

• Potentially serious risks requiring IND safety report include1

A. Suspected adverse reactions that are both serious and unexpected (as determined by either Investigator or the Sponsor)

B. Findings from other sources that suggest a significant risk in humans (next slide)

C. Increased occurrence of serious suspected adverse reactions (related to rate listed in the protocol or IB)

1 Modified from previous 21 CFR 312.32.

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IND AE Expedited Reporting Requirement (for the Sponsor) (3)

• Findings from other sources, that suggest a significant risk in humans (result in safety-related changes in protocol, IB, etc)

• From other studies*

Clinical studies, epidemiological studies or pooled analyses of multiple studies

• From animal or in vitro testing**

Such as carcinogenicity, mutagenicity, teratogenicity, or significant organ toxicity at or near the expected human exposure

• Bioavailability/Bioequivalence studies*

* New to CFR. ** Clarified from previous 21 CFR 312.32.

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Approach to Causality Assessment

• Uncommon AEs– Require detailed individual assessment

• E.g. liver failure, agranulocytosis

• Common AEs– Individual assessment won’t help to determine

attribution• E.g. Headache, nausea

Myocardial infarction in elderly population– Require comparisons using a population approach

(risk or rate on drug vs. a control group)• Placebo, active control, other doses in fixed dose study,

historical control

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Examining Individual Cases of Uncommon SAEs

• Was it “treatment-emergent”? • Did it respond to de-challenge?• Was there re-challenge? Result?• Where there concomitant medications?• Were pertinent labs/other tests done?• Was there an obvious alternative cause?

Note to Investigators: provide enough relevant information in CRF as to allow good quality narratives

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*Guidance for Industry: Premarketing Risk Assessment. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072002.pdf

Components of a Good Narrative*

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Designated Medical Events*

Acute pancreatitis Neuroleptic malignant syndrome

Acute respiratory failure Pancytopenia

AgranulocytosisProgressive Multifocal Leukoencephalopathy

Amyotrophic Lateral Sclerosis Product infectious disease transmission

Anaphylaxis and anaphylactoid reactions Pulmonary fibrosis

Aplastic anemia Pulmonary hypertension

Blind Renal failure

Colitis ischaemic Rhabdomyolyisis

Congenital anomalies Seizure

Deaf Serotonin syndrome

Disseminated intravascular coagulation Stevens-Johnson syndrome

Endotoxic shock Sudden death

Haemolysis Suicide

Hemolytic anemia Torsade de Pointes

Liver failure Toxic epidemal necrolysis

Liver necrosis Thrombotic Thrombocytopenic Purpura

Liver transplant Ventricular fibrillation

* List used by Office of Surveillance and Epidemiology. Examples of events that require extensive evaluation at pre-marketing stage too.

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Ascertainment of Adverse Events

• Clinical AEs– Spontaneously reported symptoms

• Open question– Symptoms reported as a result of a probe

• E.g. using checklist– Both

• Other: Vital Signs, ECGs, laboratory data, special safety testing – Routine (scheduled by protocol)

– By cause

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Ascertainment of AEs

• Suboptimal ascertainment of AE may lead to missing safety signal

Note to investigators: Please record relevant AE & abnormal values outside pre-scheduled protocol assessments too

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Coding of Adverse Events

• Process of converting the investigators’ “verbatim” terms to standardized terms, sometimes called “preferred” terms (PT)

• Standardization allows sorting of AEs and grouping of like events

• PT are then used to calculate AE incidences

• Currently most used: MedDRA (Medical Dictionary for Regulatory Activities)

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MedDRA Structure – Hierarchy

HLT - High Level Term (1,709)

PT - Preferred Term (18,786)

LLT - Lowest Level Term (68,258)

Represents a single medical concept

Used for analyses of AEs

AE as reported on CRF “Verbatim”

MedDRA 13.0

SOC - System Organ Class (26)

HLGT - High Level Group Term (335)

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Coding Problems

• Coding problems may lead to missing safety signals– Splitting same AE among similar PT

• Hypertension, high blood pressure, etc.

– Lumping different terms to same PT• Leg edema, face edema, etc.

