Early  Compound  Development  Programs  –The  Need  for  Translational  Medicine  and  Proven  Strategies

Luana Pesco Koplowitz, MD, PhD, FCP, FFPMPresident and Chief Medical & Scientific Officer

DUCK FLATS Pharma, LLCElbridge, New York, USA

Adjunct Assistant Professor of MedicineUniversity of Delaware School of Medicine, Wilmington, Delaware, USA

University of Miami School of Medicine, Miami, Florida, USADepartment of Clinical Pharmacology

Member of FDA Cardiac Safety Research Consortium

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Translational  Medicine  OverviewA new chemical entity (NCE) or biotechnology compound development program almost always includes translational medicine as part of the development strategy.

These areas include:

• Pharmacology

• Toxicology

• Pharmacokinetics (PK)

• Absorption, Distribution, Metabolism, Excretion (ADME) Studies

• Early clinical research (Phase 1A/1B/2A studies)

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Translational  Medicine  OverviewAll components of the development program need to work together to address the preliminary efficacy and safety of a compound. This may also be necessary in certain new applications of older approved compounds being used at different doses or in different patient populations.

This presentation will:

• Explore the various areas that contribute to the field of translational medicine

• Describe how a successful development program can ultimately help a compound reach successful regulatory approval and marketing

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Translational  Medicine  OverviewKey Roles of Translational Medicine:

• Excellent Research & Development (R & D)

• Use of biomarkers/exploratory development

• Adaptive clinical trial design

• May mix Phase 1 and Phase 2: Use of healthy volunteers and patients in SAD/MAD studies

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Drug  Designations

Chemical Entities and Biologics:• New Molecular Entity (NME)• Biologic (Large Molecules)

• Approved Compoundo New Formulation, Indication, or Dosing Regimen

• Orphan Drug

• Breakthrough Therapy

• First-time Generics

Biologic drug candidates are reviewed by the FDA via a biologic licensing application (BLA) or product-licensing application. Chemical and small-peptide derivatives go through the NDA (CTD) review process.

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Drug  Approvals  – NDAs  &  BLAs

Product 2007 20131st time Generic Drugs 99 106

New Molecular Entities (NME) 16 27

Biologics 2 18

Orphan Drugs 8 31

Breakthrough Therapies N/A 3

Comparison of Drug Approvals by Year

(Source: Center for Drug Evaluation and Research Update, US Department of Health and Human Services, Food and Drug Administration, 2007, 2013)

The drug designation and/or therapeutic area can impact the overall approval timeline and costs.

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Drug  Approval  Timeline

NOTE: Data from drugs approved since 2000, excludes those drugs without a clearly defined therapeutic area.(Source: FDA and EMA websites, BCG analysis; Karst 2012)

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Therapeutic  Areas  and  Treatment

Orphan Drugs

• Designated for any disease that affects fewer than 200,000 people in the US1

• Collectively these diseases affect as many as 25 million Americans1

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Therapeutic  Areas  and  TreatmentOncology Indications

• Cancer Prevalence: In 2011, it was estimated that over 13.4 million people were living with cancer in the US2.

• An estimated 224,210 Americans will be diagnosed with lung cancer; it is the leading cause of cancer-related deaths for both men and women3.o About 85% of lung cancers are non-small cell lung cancer (NSCLC),

making it the most common type of lung cancer3. § Approximately 2-7% are patients with metastatic anaplastic lymphoma kinase

(ALK) positive NSCLC3

o Two ALK tyrosine kinase inhibitor drugs approved for treatment, XALKORI® Xalkori® (crizotinib) and Zykadia™ (ceritinib)

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Therapeutic  Areas  and  Treatment

Pediatric Indications

• Population is defined as persons who are age 21 years or younger at the time of their diagnosis or treatment.

• Before the Food and Drug Administration initiated a pediatric program, only about 20 percent of drugs approved by the FDA were labeled for pediatric use4.

• Recent pediatric drug studies have resulted in the addition of pediatric information to the labeling for more than 80 drugs.

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Therapeutic  Areas  and  TreatmentBreakthrough Therapies• New drug that addresses unmet medical need for treatment of

serious or life-threatening condition.

