pharmaceutical claiming

PHARMACEUTICAL CLAIMING WITH AN EYE TOWARDS USFDA ORANGE BOOK

Project Assignment-3 (Module-III) Project submitted for the partial fulfillment of Degree of P.G.Diploma in Patents Law

Submitted By: Shivang A Chaudhary ID No: PLA 319_09 2009-2010

NALSAR Proximate Education, National Academy of Legal Studies & Research (NALSAR) University of Law, Hyderabad-500 027 Web: www.nalsarpro.org

TABLE OF CONTENTS Sr. INDEX

Pg.

0

Abbreviations

03

1

INTRODUCTION

04

2

RESEARCH METHODOLOGY

04

3

ENFORCEMENT OF PHARMACEUTICAL PATENTS IN THE US

05

3.1 The ANDA Process 3.2 Enforcing a Patent listed in the orange book

4

LISTING A PATENT IN THE USFDA ORANGE BOOK 4.1 4.2 4.3 4.4 4.5 4.6

5

06

Time-frame for listing a patent Re-listing / De-listing of a patent Pre-listing due diligence Hidden complexities of listing a patent How to list patents covering the active ingredient and formulation Use of terms & codes for claims drafting

HATCH WAXMAN ACT AMENDED TO STRIKE BALANCE BETWEEN BOTH FACETS

18

5.1 Patent term restoration up to 5 years for INNOVATOR 5.2 180 Days Exclusive Marketing Rights for first GENERIC applicant

6

GENERIC COMPANIES STRATEGIES TO AVOID PATENTS

20

6.1 Design around strategies-Reverse Engineering 6.2 ―Skinny labelling‖ or FDA label carve-outs

7

BIOLOGIC DRUGS AND THE STATUS OF RELATED US LEGISLATIVE PROPOSALS

24

7.1 Status of the current proposed legislation 7.2 What we can do to prepare when pursuing biologic drug patent protection

8 9

CASE STUDIES CONCLUSION

10 BIBLIOGRAPHY

26 28 29

2

Shivang chaudhary (PLA 319_09) | NALSAR Pro

Abbreviations ANDA

Abbreviated New Drug Application

BA

Bio-Availability

BE

Bio-Equivalence

CAFC

Court of Appeal for Federal Circuit

DESI

Drug Efficacy Study Implementation

FDA

Food and Drug Administration

HWA

Hatch-Waxman Act

NDA

New Drug Application

PE

Pharmaceutical Equivalence

RLD

Reference Listed Drug

TE

Therapeutic Equivalence

USFDA

United States Food and Drug Administration

USPTO

United states of Patents & Trademark Office

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1. INTRODUCTION As the world moves closer to the concept of a ―global village‖ by reduction & elimination of trade barriers, new challenges crop up in USA. 1) Cumbersome FDA Regulatory procedures for INNOVATOR 2) Absence of cheaper GENERIC drug manufacturing The Hatch-Waxman Act-HWA (Drug Price Competition and Patent Term Restoration Act) Amendments has governed the statutory generic drug approval process intended to balance two important public policy goals.1 1st to ensure that brand-name (also known as INNOVATOR) drug manufacturers would have meaningful patent protection and a 5 years period of marketing exclusivity to enable them to recoup their investments in the development of valuable new drugs during approval from FDA Regulatory procedure. 2nd

to ensure that, once the statutory patent protection and 180 days marketing

exclusivity for these new drugs has expired, consumers would benefit from the rapid availability of lower priced GENERIC versions of innovator drugs. In general, the law has been working well. Since 1984, over 10,000 generic drugs have entered the market, and generics now account for close to 50 percent of prescriptions filled. Section 505(j) of HWA established the Abbreviated New Drug Application (ANDA) approval process, which permits generic versions of previously approved innovator drugs to be approved without submitting full new drug application (NDA) i.e. clinical trials. An ANDA has proved to be bioequivalent to previously approved NDA (the ―Reference listed drug‖) and relies on the Agency’s finding of safety and effectiveness for the Reference listed drug product in ORANGE BOOK. 1

4

The Hatch-Waxman Act— 25 Years Later: Keeping the Pharmaceutical Scale Balanced Martha M. Rumore


