A Full-Service CRO

Get Your Development Program Started on the Right Foot…

Presenter Introduction

Senior Vice President, R&D

David Shoemaker, PhD

Senior Medical Officer

Jack Modell, MD

Senior Research Scientist

Dana Minnick, PhD

Senior Research Scientist

Scott Burian, PhD

Overview

• Overview• Content• Example

Target Product Profile

• Overview• Clinical Development Plans• Nonclinical Development Plans• CMC• Regulatory Strategy

Integrated Product Development Plans

What is a TPP?• Key strategic planning document that:

– Provides a clear understanding of requirements and expectations of the ultimate outcome of product development

– Is driven by unmet patient, physician and payer needs at time of launch

• Roadmap of key Go/No-Go decision points • Statement of the overall intent of the product

development program– and much more than just a draft product label

What is a TPP?

A differentiated value proposition Snapshot in time

Summary of studies that justify labeling claims

Dynamic & multidisciplinary document

Communication tool Starting point for annotated package insert (label)

Link to FDA Guidance

The purpose of a TPP is to provide a format for discussions that can be used throughout the drug development process. The TPP embodies the notion of beginning with the goal in mind.

The TPP provides a statement of the overall intent of the drug development program, and gives information about the drug at a particular time in development.

The TPP is a dynamic summary that changes as knowledge of the drug increases.

Road Map for Development

• Focuses development • Required studies – no more, no less –

become apparent• Requires comparison with similar

products• Constant updating of indication

required– With new information from your studies

& market– Go/No-Go decision points are forced

When is the TPP Needed?

• As early in development as possible– Pre-IND Meeting – IND– End-of-Phase 1 Meeting– End-of-Phase 2 Meeting – Annotated Package Insert Template– Pre-NDA or -BLA Meeting

Establish the Targets Early

• Begin with the end in mind– “If you don’t know where you’re going,

you’ll be lost when you get there.” Yogi Berra• Interdisciplinary activity

– Project teams (Clinical/Nonclinical/CMC/Regulatory)

– Labeling and marketing teams• Initial interdisciplinary and senior

management input and buy-in• Decision log

– Conflict resolution system– Go/No-Go rationale

Typical TPP Checklist Includes:• Scientific rationale• Preclinical support• Toxicology/ADME/PK• Acute vs. chronic indication• Unmet need• Clear diagnostic criteria• Target population or

subpopulation• Clinical plan• Anticipated safety profile, drug

interactions• Contraindications

• Regulatory plan• Endpoints (with estimate of

needed benefit)• Manufacturing/stability issues• Route of administration• Anticipated storage conditions• Desired shelf life• FDA guidelines available• International objectives• Competition• Patents

Indications and UsageTarget• What is the drug product? • Is it for treatment or prevention? • What disease/condition and unmet needs does it target? • Who are the target patients?

Annotations in TPP• Completed/planned studies supporting the target

Comments• Summarize the drugs currently used for treatment or

prevention in your target indication and write a brief statement on their competitive positioning

Dosage and Administration

Target

• How much drug is required?

• How is it administered?

• How often is the treatment?

• What is the duration of treatment?

Annotation

• Summarize completed & planned studies that support the safety and effectiveness of the proposed dosage and route of administration

Comments

• Summarize the positioning of the dosage and administration relative to current treatments

Adverse ReactionsTarget

• What adverse effects might be anticipated based on results of nonclinical studies?

• What adverse effects might be expected due to the drug class?

• What adverse effects have been observed in clinical studies?

• What adverse effects are acceptable based on product risk-benefit and positioning?

Annotation• Summarize

completed/planned studies that support the target (include references to reported class-related drug effects)

Adverse Reactions

Comments

• Identify AEs associated with current drug treatments that might be mitigated by your new drug candidate

Considerations

• Similar product monographs

• Acceptable thresholds for incidence of AEs

• Opportunities to demonstrate superior safety profile

Clinical StudiesTarget:

Statements regarding efficacy &

safety benefits• Clinical evidence to

support the indication claims

• Strength of evidence

• The safety profile• Endpoints in the

clinical studies to support the competitive positioning and marketing strategy for the new drug

Annotation

• Summarize completed/planned studies that will develop evidence in support of treatment

Comments

• Identify key areas of competitive advantage

Additional Considerations

Nonclinical requirements Enrollment challenges Time to market

Groundwork for subsequent indications Biomarkers Companion diagnostics

Common Pitfalls• Interdisciplinary input not sought• Late stakeholder buy-in• “Interest group”-driven targets • Lack regulatory intelligence• No prospective key decision points• Failure to revisit when new data obtained• Failure to use it as a tool for planning, development,

communication

Example Starting Point: Novel antidepressant

• Currently marketed AD’s are only effective in about 50% of patients because of problems with tolerability and/or lack of efficacy

