Anda Paragraph-IV Filings a Complete Review

Useni Redd Reddy y Mallu et al., al., IJSID, 2012 2012,, 2 (4 (4), ), 96 96-1 -112 12

ISSN:2249-5347

IJSID International Journal of Science Innovations and Discoveries Review Article

An International International peer Review Journal for Science

Available online through www.ijsidonline.info ANDA PARAGRAPH-IV FILINGS: A COMPLETE REVIEW Useni Reddy Mallu *, Sekhar Karanam and Panyala Srinath Srinath Reddy

Dept. of Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India

ABSTRACT The present review throws light on the criticalities and complexities involved in the paragraph

Received: 16.07.2012

IV ANDA filings with USFDA and the intellectual property litigations evolving around between the

Accepted: 29.08.2012

branded branded manufac manufacture turers rs and generic generic compani companies. es. Hatch-W Hatch-Waxma axman n Act grant grant generic generic manufac manufacture turers rs the ability to mount a validity challenge without incurring the cost of entry or risking enormous damages

*Corresponding Author

flowing from any possible infringement. The entry of generic product in to the market allows the public to have access to low cost medicines medicines equivalent equivalent to brand products. products. Once multiple multiple generic firms firms enter the market, prices fall, often dramatically. The current generic approval process involves submission of only an abbreviated new drug application (ANDA) that relies on FDA approval of the pioneer drug (or patented brand name drug) to demonstrate safety and effectiveness. The generic drug does not require proof that it is safe and effective--that has already been proven by the brand name drug manufacturer and through many years of clinical use in the general population. Generally, the ANDA has to establish only that the generic drug is bioequivalent to the pioneer drug (i.e., the reference-listed drug for which therapeutic equivale equivalence nce is sought sought). ). The Hatch-Wa Hatch-Waxma xman n Act gave additi additional onal protecti protection on to the inventor inventorss of new drugs,both drugs,both by lengthening patent patent terms and by providing providing guaranteed periods periods of data exclusivity.In exclusivity.In

Address:

INTRODUCTION exchange, Hatch-Waxman made it easier for generic drug manufacturers to enter the market with a copy

Name: Dr. Useni Reddy Mallu Place: Dept. of Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India E-mail: [email protected]

of the drug, either either by waiting until the patent patent expires or or by challenging challenging weak patents. patents. To To encourage generic manufacturers manufacturers to identify identify and challenge challenge weak patents, patents, Hatch-Waxma Hatch-Waxman n offered a sort of incentive incentive to the generic challenger. challenger. The first generic generic manufacturer manufacturer to file for approval with the FDA, as paragraph IV is entitled to 180 days days of “generic exclusivity exclusivity”” when it first enters the market. During that period, period, other generic drug drug makers are prohibited prohibited from entering the market. The The point was to offer an incentive, INTRODUCTION encouraging encouraging generic firms to challenge challenge and invalidate invalidate bad patents (or invent around them) early and often, and accordingly accordingly get get generic generic drugs on to the market market earlier. Multiple Multiple ANDA filings filings on the same day would lead lead to sharing the the exclusivity exclusivity between generic generic manufacturers. manufacturers. 30-month 30-month FDA stay period and patent infringement litigations became a common scenario in the growing global generic pharmaceutical industry. with very little downside and huge upside, exclusivity is the driving force to the huge increase in first-to-file Paragraph IV filings. Keywords: USFDA-A USFDA-ANDA NDA submiss submission, ion, Orange Orange book, Parag Paragraph raph-IV -IV filing filing,, 30months 30months stay stay period, period,

Litigations, Litigations, 180days 180days exclusivity, exclusivity, Multipl Multiple e ANDA submission, submission, Hatch Waxman act, CFR , First to to file and case studies.

Internationa Inter nationall Journal of Science Science Innovations Innovations and Discoverie Discoveries, s, Volum Volume e 2, Issue 4, July-A July-August ugust 2012 96

Useni Reddy Mallu et al., IJSID, 2012, 2 (4), 96-112

INTRODUCTION

Generic drugs are important options that allow greater access to health care for public. They are copies of brand-name drugs and are the same as those brand name drugs in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Health care professionals and consumers can be assured that FDA approved generic drug products have met the same rigid standards as the innovator drug. All generic drugs approved by FDA have the same high quality, strength, purity and stability as brand-name drugs. And, the generic manufacturing, packaging, and testing sites must pass the same quality standards as those of brand name drugs. The Food and Drug Administration (FDA or USFDA) is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments. The FDA is responsible for protecting and promoting public health through the regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation emitting devices (ERED), and veterinary products. The FDA also enforces other laws, notably Section 361 of the Public Health Service Act and associated regulations, many of which are not directly related to food or drugs. These include sanitation requirements on interstate travel and control of disease on products ranging from certain household pets to sperm donation for assisted reproduction. The FDA is led by the Commissioner of Food and Drugs, appointed by the President with the advice and consent of the Senate. The Commissioner reports to the Secretary of Health and Human Services. The 21st and current Commissioner is Dr. Margaret A. Hamburg. She has served as Commissioner since February 2009. USFDA have several offices and centers for monitoring the different aspects. The details are represented in figure-1.

Figure No-1: USFDA centers and offices.

