Updated General Capabilities Overview

March 21, 2016

RAISING THE STANDARD OF EXCELLENCE

Key personnel

with PhD or

Master

degrees and

over 10 years

of industry

experience

Proven strong

track record

of drug

approvals

20 year old

specialty

CRO

Strong and

stable team

Commitment

to quality and

timelines

80+ full time

employees in

the USA

Clients

ranging from

small biotech

to large

pharma

Accountability Innovation Leadership Quality Partnership

SERVICES OVERVIEW

Medical and Regulatory Consultation

Clinical Operations

Biostatistical Design and Analysis

SAS Programming CDISC Standardization

Data Management

Safety Management / Pharmacovigilance

Medical Writing

Application Development

GLOBAL BRANCHES AND OFFICES

Locations: USA, S. Korea, Armenia, Japan, HK, Taiwan, Singapore (adding UK and France)

Mainland China: first tier cities BJ, SH, TJ, GZ

second tier cities NJ, CD, SY, WH

11 Main Offices

34 Cities within China

600+ Employees Globally

GLOBAL RESOURCES

Number of Employees Per Location

USA Asia Europe

80+

500+

50+ Services by Location

USA

DM, Biostat, Prog, CO, PV

Asia

DM, Biostat, Prog, CO, PV,

MA, RA, SMO, Translation

Europe

DM, Biostat, Prog, CO, PV

U.S. RESOURCES

Statisticians – 12

Statistical Programmers /

Analysts – 40+

Data Managers – 10

Project Managers – 4

IT – 4

QA – 2

Operations & Administration

BIOMETRICS PROJECT TEAM STRUCTURE AND COMMUNICATION

Project Manager Lead Statistician

Lead Validator

Lead Programmer

Senior Statistical

Reviewer

Sponsor Team

QC Checking

Data Manager

KEY PERSONNEL DATA MANAGEMENT

Lily Zhu: MD, Director, 18 years pharma and 6 years hospital

Merck, Xiamen First Hospital

Alene Shepherd-Rose: Manager, 30+ years pharma

Merck

Jeannette Sickel: Manager, 25+ years pharma

Merck

Kelly Miller: Sr. Data Manager, 15+ years pharma

CLINLOGIX, Merck, Sanofi-Aventis, RPS

Jonathan Zimmerman: MS, Sr. Data Manager, 10 years pharma

Medidata, Covance, CoreLab Partners, ICON

KEY PERSONNEL BIOSTATISTICS

Henry Wu: PhD, VP, 15+ years pharma

Kendle, Forest Lab, Roche, Pfizer

Tiepu Liu: MD, PhD, VP, 15+ years pharma, 10 years academia

PPD, UBC, Graceway, The Medicines Company

Kevin Chen: PhD, Senior Director, 15+ years pharma, 13 years academia

UNC, Sanofi, Shering Plough, Eisai, Genta

Pei-Yun Chen: PhD, Director, 15+ years pharma

Merck

Lynn Wang: MS, MA, Director, 15+ years pharma

Eli Lilly, Pharmacia, Sanofi-Aventis, Wyeth

Weining Volinn: PhD: Director, 15+ years pharma

Averion, Actavis

Wenjiong Zhou, PhD: Director, 15+ years pharma and CRO

BMS, UBC

KEY PERSONNEL PROGRAMMING

Yuguang Zhao: MS, VP, 18 years pharma

Sanofi-Aventis, Eisai

Carrie Zhang: MS, Assoc. Director, 8 years pharma

Merck

Sheng Zhang: MS, Assoc. Director, 12 years pharma

Eli Lily, Eisai, Merck

Tina Wu: MS, Assoc. Director, 11 years pharma

Clinforce, Salix

Philamar Atienza: MS, Principal Programmer, 12 years pharma

Alcon, Schering-Plough

Dan Szeto: MS, Principal Programmer, 15 years pharma

PPD, Covance, BMS

THERAPEUTIC EXPERIENCE

• Oncology

• Anti-Inflammatory / Pain

• Neurology / CNS

• Cardiovascular

• Gastroenterology

• Ophthalmology

• Allergy

• Vaccine

• Anti-Infective / Anti-Viral

• Diabetes & Metabolic Disease

• Dermatology

• PK / PD

• Women’s Health

CURRENT PROJECTS BY THERAPEUTIC AREA

Anti-Infective

4%Autoimmune

2% Cardiovascular

2%Consumer Health

5%

Device

2%

Diabetes & metabolic

disease

8%

Musculoskeletal

6%

Neurology/CNS

28%

Oncology

14%

Ophthalmology

17%

Respiratory

5%

Urology

5%

Women’s Health

2%

Over 300 Ongoing or Completed Studies

25%

65%

10%

Sales

Phase I Phase II / III Phase IV

Phase I