• Currently marketed AD’s have relatively few significant drug interactions

• Currently marked AD’s are generally given once-daily

• Currently marketed AD’s, when they do work, may require a few weeks for significant effect

• The world doesn’t need another expensive variation of a currently marketed antidepressant

What’s known

Example: Novel antidepressant

• A once-daily antidepressant, with no significant drug interactions, and one or more of the following:• Rapid onset (placebo separation by the

end of the first week)• Good tolerability, including no sexual

dysfunction, weight gain, or sedation• Robust efficacy greater than that of

currently marketed AD’s (and not less than)

What’s needed

General Development Flowchart

Diagram source: http://qb3.org/sites/qb3.org/files/QB3Podcast20120316_2_0.pdf

Integrated Product Development Plan

(IPDP)A strategic plan covering all

components of the drug development spectrum for a

product

IPDP Transformation to Label

Integrated Product

Development Plan

Target Product Profile

Product Label (prescriber’s Information)

Collect data, revisit, refine

IPDP

Label Claim

Nonclinical

ClinicalCMC

Strategic & dynamic toolUnique & integratedGoals, activities, contingencies‘Go/no go’ decision pointsCompetitive landscapeTarget Markets

Begin with the End in Mind

•Label claims•Efficacy•Safety

Market Approval

• Intended indication & population•Efficacy•Safety

Phase III

•Target indication & population•Proof of concept•First in humans

Phase I-II•Preclinical & quality (CMC) data to support human exposure•GLP safety and toxicology testing

•Stability of IP

File IND/CTA

“The End”

Now expand on this to include all activities required to enable each other to occur…

Comprehensive & Evolving

End Goal

Plan

Evaluate

Go/No Go

Decision

Revise

From TPP!!!

New Data

A Full-Service CRO

Production

Chemistry

Pharmaceutics

Pharmacology andPharmacokinetics

Toxicology

Regulatory

Clinical

DrugSelection

18+ Mo.18 Mo. 6 Mo. 18 Mo.12 Mo. 12 Mo.24 Mo.

Phase I Phase II Phase III Data Analysis

ISS/ISE/ERs

Phase IV

Safety inhealthy

volunteers

Efficacy& safetysmallgrouppatients

Pivotallargegrouppatients

NDA PrepareSubmit

FDA Review

NDAApproval

Post-marketSurveillance

INDPrepareSubmit

PilotPlant

GMP Plant Stability, Validation Production

Formulation, Dose & Administration Stability, Tech Transfer, Validation

Healthyhumans

Humanpatients

ADME (animal)

Mutagenicity

Acute ToxicitySub-acute Toxicity

Long-term Feeding Studies (chronic toxicity and carcinogenicity)

Reproductive Toxicology

8 Years

PRODUCT DEVELOPMENT

PopPK

DISCOVERY

1O Pharm 2O Pharm

1 Year +

IPDP Basic Content

Regulatory history and strategy

Chemistry, manufacturing, & controls (CMC) plan

Nonclinical (pre-clinical) development plan

Clinical development plan

Elements of the target label (target product profile)

Introduction

Mapping TPP to IPDP for Novel AntidepressantTPP• Global market• Once daily oral dosing, rapid

onset, chronic• Multiple dose strengths • Adults and elderly with

major depression• Efficacy superior to placebo,

similar/better versus gold standard

IPDP• Phase 3 studies (US, non-

US)• Phase 2 studies• Clinical pharmacology• Nonclinical studies• Chemistry, Manufacturing

and Controls• Regulatory • Marketing

Mapping TPP to IPDP for Novel AntidepressantTPP• Global market• Once daily oral dosing, rapid

onset, chronic• Multiple dose strengths • Adults and elderly with

major depression• Efficacy superior to placebo,

similar/better versus gold standard

IPDP• Phase 3 studies (US, non-

US)• Phase 2 studies• Clinical pharmacology• Nonclinical studies• Chemistry, Manufacturing

and Controls• Regulatory • Marketing

Mapping TPP to IPDP for Novel AntidepressantTPP• Global market• Once daily oral dosing, rapid

onset, chronic• Multiple dose strengths • Adults and elderly with

major depression• Efficacy superior to placebo,

similar/better versus gold standard

IPDP• Phase 3 studies (US, non-

US)• Phase 2 studies• Clinical pharmacology• Nonclinical studies• Chemistry, Manufacturing