• Chronic lymphocytic leukemia (CLL)o Accounts for about one-third of all cases of leukemiao About 15,720 new cases of CLL in the US5

o Gazyva™ (obinutuzumab) - first breakthrough designation drug approved by FDA

• Hepatitis Co Affects approximately 3 to 4 million Americans6

o Sovaldi® (sofosbuvir) approved via breakthrough designation route§ Vastly fewer side effects than interferon therapies

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Translational  Medicine  – Drug  DevelopmentThe “right” way of drug development is often not the easiest.

Translational Medicine:

• The bottleneck between basic research and clinical benefit/safety

• Critical to the Go/No Go decision

• Allows successful programs to accelerate and sub-optimal programs to fail earlyo Failures must be reported!

• Successful program could impact other areas such as CMC

• Decision to accelerate a clinical development program might now mean that product development becomes the rate-limiting step: Need to balance these objectives.

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Translational  Medicine  – Drug  Development

Translational Medicine

• Preclinical studieso In animalso Proposal for testing in humans

• Submission and Acceptance of IND

• Phase 1 Studieso Safety, PK, Initial Efficacy, Biomarkers, Surrogate Endpoints

• Phase 2 Studieso Proof of Principle (POP), Dose-Ranging, Dose-Response

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Translational  Medicine  – Drug  Development

The following must also be considered:

• Medical viability

• Commercial viability

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Translational  Medicine  – Drug  Development

Medical Viability:

• Will medical community accept as the standard of care?

• Will doctor prescribe it?

• Will patient take it/think treatment is worthwhile?

Commercial Viability:

• Can the Sponsor company sell the product?

• Does the cost justify the price?

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Translational  Medicine  to  Clinical  Development

Troubles in Clinical Development Programs:

• Difficult therapeutic areas

• Higher regulatory standards

• As of 2010, Phase 3 failures still 20%-30%

• Cost and time

o It typically takes 12 years from the moment of discovery in the laboratory for a potential new therapy to gain approval for use and reach patients. The average cost of bringing a new therapy to market is $1.2 billion dollars7, with most of the money invested in R & D.

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Present  Drug  Development  Paradigm

• Limited, early exploratory IND studies in humans

o Conducted early in Phase 1

o Involves very limited human exposure

o Has no therapeutic or diagnostic intent (eg, screening studies)

• Proof of Concept (POC) Studies Conducted as Early as Possible

• Bulk of Supportive Phase 1 Clinical Program Conducted During Late Phase 2/Early Phase 3 Program

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Present  Drug  Development  Paradigm

Clinical Trial Phases and Parameters

Phase Purpose Study Parameters and Population

1 Metabolism, Safety,Pharmacologic actions

• Initial drug introduction into patients or healthy volunteers

• 20 to 80 subjects/patients2 Efficacy, Dose-Ranging and

Response• Patients with disease• No more than several hundred subjects

3 Confirmation of Safety and Efficacy • Several hundred to several thousand subjects• Control group (placebo or active control) and

experimental group4 Further evaluation of safety and

effectiveness (post-approval)• Several hundred to several thousand subjects

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Key  Areas  of  Translational  Medicine

• Bioanalytical Methods

• Non-Clinical Pharmacology

• Toxicology

• Safety Pharmacology

• Drug to Drug Interactions (DDI)

• PK/ADME/Transporter Studies

Non-­Clinical  Components

Clinical  ComponentsPhase 1 Studies• Safety• PK• Initial Efficacy• Biomarkers• Surrogate Endpoints

Phase 2 Studies• Proof of Principle (POP)• Dose-Ranging• Dose-Response

Key  Component  for  Both  =  PredictabilityKey  Component  for  Both  =  Predictability

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Non-­Clinical  ComponentsThe path to drug development is different for biologics (biopharmaceuticals) due to the complexity of their large protein molecules. The preclinical and clinical testing for biotechnology products differs from that of chemical compounds as the biological molecules extracted from tissues or purified from recombinant cells require additional processes.

Recent advances in science, technology, and testing have led to revisions to existing regulatory guidances regarding drug development and safety:

• Chromatographic Methods • Biomarkers

• Ligand Binding Assays (LBA) • Diagnostic Kits

• Transporter/Enzyme Interactions • Metabolite Exposure

It is therefore crucial for drug developers to ensure they are adhering to the latest guidelines to avoid possible delays or denials of their drug application.

