SMARTSTARTTM YOUR CLINICAL DRUG DEVELOPMENT

CLINICAL CONSULTING SERVICES OVERVIEW

Founded: 2005, Private LLC Employees: 80+

Our focus is getting needed drugs and devices to patients through a unique approach to:

• Strategic regulatory and clinical services from discovery through commercialization

• Clinical trial recruitment and retention • Patient support technology platform with

front-end automation and back-end data analytics

A TRUSTED PARTNER in LIFE SCIENCES Fully integrated pre-clinical, clinical, regulatory and site management service provider Founded 2005, with offices in Baltimore, MD, San Francisco, CA, London, UK, and Hyderabad, India Strategic, multi-faceted team: 80+ FTEs Global experience in 40+ countries and 20+ therapeutic areas 500+ new drugs, biologics and device products successfully commercialized

FDA is the Federal agency that is required by law to review and approve all new drugs in the US 1906: FDA Act prohibited mislabeling but did not require pre-market approval of drugs or devices 1938: Food, Drugs and Cosmetics Act required submission of evidence of a drug’s safety before it could be marketed

HISTORY of FEDERAL OVERSIGHT of the DRUG DEVELOPMENT PROCESS

Reviews and evaluates new drugs based on evidence presented from the clinical research studies performed by the sponsor Regulate interstate commerce Center for Drug Evaluation and Research (CDER) is the largest of the FDA’s five centers and is responsible for prescription and over-the-counter (OTC) drug safety and efficacy Center for Biologic Evaluation and Research (CBER) regulates biologics Primary goal: to ensure patient safety

ROLE of the FDA

• Development of new drugs is complex and costly

• Mean cost: $1.3 billion • Mean time: 12 years to bring one

drug from discovery to the patient • For every one drug that reaches

market, 10,000-30,000 compounds are screened

DRUG DEVELOPMENT PROCESS

PMA, 2015

1. What are the goals and objectives? o Early exit, commercialization vs. licensing

2. What are the desired product attributes that differentiate value?

o Indication, dosage, formulation, claims, PK/PD, safety & efficacy

3. How can you create an unmet need? o Why is it important, and what are the issues and value

4. What stakeholders and market channels are important?

o Patients, physicians, payers, VC, shareholders, etc.

5. Where will the drug be marketed? o United States, Europe, Asia, etc

6. What has been successful, or not, in the past? o What will work for product X and what issues must be

considered? Model for success!

STRATEGIC ROAD MAP FOR SUCCESS

“WHAT IF?” Contingency planning for highly probable events!

• What if API can only be made in small batches or the ship sinks from China? • What if formulation is not stable? • What if the FDA does not agree with your planned studies? • What if you fail to achieve your primary endpoint, or so what data? • What if a competitor’s product launches first?

Spend less time on the improbable and more on probable events (i.e., timelines are lagging) Create your Risk Management Plan or REMS apriori

• Ensure benefits outweigh the risks

Preclinical, nonclinical and animal studies

Investigational new drug (IND) application

Clinical studies (Phases 1-3)

New drug or biologic application (NDA/BLA)

FDA/CDER or CBER review

Approval

Post approval evaluation/Phase 4

DRUG APPROVAL PROCESS

New drug applications (NDAs) or Biologic License Applications (BLA) require clinical trials to demonstrate safety and efficacy Studies must be contacted under GLP and GCP conditions Federal law requires a drug to be FDA approved before transporting across state lines The FDA Investigational New Drug (IND) is the process by which an exemption to the law is obtained Human studies can only begin after IND is reviewed and approved by the FDA and an institutional review board (IRB)

DEFINITIONS – INVESTIGATIIONAL NEW DRUG (IND)

Submit IND protocols for review at least 90 days before anticipated start of study State in cover letter that review of protocol &/or study report is requested Provide adequate information / data

facilitates review & response to Questions

Describe role of study in overall development program and/or potential regulatory outcomes (e.g., label claim)

EFFECTIVE IND COMMUNICATION STRATEGY

Fully understand the full lifecycle of any clinical trial, regardless of the Phase (I-IV) or indication The process stays the same and here to stay! Love the process, not the compound under study

Compounds are a “dime a dozen” and come and go. (Quote: Michael Poole, MD Vice President, Wyeth)

Focus on SmartStudyTM (Study, site and patient feasibility) Most drugs fail due to the process (i.e., study)

THE PROCESS of CONDUCTING CLINICAL TRIALS

Life Cycle of a Clinical Trial

Protocol Synopsis finalized

Schedule of Activities finalized

Protocol finalized

Model ICF finalized

Sites selected

Operations Manual/MOP completed

CRFs finalized

IRB approvals obtained

Site subcontracts/ payment schedule in place

Finalize Contracts with third party vendors (labs, ECGs etc.)