and Controls• Regulatory • Marketing

Mapping TPP to IPDP for Novel AntidepressantTPP• Global market• Once daily oral dosing, rapid

onset, chronic• Multiple dose strengths • Adults and elderly with

major depression• Efficacy superior to placebo,

similar/better versus gold standard

IPDP• Phase 3 studies (US, non-

US)• Phase 2 studies• Clinical pharmacology• Nonclinical studies• Chemistry, Manufacturing

and Controls• Regulatory • Marketing

TPP IPDP• Favorable side effect profile

versus gold standard (sedation, weight gain, sexual dysfunction)

• Minimal/no drug interactions

• No cardiovascular safety issues

• Phase 3 studies (US, non-US)

• Phase 2 studies• Clinical pharmacology• Nonclinical studies• Chemistry, Manufacturing

and Controls• Regulatory • Marketing

Mapping TPP to IPDP for Novel Antidepressant

TPP IPDP• Favorable side effect profile

versus gold standard (sedation, weight gain, sexual dysfunction)

• Minimal/no drug interactions

• No cardiovascular safety issues

• Phase 3 studies (US, non-US)

• Phase 2 studies• Clinical pharmacology• Nonclinical studies• Chemistry, Manufacturing

and Controls• Regulatory • Marketing

Mapping TPP to IPDP for Novel Antidepressant

Clinical Development Plan• Phase 3

– Focus on efficacy and safety– Pivotal or confirmatory if adequate, well-controlled and agreed

with FDA– Target population & regimen for market– Generally at least 2 studies required– Major basis for marketing approval decisions and label

• Phase 2– Focus on efficacy and safety, proof-of-concept– Population - patients with target disease– Dose range finding, dose selection for phase 3– Further define outcomes/endpoints, population

• Phase 1– Focus on safety, pharmacokinetics, pharmacodynamics– First in human, SAD, MAD– Drug interactions, Thorough QT, food effect, bioavailability

Nonclinical Development Plan• Comprehensive assessment of the pharmacology,

pharmacokinetics, and toxicity of the drug substance and product

• How are data used?– Dose selection for initial clinical trials– Pharmacodynamics, MOA, biomarker development– Therapeutic index– Specific safety monitoring, use in specific populations– Labeling

• GLP requirement for some studies• Dose selection is critical for safety studies

Chemistry, Manufacturing, & Controls (CMC) Plan• Assure proper identification, quality, purity and

strength• Manufacture active pharmaceutical ingredient

(API)• Analytical assay development & validation• Pre-formulation/formulation development• Manufacture of Clinical trial material

– Release testing– Packaging and labeling– Comparators (active or placebo)

• Stability

Regulatory Strategy• Filing Pathway

– 505(b)(1), 505(b)(2), 505(j), drug-device combination

– What data are required for each pathway– Pertinent regulatory hurdles

• Understand competition– Review labels, SBAs, EPARs, financial reports

• Awareness of region specific regulations– ICH– FDA– EMA

Regulatory Strategy

• Orphan Drug Designation• Qualify for acceleration mechanisms?

– Breakthrough Therapy– Accelerated Approval – Priority Review

Know your drug to take advantage of these programs!

Type B Development Meetings with FDA

• Pre-IND Meeting

• End of Phase 1 Meeting

• End of Phase 2 Meeting

• Pre-NDA Meeting

Initial Agency Interactions• Pre-IND

– Obtain Agency buy-in on: • Clinical protocol• Nonclinical safety studies• CMC program

• What is required:– IPDP in Briefing Document– Well-written questions

• No open-ended questionsWhen is the right time to schedule meeting???

Avoiding Delays (e.g., Clinical Hold)• Unfocused development plans are

doomed to lead to delays• CDER receives approx. 1500 IND

submissions per year• Lapteva and Pariser (Journal of Investigative Medicine,

2016)

– In 2013, 9.0% were placed on clinical hold

– Most commonly cited reasons• CMC• Clinical • Toxicology

Common Reasons for Clinical Hold• Poorly organized submission and/or insufficient information• Inadequate information to assess safety• Clinical study design too aggressive, lacks needed safety

monitoring, dose limiting toxicity is not well defined and/or stopping rules inadequate, inadequate inclusion/exclusion criteria

• Unqualified impurities, excipients in clinical batch or poorly defined impurity profile

• Drug product not stable throughout the testing program• NOAEL not determined in toxicity study(ies)