COVER STORY sions hit the market as soon as patent protections on the brand-name product expire, in contrast to the case in many other countries. Before Hatch-Waxman, only 35% of pioneer drugs had generic competition after patents expired; now almost all innovator drugs face such competition, according to the Pharmaceutical Research A. M A U R E E N R O U H I , C & E N W A S H I N G T O N & Manufacturers ofAmerica. ANDA rules offer four routes for martion approval ofgeneric drugs and the abilDRUG GOING OFF PATENT paves the way for lower priced ity of innovator and generic companies to keting of generic drugs. Three routes— generic versions. That is always enter into agreements to purposely delay called Paragraph I, Paragraph II, and Paragraph III certifications—apply to ANDA great news for anyone who has entry of generics. to pay the full price of drugs. Passed in 1984, Hatch-Waxman gave filings that do not involve challenges to patents still protecting brandBut because of the law and regulations gov- rise to a robust generic drug inerning generic drugs, a brand-name drug's dustry By creating the Abbreviname products. Through these loss of patent protection does not guaran- ated New Drug Application routes, more than one generic tee timely access to lower cost generic ver- (ANDA), it allowed approval of version can hit the market at the sions. Marketing of generic products can generic products through a same time, creating a very combe delayed through various maneuvers— shorter and less costly route than petitive situation. The fourth in which generic companies and innova- for innovator drugs. It also alroute, called Paragraph IV certor drugmakers are either pitted against lowed development of generic tification, applies when patent each other or work hand in hand. versions even when the referprotection has not expired but ence product is still protected by the generic drugmaker claims eiAt present, marketing of generic drugs ther that the patent is invalid or is governed by the Drug Price Competition patents. In all other industries, that its product does not infringe & Patent Term Restoration Act, commonly this activity constitutes patent SPECIAL the patent. REPORT known as the Hatch-Waxman Act, or sim- infringement. In the pharmaply Hatch-Waxman. Among the loopholes ceutical industry it allows generGeneric drug companies aim in the current law are the ability of inno- ic companies to obtain bioequivalency da- to be first tofileANDAs with Paragraph vator companies to cause automatic mul- ta required for their drug applications. IV certification because the rules make tiple delays of Food & Drug AdministraBecause of Hatch-Waxman, generic ver- them eligible for a 180-day period of mar-
BEYOND HATCH-WAXMAN
Legislative action seeks to close loopholes in U.S. law that delay entry of generics into the market
A
ROAD MAP Various routes bring generic drugs to market Paragraph I Certification Required patent information on brand-name drug has not been filed
Paragraph II Certification Patent has expired
Paragraph III Certification Patent has not expired, but applicant seeks to enter market when patent expires
FDA may approve ANDA immediately; one or more generics may enter
FDA may approve ANDA effective on the date patent expires; one or more generics may enter
FDA may approve ANDA immediately; one or more generics may enter Paragraph IV Certification Patent has not expired, but applicant certifies that the patent is invalid or is not infringed by its product
If patent holder sues within 45 days, the action automatically triggers a 30-month stay on FDA action
1
fif
If patent holder does not sue within 45 days, FDA may approve ANDA; generic applicant is entitled to 180-day exclusivity
When 30-month stay expires
FDA may approve ANDA; first generic applicant is entitled to180-day exclusivity When 30-month stay has not expired
If patent expires, FDA may approve ANDA; one or more generics may enter; no applicant is entitled to 180-day exclusivity
If court rules in favor of brand-name company, FDA may not approve ANDA until patent expires; no generic may enter until patent expires; no applicant is entitled to 180-day exclusivity
If court rules in favor of generic company, FDA may approve ANDA; first generic applicant is entitled to 180-day exclusivity
ANDA = Abbreviated New Drug Application. SOURCE: Federal Trade Commission
HTTP://PUBS.ACS.ORG/CEN
C & E N / S E P T E M B E R 2 3 , 2002
53
We don't make your sustained release products. We help make them better.™ Kollidon® SR polyvinyl acetate/povidone mixture • matrix sustained release excipient 1 soluble PVP creates pores enabling release of active ingredients • reliable adjustment of release rate • directly compressible; excellent flowability and high plasticity
I
Kollicoat® SR 30 D polyvinyl acetate dispersion • coating swells in water creating a permeable barrier • reliable adjustment of release rate ~> minimal plasticizer needed • no curing required
Kollicoat® EMM 30 D poly (ethyl acrylate, methyl methacrylate) dispersion • coating swells in water creating a permeable barrier 1 reliable adjustment of release rate j no plasticizer needed
Call us now at 1 -800-443-0627, fax us at 973-426-5355 or E-mail us at
[email protected] to find out how we help make your products better.