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Non-­Clinical  Pharmacology

• Non-GLP

• GLP

• Relevant Animal Species

• Exposure-Response Data

ICH Guidelines (Step 5, FDA adoption)o 2010: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials

and Marketing Authorization for Pharmaceuticals

o 2010: S9 Nonclinical Evaluation for Anticancer Pharmaceuticals

o 2013: M3(R2) Questions & Answers (R2)

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Bioanalytical  Methods• Validation• Concentration Ranges (Pharmacology/Toxicology vs. Clinical)

The CDER Guidance for Industry, Bioanalytical Method Validation, is currently undergoing revision (Draft, Revision 1, September 2013) to address advances in testing methods. As it pertains to Chromatographic Methods and LBAs, emphasis has been placed on the assay differences to:

o Differentiate lower limit of quantification (LLOQ) and upper limit of quantification (ULOQ) measurements for accuracy, precision, and calibration curves

o Expand on matrix interaction differences

o Clarify stability, sampling, and stock solutions

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Bioanalytical  Methods

Additional Guidance Revisions

New sections to address issues and technology updates:

• Endogenous Compounds

• Biomarkers

• Diagnostic Kits

• Dried Blood Spot (DBS) Methodology

Generally, the use and submission of data based on new technologies should be supported with data generated by established technology, until the new approaches become accepted practice.

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Toxicology

Preclinical toxicity testing on various biological systems reveals the species-, organ- and dose- specific toxic effects of an investigational product.

Testing should be conducted with the following in mind:

• Two (2) Species Required (one rodent and one non-rodent)

• Minimum: Single Doseo Duration of repeated dose toxicity studies are usually related to the

duration, therapeutic indication, and scope of the proposed clinical trial

• Program Dependent on Clinical Program

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Safety  Pharmacology

Safety pharmacology studies should be conducted to assess the effects on the cardiovascular, central nervous, and respiratory systems.

Hepatic safety testing may also be included.

• In Vitro

• In Vivo

If needed, additional follow-up testing can be conducted during later clinical development.

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Safety  and  Efficacy  – Drug  Metabolites

Drug Metabolites in Safety Testing (MIST)Required Safety Studies

General Toxicity• Animal exposure should be ≥ than human exposure (at minimum)

• Route of administration should be the same as the planned human route, unless an alternative route is needed to obtain exposure

• Adhere to latest ICH M3(R2) guideline

Genotoxicity• Minimum: In Vitro assays to detect point mutations and chromosomal

aberrations

• A positive result triggers the full battery of tests under ICH S2(R1) guideline

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Safety  and  Efficacy  – Drug  Metabolites

MIST Required Safety Studies (continued)

Embryo-Fetal Development Toxicity• Required if drug will be used in women of child-bearing potential

• Additional reproductive toxicity studies may be required

• Adhere to latest ICH S5(R2) guideline

Carcinogenicity• Needed if drug will be administered continuously for ≥6 months or if used

for the treatment of chronic or recurrent conditions

• Adhere to latest ICH S1A, S1B, and S1C(R2) guidelines

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Safety  and  Efficacy  – Drug  Metabolites

MIST

The guidelines require the nonclinical safety assessment of disproportionate human metabolites• Where “disproportionate” refers to any metabolite that is present in

humans at levels higher than at least one of the species used in the nonclinical safety assessment

Thresholds for safety assessment:• Revised: Metabolite exposure >10% of the systemic, single-dose exposure

of drug-related material

• Alternative thresholds may also relate (on a case-by-case basis) to metabolites that are disproportionate relative to their urinary or biliary excretion

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Safety  and  Efficacy  – Drug  Metabolites

MISTExclusions• Not required for cancer drugs (ICH S9 guideline)

• Exceptions may also be made for other serious, life-threatening diseases on a case-by-case basis

Timing• Safety studies should be completed prior to initiation of large-scale

clinical trials• Requires early identification of disproportionate metabolites to

avoid delays in development

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• In Vitro

• In Vivo

• Rat tissue distribution

• CYP450 Isozymes

PK/ADME  Studies

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In  Vitro Drug-­Drug  Interaction  StudiesStudies are necessary for an early understanding of drug clearance and human metabolism (whether a DDI potential exists) and if a DDI requires dose adjustment, therapeutic monitoring, or contraindication to concomitant use.Additional work recommended by the 2012 FDA DDI Draft Guidance:• Evaluation of metabolites ≥25% of parent drug AUC

• Evaluation for potential complex DDI if multiple enzymes together account for ≥25% of systemic clearance

• Enzyme identification studies for CYPs (7-11 enzymes), UGTs (7 enzymes), and non-CYP Phase 1 (≥4 enzymes)

