This document discusses evaluating the cost to benefit ratio and end user benefits of drug delivery platforms. It covers understanding patient needs and formulation issues, benefits of matching needs and convenience, categories of drug delivery technologies, assessing cost to benefit ratios, and determining selection parameters. An example is given of an economic analysis showing a fentanyl transdermal system had the highest expected quality-adjusted life-days at a nominal increased cost compared to other long-acting oral opioids. The concluding remarks emphasize understanding needs, matching specific technologies to needs and formulations, relevance of therapeutic categories, and the importance of cost effectiveness and cost utility analyses.

1. Evaluating the Cost to Benefit Ratio
and End User Benefits Ensuring
Best Drug Delivery Platform
Presented at NextGen India — Advances in Pharma and Biopharma
Drug Delivery, Mumbai, India, 26th July 2012
Dr. Bhaswat S. Chakraborty
Senior Vice President and Chair
R&D Science Core Committee
Cadila Pharmaceuticals Ltd.
1

2. Organization of this Talk
• Understanding the key patient needs and
formulation issues
• Benefits of matching the patient needs &
convenience
• Key therapeutic categories requiring NDDS
platforms
• Criteria to choose the best technology
• Assessing the cost to benefit ratio
• Determining the key selection parameters
• Concluding remarks
2

3. Understanding the Key Needs and
Formulation Issues
• Unmet medical needs, cost of illness, cost of drugs and cost of
delivery systems
• Three main perspectives
– Patients – Most important humanistic aspect
– Drug Delivery Technology scientists and companies – LCM
– Decision Makers (Pharma Cos., Formulary, Insurance,
Hospitals…) – Balance of factors
• Health implications without an optimum delivery
• Value addition by delivery technology
• Data for appropriate cost effectiveness & budget impact
analysis
• Selection criteria for “best” technology
3

4. LCM
LCM
Cardizem BID (Hoechst Marion Roussel) achieved $260 million (1988),
Cardizem SR TID (Elan) $400 million (1989) & Cardizem CD OD (Biovail) $900
million (1996)
4
Source: Baichwal & Neville (2001) Drug Dev Del

5. Why NDDS Platforms?
•Efficacy •Penetration
•Compliance •Patent Extension
•Controlled drug delivery •Increased Pipeline
•Patient convenience •Higher Revenue
•Other needs •New Patients or
Value Addition
•Technology exists or subpopulations
by NDDS
•Technology can be •LCM
developed •Legal competitive
advantages (USP)
Science/ Technology Platform Values for Industry/Market
Challenge: Design a Good Humanistic and LCM Cost Efficient NDDS
Platform
5

6. Understanding the Key Needs and
Formulation Issues
• Key patient needs
– Improved efficacy
– Reduced side effects
– Targeted and controlled drug delivery
– Less frequent administration
– Better organoleptic properties
– More QALDs gained
• Formulation Issues
– Matching patient needs
– Technical formulation issues
– Cost of technology
– Priorities
– Market and dominance of existing intervention
Initial Cost Modeling & Risk Taking Would Depend on Accurate Estimates of the
6
Variables.

7. Categories of
Drug Delivery Technology
• Oral Modified-Release
• Oral Mucosal
• Colonic
• Ophthalmic
• Transdermal & Dermal
• Implants and Modified Injectables
• Pulmonary
• Nasal
• Vaginal
• Others
7

8. Oral sustained release
(1 per day)
s
ie nt Oral tablet/capsule
t
r pa (>1 per day)
s fo
e s Aerosol
en
c tiv
a Nasal
a ttr
g
sin Transdermal
r ea
Inc
Injectable sustained release
depot
Subcutaneous injection
Intramuscular injection
IV injection
Hierarchy of NDDS Platforms
Adapted from: Speers & Bonnano, (1999) Encyclopedia of Controlled Drug Delivery, John Wiley 8

9. Source: Frost & Sullivan (2011) 9

10. Matching Patient Needs: Oral CR
• Patient needs: improved efficacy, reduced side effects,
targeted & controlled drug delivery, less frequent
administration, more QALDs gained etc.
• The technology must be flexible enough to incorporate drugs
with varying physicochemical and PK, doses, and desired
release profiles
• BCS Class I & II are good candidates (release rate controlled)
• Level A IVIVC is a big help
• Finished dosage forms can be readily manufactured on
standard equipment
– Ease of TT & cost-effective
• Affordable
10

11. TIMERx
11

12. Geminex
12

13. Oral Osmotically Driven Systems
Source: Malaterre et al., (2009) Eur J Pharmaceutics Biopharm, 73, 311–323
13

14. OROS
14

15. Improving Solubility, Dissolution Rate,
and Absorption
• The improvement of the solubility, dissolution rate, and absorption
– remains a challenge in development of pharma products
• Two options:
– adapt release profiles
– exploit the potential to improve delivery of the drug
• Drugs with poor solubility revealed remarkably higher bioavailability when
formulated as solid dispersions
• Results
– increase the active agent’s bioavailability
– reduce side effects
– overcome solubility barriers throughout the body
– control the duration of the drug’s action in the body
• Example: Meltrex technology
15

