Evaluating the Cost to Benefit Ratio and End User Benefits Ensuring

Best Drug Delivery Platform

Dr. Bhaswat S. ChakrabortySenior Vice President and ChairR&D Science Core CommitteeCadila Pharmaceuticals Ltd.

Presented at NextGen India — Advances in Pharma and Biopharma Drug Delivery, Mumbai, India, 26th July 2012

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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

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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

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Cardizem BID (Hoechst Marion Roussel) achieved $260 million (1988), Cardizem SR TID (Elan) $400 million (1989) & Cardizem CD OD (Biovail) $900 million (1996)

LC

ML

CM

Source: Baichwal & Neville (2001) Drug Dev Del4

Why NDDS Platforms?

•Efficacy•Compliance•Controlled drug delivery•Patient convenience•Other needs•Technology exists or•Technology can be developed

•Penetration•Patent Extension•Increased Pipeline•Higher Revenue•New Patients or subpopulations •LCM•Legal competitive advantages (USP)

Science/ Technology Platform Values for Industry/Market

Value Addition by NDDS

Challenge: Design a Good Humanistic and LCM Cost Efficient NDDS Platform

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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 Variables. 6

Categories of Drug Delivery Technology

• Oral Modified-Release• Oral Mucosal• Colonic• Ophthalmic• Transdermal & Dermal• Implants and Modified Injectables• Pulmonary• Nasal• Vaginal• Others

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Increasin

g attractiveness for p

atients

IV injection

Intramuscular injection

Subcutaneous injection

Injectable sustained release depot

Transdermal

Nasal

Aerosol

Oral tablet/capsule(>1 per day)

Oral sustained release(1 per day)

Hierarchy of NDDS Platforms

Adapted from: Speers & Bonnano, (1999) Encyclopedia of Controlled Drug Delivery, John Wiley 8

Source: Frost & Sullivan (2011) 9

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

• Affordable10

TIMERx

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Geminex

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Source: Malaterre et al., (2009) Eur J Pharmaceutics Biopharm, 73, 311–323

Oral Osmotically Driven Systems

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OROS

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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 technology15

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Insoluble Drug Delivery (IDD)

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

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

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

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Challenge: permeability enhancement and dosage form retention at the site of application

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

Slowly Disintegrating Buccal Mucoadhesives

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

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.

23Very different patient needs compared to Oral CRs

Ocusert in Conjunctival sac

24Source: Modified Release Drug Delivery Technology (2002) Marcel Dekker

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.

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Pharmacoeconomics

CLINICAL ECONOMIC

Safety

Workproductivity

Direct Medical Costs

Quality of Life

Bothersomeness,tolerability

HUMANISTIC

SatisfactionEfficacy

Resourcesconsumed

Sideeffects

Source: Summers K. Purdue U 26

DURAGESIC® (Fentanyl Transdermal System)

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Economic Analysis Case StudyFentany Transdermal System

• Cost effectiveness (here a simple cost utility):

Cost of NDDS — Cost of non-NDDSQALD of NDDS — QALD of non-NDDS

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QALD = quality-adjusted life-days

Pain Management: WHO Guide

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

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

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Pain Control Model1. 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

2. 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

3. 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: 129-143

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

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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 1st 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

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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.

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Thank you Very Much

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