• Inhibition studies for 7 CYPs and induction studies for 3 CYPs

• Substrate and inhibition studies for 7 transporters

• Greatly-increased role for PBPK modeling/less focus on detailed in vitro methodology

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In  Vitro Drug-­Drug  Interaction  Studies

NCE as substrate of transporters:• All NCEs to be tested as substrates of P-glycoprotein 1 (P-gp) and breast

cancer resistance protein (BCRP)

• Also organic anion transporter (OAT):o OATP1B1, OATP1B3 (if hepatic or biliary clearance is ≥25% of total clearance;

(i.e., most drugs)o OAT1, OAT3, and OCT2 (if renal clearance is ≥25% of total clearance)

NCE as inhibitor or inducer of transporters:• Inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2

• Other transporters [e.g., multi-drug resistance protein (MRPs), multi-drug and toxic compound extrusion (MATE), bile salt export pump (BSEP)] based on drug class, observed unexpected DDIs, or as new assays become available

• Validated in vitro transporter induction assays not yet available

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US  FDA  Submission  with  Ex-­US  Clinical  Data

• Pre-IND meeting

• File US INDo Goes into effect 30 days after FDA receives it unless

investigations in the IND are subject to a clinical hold

• Prepare Phase 1B or Phase 2A/2B Program

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Clinical  Components

• Phase 1 clinical studies

• Phase 2 clinical studies

In a 10-year review of Investigational Medical Products (IMPs)only 60% progressed from Phase 1 to 2 and only

11% became a marketed product8.

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First-­in-­Human  Study

• Calculation of first dose

• Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) Studies

• Metabolism 14-C

• Safety/Cardiac Safety

• PK and/or PD/Efficacy Data

• Patients vs. Normal Volunteers

• Men vs. Women

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Phase  2  POC/POP  Clinical  Program

• Efficacy in Labeled Patient Population

• PK/PD in Patients

• PK/Safety Data in Patients

• PK/Efficacy

• Dose-Ranging/Dose Response in Patients

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Drug  Approval  DelaysNDA submission can be delayed if there are problems with the application or if more information is necessary to make an approval determination. Common problems include:• Unexpected safety issues

• Failure to demonstrate a drug's effectiveness

• Manufacturing issueso Non-compliance with good manufacturing practices (GMP)o Facility not ready for inspection

• Differences in drug manufactured for clinical trials vs. scale-upo Loss of a supplier/quality control issues

Close communication with the FDA early on in a drug's development is key to reducing the chance that an application will have to go through more than one cycle of review.

Thank  You!谢谢

Thank  You!谢谢

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DUCK FLATS Pharma, LLCElbridge, New York

USA

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Citations1. FDA. Orphan Products: Hope for People With Rare Diseases. Accessed 04/29/2014. Available from:

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143563.htm

2. National Cancer Institute. SEER Stat Fact Sheets: All Cancer Sites. Accessed 04/30/2014. Available from: http://seer.cancer.gov/statfacts/html/all.html

3. FDA. FDA News Release 04/29/2014. Accessed 04/30/2014. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm395299.htm

4. Food and Drug Administration (FDA). Drug Research and Children. Accessed 4/30/2014.http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143565.htm

5. American Cancer Society website. Leukemia--Chronic Lymphocytic Overview. Accessed 04/30/2014. Available from: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/overviewguide/leukemia-cll-overview-key-statistics

6. Donahue, M. High Price of Gilead's Sovaldi Could Deter Early Hep C Treatment. PharmExecBlog. Published: April 24, 2014. Accessed 04/30/2014. Available from: http://blog.pharmexec.com/

7. Pfizer. Phases of Development. Accessed 04/03/2014. Available from: http://www.pfizer.com/research/clinical_trials/phases_of_development

8. Febbraro, S. Safety in FIH Studies. Simbec presentation for Exploratory Clinical Development World. June 2014.

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ReferencesALS Association website. Accessed 04/30/2014. Available from: http://www.alsa.org/about-als/facts-you-should-know.html

American Cancer Society website. Leukemia--Chronic Lymphocytic Overview. Accessed 04/30/2014. Available from: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/overviewguide/leukemia-cll-overview-key-statistics