FDA's Center for Drug Evaluation and Research (CDER) regulates over-the-counter and brand name and generic prescription drugs. In this function, CDER supports innovation and plays a key role in helping to advance new drug development. CDER is the division for monitoring the pharmaceuticals, and manages the current good manufacturing practice (cGMP) regulations for pharmaceutical manufacturing and drug approvals. FDA has Legal Authorities, for saving human health and providing less cost medicines and cosmetics and even life threatening diseases also. The list of authorities, acts and amendments are tabulated in table-1. International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 97


Table No-1: List of FDA regulations and amendments Year Regulation or Amendment 1902 Biologics Control Act 1906 Pure Food and Drug Act 1938 Federal Food, Drug and Cosmetics Act 1944 Public Health Service Act 1951 Food Drug and Cosmetics Act Amendments 1962 Food Drug and Cosmetics Act Amendments 1966 Fair Packaging and Labeling Act 1976 Medical Device Regulation Act 1984 Drug Price Competition –Patent Term Restoration Act (Hatch Waxman Act) 1987 Prescription Drug Marketing Act 1988 Antidrug Abuse Act 1990 Nutrition Labeling and Eduction Act 1992 Prescription Drug User Fee Act 1994 Dietary Supplement Health and Education Act 1997 Food Drug Modernization Act 2002 Bioterrorism Act 2002 Medical Device User Fee and Modernization Act (MDUFMA) 2003 Animal Drug User Fee Act 2007 Food and Drug Administration Amendments Act of 2007 Code of Federal Regulations (CFR)

The CFR is published by federal government of the United States. CFR is the codification of the general and permanent rules and regulations. CFR can be called as administrative law. The CFR is divided into 50 titles that represent broad areas subject to Federal regulation as listed below. CFR, Title 21 governs the food and drugs within the US for the FDA, the Drug Enforcement Administration (DEA), and the Office of National Drug Control Policy (ONDCP). 21 CFR is divided into three chapters: Chapter I ,deals the FDA, Chapter II deals the Drug Enforcement Administration and Chapter III deals Office of National Drug Control Policy. Each chapter again divided in to parts. Part- 314 deals the applications for FDA approval to market a new drug from patents to ANDA submission. In this ,part 314 again divided into subparts like subpart A, B, C, D, E, F, G, H and I. Title 21 CFR Part 11 of the Code of Federal Regulations deals with the FDA guidelines on electronic records and electronic signatures in the US. Part 11, as it is commonly called, defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records In general, Part 11 insists drug makers, medical device manufacturers, biotech companies, biologics developers, contract research organizations (CRO) and other FDA-regulated industries, with some specific exceptions, to implement controls, including audits, system validations, audit trails, electronic signatures, and documentation for software and systems involved in processing electronic data that are (a) required to be maintained by the FDA predicate rules or (b) used to demonstrate compliance to a predicate rule. A predicate rule is any requirement set forth in the Federal Food, Drug and Cosmetic Act (FDC Act), the Public Health Service Act, or any FDA regulation other than Part 11. The FDA will approve the new drug products (NDA) by evaluating the safety and efficacy. The innovator should provide the scientific and clinical data, must usually from at least two well-controlled clinical studies. Once approved the drug product, FDA will assure the market protection with the forms of exclusivity which is a creation of law. Exclusivity enables the drug product to have exclusive, or monopoly, status in the market for a certain number of years (five years for a new chemical

International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 98


entity (NCE) and other periods of time for different situations.) Exclusivity means that the FDA cannot legally approve a generic drug application for that product until the exclusivity period expires. Table No-2: List of CFR titles Title Number Title 1 Title 2 Title 3 Title 4 Title 5 Title 6 Title 7 Title 8 Title 9 Title 10 Title 11 Title 12 Title 13 Title 14

Title Number Title 26 Title 27 Title 28 Title 29 Title 30 Title 31 Title 32 Title 33 Title 34 Title 35 Title 36 Title 37 Title 38 Title 39

Title Name Internal Revenue Alcohol, Tobacco Products and Firearms Judicial Administration Labor Mineral Resources Money and Finance: Treasury National Defense Navigation and Navigable Waters Education Reserved (formerly Panama Canal) Parks, Forests, and Public Property Patents, Trademarks, and Copyrights Pensions, Bonuses, and Veterans' Relief Postal Service

Title 15

Title Name General Provisions Grants and Agreements The President Accounts Administrative Personnel Homeland Security Agriculture Aliens and Nationality Animals and Animal Products Energy Federal Elections Banks and Banking Business Credit and Assistance Aeronautics and Space (also known as the Federal Aviation Regulations, administered by the Federal Aviation Administration) Commerce and Foreign Trade

Title 40

Title 16

Commercial Practices

Title 41

Title 17 Title 18

Title 42 Title 43 Title 44 Title 45 Title 46

Emergency Management and Assistance Public Welfare Shipping

Title 22

Commodity and Securities Exchanges Conservation of Power and Water Resources Customs Duties Employees' Benefits Food and Drugs (administered by the US Food and Drug Administration and the US Drug Enforcement Administration) Foreign Relations

Protection of Environment (administered by the United States Environmental Protection Agency) Public Contracts and Property Management Public Health Public Lands: Interior

Title 47

Title 23 Title 24 Title 25

Highways Housing and Urban Development Indians

Telecommunication (also known as the "FCC Rules", administered by the Federal Communications Commission) Federal Acquisition Regulations System Transportation Wildlife and Fisheries



Second form is the patent protection, which provides the market protection for a marketed branded drug. Included in the NDA is information regarding any patents on the drug product? The manufacturer applies for these patents with the US Patent and Trademark Office (USPTO) which, of course, works independently from the FDA. The FDA lists the patents in the Approved Drug Products wit h Therapeutic Equivalence Evaluations (TEE) in the Orange Book.