2. RESEARCH METHODOLOGY This review article analyses almost all facets of Pharmaceutical claiming with an eye toward USFDA Orange book. The method adopted in the study is descriptive-analytical. Presented data has been collected from several books, online publications, and other Internet sources. The first part of this descriptive analytical study (chapter 3-6) covers ―Enforcing a Pharmaceutical Patent in US with special Emphasis on ANDA filing by Orange book listing ”. And second part (chapter 7-10) covers almost all aspects of “Generics & Bio generic stratergies to avoid Patents with case study‖ INNOVATORS PERIOD

GENERIC PERIOD

5


3. ENFORCEMENT OF PHARMACEUTICAL PATENTS IN THE US 2 3.1. ANDA PROCESS While filing an ANDA, a generic firm must certify any one of the following: CERTIFICATION

INDICATION

PARAGRAPH I

Patent information on the drug has not been filed in the orange book)

PARAGRAPH II

Patent has already expired

PARAGRAPH III

Date on which patent will expire & that the generic drug will not go to the market until that date passes

PARAGRAPH IV

Patent is invalid & will not be infringed by the manufacturer , use or sale of the generic drug

3.2. ENFORCING A PATENT LISTED IN THE ORANGE BOOK In case of certification I & II, approval for manufacture can be granted immediately. In case of III, approval of ANDA can be made effective from the date of expiration. In case of IV, it is mandatory for the manufacturer to notify the original patent holder within 20 days, who can take up to 45 days to bring an infringement suit against the manufacturer; if he fills his IPRs are being violated. However, if no such action is taken within the stipulated period, certification of the ANDA applicant will be accepted by the FDA If an infringement action is brought in time, FDA must suspend approval of the ANDA until the date of court’s decision. If the court decision goes in favor of the patent owner,FDA will suspend the approval till expiry of the patent.FDA does not wait indefinitely the maximum time available for coming to decision is 30 months(2.5 years) after the expiry of 45 days i.e. filing of a reply by a drug manufacturer within 45 days will result in delay of a minimum of 2.5 years for the generic drug maker. 2

http://www.paragraphfour.com/explained.html


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4. “ORANGE BOOK” LISTINGS Each holder of an ANDA must list relevant patents it believes would be infringed if a generic drug were marketed before expiration of these patents. The FDA maintains a list of these patents & publishes patent information on approved drug products in the Agency’s publication Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the ―Orange Book.‖ It lists all approved drug products with their therapeutic equivalence codes in addition to the products’ patent and exclusivity information The process of•

• • • •

Patent certification, Notice to the NDA holder and patent owner, A 45-day waiting period, Possible patent infringement litigation and The statutory 30-month stay

may result in a considerable delay in the approval of ANDAs when an innovator company submits a new patent relisting to FDA. Therefore, ANDA applicants often closely scrutinize these listings3.

4.1. TIME-FRAME FOR LISTING A PATENT The company filing ANDA under para IV must submit full & complete information over & above what is necessary under current law & must notify the patent owner within 20 days after ANDA filing. If patent owner does not file infringement proceeding within 45 days of notification issued by ANDA applicant, the applicant may request for a declaratory judgments & thus avoid being sued. If sued, applicant may file a counter claim requiring patent owner to make changes in the orange book listing. This favors the patent holder, because he does not have to pay any damages for not modifying the orange Book listing in time & there is apparently no time limit for making such modification

3

7

www.cato.org/pubs/regulation/regv24n4/v24n4-2.pdf


4.2. RE-LISTING / DE-LISTING OF A PATENT FDA’s regulations provide that, in the event of a dispute as to the accuracy or relevance of patent information submitted to and subsequently listed by FDA, an ANDA applicant must provide written notification of the grounds for dispute to the Agency. FDA will then ask the NDA holder to confirm the correctness of the patent information and listing. Unless the patent information is withdrawn (De-listing) or amended (Re-listing) by the NDA holder, FDA does not change the patent information in the ―Orange Book.‖ If a patent is listed in the ―Orange Book,‖ an applicant seeking approval for an ANDA must submit a certification to the patent. Even an applicant whose ANDA is pending when additional patents are submitted for listing by the sponsor must certify to the new patents, unless the additional patents are submitted by the patent holder more than 30-days after issuance by the U.S. Patent and Trademark Office. Until the final rule effective date, pending generic drug applications may be subject to multiple overlapping 30-month stays if new patents are relisted for the innovator drug and those patents result in litigation. But under Medicare Prescription Drug & Modernization Act of 2003,a very important change in HWA, only one 30 month stay will be permitted i.e. non extension of 30-month statutory period 4.

