505(b)(2) opportunities for swedish biotechs: strategies

505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines

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7 December 2017

505(b)(2) Opportunities for Swedish Biotechs:

Strategies for Repurposing Known Medicines


Agenda:

What is a 505(b)(2)?

Why would you want to use it?

What products qualify?

What is the development program?

How do I lower my FDA uncertainty (risk?)

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Potential U.S. Regulatory PathwaysSmall Molecules

Type

505(b)(1) ‘Full’ Application – Data obtained from studies conducted by the Sponsor

505(b)(2) Data obtained from public data plus Sponsor studies

505j Generics - Products that are the same as U.S. - approved products

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Defining the 505(b)(2) Application

A 505(b)(2) application is one for which one or more of the investigations relied upon by the applicant for approval "were not conducted by or for

the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations

were conducted" (21 U.S.C. 355(b)(2)).

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Is it a 505(b)(2)?

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Your Idea

&

or

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505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 6

Why would you want to use 505(b)(2)?


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44

29

35

27

33

38

29

43

3739

4345 45*

63*

0

10

20

30

40

50

60

70

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Market Acceptance and Growth505(b)(2) Approvals by Year


Probability of Success by Stage

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Phase 1 to 2 Phase 2 to 3 Phase 3 to NDAFiling

NDA Approval Phase 1 to NDAApproval

New Molecular Entity 505(b)(2)

Source: Clinical Development Success Rates 2006 – 2015. A report by BIO (Biotechnology Innovation Organization), Biomedtracker, and Amplion. 2016


Median = 379 days

0

500

1000

1500

2000

2500

0 100 200 300 400 500

Days

NDAs in Chronological Order of Approval

505(b)(2) NDA Approval Times

Median


Average Revenue per 505(b)(2)-Approved Productby Launch Date


Product Selection

Launch-Aligned Monthly TRx’s Recent AED Launches

505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines12

What are the key

drivers impacting

patient, prescriber &

payer behaviors?

How can this

product disrupt the

current market

space?

What needs

are not being

met with

current

product

offerings?

Listed Drug

Product Selection

Differentiated Drug

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Commercial

Regulatory

Medical

Scientific

Strategic Drug Development

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15

MedicalTarget Product Profile

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Patient Journey


Is the perceived need, a recognized unmet need?

What is the the future target audience and how do they think about the therapeutic space?

Medical


• Map and roughly quantify the customer/patient journey

• What is happening with the consumer before they talk with an

HCP?

• When and how do they present to the HCP as a patient?

• What tests, questions, procedures are critical to the HCP making

the diagnosis and how is this communicated to the patient?

• Does treatment occur or is there a referral

• How and when are current products used and why?

• Do patients follow the HCP recommendation, how does fulfillment

occur and what drives adherence and persistency?

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Pre-Origination

Origination

Evaluation / Diagnosis

Treatment / Class

Class / Brand Choice

Fulfillment /

Compliance

➢ Identifies where the opportunity exists for your product and the key leverage points

that can drive the strategic choices for the product.

➢ Not a forecast, but informs one.

How do you obtain insights and

what do they tell you about the patient journey?

Medical



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Early commercial opportunity assessment can help guide not only candidate selection, but also protocol design

Candidate

Selection

• Unmet need

• Competitive set

• Market opportunity

Protocol Design

• Clin/Reg Team focuses on approval

• Commercial Team focuses on the

• Scientific narrative

• Future marketing claims

Product Claims

• “Base case” claims

• Differentiated claims

• Why are these important

• To whom?

2020


Understanding the patient journey helps you to identify key

customers who will influence decision making and product

choice, based upon where interaction occurs

– Dig deep and seek to qualitatively understand behaviors and

needs of your future customers

• HCPs- FP/GP/Specialists/NP and PA/hospitalists

• Caregivers

• Patients

• Payer- Commercial, Government

• Distributers- Wholesaler, Specialty Pharmacy

• Policy Developers and Influencers

• Advocacy Organizations

Commercial


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Strategic Assessment Will Outline the Path to Market

Path to market

• Product opportunity

• Competitive landscape

• Situation analysis

Product Valuation

• Thought leader

• Patient

• Payer

• Prescriber

• Value

Proposition

• Forecast

• Infrastructure

& budget

to launch

Competitive Assessment

Stakeholder Feedback

Critical Success Factor:

Compelling Commercial Story

Identify value propositions that

resonate for successful

commercial launches

Commercial



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Regulatory

• Indication

• What public information can be relied on?

• What studies need to be conducted

• When?

• How?

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What is public?