Orange book: Approved Drug Products with TEE , commonly known as the “Orange Book,” is compiled by the FDA and lists all

approved drugs along with official and proprietary names of the drug.Since 2005, FDA has been providing the daily Electronic Orange Book (EOB) product information for new generic drug approvals which is important for substitution purposes. International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 99


Previously, a first-time-generic product approved early in the month would not be published in the EOB for several weeks. The monthly EOB update goal is by the end of the following month’s second work week (e.g., January’s EOB will be updated by the end of the second full work week in February). The EOB content includes NDA approvals in the EOB month they were approved. NDA application numbers are preceded with “N”; ANDA or Generic product as of the date of the daily update. Generic application numbers are preceded with “A”; All product changes received and processed as of the monthly update date and Discontinued products will be processed as of the date of publication. There will be circumstances where a product is discontinued in one month, however, it will be reported in a different month's EOB. For example, the Orange Book Staff received a letter November 7 that the product has been discontinued from manufacturing and marketing. The Orange Book subsequently updates the October EOB on November 14. The product will show in the October EOB that it is discontinued even though the date of discontinuance is the day that the Orange Book Staff receives notification (November 7)). Patent information, also updated daily in the EOB, as of the date of the daily update. You can download the orange book annual edition in PDF form from the FDA site. FDA Requirements for Generic Drugs 

Same active ingredients, same dosage form, same labeled strength, labeling as the brand-name product.



Generic drug manufacturers must show that a generic drug is bioequivalent to the brand-name drug, which means the generic version delivers the same amount of active ingredients into a patient's bloodstream in the same amount of time as the brand-name drug.



Generic drug manufacturers must fully document the generic drug's chemistry, manufacturing steps, and quality control measures.



Firms must assure the FDA that the raw materials and finished product meet specifications of the U.S. Pharmacopoeia, the organization that sets standards for drug purity in the United States.



Firms must show that a generic drug will remain potent and unchanged until the expiration date on the label.



Firms must comply with federal regulations for good manufacturing practices and provide the FDA a full description of facilities they use to manufacture, process, test, package, and label the drug. The FDA inspects manufacturing facilities to ensure compliance

HATCH WAXMAN (HW) Act:

The Drug Price Competition and Patent Term Restoration Act of 1984, usually refered to as the Hatch-Waxman Act, was designed to promote generics while leaving intact a financial incentive for research and development. It allows generics to win FDA marketting approval by submitting bioequivelence studies (as opposed to clinical data, which is costlier to compile). It also grants a period of additional marketing exclusivity to make up for the time a patented pipeline drug remains in development. This extension cannot exceed five years, and it is in addition to the 20 years exclusivity granted by the issuance of a patent. Additionally, the generic manufacturer must file a certification regarding patents listed in the Orange Book (also known as Approved Drug Products with Therapeutic Equivalence Evaluations). A paragraph IV certification states that the patent is invalid or will not be infringed and begins a process by which that question may be answered by the courts prior to expiration of the patent. Under Hatch-Waxman, FDA approval of an ANDA is automatically stayed for 30 months when a patent owner files a patent infringement lawsuit within 45 days of receiving a paragraph IV notification. During the stay, the FDA is prohibited from approving another ANDA. Additionally, the first ANDA is granted a 180-day exclusivity period, as an incentive



whereby the generic company does not have competition from other generic companies and can both establish market share and charge a higher price. Although the net effect of HW on pharmaceutical innovation is ambiguous, its effect on generic drug development has been explicit, and the effect on consumers has been beneficial. Hatch-Waxman resulted in increased ANDA applications and paragraph IV (P-IV)challenges, especially since 1998. There has also been a high success rate for patent invalidation, particularly formulation and polymorph patents. Since Hatch-Waxman, virtually all top-selling drugs not covered by patent face generic competition; whereas pre–Hatch-Waxman, only 35% had generics available. Similarly, today more than 70% of prescriptions are for generics. An unexpected consequence resulting from HW, especially over the past 10 years, has been the filing of patent applications by generic companies and increased generic research and development for branded products. Table-3 represents the major loopholes in HW act. Table No-3: Major loopholes in HW act Major Loopholes of Hatch Waxman Act

1

Sharing of 180 day exclusivity by several generic manufacturers

2 3 4

Filing “Citizen petitions” to freeze the ANDA application Risky generic launch strategies No prohibition against “authorized generics”

HATCH WAXMAN (HW) Amendments:

HW was amended several times to close these loopholes and/or decrease generic drug approval times. Additionally, over the years, the FDA issued many guidance documents clarifying Hatch- Waxman with the goals of reducing generic approval time; improving ANDA application quality to avoid multiple review cycles; avoiding time-consuming legal delays; and closing “loopholes” which delayed competition. Unfortunately, anticompetitive strategies and loopholes continue today and fuel the momentum for further legislative Hatch-Waxman reform. HW act amendments were tabulated in table-4. Table No-4: HW act amendments Amendments of Hatch Waxman Act