4.3. PRE-LISTING DUE DILIGENCE Over the past few years, new patents have occasionally been submitted to FDA for listing in the ―Orange Book‖ shortly before patents already listed in the ―Orange Book‖ were scheduled to expire. These new patents have been submitted to FDA within the required 30-days of issuance by the Patent and Trademark Office. If the NDA sponsor complies with the requirements of the statute and regulations in submitting a patent for listing in the “Orange Book,” the Agency may not reject a patent merely on the basis that, but for the filing of the patent, ANDAs would be eligible for final approval. 4


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4.4. HIDDEN COMPLEXITIES OF LISTING A PATENT The Agency believes that, even if it had the authority and expertise (which it does not), such a review would not speed the availability of generic drugs. Rather, it would instead add a layer of complexity and delay, leading to litigation between FDA and the generic or innovator, in addition to any litigation between the generic and innovator. Moreover, FDA review of patents would be unlikely to speed approval and marketing of generic drugs in a meaningful way. Even if FDA were to decide not to list a patent, the innovator company could obtain an injunction against approval or marketing of the generic drug until the patent listing question is resolved. In such a case, FDA’s review of the patents would have done nothing to speed approval of generic drugs. Patent reviews would lead to substantial litigation that will impose a new and substantial burden on FDA’s Office of the Chief Counsel and Department of Justice litigation resources. Finally, the Agency does not have the resources or expertise to review patents.

4.5. How to list patents covering the active ingredient and formulation?5

9

5

Orange Book: Approved Drug Products with Therapeutic Equivalence www.accessdata.fda.gov/scripts/cder/ob/default.cfm


4.6. USE OF TERMS & CODES FOR LISTING 6 REFERENCE LISTED DRUG (INNOVATOR DRUG PRODUCT) A reference listed drug (21 CFR 314.94(a)(3)) means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA.

BIOAVAILABILITY. The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

PHARMACEUTICALLY EQUIVALENT DRUG PRODUCTS are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity), but they may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration time, and, within certain limits, labeling.

PHARMACEUTICAL ALTERNATIVES. contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or are different dosage forms or strengths.

BIOEQUIVALENT DRUG PRODUCT (GENERIC DRUG PRODUCT) Pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions.

STATISTICAL CRITERIA FOR BIOEQUIVALENCE For Bioavailability FDA uses the ±20% test (for generic) i.e..the amount of active ingredient in the blood serum over a period of time has to come within ±20% of that which is observed with the patented drug (of innovator) 6

10 th

APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE EVALUATIONS 29 EDITION


FDA has identified in the Prescription Drug Product and OTC Drug Product Lists those reference listed drugs to which the in vivo bioequivalence (reference standard) and, in some instances, the in vitro bioequivalence of the applicant's product is compared.

FDA classifies as therapeutically equivalent those products that meet the following general criteria:

(1) they are approved as safe and effective;

(2) they are pharmaceutical equivalents in that they (a) contain identical amounts of the same active drug ingredient in the same dosage form and route of administration, and (b) meet compendial or other applicable standards of strength, quality, purity & identity

(3) they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b) if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard;

(4) they are adequately labeled;

(5) they are manufactured in compliance with Current Good Manufacturing Practice regulations. The concept of therapeutic equivalence, as used to develop the List, applies only to drug products containing the same active ingredient(s) and does not encompass a comparison of different therapeutic agents used for the same condition (e.g., propoxyphene hydrochloride vs. pentazocine hydrochloride for the treatment of pain). Any drug product in the List repackaged and/or distributed by other than the application holder is considered to be therapeutically equivalent to the application holder's drug product even if the application holder's drug product is single source or coded as non-equivalent (e.g., BN).


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FDA considers drug products to be THERAPEUTICALLY EQUIVALENT if they meet the criteria outlined above, even though they may differ in certain other characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients. "A" CODES

Drug products that are considered to be therapeutically equivalent to other pharmaceutically equivalent products.