Your Development Program

FDA Requirements

for NDA Approval

Regulatory

Your Path

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Public Information

Regulatory

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Repurposed Drug

505(b)(2)New Drug

505(b)(1)

Regulatory

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Levels of Evidence

The rank-order for all publicly-available information is as

follows:

• Agency’s findings of safety and efficacy for a Listed Drug

from the approved product labeling

• Final OTC monograph

• Inactive Ingredient Database (IID) (for excipients)

• Literature/credible public databases

Blinded provide higher level of evidence than open-label trials:

1. Placebo-controlled trials

2. Dose-response trials

3. Active-controlled trials


FDA GuidancesRegulatory

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Public Sources• FDA 505(b)(2) Reviews

(Drugs@FDA)

• CenterWatch

• ClinicalTrials.gov

• NCI’s Cancer Clinical Trials Registry

• NIH

Regulatory

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What products qualify?



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• CMC must be at commercial stage at Phase 1

• Do NOT rely on CMO to establish your

specifications and protocols

Scientific

CMC failure is #1 reason products

do not get approved or launched

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New Chemical Entities

• Caffeine Citrate (1999) for primary apnea of premature

newborns

• Thalidomide (1998) for Erythema Nodosum Leprosum

• Benzyl Alcohol (1999) for Head Lice

• Bendamustine HCl (2008)

• Fospropol Disodium (2008)

• Gabapentin enacarbil (2011)

• Sodium picosulfate, magnesium oxide and citric acid for Oral

Solution (2012)

Drugs@FDA; www.camargoblog.com

Scientific

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New Chemical Entities


Scientific

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• Drugs approved outside U.S.

• Drugs developed outside U.S. and not approved


New Indications

Established Name Proprietary Name

Current indication/Route New indication/New Route

Acyclovir and Hydrocortisone Cream

Lipsovir herpes labialis for acyclovir and various skin

conditions for hydrocortisone

hydrocortisone was shown to treat herpes labialis

Tranexamic Acid Lysteda hemophilia for short-term use to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction /injection

treatment of cyclic heavy

menstrual bleeding/tablets

Ciprofloxacin HCl otic solution

Cetraxal Current products are combinations of ciprofloxacin with hydrocortisone or dexamethasone otic suspensions

Treatment of acute otitis externa due to susceptible isolates of Pseudomonas aerugenosa or Staphylococcus aureus.

Ibuprofen Lysine NeoProfen Pain/various routes Closure of clinically significant patent ductus arteriosus in premature infants/IV

Lidocaine and Tetracaine

Synera Lidocaine: dermal analgesia, etc. Tetracaine is an NME/various semi-solids

local dermal analgesia for superficial venous access and superficial dermatological procedures such as excision, electrodessication and shave biopsy of skin Lesions transdermal patch


Scientific

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Excipients

CIP-Fenofibrate:

• Three unique fenofibrate dosages: 50, 100 and 150 mg,

with the 150 mg strength equivalent to Tricor(R) 160 mg

under fed conditions.

• With CIP-Fenofibrate, the extent of absorption is

increased under high-fat conditions relative to low-fat

conditions

Cipher Pharmaceuticals, Inc. Press Release, 1/13/2006

Scientific

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Dosage Form Changes

• Propofol Lingual Spray (RLD=IV)

• ESTRASORB topical gel (RLD=Tablets)

• CAYSTON® Aztreonam for Inhalation

• Solution (from injectable). Indication change also.

http://sec.edgar-online.com/2005/09/23/0001144204-05-029785/Section8.asp

http://www.novavax.com/images/TWST%200205%20Final.pdf

Scientific

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2001

505(b)(2) NDA2007

505(b)(2) 0NDA > OTC

Fixed Dose Combination

Scientific

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Pharmacokinetic Alterations

• BA

• Targeted Release

• IR to ER

• Reduced variability

Scientific

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Patents only 28%

Excl only 11%

Both 29%

Neither 33%

505(b)(2)s With Patents and/or Exclusivity

209 NDAs approved 7/2012 - 6/2017


RLD 78%

Not RLD 22%

505(b)(2)s As Orange Book RLD

209 NDAs approved 7/2012 - 6/2017


Commercial

Regulatory

Medical

Scientific


Summary: The Importance of Early Strategic Design for Success

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How do I lower my FDA uncertainty ?


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505(b)(2) Process

FDA

OK?Start

ND

A S

ubm

issio

n

Clinical Trial Materials

Analytical Methods

Preclinical

Regulatory Process

Medical Communications

Feasibility Pre-IND Phase 3Form

ula

tion

Phase 2Phase 1

Stop

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What is a Successful Pre-IND Meeting?