1 2 3

Medicare prescription drug, Improvement and Modernization Act of 2003(MMA) FDA Amendments act of 2007 QI programme supplemental funding Act of 2008

ANDA submission and Approval Process:

An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the public. When patent information is submitted for a new drug application the patent information is included in the Orange Book. Through the abbreviated new drug application (“ANDA”) process, a party may obtain FDA approval of generic drugs without clinical trials if the drug is a bioequivalent of a drug previously granted NDA approval. ANDA approval requires that an applicant make a patent certification “with respect to each patent issued by the United States Patent and Trademark Office International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 101


that, in the opinion of the applicant and to the best of its knowledge, claims the reference listed drug or claims a use of such listed drug for which the applicant is seeking approval Certification requires the ANDA applicant to state that: (1) the NDA holder submitted no patent to the FDA; (2) any patent submitted has expired; (3) the date the applicable patent expires; or (4) that “the patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the drug product for which the abbreviated application is submitted.” Patent Exclusivity

ANDA has four types of submissions, Paragraph-I (P-I): patent information relating to the innovator drug has not been filed; Paragraph-II (P-II): the patent has expired; Paragraph-III (P-III) : ANDA will be approved after the particular patent expires and Paragraph-IV (P-IV): Challenging a particular patent that is listed by the Innovator in the "Orange Book." Paragraph I, II and III:

A certification under P-I or II permits the ANDA to be approved immediately when otherwise eligible. A certification under P-III indicates that the ANDA may be approved on the patent expiration date. A certification under P-III indicates that the ANDA may be finally approved when the patent expires.

Figure No-2: Types of Paragraph filings for ANDA submission. Paragraph IV (P-IV) Certification

The basis of P-IV certification is The Drug Price Competition and Patent Term Restoration Act that came to be known as the “Hatch-Waxman Act.” The Hatch-Waxman rules created processes and incentives for both branded and generic companies involving challenges to patents. 

Branded pharmaceutical companies are required to list patents involving composition of matter (substance), formulation, and method of use in the Food and Drug Administration “s (FDA) Orange Book.



When applying to enter the market with a generic form of a reference product, the generic company files an Abbreviated New Drug Application (ANDA) and certifies against patents listed in the Orange Book. The certification states that its generic product does not infringe on the listed patents or that those patents are not enforceable, called a Paragraph IV filing. International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 102

Useni Reddy Mallu et al., IJSID, 2012, 2 (4), 96-112 

If the generic company files an ANDA with a Paragraph IV certification, then the branded company is notified within 20 days. After the notice, the branded company has 45 days to file a patent infringement action against the generic company. After the suit has been filed, the FDA cannot approve of the application until the generic company successfully defends the suit or until 30 months, whichever comes first.

“30 MONTH STAY” PERIOD

In patent litigations between branded pharmaceutical companies and generic manufacturers, where the generic company files a P-IV certified ANDA and is attempting to sell a product that is equivalent to the branded company’s product, much of the litigation focus and drama revolves around the so-called “30-month” FDA stay date. Under the HW Act, once the branded pharmaceutical company files a timely complaint, the FDA will not grant the generic company final approval of its product for “30-months,” absent a court decision that the patent is not infringed, invalid or unenforceable.

USFDA-ANDA Paragraph-IV applicant

eCTD submission through ESG

CTD submission (Hard copy)

Submission Rejection

FDA Acceptance Letter

Submission Rejection

ANDA applicant raises the letter to innovator by explaining existing patent is invalid

Innovator can file a patent infringement lawsuit, even if authentic claim by the ANDA applicant

Suit on ANDA

30months stay is effective

No Suit on ANDA

No 30months stay , FDA will give the approval

Figure No-3: Paragraph-IV submission and 30months stay International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 103


In principle, the 30-month FDA stay period is designed to provide the court enough time to resolve the branded pharmaceutical company’s patent issues, and the FDA sufficient time to review the generic company’s ANDA. Recognizing that delay in the litigation by either party could have serious implications, the HW Act states that a court may either shorten or lengthen the 30-month period if “either party to the action failed to reasonably cooperate in expediting the action.” Because the generic company would like to enter the market sooner than the 30-month FDA stay period, it must invoke the statute to try to shorten the stay period, alleging that the branded company has improperly delayed the litigation 

The submission of an ANDA for a drug product application containing a P- IV certification may be sued for patent infringement. If the NDA holder or patent owner files a patent infringement suit against the ANDA applicant within 45 days of the receipt of notice, FDA could not give final approval to the ANDA for at least 30 months from the date of that notice.



This 30-month stay will delay approval of the generic drug product unless the court reaches a decision earlier in the patent infringement case or otherwise orders a longer or shorter period for the stay. A court may modify the length of a stay, under the FD&C Act, “if either party in the action failed to reasonably cooperate in expediting the action.” (21 U.S.C. 335(j)(5)(iii))



Under FDA’s traditional interpretation of the HW Amendments, multiple 30-month stays have been possible. Submission of newly issued patents after an ANDA application has been filed with FDA has required the appropriate certification and notice to the NDA holder and patent owner with the possibility of a 30-month stay if patent infringement litigation resulted. As a result, there have been a number of instances in which delays in ANDA approval have exceeded 30-months.



