FDA Applications in a NutshellFDA Applications in a Nutshell

“Good science and good regulatory practice often part company” …..*

*(sometimes..) park the science and follow the rules

Some Thoughts on “FDA in a nutshell” (??)( )

• Perceived as Formulaic • Perceived as Formulaic …

• In RealityP S ifi– Program Specific

– Remains Subject to ChangeOft di t bl– Often unpredictable

– Risky– Subject to “intangibles”

F il – Failure prone

Development Landscape

• Biopharma development – among the most highly regulated of any commercial activity highly regulated of any commercial activity

• Sheer Number of Regulations = complexity

• Even well- run, and compliant programs fail

• Program risk has discouraged innovation

• Understanding the intangibles mitigates risk

Changing Scope of Development

Ph m e ti l de elopment i no • Pharmaceutical development is now conducted to facilitate GLOBAL approval

– Pharmaceutical products are “similarly” regulated in essentially every country.

– Most countries have their own health authorities with individual “personalities”

– Regulations are applicable to both the investigation and marketing of compounds.g g p

Intangibles a critical facet of complexity

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Drug Development is (deceptively) formulaic

• Find a compound with activity• Chemically define it (characterize)• Explore its basic pharmacology and toxicology• Explore its basic pharmacology and toxicology• Define safety and efficacy via clinical research• Develop a dosage form

l d d f l f l• Compile data and file for approval• Wait patiently..Same formula for years --- why study and y y y

strategize the process

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Regulatory Framework

• Regulations are complex systems of interrelated rules interrelated rules

• Govern both development and post approval activities

• Continuously undergoing amendment and supplementation

• Intended to assure that products are te ded to assu e t at p oducts a esafe (do no harm) and effective ( do some good)

• Most have arisen from adversity • Most have arisen from adversity

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US Base Standards for Drugs / Biopharmaceutic Approval

• Products must be recognized as safe

• Product must be demonstrated to be effective• Product must be demonstrated to be effective– 2 adequate and well controlled trials

B fi f l i h i l • Benefits of use must always outweigh potential risk

• Identified risks must be mitigated

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Why we (over)Regulate• All Regulation grew out of adversity

Proven Safety counters impure adulterated unsafe– Proven Safety counters impure, adulterated, unsafe• Elixir of Sulfanilamide• Thalidomide

P Effi t thl “ ll ”– Proven Efficacy counters worthless “cure alls”• Snake oil• Medicine shows

Development Metrics

• 1 in 1000 candidates make it to phase 1 clinical trial 

• 8 to 15 years to develop a new drug/biologic product8 to 15 years to develop a new drug/biologic product

• $802 million spent before the medicine is available for sale

• When failures are factored in (not a rare occurrence) Avg costsWhen failures are factored in (not a rare occurrence), Avg. costs exceeds $ 5 billion per drug

• 2012 :Nature Reviews Drug Discovery – Number of drugs invented per billion dollars of R&D reduced by– Number of drugs invented per billion dollars of R&D reduced by 

half every 9 years 

• Attention to early development, successful execution of significant clinical studies helps to reduce number of development failuresclinical studies helps to reduce number of development failures.

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Approval Outcomes and Costs• 400+ Medications Approved in 2000 -2012• 35 Approved in 2012• Current Development Time: 10 – 15 years

Medi ine in De elopment• Medicines in Development– 1999 – 1,800– 2009 – 2,900– 2013 - 3,400– 40% increase since 2005

• Total Development Costs ($), factoring failure– 1975 – 138 mio– 1987 – 318 mio– 2001 – 802 mio– 2006 – 1.318 billion– 2012 – 5.0 billion

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Risky…

..its also complex

Drug Development: Changing Landscape To Reduce Risk

• Targeted • Outcome / patient focused

– Defined Outcome– Best Population– Measurable effect– TRUE Clinical Effectiveness– Anticipated Risk / Benefit– Mitigated Risks

• US Approvals Up in 2011 & 2012pp p– Most approved first pass– Application Quality = Shared Sponsor execution

• FDA Remains unpredictable -- Congressional Oversight remains high

So what’s a drug ?

Drug describes [any] articles intended for use in the diagnosis cure mitigation treatment or the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.

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What is a “new” drug• The regulatory definition of "new drug“ is critical as it establishes

both the need for, and requirements for approval

A Ne D g i n ti e b t n e hi h i not gene ll • A New Drug is an active substance which is not generally recognized, among experts qualified to evaluate the safety and effectiveness of drugs (FDA), as safe and effective for use under the conditions prescribed, recommended, or suggested in the p , , gglabeling thereof

• Approved via IND/NDA

• Active compounds recognized under the Food and Drugs Act of June 30, 1906 are the exception [“Old Drug”]

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Development Gating – Best Practice

low “probability of success” compounds get “pushed along” by inertiaalong by inertia

h k d d dTo mitigate this risk candidate compounds are typically “gated”

Pre-specified criteria are established to prevent blindly moving products alongblindly moving products along

General Development Gating

Gated Approaches to Regulated Development

• Target Identification • IND Enabling Activities• IND Filing• IND Filing• NDA Filing• Postapproval Actions

Candidate Definition – General Investigational Plan

A Priori….

