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Welcome

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Current industrial Scenario

With conduct to regulatory affairs

Presented by:

Swapnil N. DharmshaleM.Pharm-1st (Q.A).

D.S.T.S Mandal’s College of Pharmacy, Solapur.

Date:-12-11-2013

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IntroductionNew drugOverview of global Pharma. IndustryGlobal generic marketIndian relevance to global generic industryFDA requirements for generic drugsHatch-Waxman ActOrange bookUSFDA approval processConclusion

Content

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Introduction

New drug : Generic name /Brand name

A generic drug is exactly the same molecule as branded drug.

Generic drug cost effective Alternative to branded drug.

Drug Approval:

Investigational New Drug (IND)

New Drug Application (NDA): New chemical entities

Abbreviated New Drug Application (ANDA): Generic Drug

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Overview of the world Pharmaceutical

Industry

The data as per the year 2007 - the generic industry is growing at a rate faster than the overall pharmaceutical industry

Reasons –

Economic changes

Changing consumer demands for low prices high quality drugs

Changing societal values

Significant health-care demands

Changing composition of workforces

The major contribution being the increase in competition amongst the generic and the brand name industry which has come due to the change in the USFDA approval process from a slow time consuming to a comparatively faster process

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GLOBAL GENERIC MARKETS

The global pharmaceuticals industry generated total revenues of $615.1 billion in 2008.

The global market for generic drugs was worth $84 billion in 2009.

In 2014, the market is expected to amount to $129.3 billion, for a compound annual growth rate (CAGR) of 9% in the 5-year period.

Sales of U.S. generic drugs currently dominate the market, at $34 billion in 2009 and projected to increase at a CAGR of 9.7% to $54 billion in 2014.

Japan’s generic drugs market is expected to have the highest rate of growth among major markets at 12.2%, increasing from $5.4 billion in 2009 to $9.6 billion in 2014.

Major Pharma company share will decrease due number of patent expiries and intensifying competition from generics.

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GLOBAL GENERIC MARKETS

Parameters Global pharmaceutical industry

Generic share

Size ($bn) 643 55

Growth rate 7% 11%

Key players US ($245 bn)Japan ($60 bn)Germany ($27 bn)France ($24 bn)UK ($15 bn)

US ($28 bn)Japan ($5 bn)Germany ($6 bn)UK ($3.4 bn)France ($2 bn)

Expected growth 5-7% 13-15%

Projected size (by 2010)

$812 bn at 6% growth rate

$93 bn at 14% growth rate

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WHY GENERICS: A $90B GLOBAL OPPORTUNITY

US, Canada: $50bn

Western Europe

$17bn

Latin America: $2bn

Rest of World: $4bn

Eastern Europe & Russia: $10bn

China: $3bn

Japan: $4bn

Total World Pharmaceutical Sales: $600bn

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Drugs Brand Price $/30

Generic price $/30

Lisinopril (Zestril® ) 20 mg 46.69 20.69

Citalopram (Celexa® ) 20 mg 100.99 52.99

Ciprofloxacin (Cipro®) 500 mg 215.99 88.59

Merformin (Glucophage®) 1000mg 71.59 30.69

Fluconazloe (Diflucan®) 200mg 609.99 372.99

Fluoxetine(Prozac®) 20mg 139.99 32.29

BRAND V/S GENERIC PRICES

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Drug Therapeutic Area

Company Expiry Year

Global Sales (2008 billion $)

Lipitor (Atrovastin Calcium) CVS Pfizer 2011 13.5

Plavix ( clopidogrel bisulfate) CVS Sanofi Aventis BMS 2011 9.4

Advair ( Fluticasone Propionate & Salmetraol)

Respiratory GSK 2010 7.8

Diovan (Valsartan) CVS Novarties 2012 5.8

Zyprexa (Olanzapine) CNS Ell lily 2011 4.7

Singular (Montelukast) Respiratory Merck 2012 4.6

Seroquel(Quetiapine fumarate) CNS Astrazeneca 2011 4.6

Lovenox (Enoxaporin sodium) CVS Sanofi Aventis 2012 4.0

Actos (Pioglitazone) Antidiabetic

Takeda 2011 3.9

Prevacid ( Lansoprazole) GIT Takeda 2010 3.7

Cozaar ( Losartan Potassium) CVS Merck 2010 3.6

Aricept (Donepezil) CNS Pfizer 2010 3.6

Lexapro (Escitalopram) CNS Forest Lab 2011 3.4

Eloxatin (Oxalipaltin) Oncology Sanofi Aventis 2013 3.0

TOP 14 DRUG GOING OFF PATENT IN 4 YEARS

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Major Indian Players:

Ranbaxy : Amongst Top 10 global players Dr Reddys Cipla Wochardt Sun Pharmaceuticals Glenmark Lupin Nicholas Piramal Torrent Matrix Laboratories

Indian Relevance to global generics industry

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INDIAN GENERICS APPROVED BY FDA

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1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Tentative

Final

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GENERIC DRUG

Brand Name Drug - The brand name drug is the name under which a new innovator medication is developed and marketed. When a pharmaceutical company develops a new medication, they obtain patent for it.

Generic Drug – Generic drugs are considered identical, or bioequivalent to the brand-name originals.

They contain the same active substances and have the same quality, efficacy and safety.

Definition:

•GENERIC DRUG IS A PHARMACEUTICAL PREPARATION THAT IS

ESSENTIALLY SIMILAR TO AN ORIGINAL PRODUCT, INVOLVING AN

ACTIVE INGREDIENT THAT IS NO LONGER PROTECTED BY A PATENT*

AND IS SOLD UNDER A COMMON NAME WITH LITTLE OR NO

PROMOTION.

* THOUGH THE FORMULATION MAY OR MAY NOT BE PATENTED

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FDA REQUIREMENTS FOR GENERIC DRUG

Phases Of validation

Contain the same active ingredients (Pharmaceutical equivalent)

Be identical in strength, dosage form, and route of administration

Have the same indications

Be bioequivalent

Meet the same batch requirements for identity, strength, purity, and quality

Be manufactured under the same strict standards of FDA's good manufacturing practice regulations required for reference Listed drug (RLD)-brand name Product listed in “Orange book” (www.fda.gov/cder/ob).

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DEFINITIONS

Pharmaceutical Equivalence Same active drug ingredient ,same strength, same dosage form and route of administration, comparable labeling, meets compendial or applicable standard of strength.

BioavailabilityThe rate and extent to which the active moiety is absorbed from a drug Product and become available at site of action.

BioequivalenceTwo pharmaceutical equivalent drug product are bioequivalent if after drug administration, the bioavailabilities (rate and extent of drug availability) provide similar effect with respect to efficacy and safety.

Therapeutic EquivalenceTherapeutic equivalence means that a chemical equivalent of adrug product (i.e., containing the same amount of the same drug in the same dosage form) when administered to the same individuals in the same dosage regimen will provide essentially the sameefficacy and toxicity.

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ACT GOVERNING DRUG APPROVAL

The act governing generic drug approval process of the

USFDA

“Hatch-Waxman Act of 1984”

or “Drug Price Control and Patent Term Restoration Act of

1984”.

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Market was ruled by brand name drug manufacturers – innovators

Lack of competition

Innovator enjoyed his elite monopoly period within which no other brand of the same drug can enter into the market

Highest prices of the drugs

To stop these practices and to make user friendly drug market, the US congress passed the Hatch Waxman Act in 1984

Earlier Scenario (before “Hatch-Waxman Act of 1984” )

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The Drug Price Competition and Patent Term Restoration Act of 1984, signed into Law on September 24, 1984

Hatch-Waxman was designed to speed entry of generic drugs to compete with patented pharmaceuticals

The results of the act seek to balance the interests of the branded manufacturers with those of generics

Birth of Generics: The Hatch-Waxman Act

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Types of Process validation

Offset the drug approval delay:

Earlier innovators used to encounter delay in approval of their NDA which affected their brand entry in the market and hence financial loses!!!!!

Bring healthy competition and to avoid price rise:

Earlier no scope for generics to enter the market until innovator patent term expired as no provisions to challenge the validity of innovator patent. This product monopoly kept competion away and drug prices high as per innovator will!!!!!!

Make life easier for the generic:

Generic manufacturers used to face a lot of difficulties in doing all the pre-clinical and clinical studies as done by brand manufacturer to get generic approved!!!!!