A recent review of FDA’s records indicates that out of 100 ANDA applications 4 are filed under paragraph IV certifications with patent challenges. However, we note that a significant number of these products have high dollar value annual sales.



Once 30 months stay period have passed, the FDA can approve the ANDA application, though litigation is ongoing and the approved generic firm can market their product based on the favorable court decisions.

Strategies adopted by generics and brands on grounds of HW Loopholes

1.

One such strategy is the “at risk” product launch by generic companies which basically involves launching the product prior to a district court clearance on litigations.

2.

Another strategy involves filing an ANDA ,for the sake of filing and having little chance for success. Under HW, the first ANDA filer, regardless of the outcome of the subsequent patent infringement litigation, is entitled to the 180day exclusivity. For patents found valid, upon expiration, a new ANDA need not be filed. While the intent was to provide other generic companies from benefiting when they had risked nothing, the actual result is the maximum number of P-IV filings on day one.

3.

Yet another strategy is the market entry of “authorized generics” (“AG”), which are brand companies’ own “generics” marketed either through brand product relabeling (perhaps through a subsidiary) or licensing agreements with another company. The company entitled to 180- day exclusivity loses revenue, even if the “authorized generic” is the result of a P-IV litigation settlement agreement between itself and the brand manufacturer.

4.

The brand company benefits from AG sales even after expiration of the brand drug patent. Marketing an AG during the 180- day exclusivity period violates the first ANDA’s statutorily granted “exclusivity,” ie, the policy and intent of



HW, and may run afoul of the Sherman Act or State Unfair Competition Acts. Moreover, critics of AG argue that packaging and labeling the branded drug as a generic are tantamount to “misbranding.” 5.

The generic history reveals that, the generic companies must choose to either incur the cost and risk of continuing patent litigation and face fewer returns during the 180-day period, or settle. Via a “reverse payment agreement” a brand company pays a generic company a substantial amount of money to either not file an ANDA application or stay out of the market for a specified period of time. In some cases, the amount is actually greater than the generic company would actually make if it were to market the generic.

6.

While under the MMA the 180-day exclusivity is forfeited for generic applications entering anticompetitive agreements as determined by the Federal Trade Commission (FTC) or attorney general or failing to enter the market within 75 days of effective approval or 30 months after submission of an application entitling the 180 days, most often the forfeiture is avoided by legal maneuvers and “bottlenecks” continue. Legislation to prohibit “reverse payment” agreements and “bottleneck” strategies has been unsuccessful many times.

7.

The FDA has no expertise or resources with which to resolve complex questions of patent coverage. Generic and brand companies may only resolve any patent disputes in private litigation. Patent “evergreening”—that is, obtaining additional patents on specific features of a drug product, eg, isomers, polymorphs, metabolites, intermediates, process patents, or double patenting— became a popular practice among brand companies with expiring Orange Book patents to extend the monopoly on a drug. Multiple 30-month stays were triggered when the NDA holder added new patents to the Orange Book, whereas each patent required a separate paragraph IV certification, thereby resulting in a new lawsuit hence, new 30-month stays. In some cases, companies had chains of patents which were added to the Orange Book in a staggered manner to keep generics out of the market. Under the medicate modernization act (MMA), generic companies must now only certify to Orange Book patents listed at the time of initial ANDA filing, effectively preventing multiple 30-month stays.

8.

A Citizen Petition is a request that anyone can make to the FDA regarding a specific aspect of a pending application. Questioning the quality of a competitor’s product through last minute Citizen Petitions with dubious or frivolous claims is yet another method to delay generic competition. Additionally, the Citizen Petition results in a “hold” on the ANDA until decided.

9.

Although statutorily the FDA commissioner may take up to 90 days to investigate the petition, it often takes much longer. Generic manufacturers would like to prohibit or limit the filing of Citizen Petitions by innovator manufacturers.

Multiple ANDA’S:

The related issues of “shared exclusivity”” arise in the following situation 1) Multiple generic applicants submit ANDAs with paragraph IV certifications to the same patent(s) on the same first day; The agency explained that when, on the same day, more than one applicant submits an ANDA for the same drug containing a paragraph IV certification to a listed patent, and no such certification was submitted previously, all the applicants will share exclusivity. Exclusivity will be triggered for all first applicants for a specific listed patent when one of them begins to market its product (or on the date of any court decision finding that patent invalid, unenforceable, or not infringed, if earlier).