• Define intended Indication • Define intended Indication • Define target population• Determine Optimal Dosage form

/ l• IP / Exclusivity Assessment• Develop Global Regulatory Strategy

Strategic Approaches to Development • Target Identification

– Clinically meaningful– Commercially attractive– Measurable effect

Initiation of clinical investigation of Target

Virtually everything is hinged off clinical studies

Problem: How to administer an unapproved drug to Problem: How to administer an unapproved drug to a human for testing

• US: IND – Investigational New Drug (Application)

• EU: CTA – Clinical Trial Authorization

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IND Defined • IND - Investigational New Drug (Application)

– Documentation submitted to and accepted by FDA before new drug can be shipped interstate for human testing.

– IND includes all evidence that studies can be done with reasonable safety – IND includes all evidence that studies can be done with reasonable safety to subject/patient.

– Following initial filing, becomes repository for all subsequent amendments, protocols, preclinical/ clinical data

• CTA - Clinical Trial Application– EU version of US IND

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So…When do I need an IND• New Drug• Old Drug –New indication• New Patient population • New Patient population • New manner of use significantly different from

the approved label

Strategic Approaches to Development • Target Identification

– Clinically meaningful– Commercially attractive– Measurable effect

• IND Enabling ActivitiesIND Enabling Activities– Preclinical Pharmacological

Characterization – Proof of ConceptP li i l T Ch t i ti – Preclinical Tox Characterization –Proof of Safety

– Chemistry and Manufacturing Chemistry and Manufacturing – Clinical Development Plan– PK Characterization – Metabolism,

F tFate– Target Indication Definition

• Measure

IND Development: Drug Substance - API

• Synthesis• Reliable supply• Quality of Supply Reproducibility• Quality of Supply – Reproducibility• Stability• Impurities

IND Development : Preclinical Pharmacology

• Proof of Concept• Mechanism of Action• Target• Target• Characterisation of possible “class”off target

effectsb b• Absorbtion

• Distribution• Metabolism• Excretion

IND Development : Preclinical Toxicology

• Genotox• Cellular Toxicities• Whole Animal Studies• Whole Animal Studies• Tox Characterisation of major impurities and

metabolitesh h ld bl l d• Threshold toxicity to enable investigational study (i.e.

Gating: Filing Readiness - IND • You have a compound with a justified proof of

concept• You have conducted the minimal required animal • You have conducted the minimal required animal

toxicology testing• You have a dosage form that is chemically

h dcharacterized• The dosage form has demonstrated stability for

the proposed duration of initial clinical testingp p g• To initiate testing of safety and efficacy in

humans..you need to open an IND….

Strategic Approaches to Development • Target

• (Pre-IND Meeting)• IND Filing

– Chemical Characterization (API, DPI) to support Clinical Developmentsupport Clinical Development

– Protocol/Investigator/Clinical Development Plan

– Phase 1 : Gross Safety– Phase 2 : Dose Finding / Optimization

h l l ( )– Phase 3 : Pivotal Trials (2)• Measure

IND Support: Initiation of Clinical (Trials)

• Enabling work Complete• IND filed and “may proceed”• Clinical Dosage Form Developed • Clinical Dosage Form Developed • Stability Consistent with longest proposed trial• Clinical packaging

l l l• Clinical Trials– Phase 1– Phase 2– Phase 3– Phase 4

Clinical Research Basics• Clinical Development Plan (volatile..)

– Established Protocol – Qualified InvestigatorQualified Investigator– Prospective Analysis Plan….

• Phase 1: safety of product in small numbers of healthy volunteers (n=20-80)

• Phase 2: efficacy and safety in small number of Phase 2: efficacy and safety in small number of patients with target indicated condition – dose range finding (n =100 – 300)

• Phase 3: Pivotal market enabling trials – Safety Phase 3: Pivotal market enabling trials Safety and efficacy compared to PBO and/or standard of care (n = 1,000 – 3,000)

• Phase 4: Postmarketing Studies Phase 4: Postmarketing Studies

A word on endpoints• Proper choice of endpoint (or outcome measured

following intervention) is PIVOTAL

• A primary efficacy endpoint must be something that has a substantial impact on the course of the

d d h ’ ll btarget disease, and the patient’s well-being

• There needs to be a validated way to measure ythis outcome

Clinical Stage Gating• Phase 1 – no untoward effects, acceptable

kinetics• Phase 2 Supports dose selection• Phase 2 – Supports dose selection• Phase 3 – Supports S&E in endpoints related to

intended indication, and in target patient lpopulation

Pre NDA• CMC full scale up and final production process

validation• Container / Closure• Container / Closure• Shelf life supporting stability• Proposed labeling

d b d d• Agreement on data sets to be presented and manner of presentation

Strategic Approaches to Development • NDA Filing

– Chemistry / Manufacturing Scale Up– Preclinical Analyses– Preclinical Analyses– Clinical Analyses (safety, efficacy)– Integrated Analysis -- Labeling

P t l A ti• Postapproval Actions– Risk Mitigation – Post approval Measure

Marketing Approval Applications• MAA – Marketing Authorization Application - EU

– Registration documents seeking approval to market a drug product Ex-US A general term for a drug product Ex-US. A general term for registration document. In EU, the MAA implies a document used for multi-national submission as opposed to seeking approval in one specific opposed to seeking approval in one specific country.