Phase II / III

Phase IV

PROJECT SUMMARY:PAST 36 MONTHS

Agency Submissions

15 US NDAs: 11 approved and 4 are pending

Submissions in other regions include EMA, PMDA,

Canada, Mexico, Singapore, South Korea, and others

PROJECT SUMMARY:PAST 36 MONTHS

DATA MANAGEMENT SERVICES

Study Set-Up Study Conduct Study Close-Out

- CRF Design

- Data Management Plan

- Data Validation Plan / Data

Review Plan

- CRF Tracking and Review

- EDC Site Support for Study

Conduct

- All DM Activities

Completed

- Final SAE Reconciliation

Before Database Lock

- eCRF Completion Guidelines

- Data Entry Guidelines

- CRF Annotation

- Database Design, Testing, and

Activation

- Data Validation and Discrepancy

Management

- Serious Adverse Events

Reconciliation

- Ongoing Dictionary Coding

- Final Clinical Review

Listings to Sponsor

- Final Data Management

Status Report to Sponsor

- Edit Check Programming, Testing

- External Data Import and Export

Set-up

- Dictionary Set-up

- External Data Transfer and

Management

- Ongoing Critical Data Points

Quality Control

- Database Audit as Specified

by Sponsor

- Database Lock and Freeze

- Data Transfer

- EDC Site Support Set-up

- Study Site Training

- Ongoing Data Management

Status Report

- Ongoing Clinical Review Listings

- Study Documentation

Maintenance, Return,

Archive, and Destruction

DATA MANAGEMENT – EDC

EDC Technology

Medidata® Rave and Balance - Accredited Services Partner

Oracle Clinical RDC - Certified

Oracle InForm – Certified

Oracle Argus - Certified

OpenClinica Enterprise Edition - Services Partner

“We couldn’t have accomplished this without K&L. You accomplished the impossible with our data! It was really

challenging and we couldn’t have done it without your heroics! I hope we work together again.”

Associate Director of Clinical Research

Major Pharmaceutical Company

DATA MANAGEMENT SYSTEMS & OPERATION MODELS

Work on K&L System

& SOPs, Processes,

and CDISC Standards

Work on Sponsor’s

SOPs and Processes

Use per Sponsor

required Data

Standards

EDC & DDE

IWR

Medical Coding

SAS Programming

Labs

DATABASE BUILD

Protocol Design/Review

Database Build Workflow

eCRF Spec/CRF Design/Review

Data Validation/Edit Check Testing

Data Validation/Edit Check Programming

Data Review /Validation Plan

Define/Construct Study Database

Setup Data Entry Screen

Validate Study Data Entry Screens

Database in Production

DATA MANAGEMENT

Statistics Analysis

External Data Reconciliation

Study Site Data Entry

Query Generation/Resolution

Medical Review

DMReview

Medical Coding

SAE Reconciliation

Medical Review

All Queries Resolved

Medical & Statistics Report

PI Signature

Study

Site

Lock Study Database

SDV

BIOSTATISTICS SERVICES

Exploratory Analysis

Clinical Study Report

Statistical Report

Annual Report (DSUR and PSUR)

ISS / ISE

Publications

Clinical Development Plan

Power / Sample Size Estimation/ Protocol Development

Randomization

Statistical Analysis Plan

Interim Analysis / DMC

Statistical Modeling and Simulation

STATISTICIAN’S ROLES

• Communicate with Sponsor to ensure key statistical considerations are incorporated into study design and planned analysis (Protocol and SAP).

• Interact with programmers to ensure analysis plans are accurately carried out.

• Statistical review and check analysis results.

• Programmatically verify the key results.

• Support interim and ad hoc analyses.

• Provide statistical interpretation of the results.

“I am extremely impressed with your sophisticated theoretical and applied statistical and programming

capabilities; especially the professionalism, quality and customer focus of your team.”

