505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
1
7 December 2017
505(b)(2) Opportunities for Swedish Biotechs:
Strategies for Repurposing Known Medicines
505(b)(2) Seminar | SwedenStrategies 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?)
2
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
3
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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)).
4
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Is it a 505(b)(2)?
5
Your Idea
&
or
5
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 6
Why would you want to use 505(b)(2)?
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 7
19
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 8
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 9
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 10
Average Revenue per 505(b)(2)-Approved Productby Launch Date
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 11
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
12
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Commercial
Regulatory
Medical
Scientific
Strategic Drug Development
13
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
15
MedicalTarget Product Profile
15
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 17
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
• 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?
18
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 21
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 23
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Strategic Drug Development
Regulatory
• Indication
• What public information can be relied on?
• What studies need to be conducted
• When?
• How?
25
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
What is public?
Your Development Program
FDA Requirements
for NDA Approval
Regulatory
Your Path
26
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Public Information
Regulatory
27
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Repurposed Drug
505(b)(2)New Drug
505(b)(1)
Regulatory
28
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 29
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Public Sources• FDA 505(b)(2) Reviews
(Drugs@FDA)
• CenterWatch
• ClinicalTrials.gov
• NCI’s Cancer Clinical Trials Registry
• NIH
Regulatory
31
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Strategic Drug Development
• 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
34
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
35
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
New Chemical Entities
Drugs@FDA; www.camargoblog.com
Scientific
36
• Drugs approved outside U.S.
• Drugs developed outside U.S. and not approved
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
Drugs@FDA; www.camargoblog.com
Scientific
37
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
38
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
39
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
2001
505(b)(2) NDA2007
505(b)(2) 0NDA > OTC
Fixed Dose Combination
Scientific
40
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Pharmacokinetic Alterations
• BA
• Targeted Release
• IR to ER
• Reduced variability
Scientific
41
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 42
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 43
RLD 78%
Not RLD 22%
505(b)(2)s As Orange Book RLD
209 NDAs approved 7/2012 - 6/2017
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Commercial
Regulatory
Medical
Scientific
Strategic Drug Development
Summary: The Importance of Early Strategic Design for Success
44
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 45
How do I lower my FDA uncertainty ?
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
29
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
46
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
47
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
48
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
505(b)(2) Process
Form
ula
tion
FDA
OK?Pre-INDand/or
50
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Experience with:
• 1 in 5 recent 505(b)(2) NDAs
• 30+ Orphan Drugs with 8 in process
• 80+ products in development
51
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)
52
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines
Mitosol® Sources of Information
54
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
505(b)(2) Seminar | SwedenStrategies for Repurposing Known Medicines 55
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