Bipeta, R.; Yerramilli, S. SRR; Pingali, S.; Karredla, A. R.; and Ali; M. O . A cross-sectional study of insight and family accommodation in pediatric obsessive-compulsive disorder. Child and Adolescent Psychiatry and Mental Health 2013, 7:20. DOI:10.1186/1753-2000-7-20. Accessed 04/30/2014. Available from:http://www.capmh.com/content/7/1/20#B2

Center for Drug Evaluation and Research Update, US Department of Health and Human Services, Food and Drug Administration, 2007, http://www.fda.gov/Drugs/NewsEvents/ucm130961.htm, http://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/default.htm

Food and Drug Administration (FDA). Drug Research and Children. Accessed 4/30/2014.http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143565.htm

FDA. Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review Expediting Availability of New Drugs for Patients with Serious Conditions. Accessed 04/01/2014 Available from: http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/speedingaccesstoimportantnewtherapies/ucm128291.htm

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ReferencesFDA. FDA News Release 04/29/2014. Accessed 04/30/2014. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm395299.htm

FDA. Orphan Products: Hope for People With Rare Diseases. Accessed 04/29/2014. Available from: http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143563.htm

Ho, Rodney J. Y, PhD. Distinctions of Biologic Versus Small Molecule Platforms in Drug Development. Biotechnology and Biopharmaceuticals: Transforming Proteins and Genes into Drugs. Published Online: 25 OCT 2013. DOI: 10.1002/9781118660485.ch2.

Karst, K. New Reports on FDA Drug Approval Performance Emerge as House Committee Considers User Fee Reauthorization Legislation. May 10, 2012. Accessed 04/02/2014. Available from: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2012/05/new-reports-on-fda-drug-approval-performance-emerge-as-house-committee-considers-user-fee-reauthoriz.html

National Cancer Institute. SEER Stat Fact Sheets: All Cancer Sites. Accessed 04/30/2014. Available from: http://seer.cancer.gov/statfacts/html/all.html

Pfizer. Phases of Development. Accessed 04/03/2014. Available from: http://www.pfizer.com/research/clinical_trials/phases_of_development

Wang, H.F. PhD. What’s Unique about Ligand Binding Assay Bioanalysis and What Have We Learned from Outsourcing? Pharmaceutical Outsourcing. Posted: May 01, 2010 (accessed 10/2013). Available from: http://www.pharmoutsourcing.com

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ReferencesCDER, EMA, FDA, and ICH Guidances:

Center for Drug Evaluation and Research (CDER). Bioanalytical Method Validation. May 2001. Available from: http://www.fda.gov/cvm.

CDER. Bioanalytical Method Validation. Draft (Revision 1) September 2013.

CDER. Expedited Programs for Serious Conditions – Drugs and Biologics. June 2013 (Draft).

European Medicines Agency (EMA). Guideline on Bioanalytical Method Validation. 21 July 2011.

EMA. Guideline on the Investigation of Drug Interactions (Revised) 2012.

FDA. Drug Interaction Studies — Study Design, Data Analysis, and Implications for Dosing and Labeling (Draft) 2006.

FDA. Safety Testing of Drug Metabolites. 2008

FDA. Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations (Revised Draft) 2012.

International Conference on Harmonisation (ICH). Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. M3(R2) 2010, M3(R2) Q&A (R2) 2013.

ICH. S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. 2010.

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Back-­up  SlidesTherapeutic Areas and Treatment

In Vitro Drug-Drug Interaction Studies

End-of-Phase 2 Meeting

Additional Critical Development Functions

NDA

Drug Approval Designations

Phase 3 Studies to Marketing

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Therapeutic  Areas  and  Treatment

Orphan Drugs: Example• Amyotrophic lateral sclerosis (ALS)/Lou Gehrig's Disease

o Approximately 5,600 people in the U.S. are diagnosed with ALS each year.

o It is estimated that as many as 30,000 Americans may have the disease at any given time.

o FDA approved the first drug treatment for the disease, Rilutek, in 1995.