• NDA – New Drug Application - USAR i t ti d t ki l t k t – Registration document seeking approval to market a drug product (NOT biological product).

• BLA – Biological License Application – USA– Think NDA for a biological drug product.– Heavily focused on process

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Marketing Approval ApplicationsUS• NDA – New Drug Application

– 505(b)(1), 505(b)(2)– 505(b)(2),

– 505(j) ANDA - Abbreviated New Drug Application

• BLA – Biologic License Application• BLA Biologic License ApplicationEU• MAA – Marketing Authorization Application• CTD – Common Technical Document;

– Harmonized common format for organization of information in marketing authorization (registration) applications.

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Endgame: Label Development• Label—The label is the document physically attached

directly to the packaging materials that are in direct contact with the excipient, drug substance, or drug product.

• Labeling—Labeling includes the label and the documents included with, but not attached to, the packaging mate ials that a e in di ect contact ith the packaging materials that are in direct contact with the excipient, drug substance, or preparation (e.g., package insert).

Label and labeling define the claims made for the drug product in terms of the target for use and the intended patient populationpatient population

It is directly substantiated by the integration of all clinical data

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Strategic Approaches to Development • Target Identification

– Analysis -- Labeling • Postapproval Actionspp

– Risk Mitigation – Post approval Measure

Schematic of FDA Development and Review Review

NDA Review Steps Simplified• Preclinical (animal) testing is completed.• API and DP is initially characterized • Pre IND Meeting held.• Investigational new drug application (IND) supports

initiationof human testing in clinical trials.• Chemistry and Manufacturing is further characterized

P e NDA meeting held • Pre-NDA meeting held • NDA Submission • NDA Acceptance -- FDA has 60 days to decide

whether to file it so it can be reviewedwhether to file it so it can be reviewed.• FDA “files” the NDA, an FDA review team is assigned• The FDA reviews S/E information and adjudicates to

proposed professional labeling proposed professional labeling • The FDA inspects the facilities where the drug will be

manufactured • FDA approves application, or issue a complete

response letter.

Bumps in the RoadIf FDA review supports the benefits of a drug outweigh the known risks, the drug will receive approval.

Common impediments:

• Unexpected safety issuesF il t d t t ff ti• Failure to demonstrate effectiveness.

• Need additional studies--more people, different types of people, a longer period of time.

• Manufacturing issues. Manufacturing issues. • Drug for clinical trials does not match market product. • Scale up, supplier or quality control issues • MOST OFTEN a combination of problems that prevent

approvalapproval.

FDA outlines the justification for its decision in a complete response letter to the drug sponsor.

Remember the intangibles…• Drug /Biotech Development requires cutting edge

science, but that’s not all its about• Regulation is supported by science, but science and

l ti ft t g pp y ,

regulation often part company• Industry and academic groups lead (and precede)

regulation• Novelty lowers hurdles for approval, but often

complicates review process• Product is defined (both) by its active, and the

associated claims of actionassociated claims of action• Product needs to have a meaningful clinical effect• Burden of proof is always on the sponsorBurden of proof is always on the sponsor• Never, Ever, Forget the value of Regulator

relationship

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Thoughts on Innovation Breakdown • Promising drugs are not being developed because

of the expense and risk of developing them.• Promising acquisitions are not made because of • Promising acquisitions are not made because of

unacceptable/ un-evaluable Regulatory Risk• The promise of great candidate products is being

b d b f f hobscured by focus of their presentation • FDA is unpredictable and risk averse

Thoughts on Innovation Breakdown • The only way to promote innovation is to de-risk

development• This will require new approached to • This will require new approached to

– Target Choice– Testing Standards– Data Collection– Evaluation

• A “disruptive” approach to “de-Risk”

Innovation Risk influences Value Inflection Points

Development Stage Acquisition Cost Development Stage• Discovery• Proof of Concept

Acquisition Cost • $• $$

• First in Human• End of Phase 2• Pre-NDA

• $$$• $$$$• $$$$$

• Post Approval • $$$$$$$$$$

"It must be considered that there is nothing more difficult to carry out, nor more doubtful of success nor dangerous to handle, than to initiate a new order of things.

Niccolo Machiavelli, 1513