Note to Investigators: Please be consistent and use the most scientific term when recording AE in CRF

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Adverse Event Follow Up

• Follow up AE until resolution• Discontinuations due to AE is an important

component of safety evaluation in a clinical study

Note to Investigators: please provide adequate categorization for study withdrawal; minimize use of “patient withdrew consent”

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Other safety evaluations

• Studies in special populations– Hepatic and renal impairment– Pregnancy– Pediatric– Elderly

• Evaluations with established recommended approach, Guidance for Industry: – Drug induced liver injury. Premarketing clinical evaluation

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf

– Clinical evaluation of QT/QTc interval prolongation

http://www.fda.gov/RegulatoryInformation/Guidances/ucm129335.htm

• Special considerations – Malignancy, immunogenicity

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Pharmacogenomics and Safety

• Pharmacogenomics may help improve the safety of drugs on an individualized basis. Many AE are due to individual “overdosing” because of drug metabolism differences.

• Examples that made it into labeling– Coumadin: increased risk of bleeding with certain genetic

variants of CYP2C9 and VKORC1 enzymes

– Abacavir: hypersensitivity and HLA-B*5071

– Carbamazepine: Stevens-Johnson syndrome and HLA-B*1502

– Tricyclic antidepressants: increased toxicity in poor CYP2D6 metabolizers

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Outline




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Limitations of Premarket Database to Assess Safety (1)

• Inherent to the database

• Limited exposure (size, duration)

• Narrow population

• Lack of pre-defined safety endpoint(s)– Multiple comparisons

• Imprecision of estimates due to small numbers

[However, no need to get a p<0.05 to suspect a safety signal]

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Limitations of Premarket Database to Assess safety (2)

• Related to adequacy/quality/integrity of trials* e.g.– Incomplete ascertainment of AE

– Inadequate follow up

– Suboptimal recording in CRF

– Suboptimal narratives

– Suboptimal source data availability

– Coding problems

* Also applies to postmarketing trials

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Outline




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Postmarketing Safety

• Major source: Spontaneous reporting from FDA AERS (Adverse Event Reporting System)– Big issues: Under reporting/ Incomplete reporting/

No denominator. No control. Note to Investigators: Please continue AE reporting after drug is approved.

• Spontaneous reporting from other regulatory agencies and World Health Organization

• Postmarketing studies by sponsors, academia, FDA– Clinical trials, observational studies, registries, meta-

analyses• Sentinel Initiative

– Active surveillance system that will enable FDA to actively query diverse automated healthcare data holders

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Outline




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Example of Drug that was Withdrawn from the Market: VIOXX*

• Rofecoxib: Cyclooxygenase-2 (COX-2) selective non steroidal anti-inflammatory drug (NSAID)

- Does not block COX-1 mediated PG synthesis in GI mucosa (GI sparing) at clinically relevant doses

- COX-2 mediates PG I2 synthesis in endothelium and it is not expressed in platelets

Could unopposed platelet thromboxane A2 be pro-thrombotic?1

* NDA submitted December 19981McAdam et al. PNAS, January 1999

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Vioxx NDA- Serious and Non-serious, CV “Potentially Thrombotic” Events*

6-week to 6-month controlled OA studies

Vioxx 12.5, 25 & 50 mg/d

Ibuprofen

800mg TID

Nabumet.

75mg BID

Diclofenac

75mg BID

Placebo1

N= 3305

n (%)

N= 847

n (%)

N= 115

n (%)

N= 498

n (%)

N= 783

n (%)

All 32 (1.0)

MI 7 (0.2)

4 (0.5)

-

-

-

10 (2.0)

2 (0.4)

4 (0.5)

2 (0.3) * Investigator reported events (Includes terms such as MI,

coronary artery disease, ischemic heart disease, cerebrovascular accident and TIA). N = patients randomized. n= patients with event. 1 Placebo exposure: 6-18 weeks only.

CV safety: Vioxx between ibuprofen and diclofenac

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VIOXX NDA- Approved 4/99

• ~5000 subjects; exposure > minimum ICH• Safe and effective for intended indications at

intended dose (12.5 & 25mg for OA; 50mg for pain)

• Safety profile similar to other NSAIDs

– Caveats• 75% women with OA • few used low dose aspirin for CV prophylaxis • NSAID comparators: ibuprofen & diclofenac*

• Vioxx GI Outcomes Research study (“VIGOR”) already ongoing. Postmarketing trial to support removal of GI WARNING from NSAID template

* Cox-2 selectivity of diclofenac similar to that of celecoxib

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VIOXX- VIGOR Study

• Design• ~8,000 subjects with RA, 1:1 randomization • Vioxx 50mg/d vs. naproxen 1000 mg/d• Excluded subjects taking low dose ASA

• Primary endpoint • Perforation, Symptomatic ulcer, Bleeding (PUBs)

• Primary analysis: Superiority to comparator

• Results• Succeeded on primary endpoint but found excess of

MI with Vioxx (0.5%) vs. naproxen (0.1%)• Did Vioxx increase risk of MI (FDA) or did naproxen decrease

risk of MI (Sponsor)?• Did it apply to the 25 mg dose?