DSMB established

Build database

Finalize Study drug packaging/labeling

Enroll subjects Distribution of study drug to sites Answer Protocol/CRF questions Take incident calls SAEs Dosage Adjustments Premature Withdrawals Drug Disclosure

Data query process Clean/Close database Transfer database to

Biostatistics

Perform primary/ secondary analysis Submit abstract Submit manuscript Submit CTR Post results on

www.clinicaltrials.gov Post-hoc analysis

Orientation or Initiation Meeting

Database Locked

Analysis

CONCEPTUAL PHASE

PLANNING PHASE

IMPLEMENTATION PHASE

ANALYSIS/ PUBLICATION

PHASE

Grant Award and/or Parent

contract established

IRB’s ensure the rights and welfare of subjects participating in clinical trials, both before and during trial participation Ensure subjects are fully informed and have given written, informed consent before participating in studies Risks, benefits and protection of human subjects and data IRB’s are located in hospitals, research centers and private (Central) Local vs. Central IRB’s IRB approval varies from days to > year, and often after contracting

ROLE of the INSTITUTIONAL REVIEW BOARD (IRB)

• Emphasis on drug safety, PK/PD, biomarker

• SAD, MAD, Asian bridging study • Identify major side-effects (NIH Grade

1-4), metabolism, routes of excretion • Sufficient information about PK/PD to

permit design of well-controlled Phase 2 studies

• 70% of drugs that make it to this phase will pass this phase

PHASE 1 CLINICAL STUDIES

Duration: 1-2 years

Cost:

$1.5-$6+ mil

20-80 healthy volunteers

• Emphasis on effectiveness, safety, dosage, biomarker

• Closely monitored, evaluate short-term side-effects and risks

• Often 2+ studies are conducted • Patients receiving the drug are

compared to similar patients receiving a placebo or another drug

• 33% of drugs will pass this phase • Adaptive designs may lead to

registration

PHASE 2 CLINICAL STUDIES

Duration: 2-4 years

Cost:

$6-20+ mil

100-300 people with target disease

• Emphasis on safety, effectiveness, QOL, Costs

• Investigates different populations and dosages as well as combination with other drugs, surrogate biomarkers

• Randomized, placebo controlled • Typically, 2 confirmatory studies

required • Extrapolation to a general target

population • Acquire data used for physician

labeling • 25-30% pass this phase

PHASE 3 CLINICAL STUDIES

Duration: 2-8 years

Cost:

$20 - $600+ mil ($30--$150+K per patient)

300-10,000+ people with target disease

• Post-market surveillance of the drug to continually assess safety of the drug

• Risk Evaluation Mitigation Safety surveillance (REMS) • Required under accelerated basis of approval • May include: incidence and severity of rare adverse

reactions, cost-effectiveness analyses, comparative trials, and quality of life studies

• Tool to leverage FDA with reporting requirements • May have a “Big Data Play”

PHASE 4 CLINICAL STUDIES

• Avoid intellectual curiosity and dysentery

• KOLs or Dept. Chairs do not influence regulators

• Academic planned studies may not satisfy regulators

• Limit drug exposure and risk • All data and failed studies are

reportable • GLP and GCP is a must

ACADEMIC vs. REGULATORY DRUG DEVELOPMENT

PMA, 2015

Orphan Well defined by FDA and OOPD, yet subject to agency interpretation Common EMEA/FDA Application with different Sponsor benefits Clinically superior to existing or previous unapproved or new orphan indication for same disease Establish rationale for indication(< 200K US cases) and Rx with medical plausibility Benefits: Patent protection (7 yrs.), protocol assistance, grants, contracts, tax incentives

FDA ORHPAN & FAST TRACK DESIGNATION

Fast Track Serious unmet medical need Preliminary safety and clinical activity superior to SOC Accelerated approval and priority review More frequent FDA meetings and engagement Sponsor requested after IND or EOP1

FDA Priority REVEIW and GAIN PROGRAMs Priority Review • FDA voucher program • Intended for Rx to treat rare and neglected diseases • Set to expire, Oct. 2016. Publically, FDA is not in favor • Priority review < 6 months • Transferable FDA GAIN Act • Generating Antibiotics Incentives Now (est. 2012) • Goal: generate new anti-microbial Rx for world pathogens • FDA qualified list of pathogens • 5 year market exclusivity, agency commitment and

engagement

Breakthrough Therapy Superior improvement over existing Rx. Fast Track benefits plus: intensive FDA guidance and commitment File no later than EOP2

Accelerated Approval Superior surrogate end point Post marketing pharmacovigilance and REMS commitment Agency commitment and engagement

FDA SPECIAL DESIGNATIONS

• NDA/BLA: Formal step asking FDA to consider approving a drug for marketing • Starting in 1938, all data; preclinical and clinical data of an IND are required to become

part of the NDA/BLA • Plan studies wisely, nothing out of FDA/EMA reach

• Electronic submission of all data, IND and NDA/BLA • e Publishing requirements

• Consist of as many as 15 different sections • Pre-NDA/BLA period: FDA and drug sponsors meet • FDA has 1 year to decide whether it will file the NDA/BLA for approval consideration • If filed, a FDA review team is assigned to evaluate the new drug • 2017, preclinical data must follow current electronic data and requirements for IND