Vice President Clinical Development

Massachusetts Biotech

STATISTICAL PROGRAMMING QUALITY STANDARD / PROCESS

Analysis Data

• Based on SDTM with stable SAP and TLF shells

• Specifications development and team review

• Programming based on the specifications

• Double programming validation

• Key analysis data with stat verification

TLF Output Delivery

• Double programming validation

• Stat review and verification

• QC review

KEY STATISTICAL AND PROGRAMMING PROCESS

Stats and Programming Process

SAP

- First draft starts after protocol

and CRF finalization

- Senior statistical review before draft delivery

- Stable working draft: change tracking and summary to team members

- Sign off before DB lock (or at

other milestone per sponsor

requirement)

Dry Runs

- Start programming with a stable SAP

- First dry run to be conducted when

~30% of data become available.

Review of the first dry run is mainly

to ensure the format of the outputs are

appropriate.

- Second dry run (BDRM) to be

conducted when ~90% of data

become available. Review of the

second dry run is mainly to prepare

for DBL and ensure the contents of

the outputs are accurate.

Delivery after DB Lock

- The top line results are available in 1-3 days.

- All TLFs are available in 1-2 weeks.

SDTM DATA PACKAGE

PROCESS FLOW CHARTSDTM e-Submission Data Package Process Flow Chart

Raw

Data

aCRFs

Raw

Data

SDTM

Data

ADaM

Data

SDTM aCRFs

(aCRF.pdf)

SDTM Mapping

Specification

SDTM Mapping

Programs

SDTM Define

SDRG

Initial

Request ?

Change in

Raw Data

CRFs ?

Mapping Spec

Update ?

Final SDTM Mapping Spec

Approved ?

Validation

Y Y Y Y

N N N

ADaM DATA AND TLF FLOW CHART ADaM Data and TLF Flow Chart

Initial

Request ?

Change in

SAP or

TLF Shell ?

ADaM Spec Needs

Update ?

Validation

Y YY Y

N

Protocol Raw

DataaCRF Tables, Listings and

Figures

TLF Creation

Programs

SDTM

Data

ADaM

Data

ADaM Creation

Programs

ADaM

SpecificationADaM define

ADRG

SAP + TLF

Shell

Final ADaM Spec

Approved ?

NN

REGULATORY SUBMISSION EXPERIENCE

• Submission of CDISC compliance e-Submission data package• SDTM / ADaM / BIMO

• Submission package supporting eCTD• ISE / ISS / ISI

• Filing compliance check

• FDA response consultation

• Statistics / programming advisor committee• Agency defense rehearsal

• Post filing agency ad-hoc support

CDISC COMPLIANT NDA SUBMISSION SUPPORT

Legacy data conversion

SDTM & ADaM creation

Comprehensive eSubmission data

package for FDA submission

Metadata driven process for

development of data mapping

specifications

Create SDTM annotated CRF

(acrf.pdf)

Create SDTM / ADaM

eSubmission packages

Comprehensive tools and processes

for creating define.xml / define.pdf

Proven validation process of

SDTM & ADaM: accuracy and

compliance

Compliance checks with Pinnacle

21 and K&L’s toolkit

(SDTMChecker)

Create the reviewer’s guide

associated with SDTM / ADaM for

FDA reviewers

REGISTERED CDISC FOUNDATIONAL STANDARDS

K&L has worked with CDISC SDTM / ADaM since 2002

• CDISC Gold Member

• CDISC Registered Solution Provider

• Co-led a CDISC / FDA Data Integration Pilot

• Formal member of CDISC SDS Working Group

• Active Member of CDISC and ADaM Working Group

SDTM / ADaM EXPERIECE

From 2013 to 2016

Created SDTM / ADaM

for ISS / ISE packages.

One ISS included 38

protocols, from Phase I to

III. The studies were

conducted in the U.S.,

Europe, and Asia.

Submitted 15 NDA data

packages to the FDA

including SDTM /

ADaM. All were

accepted and 11 drugs

have been approved and

are on the market.

Prepared 400 SDTM /

ADaM study packages

across 75 compounds for

20 biotech /

pharmaceutical

companies.

EXPERIENCE OF LARGE STUDY DATA INTEGRATION

Legacy Data Processing

• 67 legacy studies for acetaminophen were included in this data

mapping project.

• The scope of work include data re-entry (18 studies), MedDRA

coding, SDTM mapping, ADaM derivation, and also key CSR result

verification.

• The mapped data sets will be used to perform meta data analysis and

to answer agency questions.

• Results were used to support Canadian filing.

• Project was successfully completed in 2013.

• The experience was shared with the industry at the PhUse conference

and CDISC User Group Meeting.