(Sources: FDA. Orphan Products: Hope for People With Rare Diseases. ALS Association website)

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Therapeutic  Areas  and  Treatment

Pediatric Indications: Example

• Childhood obsessive-compulsive disorder (OCD)o Estimated to affect 1 to 4% of the populationo Four OCD medicines approved by the FDA for use in children:

Anafranil, Prozac, Luvox, and Zoloft

(Sources: FDA. Drug Research and Children. Bipeta, et al, 2013)

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In  Vitro Drug-­Drug  Interaction  Studies

Enzyme/ Transporter NCEas Substrate

NCEas Inhibitor

NCEas Inducer

CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4

Yes Yes 1A2, 2B6, 3A4 (2C)

CYP2A6, 2J2, 4F2, 2E1 Case-by-Case As Available As Available

MAO, FMO, XO, A/ADH Case-by-Case As Available As Available

UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B15

Yes In Vivo As Available

P-gp, BCRP Yes Yes Not Available

OATP1B1/B3, OAT1/3, OCT2

Yes Yes Not Available

MRPs, MATE, BSEP Case-by-Case As Available Not Available

Overview of Recommended Enzyme/Transporter Testing

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In  Vitro Drug-­Drug  Interaction  StudiesThe effect of concomitant drugs on the metabolism of NCEs:• Evaluate if a single enzyme accounts for ≥25% of clearance in humans -

OR- if multiple enzymes together account for ≥25% of clearance

• Need to consider P450s CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A and UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B15

• Consider case-by-case CYP2A6, 2J2, 4F2, and 2E1 and other non-CYP Phase 1 enzymes (MAO, FMO, XO, alcohol/aldehyde dehydrogenase)

• Complex DDI: Consider minor elimination pathways in special populations (renal/hepatic impairment, polymorphic enzyme responsible for major pathway, subjects on strong inducer of minor pathway)

• Complex DDI: Additional assessment if NCE is metabolized by polymorphic enzyme (CYP2D6, 2C9, 2C19, UGT1A1)

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In  Vitro Drug-­Drug  Interaction  StudiesThe effect of NCEs on concomitant drugs via inhibition:• Need to consider CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4

• Reversible and time dependent inhibition (TDI)

• Basic models (conservative approach)o Reversible: R1 = 1 + [I]/Ki (where I is steady-state Cmax total and Ki is unbound) o TDI: R2 = (Kobs+Kdeg)/Kdeg (where Kobs = (kinact[I])/(Ki+I)]

• If R>1.1 (R>11 for oral CYP3A inhibitors), recommend in vivo study and/or thorough evaluation using mechanistic PBPK dynamic model

The effect of NCEs on concomitant drugs via induction:• Consider CYP1A2 (AhR), 2B6 (CAR), 3A4 (PXR), and CYP2C (if 3A4

positive)

• Measure mRNA change in hepatocytes (n=3 donors) rather than CYP activity

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End-­of-­Phase  2  Meeting

• Prepare for Phase 3 program

• Obtain FDA agreement on efficacy parameters and statistical analyses

• Obtain FDA agreement on supportive Phase 1/Phase 2 clinical program and rest of nonclinical development program

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Additional  Critical  Development  Functions• Project Management

• Non-clinical and Clinical Trial Management

• Product Development

• Regulatory Affairs (Operations)

• Pharmacovigilance

• Data Management/IT Functions

• Medical/Scientific Writing

• QA/QC

• Pharmacokinetics

• Statistics

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NDA

• Final Efficacy/Safety(Integrated Summary of Efficacy/Integrated Summary of Safety)

• Supportive Clinical Pharmacology Packageo Overall PK and PK/PD Analyseso POP PK

• Adequate Toxicology Package

• CMC Package

• Package Insert/Label

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Drug  Approval  DesignationsIn accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90% of NDAs for standard drugs no later than 10 months after the applications are received. The review goal is six months for priority drugs.

• Accelerated Approval: Approval based on a surrogate endpoint; drugs for serious conditions that fill an unmet medical need.NOTE: In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint.

• Breakthrough Therapy: Expedites the development and review of drugs that are intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

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Drug  Approval  Designations• Fast Track: Facilitates the development and expedites the review of

drugs to treat serious conditions and fill an unmet medical need.

• Priority Review: Action taken on an application within 6 months . Directs overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications.NOTE: FDA decides on the review designation for every application. However, an applicant may expressly request priority review as described in the Guidance for Industry, Expedited Programs for Serious Conditions – Drugs and Biologics.

• Standard Review: Designation means FDA’s goal is to take action on an application within 10 months.

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Drug  Development  to  Marketing  -­ Overview

Phase 3 Studies to Marketing

• FDA/Sponsor determine conduction of Phase 3 studies

• Phase 3 Studies

• NDA Submission (FDA has 60 days to decide whether to file for review)

• FDA Review

• Application Approval

• Phase 4 (post-approval, marketed drug studies)