Objectives of the act

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Regulatory delays in brand approval were deciphered

The market exclusivity and the ‘effective patent life’ was extended from 8.5years (1980) to 13 years (late 1980s) and now it’s nearly 16-17years

Benefits received by the brand name manufacturers

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The generic could challenge the validity of the patent issued to the innovator

The act provided with the stipulation to file an ANDA to leave out the expensive pre-clinical and clinical trials as done by the innovator

Provided with the provision of relying on the safety and efficacy data of the innovator drug and to perform a much cheaper ‘bioequivalence’ to establish equivalence with the innovator

Once approved the generic gets an exclusivity period of six months to market the product along with the innovator during which no other generic can be given approval

Benefits received by the generic manufacturers

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The Orange Book

The FDA publishes a list of all drugs approved for marketing in the US under the title “Approved Drug Products with Therapeutic Equivalence Evaluations” - “Orange Book”

Lists the NDA’s and ANDA’s along with the expiry dates of patents and generic exclusivities

Ready reference of brand drug products for the generic companies who usually use this information to identify the reference for developing their generic version

Also contains therapeutic equivalence codes (two letter coding system e.g. AB)

A- prefixing product is considered to be substitutable

B- prefixing is a safe and effective product for use but is regarded in-equivalent and non-substitutable with the brand name drug product

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Para I – there is no patent for the drug listed in the Orange Book

Para II – patent is listed but has expired

Para III – patent is listed, is valid but the generic wants approval to market the drug once the pertinent patent expires

Para IV – the generic manufacturer either challenges the validity of the patent asserting it to be invalid or fake, or it affirms the non-infringement of the brand name patent claims.

Most critical and gives rise to anti- competitive practices

ANDA certifications

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The generic must have –

Same active ingredient,

Same route of administration,

Same dosage form,

Same strength,

Same condition of use

USFDA approval requirements: Brand name (NDA) vs Generic (ANDA)

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NDA vs ANDA Review Process

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The ANDA applicant must provide appropriate notice of a paragraph IV certification to each owner of the patent that is the subject of the certification and to the holder of the approved NDA to which the ANDA refers

The ANDA applicant may certify with a legal ground that a listed patent is invalid or will not be infringed by the manufacture, use, or sale of the generic product.

This gives an immediate right to innovator to file a patent infringement lawsuit against the generic manufacturer

The innovator can file this lawsuit within 45 days of the ANDA filing notice from the generic

This sets in a process which detains the FDA from giving approval to the generic for a period of 30 months

FDA is free to grant approval after 30 months which depends upon the result of the pending litigation

USFDA Approval Process (Para IV certification)

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An incentive to the ‘first approved generic’ after filing a Para IV certification

This incentive gives the first generic an exclusivity period of 180 days to market and earn profits

During this period, the brand name drug is the only competition and FDA can not approve any other generic until this exclusivity period perishes

The 180 day cycle begins on the day the generic comes into the market for the first time or the day of courts decision in favor of the generic

The six month generic exclusivity

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Warehousing patents and frivolous lawsuits

Also referred to as “Evergreening” of patents

Innovator may patent multiple attributes of a product like manufacturing process or metabolite and keeps on adding patents in the Orange Book, forcing the generic to wait for the patent to expire or file para IV which brings along risk of litigation and associated cost and delays!!!

Loopholes in Hatch-Waxman Act

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CASE STUDY

Case Study – Buspar Case : BMS v Mylan Pharmaceuticals

BMS had US Patent 4,182,763 (Expiry – July 21, 2000)

Claims cover buspirone as an anxiolytic agent

Mylan filed para III against this patent and obtained tentative approval to market the drug not before July 22, 2000

BMS obtained another patent just 12 hours before the expiry of first patent covering the active metabolite of the buspirone having anxiolytic activity and listed it in the OB

Mylan filed para IV against this newly listed patent

BMS responded by filing infringement lawsuit immediately halting the final market approval

This gives the brand name manufacturer at least an additional two and a half years of product monopoly

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Commonly referred to as “Sweetheart deals”

Allows the first generic manufacturer and the innovator to enter into an agreement and to have control when to introduce the generic

This would not trigger the 180days generic exclusivity period offered to the first generic

The FDA is bound not to approve another generic until the 180 day generic exclusivity period perishes

This allows the innovator and first generic to share financial awards keeping other generic competitors in an indeterminate state