"A" products are those for which actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bio-equivalence. Drug products designated with an "A" code fall under one of two main policies:

(1) for those active ingredients or dosage forms for which no in vivo bioequivalence issue is known

or suspected, the information necessary to show bioequivalence between

pharmaceutically equivalent products is presumed and considered self-evident based on other data in the application for some dosage forms (e.g., solutions) or satisfied for solid oral dosage forms by a showing that an acceptable in vitro dissolution standard is met. A therapeutically equivalent rating is assigned such products so long as they are manufactured in accordance with Current Good Manufacturing Practice regulations and meet the other requirements of their approved applications (these are designated AA, AN, AO, AP, or AT, depending on the dosage form, as described below); or

(2) for those DESI drug products containing active ingredients or dosage forms that have been identified by FDA as having actual or potential bioequivalence problems, and for post1962 drug products in a dosage form presenting a potential bioequivalence problem, an evaluation of therapeutic equivalence is assigned to pharmaceutical equivalents only if the approved application contains adequate scientific evidence establishing through in vivo and/or in vitro studies the bioequivalence of the product to a selected reference product (these products are designated as AB).


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CODE A

Products are those for which actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.

AA

  

Cetirizine hydrochloride oral syrup Chloroquine phosphate oral tablet Folic acid injectable; injection

AB, AB1, AB2, AB3

Conventional dosage forms not presenting bioequivalence problems. All oral dosage forms must, nonetheless, meet an appropriate an in vitro bioequivalence standard that is acceptable to the Agency in order to be approved. Multisource drug products listed under the same heading (i.e., identical active ingredients(s), dosage form, and route(s) of administration) and having the same strength generally will be coded AB if an in vivo study is submitted demonstrating bioequivalence. Three-character codes are assigned only in situations when more than one reference listed drug of the same strength has been designated under the same heading.



Nifedipine tablet.extended release,oral

AN

Solutions and powders for AEROSOLIZATION

 

Albuterol sulfate solution; inhalation Albuterol sulfate; ipratropium bromide aerosol, metered; inhalation

  

Progesterone injectable; inj. Testosterone cypionate injectable; inj. Estradiol valerate injectable; inj.

OR

NEBULIZATION

AO

INJECT ABLE OIL solutions

AP

Inject able aqueous solutions (PARENTERAL)   and, in certain instances, intravenous nonaqueous solutions Injectable products available as dry powders for reconstitution, concentrated sterile solutions for dilution, or sterile solutions ready for injection are pharmaceutical alternative drug products.

AT

TOPICAL DOSAGE FORMS for dermatologic, ophthalmic, otic, rectal, and vaginal administration, including creams, gels, lotions, oils, ointments, pastes, solutions, sprays and suppositories.



Theophylline injectable; injection Vancomycin hydrochloride injectable; injection

Hydrocortisone and acetic acid Otic,solution/drops


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"B" CODES

"B" products, for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence, often have a problem with specific dosage forms rather than with the active ingredients. Drug products designated with a "B" code fall under one of three main policies:

(1) The drug products contain active ingredients or are manufactured in dosage forms that have been identified by the Agency as having documented bio-equivalence problems or a significant potential for such problems and for which no adequate studies demonstrating bioequivalence have been submitted to FDA; or

(2) The quality standards are inadequate or FDA has an insufficient basis to determine therapeutic equivalence; or

(3) The drug products are under regulatory review.

The CODE “B*” is assigned to products previously assigned an A or B code when FDA receives new information that raises a significant question regarding therapeutic equivalence that can be resolved only through further Agency investigation and/or review of data and information submitted by the applicant. The B* code signifies that the Agency will take no position regarding the therapeutic equivalence of the product until the Agency completes its investigation and review.

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CODE B

Products are those for which Actual or potential bioequivalence problems have not

BC

CONTROLLED (EXTENDED)-RELEASE



dosage forms (capsules, injectables and tablets)



been resolved by adequate evidence of bioequivalence, often have a problem with specific dosage forms rather than with the active ingredients.