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VIGOR Confirmed CV Thrombotic Events, Time to Event Plot

Hazard Ratio Vioxx vs. Naproxen

Overall = 2.4

> 8 months = 4.0

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VIOXX after VIGOR (1) • VIGOR presented to FDA Arthritis AC

meeting to discuss GI claim (02/2001) • Panel (including two cardiologists)

concerned but inclined to believe sponsor’s interpretation

• Recommended inclusion of CV information in labeling and evaluation of additional data

– Submissions for completed studies were pending: ADVANTAGE (5500-pt study in osteoarthritis) and Rheumatoid Arthritis efficacy database*

– Additionally, studies in prevention of Alzheimer’s (3000 patients) were ongoing (placebo-controlled, 25 mg dose, elderly, allowed use of low dose ASA)**

* ADVANTAGE: supported increased CV risk of Vioxx vs. naproxen **Alzheimer’s studies: no increased risk of MI compared to placebo

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VIOXX after VIGOR (2)

• Sponsor’s meta-analysis of CV events in Vioxx controlled studies – No excess CV risk as compared to placebo

• April 2002: RA supplement approved; VIGOR GI and CV data included in labeling

• Epidemiologic data – Increased CV risk for 50 mg dose but conflicting

results for 25 mg dose

• October 2002, sponsor submitted protocol– Pooled analysis of CV/Thrombotic events in 3

randomized, DB, PC, chemo-prevention studies (25,000 patients for up to 6 years)

• - Adenomatous polyp prevention (APPROVe) ongoing• - Prostate cancer (PCC) just started• - Recurrent colon cancer (VICTOR) planned

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Vioxx – September 2004

• Merck withdrew Vioxx from the market upon 1-year interim results of the APPROVe study– Vioxx 25 mg/day vs. placebo

– 3 year duration planned

– ~1300 patients per arm

– 62% male

– 19% low dose aspirin

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Vioxx – APPROVe1

1-year Interim Analysis of APTC2 events

1 APPROVe: Adenomatous Polyp Prevention trial. 2 Anti-Platelet Trialist Collaboration composite endpoint (CV & unknown cause of death + non-fatal MI + non-fatal stroke). 3 Rate per 100 patient-years at risk. PYR= patient years at risk: Vioxx= 3070 and placebo= 3334. 4 RR= Overall relative rate Vioxx to placebo. *p< 0.05.

Vioxx 25 mgN=1287

n Rate3

PlaceboN=1299

n Rate RR4

APTC (patients) 34 1.11 18 0.54 2.05* CV Deaths 6 0.20 5 0.15 1.30 MI (all) 21 0.68 9 0.27 2.53*

NF Isch Stroke 10 0.33 6 0.18 1.81 NF Hem. Stroke 1 0.03 1 0.03 1.09

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Vioxx Follow up

• CV data (clinical trial and epidemiological) from all selective and non-selective NSAIDs discussed at FDA Arthritis/DSaRM AC meeting (2/05)

• Conclusion on NSAIDs and CV risk*

– All COX-2 selective agents increased CV risk (no ranking)

– Available data do not clearly demonstrate that COX-2 selective agents confer a greater CV risk than non-selective agents.

– New Class labeling for potential increase in CV risk added to all NSAIDs.

* John Jenkins & Paul Seligman. FDA Memorandum. NSAIDS and CV risk (April 2005)

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What to do with a safety signal?

• Once a signal is identified or suspected– Is there other supportive evidence?– Is it biologically plausible?– Could it be explained by chance?– How can it be studied further?

• Observational study (ies)

• Clinical trial – Feasible? Ethical?

– Is a regulatory action needed?• Risk/benefit

• Additional tools since FDAAA1

1 FDA Amendment Act of 2007

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Outline




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Summary

• Evaluation of safety is an evolving process– Premarketing database is not expected to identify

rare events – Once a safety signal is identified ask how to best

evaluate further (in the pre- or postmarketing setting)

• Investigators may improve quality of safety assessments by• Providing relevant/complete AE information • Using the most scientific term when reporting• Recording AEs from non-scheduled tests too • Continuing to report AE once drug approved

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Questions?

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Acknowledgements

Judy Racoosin, M.D., M.P.H.

Robert Temple, M.D.

Sally Yasuda, Pharm. D.

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