Paragraph IV ANDA Submission

Generic Companies A & B filing on Day 1

Generic Companies C & D filing on Day 2

Within 20 days’ notice by generic firms to brand manufacturer about patent invalidation

Within 45 days’ brand manufacturer will sue the generic applicant Applicant-A and B are eligible for 180days and C and D are considered for normal approval (no 180days)

If sued “30 month Stay period” for FDA approval begins

FDA extend final approval after expiry of “30 months stay” for first a licants A & B

After final approval Generics A & B receives 180 day exclusivity and can start marketing based on litigation status

If not sued FDA can review and approve the ANDA

Generics C & D receives final approval only after completing the 180 day exclusivity by either generic firm A or B

Figure No-4: Multiple ANDA submission with Paragraph-IV certification ANDA Review Process

ANDA review can be proceeded in different parts like BABE review, Chemistry and micro review and Labeling review procedures. Drug substance critical review points are API characterization, Synthesis, In-process methods, Specifications and stability studies. Drug product critical review points are formulation development, QbD approach, manufacturing process, Inprocess controls, Analytical methods for in-process and finished product, specification limits and stability. Litigation & Settlements

Paragraph IV of the HW Act provides a mechanism for the litigation of pharmaceutical patent infringement disputes. Many of these cases have been settled with reverse payments by the brand to the generic in return for delayed generic product entry by using the available loop holes of HW Act. International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 106


The Federal Trade Commission (FTC) has contested several of these settlements with good but not complete success. Many of the off court litigation settlement involves

USFDA-ANDA Review process

BA-BE Review

Chemistry, Micro Review

BA-BE review is acceptable?

NO

Chemistry and Micro review is acceptable?

YES

NO

YES

Approval deferred pending, satisfactor

Approval deferred pending, satisfactory results

Review process is success full

Labeling review

Labeling review is acceptable?

NO

YES


Request for plant

NO

Pre-approval inspection is acceptable?


YES

ANDA Approval

Figure No-5: ANDA review process

1.

Settlements where the brand-name company pays financial settlement to generic firms as part of a deal that leads to delayed entry into the market. There are good reasons why a generic might choose to stay away from the market until litigation is resolved. If it enters, it would be liable for damages equal to the lost profits of the brand. But that International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 107


stipulation does not require allowing for payments to the generic. There are also good reasons why a brand might request a stay against a generic's entry, especially if it feels that it has a good case and the generic is unlikely to have the money to pay a damage claim The reason is that the payment structure can create an incentive for the generic to drag out the litigation, particularly if either (1) it is likely that it will lose, or (2) there is a second generic who will likely be able to enter after 180 days, regardless of when the litigation is resolved. 2.

But the pure cash deals would lead to an antitrust problem, and to overcome that some firms have attempted the following structure. The generic agrees for delayed entry, the brand-name company provides the entrant with cash, and the generic entrant provides the brand manufacturer with some alternate considerations like licensing to patents that the generics hold. This was the basic structure of the Schering-Upshur-Smith deal that the FTC ultimately challenged.

3.

Some deals have involved Royalty Payments like receiving licenses to enter the market, either immediately or on a delayed basis, with the generic entrant paying royalties to the brand

4.

One final device that has been used to game the system involves the licensing of pseudo-generics (Authorized generics) in settlements. A pseudo-generic is the branded drug sold as a generic under license from the brand.

5.

However the Federal Trade Commission monitors these sort of gamings and if found antitrust, sues both the parties with charging them as anticompetitive behavior in market.

180 Days Market ‘EXCLUSIVITY”

HW Act provides an incentive of 180 days market exclusivity to the “first” ANDA applicant who challenges a listed patent by filing a paragraph IV certification and thereby runs the risk of having to defend a patent infringement suit. After USFDA approval and successful court litigations, begins commercial marketing of the generic drug product with 180 days market exclusivity. In some cases, a generic manufacturer who obtains 180-day exclusivity may be the sole marketer competing with the brand product for market share In some cases, if there is no court decision and the first applicant does not begin commercial marketing of the generic drug, there may be prolonged or indefinite delays in the beginning of the first applicant’s 180-day exclusivity period. Until an eligible ANDA applicant’s 180-day exclusivity period has expired, FDA cannot approve subsequently submitted ANDAs for the same drug. This is possible even if the later ANDAs are otherwise ready with tentative approval and the sponsors are willing to begin marketing immediately. Therefore, an ANDA applicant who is eligible for exclusivity can often delay other generic competition for the brand product by delaying the market entry. Only a “first” ANDA applicant filing a paragraph IV certification shall be eligible for exclusivity. If an applicant changes from a paragraph IV certification to a paragraph III certification, for example, upon losing its patent infringement litigation, the ANDA will no longer be eligible for exclusivity. The 180-day exclusivity provision has been the subject of considerable litigation and administrative review in recent years, as the courts, industry, and FDA have sought to interpret it in a way that is consistent both with the statutory text and with the legislative goals underlying the HW Amendments. A series of Federal court decisions beginning with the 1998 Mova case describe acceptable interpretations of the 180-day exclusivity provision, identifiying potential problems in implementing the statute, and establish certain principles to be used by the Agency in interpreting the statute. As described in a June 1998 guidance for industry, FDA currently is addressing on a case-by-case basis those 180-day exclusivity issues not addressed by existing regulations. International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 108


One of the most basic changes to the 180-day exclusivity program, in view of the legal challenges to FDA’s regulations, is the determination by the courts of the meaning of the phrase “court decision.” The courts have determined that the “court decision” that can begin the running of the 180-day exclusivity period may be the decision of the district court, if it finds that the patent at issue is invalid, unenforceable, or will not be infringed by the generic drug product. FDA had previously interpreted the “court decision” that could begin the running of 180-day exclusivity (and the approval of the ANDA) as the final decision of a court from which no appeal can be or has been taken - generally a decision of the Federal Circuit. FDA’s interpretation had meant that an ANDA applicant could wait until the appeals court had finally resolved the patent infringement or validity question before beginning the marketing of the generic drug. FDA had taken this position so that the generic manufacturer would not have to run the risk of being subject to potential treble damages for marketing the drug, if the appeals court ruled in favor of the patent holder. The current interpretation means that if the 180-day exclusivity is triggered by a decision favorable to the ANDA applicant in the district court, the ANDA sponsor who begins to market during that exclusivity period now may run the risk of treble damages if the district court decision is reversed on appeal to the Federal Circuit. As a practical matter, it means that many generic applicants may choose not to market the generic and thus the 180-day exclusivity period could run during the pendency of an appeal. Recent P-IV Litigations- Case Studies 1.