NEW DRUG or Biologic APPLICATION (NDA/BLA)

• FDA review team evaluates the research on safety and effectiveness • Labeling information reviewed • Study audit • Inspection of GMP production facilities; methods and validation processes • Decision and justification letter:

Not approvable: Lists deficiencies in application and why it cannot be approved Approvable: Ultimately can be approved and lists deficiencies that can be corrected, including labeling changes and requests for post-approval studies Approval: Drug is approved

FDA APPROVAL

Developed in the conceptual and planning phase Develop a REALISTIC timeline and work scope Keep It Simple Stupid! whenever possible Plan for contingencies It always costs more and takes longer

KEYS to STAYING on SCHEDULE

Create a scope of work document clearly delineating who is responsible for what: sponsor, Project Team, External Vendors, Sites, Monitors

Create a detailed timeline of all activities that need to complete in each phase of the Project Lifecycle

Both documents will provide the roadmap for the overall project Tools for timeline development:

Excel Microsoft Project

Copyright © 2009 Clinical Trials Coordination Center/University of Rochester: All Rights Reserved

TIMELINE and WORK SCOPE

Select DSMB members Typically 3-5 independent scientists with no conflicts-of-interest and no other role in the study (should include: a biostatistican, disease expert, expert on drug under study, expert in body system with AE profile of greatest concern, ideally most have prior clinical trials experience)

Create/Finalize DSMB charter Specifies exactly what the DSMB is charged to monitor, stopping rules for efficacy/safety, major areas of concern (e.g., renal, hepatic etc.)

DMSB members and final charter should be in-place prior to FPFV

ESTABLISH DATA SAFETY MONITORING BOARD (DSMB) and CHARTER

Food and Drug Administration Amendments Act of 2007 or FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register and report results of certain "applicable clinical trials":

Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations, of a product subject to FDA regulation; Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation (other than small feasibility studies) and pediatric postmarket surveillance studies.

"Applicable clinical trials" generally include interventional studies (with one or more arms) of drugs, biological products, or devices that are subject to FDA regulation, meaning that the trial has one or more sites in the U.S, involves a drug, biologic, or device that is manufactured in the US (or its territories), or is conducted under an investigational new drug application (IND).

REGISTER TRIAL WITH WWW.CLINICALTRIALS.GOV BEFORE FPFV

21 CFR 320

ICH Guidance Documents (15+)

EMEA Guidance Documents (30+)

General BA/BE Guidance

Population PK Guidance

Exposure/Response Guidance

USDA (Animal Welfare Act)

Good Laboratory Practices

BCS Guidance

IVIVC Guidance

SUPAC Guidance documents (IR, MR and SS)

REGULATIONS and a FEW GUIDANCE DOCUMENTS

http://www.fda.gov/cder/guidance

Open, timely, exchange of ideas between Sponsor and regulatory agencies Obtain Agency’s views on questions / issues

Opportunity for specific questions to be addressed – (e.g., # of special population, interaction studies, biomarker) Request a SPA (Special Protocol Assessment) Minimize regulatory decision surprises Facilitates good review management principles

COMMUNICATION: WHY?

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2008 2009 2010 2011 Source: Forbes, August 2015

2012 2013 2014 2015

Total new drug approvals Only new molecules

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30

35

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45

50

2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

NME Approvals NME Applications Filed

Source: CDER 2015 Novel New Drugs Reports

• 2013/2014 had several biotech blockbuster launches (Sovaldi/Harvoni, Tecfidera, Imbruvica, Eyelea), but 2015 was relatively quiet (Praluent, Repatha)

• Streamlined FDA approval pathways in 2015 (31% Fast Track, 22% Breakthrough, 53% Priority Review, 13% Accelerated Approval)

Record 45 FDA drug approvals in 2015 Drug Approval Rate Reaches New High

• Orphan Drugs were 47% of all approvals in 2015; First-in-Class drugs were 36%

ROBUST RATE of DRUG APPROVALS

PAGE 32

• Immuno-oncology technologies

High valuations and hype – defensible given limited clinical data, growing competition, and demonstrated impact only in liquid tumors?

• Gene Therapy and Gene Editing

Early successes in narrow indications but failures in heart failure and back-of-eye diseases • Cell based therapies

• Companion Diagnostics

Tailored medicines based on a patient’s specific genetic profile or disease subtype • M&A

Buyer’s market among large pharmaceutical players with patent expirations and slow growth to acquire higher growth biotechnology products

• Pricing Pressure

Pharmacy benefit manufacturers, physician groups, politicians and media have been proactive with specialty drugs • Valuations and Financing Environment

What is fair value and is the financing window “open”? Greatest valuation is Phase 2 data.

VC “watch and wait” till after Phase 1 or 510(k) cleared

CURRENT “Hot” TOPICS IN Bio-Pharma Investing

SMARTSTARTTM YOUR CLINICAL DRUG DEVELOPMENT