 

Morphine sulfate, extended release; oral, tablet Theophylline, extended release; oral , capsule Penicillin g benzathine injectable; injection Propylthiouracil; oral , tablet

BD

Active ingredients and dosage forms with DOCUMENTED BIOEQUIVALENCE PROBLEMS

BE

DELAYED-RELEASE ENTERIC COATED oral dosage forms



Erythromycin, delayed release; oral, tablet

BN

Products in AEROSOL-NEBULIZER drug delivery systems



Albuterol sulfate; ipratropium bromide aerosol, metered; inhalation

BP

Active ingredients and dosage forms with potential bioequivalence problems. Injectable suspensions containing an active ingredient suspended in an aqueous or oleaginous vehicle



Iron dextran injectable; injection

BR

Suppositories or enemas(RECTAl) that deliver drugs for systemic absorption



Promethacon suppository

BS

Products having drug STANDARD DEFICIENCIES

 

Gallium citrate, ga-67 injectable; injection Technetium tc-99m albumin aggregated kit injectable; injection

BT

TOPICAL PRODUCTS with bioequivalence issues

 

Clindamycin phosphate gel Benzoyl peroxide; clindamycin phosphate gel; topical,gel

Drug products for which the DATA ARE INSUFFICIENT TO DETERMINE THERAPEUTIC EQUIVALENCE

  

Ciprofloxacin hydrochloride;oral,tablet Fluconazole; oral, tablet Methylphenidate hydrochloride, extended release; oral, capsule

BX

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5. HATCH WAXMAN ACT AMENDED TO STRIKE BALANCE BETWEEN BOTH FACETS The HWA was crafted to strike a balance between 2 competing goals (i)

stimulation of new drug innovation

(ii)

cost containment via easier access to lower cost generic alternatives

The goal of the act is to balance long term need for research & development of life saving drugs against the relatively short term goal of providing low cost, high quality pharmaceuticals for consumers. 5.1 Patent term restoration up to 5 years for INNOVATOR

In fulfillment of the first objective ,the act added section 156,granting branded pharmaceutical companies upto five years of extra patent life to compensatre for time lost due to FDA Regulatory delays. The idea was to provide innovator drug companies with IPR Protection sufficient to recoup their investment, thus ensuring the financial incentives necessary for continued research & development of new drugs. 5.2 180 Days Exclusive Marketing Rights for first GENERIC applicant

At the same time, the act made it easier for generic drugs companies to market their products through the use of an abbreviated new drug application (ANDA).Under this procedure, generic companies were no longer required to duplicate the safety & efficacy testing required of the brand name companies for FDA approval of branded pharmaceuticals. Moreover they are given marketing exclusivity for 180 days to generic drug companies that successfully challenges & spurs competition. Market exclusivity affords generic drug companies the benefit of marketing a generic drug without competition from other generic companies for 180 days. Generic drug companies are able to reap significant profit during this time. Once several competitors enter the market & begin selling the generic, the price typically falls by 75-80 16

percent.


HATCH – WAXMAN ACT : A DELICATE BALANCE BETWEEN GENERIC MANUFACTURERS

BRAND MANUFACTURERS

Encourage competition

Reward Technological Advances

• ANDA Process:only Bioequivalence required

Defines the condition for patent extensions

• Allows testing before the brand expires

• • •

• Creates incentive 180-Days Exclusivity- for first successful ANDA filer

100% approval time+ 50 % testing time Upto max extension of 5 years Patent cannot be extended beyond 14 years

Non Patent Exclusivity • • • •

NDA data kept as proprietry by FDA 5 years data exclusivity for NCE Excluding sals or esters 3 years data exclusivity for improvement to approved brand procduct via clinical trials.

Sets forth a process for patent challengesOrange book listings

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6. GENERIC COMPANIES STRATEGIES TO AVOID PATENTS 6.1. DESIGN AROUND STRATERGIES - Reverse Engineering7 Being the first to gain the most is a fundamental principle in the generics business because several companies compete to create generics of successful products going off patent. For a generics company to maintain revenue growth in a market in which product prices continue to fall, it must secure a continuous flow of new products, with quality and speed to market being key drivers. Thus, generics companies must be highly skilled in product and process development

(1) The generics business, and achieving bioequivalence—the most critical development area. Most generics are oral solid dosage forms (e.g., tablets and capsules) that are composed of various excipients, each having a specific purpose.

(2) Although excipients are clinically inactive, they are pharmaceutically active and, therefore, can affect all aspects of drug product performance.