ANDA litigation over Lupin's generic version of FORTAMET (metformin extended-release tablets). Sciele Pharma v. Lupin, No. 2012-1228 (Fed. Cir.)- Presently the case under litigation in district court

2.

Genzyme and against ANDA applicants Roxane, Sandoz, and Anchen in the paragraph IV litigation concerning HECTOROL (doxercalciferol),- District court decision was in favour of the brand company and concluded that the ANDA holders had infringed the claims in OB patent and can go for appeal in Federal court if required.

3.

Cephalon in connection with its ANDA for a generic version of Cephalon's FENTORA (fentanyl citrate) buccal tablets. Cephalon v. Watson-In the court decision Cephalon could not prove infringement of patents by Watson for two patents ,but Watson failed to prove invalidity of Cephalon patent 6,264,981 and declared a permanent injuction against Watson till the expiry of this patent in October,2019.

4.

5.

6.

Generic version of sumatriptan/naproxen sodium that competes with Treximet(R) (sumatriptan and naproxen sodium) sold by GlaxoSmithKline in patent infringement lawsuit against Par, Alphapharm Pty Ltd., Teva Pharmaceuticals USA, Inc., and Dr. Reddy's Laboratories, Inc - The District Court ruled U.S. Patent Nos. 6,060,499 (the ‘499 patent) and 6,586,458 (the ‘458 patent) to be valid, enforceable and infringed by Par Pharmaceutical, Inc. (Par), Alphapharm Pty Ltd. (Alphapharm), and Dr. Reddy’s Laboratories, Inc. (DRL). A third patent, U.S. Patent No. 7,332,183 (the ‘183 patent) covering the Treximet formulation was held to be valid, enforceable and infringed by Par and DRL. The ‘183 patent was not asserted against Alphapharm. Atorvastatin litigations,Pfizer Vs Ranbaxy;Ranbaxy will Market Generic Atorvastatin in the U.S. with 180 Days Exclusivity from Nov. 30, 2011 - RANBAXY AND PFIZER SETTLE LIPITOR LITIGATION WORLDWIDE,Under the terms of the agreement, Ranbaxy will have a license to sell generic versions of Atorvastatin and the fixed-dose combination of Atorvastatin-Amlodipine besylate in the United States effective Nov. 30, 2011. Mylan's 10 mg and 20 mg omeprazole delayed-release capsules, which are the generic versions of AstraZeneca LP's Prilosec ;Mylan wins Omeprazole patent litigation

7.

AstraZeneca’s Crestor(Rosuvastatin Calcium tablets) Patent litigation, case against Teva Pharmaceuticals, Mylan Labs, Par Pharmaceutical, Aurobindo Pharma, Sun Pharmaceutical-Litigations are in progress and all the generic firms got tentative approval



180 Days Exclusivity-Forfeiture Provisions Forfeiture Events

(I) Failure to Market (II) Withdrawal of Application (III) Amendment of Certification (IV) Failure to Obtain Tentative Approval within 30 Months (V) Agreement with another Applicant, the Listed Drug Application Holder, or a Patent Owner (VI) Expiration of All Patents FDA Practice

• “It is FDA’s practice to make decisions on eligibility for 180-day exclusivity only in the context of specific ANDAs those are otherwise eligible for approval.” • When FDA must make an approval decision for an ANDA, it will inform the applicant that it is (1) A first applicant and entitled to exclusivity (2) A first applicant that has forfeited its exclusivity (3) Eligible only for tentative approval (TA) due to another’s exclusivity (4) Eligible for final approval (FA) because another forfeited exclusivity • FDA will consider whether there has been forfeiture when approval of a subsequent ANDA may be blocked by a first applicant’s exclusivity. Failure to Market

The first applicant fails to market the drug by later of (aa) the earlier of 75 days after final approval; or 30 months after ANDA submission; or The date that is 75 days after the date as of which, as to each of the patents that qualified the FA for exclusivity, at least one of the following has occurred: 

Final decision of invalidity or non-infringement.



Settlement order entering final judgment.



NDA holder delists patent from Orange Book.



Withdrawal of Application



“The first applicant withdraws the application or the Secretary considers the application to have been withdrawn as a result of a determination by the Secretary that the application does not meet the requirements for approval under paragraph (4).”



Administrative withdrawal due to poor quality ANDA?