16. 16

17. Insoluble Drug Delivery (IDD)
Source: Modified Release Drug Delivery Technology (2002) Marcel Dekker 17

18. 18
Source: Modified Release Drug Delivery Technology (2002) Marcel Dekker

19. Mucoadhesive Delivery Systems
• Mucoadhesive delivery systems offer several
advantages
– Prolongation of residence time of drug in gastrointestinal
tract (GIT).
– Targeting and localization of the dosage form at a specific
site
– Intimate contact between dosage form and the absorptive
mucosa, results in high drug flux at the absorbing tissue
– Low contact angle and reduction of surface and interfacial
energies achieve good amount of mucoadhesion
Challenge: permeability enhancement and dosage form retention at the
site of application 19

20. Diagram to show the anatomic location and extent of masticatory, lining, and specialized
mucosa in the oral cavity. [Modified from reference (2).].
Squier C A , Kremer M J J Natl Cancer Inst Monogr
2001;2001:7-15
© Oxford University Press 20

21. Slowly Disintegrating Buccal
Mucoadhesives
21

22. Source: Modified Release Drug Delivery Technology (2002) Marcel Dekker 22

23. Ophthalmic MR: Patient & R&D Needs
• Deliver the active ingredient to the right place
– high conjunctival levels are useless when targeting the ciliary body
• Improve the ratio of local activity vs. systemic effects.
• Reduce the number of installations per day, once-a-day is optimum
• Be easy to self-administer.
• Not induce a foreign-body sensation, long-lasting blurring, or a very bad
aftertaste.
• Not rely on “exotic” ingredients like new chemical entities or difficult-to-
source excipients (unless this is a key element).
• Be sterilizable at industrial scale by a recognized process.
• Be compatible with an efficient antimicrobial preservative.
• Preferably be stored without specific conditions.
• Be covered by a patent, since manufacturers can legitimately expect a
return on R&D investment.
Very different patient needs compared to Oral CRs
23

24. Ocusert in Conjunctival sac
Source: Modified Release Drug Delivery Technology (2002) Marcel Dekker 24

25. Economic Analysis
“A comparative analysis of alternative
courses of action in terms of both their
costs and consequences.”
Cost Effectiveness Analysis (CEA) or its
variations are the clearest way to estimate
and promote (health) value for money.
25

26. Pharmacoeconomics
CLINICAL ECONOMIC HUMANISTIC
Efficacy Side Satisfaction Quality of
effects Life
Safety Bothersomeness,
tolerability
Work Resources
productivity consumed
Direct Medical
26
Costs Source: Summers K. Purdue U

27. DURAGESIC®
(Fentanyl Transdermal System)
27

28. Economic Analysis Case Study
Fentany Transdermal System
• Cost effectiveness (here a simple cost utility):
Cost of NDDS — Cost of non-NDDS
QALD of NDDS — QALD of non-NDDS
QALD = quality-adjusted life-days
28

29. Pain Management: WHO Guide
29

30. Source: Neighbors et al (2001). J Pain & Sympt Mgmt, 21: 30
129-
143

31. Source: Neighbors et al (2001). J Pain & Sympt Mgmt, 21: 31
129-
143

32. Pain Control Model
1. Model allows patients to experience up to three dose titrations
following the starting dose.
– If adequate pain control is not achieved with the third titration (i.e., the fourth
dose level), the patient is assumed to switch to a different method of pain
control
1. Patients who successfully complete the titration phase move
immediately into the stabilization phase
– Mimics the time frame of several clinical trials of opioids, approximately 1
month. The stabilization phase distinguishes the short-term success of therapy
based on toxicity
1. Patients who experience sustained pain control without
unacceptable toxicity during the stabilization phase are moved
immediately into the third and final long term use phase of the
model.
– Events considered in the third phase of the decision-analytic model, moving
beyond safety and efficacy
Source: Neighbors et al (2001). J Pain & Sympt Mgmt, 21: 32
129-
143

33. Source: Neighbors et al (2001). J Pain & Sympt Mgmt, 21: 33
129-
143

34. author
platform+m
yes
Economic Evaluation of the Fentanyl
Transdermal System
• The fentanyl transdermal system (Duragesic) is adequate to
treat chronic moderate to severe pain
• Economic value was compared to two long-acting oral opioids
– CU analysis was performed using a three-phased decision analytic
model
– The transdermal system had the highest expected cost in 1 st year of
therapy ($2,491)
– A little higher than CR morphine ($2,037) or CR oxycodone ($2,307)
– It had highest expected number of quality-adjusted life-days (QALDs)
(244 vs 236 for morphine and 231 for oxycodone)
– It achieved incremental cost-utility ratios of $20,709 (vs. morphine)
and $5,273 (vs. oxycodone) per QALY gained
– In a conservative modeled analysis, the fentanyl transdermal system
led to increased QALDs at a nominal increased cost
34

35. Concluding Remarks
• NDDS cover a wide range of technologies and routes of administration,
such as oral, buccal-mucosal, ophthalmic, transdermal, pulmonary and
colonic – to name a few.
• Understanding the key needs and formulation issues provide the best
delivery platform
• Specific delivery technologies match the patient’s convenience
• Need and Formulation Matching:
• In oral modified release (MR) technology, the key need is to optimize bioavailability with
much fewer dosing frequency, whereas in ophthalmic MRs, the principal requirements
are absence of local toxicity, tolerance, ease of dispensing, sterility, and osmolarity, etc.
• Therapeutic categories are very relevant in the context of matching needs
to technology
• Cost Effectiveness and Cost Utility Analyses are reliable economic analyses
• In the absence of head-to-head clinical trials, economic analysis models
help clarify cost and outcome trade-offs and provide a consistent
theoretical framework for use by individual decision-makers.
35

36. Thank you Very Much
36