(3) For example, functional excipients such as stabilizers and dissolution modifiers contribute to the dissolution and bioavailability of drug products.

Determining the original drug's excipient content and other formulation optimization steps can be facilitated using REVERSE ENGINEERING, which is the decoding of an innovator product's formulation parameters. Such parameters include the quantitative composition of the innovator product, the solid-state characterization of the active pharmaceutical ingredient (API), and the manufacturing process. 18

7

The Role of Reverse Engineering in the Development of Generic Formulations By Arvind K. Bansal, http://pharmtech.findpharma.com/pharmtech/Article/The-Role-of-ReverseEngineering-in-the-Development/ArticleStandard/Article/detail/173676?contextCategoryId=40616 Shivang chaudhary (PLA 319_09) | NALSAR Pro



PROTOCOL FOR REVERSE ENGINEERING

Figure 4 shows a decision tree for performing reverse engineering on a tablet dosage form. The functionality of the excipient and the API's physicochemical properties strongly affect the amount of effort needed for reverse engineering to be successful.

19




A judiciously performed reverse engineering exercise can facilitate the decisionmaking process at various stages of product development (see Figure 5).

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6.2. THE SKINNY ON “SKINNY LABELING” – A GENERIC DRUG LABELING CARVE-OUT CITIZEN PETITION SCORECARD8 Over the past several months, FDA has responded to or companies have submitted citizen petitions to FDA requesting that the Agency refrain from approving ANDAs for generic drugs with less than complete labeling – so-called ―skinny labeling.”

In the report accompanying the 1984 Hatch-Waxman Amendments, Congress stated that a generic applicant: need not seek approval for all of the indications for which the [Reference Listed Drug (―RLD‖)] has been approved. For example, if the [RLD] has been approved for hypertension and angina pectoris, and if the indication for hypertension is protected by patent, then the application could seek approval for only the angina pectoris indication.

This view was codified in FDC Act § 505(j)(2)(A)(v), which states that an ANDA must contain “information to show that the labeling proposed for the new drug is the same as the labeling approved for the [RLD] except for changes required because of differences approved under a [suitability petition] or because the new drug and the [RLD] are produced or distributed by different manufacturers.‖

In addition, FDA’s implementing regulations at 21 C.F.R. § 314.94(a)(8)(iv) state:Labeling (including the container label and package insert) proposed for the drug product must be the same as the labeling approved for the [RLD], except for [certain differences] . . . . Such differences between the applicant’s proposed labeling and labeling approved for the [RLD] may include. . . omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under [FDC Act § 505(j)(5)(D)].

However, FDA’s regulations at 21 C.F.R. § 314.127(a)(7) further provide that to approve an ANDA that omits an aspect of labeling protected by patent or exclusivity, FDA must find that the ―differences do not render the proposed drug product less safe or effective than the listed drug for all remaining, non-protected conditions of use.” 21

8

FDA Law blog: The Skinny on “Skinny Labeling” – A Generic Drug Labeling Carve-Out Citizen Petition Scorecard


7. BIOLOGIC DRUGS AND THE STATUS OF RELATED US LEGISLATIVE PROPOSALS 9 Currently, biologics represent about one third of the total therapeutics in development, with the number expected to rise significantly in the future.19 Brand biologics may be extremely expensive, with some per-patient costs being as high as $100,000 per year. Generic biologics would result in savings for consumers. For example, global sales of Epogen before generic launch were $2.5 billion. Marketing of generic erythropoietin outside the United States has resulted in a significant decrease in that number. A number of biologics went off patent this year, and others are close behind (eg, darbepoetin alfa [Aranesp; 2016], etanercept [Enbrel; 2012], imiglucerase [Cerezyme; 2010], and filgrastim [Neupogen; 2013]). The estimated value of BIOLOGICS TO LOSE PATENT PROTECTION IN THE NEXT 10 YEARS IS $20 BILLION.