Amendment of Certification o

“The first applicant amends or withdraws the

o

certification for all of the patents with respect to

o

which that applicant submitted a certification

o

qualifying the applicant for the 180-day exclusivity

o

21 CFR 314.94(a)(12)(viii)(A) requires amendment of

o

a p.IV to a p.III after a final judgment of infringement



Pseudo Generics:

To prevent generic completion from increasing their market sharing, some brand-name forms produce generics themselves called pseudo-generics. Literature and practical experiences are provide strong evidence that brand-name drug product prices are decreasing drastically after entering the generic drug product in to the market. Brand-name companies always have an incentive to purchase its competitor. By developing pseudo-generics product brand-name Company can increase its market value. CONCLUSION

Greater access to generic drugs will reduce health care costs because the price of generic drugs is typically much lower than the brand-name drug. Reducing expensive lawsuits over drug patents and making the approval process more efficient will also help to lower national health care costs by reducing the cost of bringing safe and effective generic drugs to market. Throughout the years since enactment of Hatch-Waxman, the US patent and regulatory systems continued to evolve. The average drug research and development time is now 10 years, and the total costs often exceed $750 million. At 5 years, the United States currently has the shortest data exclusivity protection for innovative drugs.. The Hatch-Waxman Act did encourage growth of the generic industry and provided brand companies with incentives. The incentives led to gaming of the system, however. While some maintain that the FTC has adequate authority to challenge litigation settlements that may be anticompetitive, others believe the judicial system is not the appropriate venue to resolve these issues.. Clearly, there is a need to promote an “innovation culture,” not a “litigation culture.” Looking back at history of the Hatch-Waxman Act, its successes and failures, and looking forward at proposed legislative reforms, it is clear that the pharmaceutical scale must remain balanced. DISCLAIMER

The purpose of this review article is solely educational. This review article is built from authors work and experience. REFERENCES CFR:

1.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm/

2.

http://www.fda.gov/medicaldevices/deviceregulationandguidance/databases/ucm135680.htm

3.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.30

Pseudo Generics:

4.

Aidan Hollis, 2003. "The Anti-Competitive Effects of Brand-Controlled "Pseudo- Generics" in the Canadian Pharmaceutical Market, "Canadian Public Policy, University of Toronto Press, vol. 29(1), pages 21-31.

5.

Jorge Mestre Ferrándiz, 1999. "The impact of generic goods in the pharmaceutical industry, "Health Economics, John Wiley & Sons, Ltd., vol. 8(7), pages 599-612.

6.

FerrÆndiz, J. The impact of generic goods in the pharmaceutical industry. Health Economics 1999; 8: 599-612.

7.

Kong, Y. and Seldon, J. Pseudo-generic products and barriers to entry in pharmaceutical markets. Review of Industrial Organization 2004; 25: 71-86.

180DAYS:

8.

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079342.pdf

9.

http://www.ftc.gov/be/v990016.shtm International Journal of Science Innovations and Discoveries, Volume 2, Issue 4, July-August 2012 111


10. http://www.orangebookblog.com/files/180day_exclusivity_forfeiture.pdf 11. http://aspe.hhs.gov/mits/text/titleXI/1102.html 12. http://www.fda.gov/downloads/Drugs/Gu idanceComplianceRegulatoryInformati on/Guidances/ucm072851.pdf 13. http://www.cov.com/files/Publication/1d6a8448-b41b-4909-a3853363886a80cd/Presentation/PublicationAttachment/a13273a4-65a3-498f-9a59-371017d71f42/761.pdf Paragraph-IV:

14. http://thomsonreuters.com/content/science/pdf/ls/newport_paragraphIV_webinar_slides.pdf 15. http://leehu.myweb.uga.edu/papers/lee_hu_jmp.pdf HW litigation:

16. http://www.orangebookblog.com/hatchwaxman_litigation/ 17. Weiswasser, E.S. and S.D. Danzis. 2003. \The Hatch-Waxman Act: History, Structure, and Legacy." An-titrust Law Journal 71:585. 18. Wiggins, S.N. and R. Maness. 2004. \Price competition in pharmaceuticals: the case of anti-infectives."Economic Inquiry 42(2):247{263. 19. Scott Morton, F.M. 1999. \Entry Decisions in the Generic Pharmaceutical Industry." The RAND Journal of Economics 30(3):421{440. 20. Scott Morton, F.M. 2000. \Barriers to entry, brand advertising, and generic entry in the US pharmaceutical industry." International Journal of Industrial Organization 18:1085{1104. 21. Derzko, N.M. 2005. \The Impact of Recent Reforms of the Hatch-Waxman Scheme on Orange Book Strategic Behavior and Pharmaceutical Innovation." IDEA 45(2):165{265. 22. DiMasi, J.A., R.W. Hansen and H.G. Grabowski. 2003. \The price of innovation: new estimates of drug development costs." Journal of Health Economics 22(2):151{185. 23. Chen, T. 2007. \Authorized Generics: A Prescription for Hatch-Waxman Reform." Virginia Law Review 93(2):459{513. 24. http://www.mcguirewoods.com/news-resources/publications/commercial_litigation/ANDA_patent_issues.pdf 25. Terry G. Mahn, The Hatch-Waxman Act During Patent Prosecution and Beyond, Food and Drug Law J. (1999) 26. http://www.pm360online.com/f4_0712_Bio_Pharma_medicine_healthcare_patent_expiration_Pfizer_180_Day_War_for_Li

pitor 27. http://regulatory.usc.edu/Articles/LabelingConsiderations.pdf 28. http://www.regulatoryone.com/2012/01/anda.html


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