Maneuvering the six month Generic Exclusivity

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CASE STUDY

1) Diltiazem hydrochloride (Cardizem CD by Hoechst-Marion Roussel, Inc. (“HMRI”))Used to treat angina and hypertension

Andrx Pharmaceuticals Inc. was first ANDA filer with para IV for Cardizem CD; HMRI filed suit against Andrx

In September 1997, FDA tentatively approved Andrx’s generic product

Andrx would have been expected to be able to enter the market upon the expiration of 30 month stay in July 1998

However, Andrx and HMRI settled the litigation

In settling the litigation, both the parties agreed that, beginning upon the final FDA approval of Andrx’s generic product, HMRI would pay Andrx $10 million per quarter not to enter the market with its generic product until the conclusion of the patent litigation

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CASE STUDY

2) Terazosin hydrochloride (Hytrin by Abbott)

Used for the treatment of high blood pressure and enlarged prostate

Litigation involves agreement between Abbott and Geneva Pharmaceuticals Inc. and also between Abbott and Zenith Goldline Pharmaceuticals Inc.

Agreement between Abbott and Geneva was an “interim” settlement that did not finally resolve the patent issues

Geneva agreed to accept $4.5 million per month from Abbott to refrain from marketing generic product of Hytrin until another generic maker sold a generic version in the USA or Geneva received a final, unappealable judgement that its proposed generic tablet did not infringe Abbott’s patents

Also, as part of the agreement, Geneva and Abbott allegedly agreed to continue the patent infringement litigation on Geneva’s generic tablet

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Generic manufacturer must establish equivalence with the RLP developed by the innovator

FDA has established two basic criteria for the generic to be equivalent with the innovator –• In vitro equivalence criteria• In vivo bioequivalence

FDA Generic Approval Criteria: Establishing In Vitro Equivalence and Bioequivalence with the Reference Listed Product (RLP)

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Comparison of the dissolution profile of generic drug and brand name drug by similarity factor of f2

f2 = 50 * log ( 1 + (1/n) summation (Rt –Tt) 2 ) 0.5 * 100 Comparison is done especially to assure similarity in product performance

Regulatory interest is knowing how similar the two curves are and to have a measure which is more sensitive to large differences at any particular time point

When the two profiles are identical, f2 = 100

FDA has set a public standard of f2 value between 50-100 to indicate similarity between dissolution profiles

In vitro equivalence criteria

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Single dose; two-way crossover fasted or fed state studies - This means all the test subjects receive both the generic and the brand name product, done in a cross-over manner and products are given once to each subject on different occasions and the pharmacokinetic data are compared between the two treatments between each subject

This study gives an idea of the inter-subject variability

Replicate design – This design gives the same product to each subject more than once.

The overall number of subjects is reduced but the number of times each subject has to come increases

Two most common parameters which are studied and compared are Cmax and the AUC related to rate and extent of drug absorption in the blood respectively

These parameters are accessed using the 90% confidence intervals that must fit between 80-125%

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The dissolution measurements of the two products (test and reference) should be made under the same test conditions

Dissolution time points should be same for both the products

f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two curves, and, thus, the performance of the two products

f2 value less than 50 does not necessarily mean lack of similarity

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Generic manufacturer has to conduct bioequivalence study in place of pre-clinical and clinical studies to establish equality with the innovator

Purpose of bioequivalence is to have a generic drug product which is substitutable for a reference product ‘without any additional prescriber intervention’

There should not be any change in the efficacy and no additional incidents of side effects

The usual study designs are single dose; two-way crossover fasted or fed state studies and replicate designs

In vivo equivalence

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FDA allows the generic manufacturers to not have to study every single strength of a product and requires some in vitro tests for the same

e.g. the testing on the low strength version of an already bioequivalence established product. As lower strengths are proportional to their matching higher strengths; FDA only requires some in vitro testing

Other types of products which may be granted biowaiver include –

Parenteral solutions

Inhalational anaesthetics

topical solution

Oral solutions

Biowaivers

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CONCLUSIONS

US congress passed the Hatch Waxman Act in 1984 for the benefit of consumers in an attempt to stop dominance and monopoly of the innovator and to encourage the use of cheaper and equally effectivedrugs.ie. GENERICS

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Thank you

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