7.1. STATUS OF THE CURRENT PROPOSED LEGISLATION

At present, there is no express mechanism for abbreviated approval similar to HatchWaxman procedures for generic biologics or biogenerics (also known as follow-on biologics). In September 2006, the FDA approved omnitrope, a generic version which referenced the brand product Genotropin. Similarly, the FDA approved a slightly different isoform generic version of Pergonal (Repronex) under the ANDA process, deeming the slight variation ―not clinically significant.‖ The FDA explicitly stated that this approval did not create a pathway for all generic biologics, however. Under Hatch-Waxman, a generic pathway exists for NDA products but not for biologics. There are no 180-day exclusivity provisions for biologics, nor are such products listed in the Orange book.

22

9

Biogenerics: myth or reality? www.iptonline.com/articles/public/IPTNINE63NoPrint.pdf


7.2.

WHAT WE CAN DO TO PREPARE WHEN PURSUING BIOLOGIC DRUG PATENT PROTECTION One possibility is for Congress to simply amend the FDCA and classify “biologics”

that meet the statutory definition of drugs as “drugs,” thereby opening up Hatch-Waxman to them. Other options include the partially abbreviated approval process under the §505(b) route of Hatch-Waxman, where the drug has significant difference from, but is still sufficiently similar to, the brand drug. Still another option is the ―petitioned‖ ANDA process often used in the case of minor modifications from the brand drug. Congressional bills to allow for generic biologics were rejected in 2007 and 2008 but are on the legislative agenda for 2009—exclusivity being the difficult parameter to agree upon. HR 1427, the Promoting Innovation and Access to Life-Saving Medicine Act10, introduced in March by Rep Henry Waxman of Hatch-Waxman fame, authorizes the FDA to approve abbreviated applications for “biogenerics” and mirrors the market exclusivity provisions for drugs, whereas the biotechnology brand industry is seeking between 14 and 20 years of exclusivity. Additionally, President Obama’s budget proposal includes plans to establish a regulatory pathway for approval of generic biopharmaceuticals. Looking at the issue from the brand manufacturers’ point of view, they argue that disclosure of information presented in an NDA is prohibited and is tantamount to an unconstitutional ―taking‖ of a property interest without compensation or, alternatively, a violation of the Trade Secrets Act.24 Therefore, the question remains whether it would be beneficial to apply generic biologics to the established HatchWaxman process.

23 10

www.biogenerics.net Shivang chaudhary (PLA 319_09) | NALSAR Pro

8. CASE STUDY BARR LABBORATORIES Vs. LILLY 11 Generic company Barr Laboratories identified Lilly's megabrand Prozac® (fluoxetine) as a product with a large market potential and a patent position that could be challenged. In 1996, Barr filed its ANDA with a Paragraph IV certification, claiming that its version of fluoxetine did not infringe on the Lilly patents or that the patents were unenforceable. After five years of litigation, on August 9, 2000, the Court of Appeals vacated a lower court decision, ruling in favor of Barr and invalidating one of the patents for Prozac.

After the

compound patent expired and a pediatric exclusivity expired Prozac on August 2, 2001, Barr launched its generic form of the 20mg strength of fluoxetine which alone took 65% of the Prozac share in the first two months after it launched.

(Source: IMS Health NPA Plus )

This graph shows the dramatic uptake of generic fluoxetine. Within the first month of the introduction of the Barr form of fluoxetine, Prozac lost 46% of its total prescriptions. By the end of the six month time period of exclusivity for Barr, Prozac had lost 82% of its prescriptions to the generic form and held onto only 16% of the Prozac/fluoxetine market. 24 11

How Barr Managed to Kill Eli Lilly's Patent on Prozac? www.liebertonline.com/doi/abs/10.1089/107632701753337771


The Hatch-Waxman incentives enabled Barr to successfully challenge the fluoxetine patent and reap the economic benefits of its own exclusivity period. In the eleven months after launch, the sales of Barr's generic fluoxetine reached $367.5M which accounted for 31% of the company's total product sales.

After other generic companies entered the market with their

forms of fluoxetine and eroded the price, the company estimated that the sales of its form of fluoxetine decreased to 1% of its total product sales.

When comparing profit margins generated by the fluoxetine case, it becomes quite obvious why Paragraph IV filings are part of its core business strategy.

During the last

quarter of 2000, Barr reported Product Sales of $142M and a gross margin (deducting the Costs of Sales and Selling & Administration Costs) of $24M, leaving a gross profit margin of 16.8%.However, during the last quarter of 2001, when it had a monopoly on generic fluoxetine sales, Barr took in $360M in Product Sales. With a gross margin of $103.9M, Barr increase its gross profit margin to 28.7%. 5 Hence, by succeeding with its Paragraph IV challenge, it nearly doubled its gross profit margin.