• It’s about getting to Yes, not being right.

• You & FDA have a complete picture of your development

plan

– What you can rely on, what you cannot

– What studies you need to do

• Endpoint(s)

• Approximate design (sample size, comparator, arms, etc.)

• You have a reasonable idea of what the NDA will contain

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Research & Strategy

• 2-6 weeks

Meeting request

• 60 -120 days to meeting

Submission Package

Pre-IND Preliminary Comments

• 48-12 hours before meeting

PIND Meeting

FDA Meeting Minutes

• 30 days post-meeting

PIND Meeting Process

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505(b)(2) Process

Form

ula

tion

FDA

OK?Pre-INDand/or

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Experience with:

• 1 in 5 recent 505(b)(2) NDAs

• 30+ Orphan Drugs with 8 in process

• 80+ products in development

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About Camargo:

The Camargo Team:

• 40+ PhDs

• In-house staff experts

• Toxicology, pharmacokinetics, and CMC

• Current understanding of FDA thinking

Camargo works to reduce drug development costs

(time and money) and increase return on investment.

• Efficacy: Single clinical study conducted by the NIH(2)

• Safety: Literature, Clinical Trial, Clinical Trial Follow-up(3)

• Post-Approval: – Pharmacokinetic data on hydroxyprogesterone caproate and

its metabolites in plasma and urine of pregnant women

throughout different stages of gestation

– Confirmatory clinical trial that includes an appropriately

powered clinical endpoint of neonatal morbidity and mortality

Makena®17ɑ-hydroxyprogesterone caproate injection(1)

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1. http://blog.camargopharma.com/?p=1213

2. http://www.mombaby.org/PDF/MeisStudy2003.pdf

3. http://journals.lww.com/greenjournal/fulltext/2007/10000/follow_up_of_children_exposed_in_utero_to_17.21.aspx

http://blog.camargopharma.com/?p=1213

http://www.mombaby.org/PDF/MeisStudy2003.pdf

http://journals.lww.com/greenjournal/fulltext/2007/10000/follow_up_of_children_exposed_in_utero_to_17.21.aspx


Mitosol®

Mitomycin

Changes

Route of Administration

IV → Topical (sponges)

Indication

adenocarcinoma of the stomach or pancreas →

adjunct to ab externo glaucoma surgery

Dose

5-40mg/Vial → 0.2 mg/Vial

Mitosol Labeling accessed at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022572s000lbl.pdf

Mitozytrex Labeling accessed at http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/50763_Mitozytrex_lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022572s000lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/50763_Mitozytrex_lbl.pdf


Mitosol® Sources of Information

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NDA Requirement Source of Data

Non-clinical

Pharmacology/ToxicologyANDA 062336

Clinical

Pharmacology/BiopharmaceuticsANDA 062336

Clinical Microbiology/Immunology Not applicable

Clinical Efficacy 9 Randomized Controlled Trials

Clinical Safety 23 controlled trials; 32 observational

studies; 9 case series; 65 case reports

PREA Not applicable – Orphan Indication


7 December 2017

Conduct an in vivo comet assay testing lofexidine in the liver and stomach.

Conduct a pharmacokinetic study in the rat to characterize the plasma levels of lofexidine and the lofexidine

metabolites

Conduct a juvenile animal study in rats from PND 7 to 90 to support pediatric drug development in children and

neonates

Conduct a fertility and early embryonic development study in rats

Conduct a 90-day GLP repeat-dose toxicology study in the rat testing lofexidine HCl to establish a NOAEL to

support clinical studies that are longer than 14 days in duration.

Conduct a dose-ranging pharmacokinetic and safety study of lofexidine in children age 6 to 17 years with

iatrogenic opioid withdrawal

Conduct a dose-ranging pharmacokinetic and safety study of lofexidine in children age >7 days to 6 years with

iatrogenic opioid withdrawal.

Conduct a randomized, controlled clinical trial to assess the safety and efficacy of lofexidine for use beyond 14

days duration in the setting of gradual opioid taper

Conduct a safety and efficacy study of lofexidine in children and adolescents age 6 to 17 years with iatrogenic

opioid withdrawal.

Conduct a safety and efficacy study of lofexidine in subjects age > 7 days to 6 years with iatrogenic opioid

withdrawal. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/209229Orig1s000ltr.pdf

Delay/Postpone StudiesLofexidine: Post-Approval Requirements

505(b)(2) opportunities for swedish biotechs: strategies

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