Providing Regulatory

Submissions

In Electronic Format

Standardized Study Data

Guidance for Industry

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

December 2014

Electronic Submissions

COALITION FOR ACCELERATING STANDARDS & THERAPIESTHERAPEUTIC AREA STANDARDS INITIATIVECDASH (CRF/EDC) > SDTM > ADAM > TLF > ECTD

UTILIZING A COLLABORATIVE APPROACH TO CREATE EFFICIENCIES WITH CDISC – CDASH STANDARDS

IDMC SUPPORT SERVICES

• Started offering this service since 2007 for anti-infectious and oncology studies

• Both as voting member and as independent supporting statistician

• Average about ~10 IDMC project support per year in recent years with a steady increasing trend both in the US and globally

• Services include:

• Project management: organization, coordination, and documentation

• IDMC charter and interim SAP

• Data analysis and presentation

• Follow up ad hoc analysis

• Project startup and ongoing management

• IDMC charter development / review

• IDMC SAP and shell

• Internal review and sponsor review

• Consideration of consistency to CSR SAP

• Programming support for IDMC and ongoing safety review

• Dry run for IDMC

• Support for ongoing safety review (blinded / unblinded outputs, patient

profiles, summary tables)

• Document and data transfer

• sFTP portal for sponsors and vendors

• sFTP portal for IDMC members

• Flash drive / card, etc.

KEY IDMC PROCESSES

DMC PROJECT TEAM STRUCTURE AND COMMUNICATION

Lead Statistician IDMC

Programming Lead

Project Manager

Sponsor

GLOBAL SAFETY MANAGEMENT

Client System Under FSP Arrangement (ARISg)

Staff are trained on the sponsor’s system and SOPs

B2B connection was set up in order to access the sponsor’s servers from our

server. Alternatively, sponsor-built laptops are distributed to the FSP staff in

order to access the sponsor’s VPN.

In-house Argus System

Installed and fully validated

State-of-art IT platform to support the Argus application. High performance

and high availability server. Rigorous system SOPs that have been audited by

many sponsors.

SAFETY MANAGEMENT EXPERIENCE

• Safety information translation and reporting to the customer • Multiple sponsors under paper process

• Data entry and processing of ICSRs in customer company database

• Global / local search of the scientific literature for adverse drug reactions• Multiple sponsors: FDA AERS, WHO ADR, company specific safety

DB, literature

• Scope of services including AE searching, trend detection, summary reporting, and medical writing for DSUR, PSUR

• Case submission• FDA, EMEA, CFDA

PROJECT MANAGEMENT PROCESS AND COMMUNICATION FLOW

Project Management Process and

Communication Flow

Kick-off Meeting

(internal/

external)

Internal

Management

Meeting

Project Closing

Meeting

Planning

Execution /

Implementation

Initiation

Closing

Project initiated, assign project manager, start initiation activities

Define project scope, deliverables and requirements, create project charter

Resource loading, form project team, develop project plan, timeline,

communication plan, perform risk assessment

Track and report project status, manage project issues, re-plan timeline and

resources and update budget as needed; ongoing risk assessment

Deliver final deliverables, project sign-off by sponsor, complete QA

documentation

Ensure work is performed within scope as agreed, manage change request/order, milestone

performance review

Project Team

Mtg, Status Mtg,

Status Report

Monitor &

Control

STATE-OF-THE-ART IT INFRASTRUCTURE

Heavily invested in advanced IT systems

and technology to ensure:

Availability

Confidentiality

Reliability

SecurityIT Infrastructure:

High Performance and Processing Power

Multiple Data Backups

System Redundancy

Disaster Recovery Site

We passed on-site audits from all of our clients.

QUALITY SYSTEM – KEY SOPS AND POLICIES

CATEGORY NUMBER

General Policy POL 01 - 08

General Procedure SOP 001 - 010

BioStat - Programming SOP 101 - 108

Facility / Project Management SOP 109 - 113

Data Management SOP 201 - 261

IT Management SOP 306 - 317

KEY SOPSBIOSTATISTICS AND PROGRAMMING

NUMBER SOP

101 Programming Standards

102 Good Programming Practice

103 SAS Programming Validation Procedure

104 Data Transfer Procedure

105 Development of Statistical Analysis Plan

106 Interim Statistical Analysis Plan

107 Randomization Schedules

108 Unblinding Clinical Studies

WHY K&L?

Our high standards for precision, quality, and rapid response combined with our ability to provide

solutions to complex issues will make K&L a valuable member of your team.

State-of-the-Art IT

Infrastructure

Strong and Stable

Global Team

Commitment to

Quality and

Accuracy

Effective

Communication