In addition, Barr also had a dramatic increase in its stock price.

During the month of

July 2001, when the favorable Court decision was rendered, Barr's stock price was at a low of $66.00. By the end of the month, it had spiked to $89.38, realizing a gain of over 35%.

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9. CONCLUSION Hatch Waxman act with its amendments reduces & eliminates problems of Cumbersome FDA Regulatory procedures for INNOVATOR & Absence of cheaper GENERIC drug manufacturing in USA, by ensuring that

INNOVATOR would have meaningful patent protection and a

5 years period of marketing exclusivity to enable them to recoup their investments in the development of valuable new drugs during approval from FDA Regulatory procedure & by confirming that once the statutory patent protection and 180 days marketing exclusivity for these new drugs has expired, consumers would benefit from the rapid availability of lower priced GENERIC versions of innovator drugs. HWA established the Abbreviated New Drug Application (ANDA) approval process, in which ANDA has to be proved bioequivalent to previously approved NDA (the ―Reference listed drug‖) and relies on the Agency’s finding of safety and effectiveness for the Reference listed drug product in ORANGE BOOK with proper Therapeutic Equivalalence (TE) coding. which permits generic versions of previously approved innovator drugs to be approved without submitting full new drug application (NDA) i.e. clinical trials. In general, the law has been working well. Since 1984, over 10,000 generic drugs have entered the market, and generics now account for close to 50 percent of prescriptions filled. *********************

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10. BIBLIOGRAPHY 

Rajbhanshi N. ―Overview of the WorldPharmaceutical Industry‖. Presented at the IPAconference ―Workshop on GMP and RegulatoryAffairs‖, Indian Pharmaceutical Association Delhi Branch, 28 October 2007, India Habitat Centre, New Delhi.

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Buehler GJ, Conner D. The FDA Process of Approving Generic Drugs, Office of Generic Drugs[online]. Available from:URL:www.fda.gov/CDER/meeting/CTP2005/Generic.ppt.

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Mossinghoff GJ. Overview of the Hatch WaxmanAct and its impact on the drug development process. Food and Drug Law Journal Vol. 54. [online]. 1999 Availablefrom: URL:www.fdli.org/pubs/Journal%20Online/54_2/art2.pdf.

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Himes JL, Zain S. Anti-competitive Innovation: Is There a Role for Antitrust In Evaluating Product Line Extensions? American Conference Institute, Pharmaceutical Antitrust, New York [online] May 15-16, 2007 Available from: URL:www.oag.state.ny.us/bureaus/antitrust/pdfs/anti_competitive_innovation_ProductLi ne_Extension_by_himes.pdf.

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Flor VS. The Approaching Storm. Intellectual Asset Management [online]. October/November 2006 Available from: URL:www.skgf.com/media/news/news.286.

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Consent Agreement Resolves Complaint Against Pharmaceutical Companies Hoechst Marion Roussel, Inc. and Andrx Corp. Commission Alleged that Companies' Agreement Likely to Stifle Competition in U.S. Drug Market. Federal Trade Commission. Protecting America’s Consumers [online] 2004 Available from: URL:http://www.ftc.gov/opa/2001/04/hoechst.shtm.

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Gordon GG. Recent Pharmaceutical Industry Antitrust Cases Raising Intellectual Property antitrust Issues Antitrust Enforcement: Cutting Edge Lessons from the Pharmaceutical Industry American Bar Association, Section of Antitrust Law, Spring Meeting [online]. 2003] Available from: URL: www.abanet.org/antitrust/committees/intell_property/recentpharmcases.doc.

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Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence studies for Immediate-Release Solid Oral Dosage FormsBased on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) [online]August 1997 Available from:URL:www.cop.ufl.edu/safezone/pat/pha5128/resources/waiver.pdf. 27 **********


PREPARED BY:

SHIVANG A. CHAUDHARY B.Pharma,NIRMA University of Science & Technology, M.S,(Pharm) PHARMACEUTICS, NIPER-Ahmedabad PGDPL ID No: PLA 319_09 28