HELPING MAKE PRODUCTS BETTER 1
BASF
COVER STORY keting exclusivity During this period, FDA may not approve other ANDAs for the same product. The 180 days start on the earlier of two dates—that on which the generic product goes on sale or the date of a court decision declaring the patent invalid or not infringed. The exclusivity period motivates generic drug companies to innovate around patents for brand-name drug products—which are listed in an FDA publication called the Orange Book. During this time, a generic drug can be sold at good margins, at a price only slightly lower than that of the brand-name product. Huge profits can be made. For example, Barr Laboratories, Pomona, N. Y, launched a generic version of Prozac (fluoxetine hydrochloride) in 2 0 - m g capsules in August 2001 after successfully challenging Eli Lilly's patents. Being first to file, the company gained exclusivity for six months, during which sales of the generic drug reached $311 million. Barr reported earnings per share of $4.63 for its fiscal 2002, compared with $1.66 for fiscal 2001. So Paragraph IV ANDAs promise the greatest reward, but they also entail the highest cost and risk because of the ensuing litigation.
When a Paragraph IV ANDA is filed, the innovator company almost always sues the generic company for patent infringement. This action automatically triggers a 30-month stay, during which FDAmay not act on the application. Through strategic timing of Orange Book listing of laterissued patents on the product under dispute, innovator companies can obtain multiple 30-month stays. An example is GlaxoSmithKline's effort to protect the antidepressant Paxil (paroxetine hydrochloride) from generic competition. Sales of Paxil in 2001 were $2.67 billion. Apotex, a Canadian-owned pharmaceutical company, filed a Paragraph IVANDAfor a generic version of Paxil in March 1998. GSK sued for infringement, t r i g g e r i n g an initial 3 0 - m o n t h stay, which expired in November 2 0 0 0 . However, GSK subsequently listed additional patents in the Orange Book and has brought more infringement suits against Apotex. In all, the suits have created an automatic stay on FDA approval of more than five years. The earliest that Apotex can be finally approved to market its generic version is in late 2003, unless the cases are settled first.
The beauty of the automatic stay is that it is an ironclad guarantee that generic entry prior to patent expiration is delayedp because without FDA approvalp entry is impossible.
The generic industry decries the maneuvers that lead to multiple automatic
stays on FDA action. In many cases, patents being added are based on modifications irrelevant to safety and efficacysuch as in a pill's shape or color, according to a spokesman for the Generics Pharmaceutical Association. Sometimes, patents that should not be listed in the Orange Book— such as process patents—are listed anyway Part of the problem is that FDA has no authority to evaluate patents; it simply lists them. And once a patent is listed, it cannot be unlisted, unless it's done voluntarily by the listing company "The big pharma companies have abused the system," Cornel C. Spiegler, chief financial officer of Impax Laboratories, Miami, tells C&EN. "Trie litigation is crazy, and consumers, employers, states, and various associations end up paying for it." THE GREATER Access to Affordable Pharmaceuticals Act (GAAP), passed by the Senate in July, limits the number of automatic 30-month stays to one, consistent with a recommendation in a recent Federal Trade Commission (FTC) report (C&EN, Aug. 5, page 11). Innovator drug companies vigorously opposed this provision on the basis that it undermines intellectual property protection. But according to Michael S. Wroblewski, F T C assistant general counsel for policy studies, "The 30-month stay is in addition to the ability of the brand-name company to sue. What we're saying is eliminate the ability to block FDA action so FDA can then approve, for example, generic Paxil. Companies can still litigate." According to the FTC study, even with
peakdale
• M
O
L
E
C
U
L
A
R
Bringing you t o m o r r o w ' s d r u g i n t e r m e d i a t e s
jrpose :ilit to y
Peakdale Molecular is the fastest growing contract chemistry company in the UK, supporting the research and development activities of pharmaceutical and
0 staff.
biotechnology companies. Through our US and UK operations, we offer a variety of chemistry services: om
UK: +44 1298 816700
HTTP://PUBS.ACS.ORG/CEN
Chemistry Services: Custom synthesis Process research Intermediates catalogue Screening compounds
V
N
^CQ 2 H
N
"N
X02H
Special Skills: Heterocyclic chemistry Carbonylation High pressure hydrogenation US: +1 302 838 0420
^C0 2 H
^
C & E N / S E P T E M B E R 2 3 , 2002
55
COVER STORY Augmentin. Last year, GSK sold $2.03 bilapproved ANDAs, generic companies usulion worth ofAugmentin worldwide. ally do not market drugs that are still the subject of lawsuits. A current example is Geneva Pharmaceuticals and two othgeneric Prilosec. Prilosec (omeprazole) is er generic companies challenged three U.S. AstraZeneca's blockbuster drug for heartpatents protecting Augmentin until 2017 burn, with worldwide sales in 2001 of $5.7 A federal district court ruled that those billion. Last November, FDA patents were invalid, leaving gave final approval to Andrx Augmentin with patent protecPharmaceuticals, based in Wetion only until December of this ston, Fla., to market its generic year. GSK is now appealing that version after the 30-month stay decision. had expired. But the lawsuit be"We found no reasons to wait tween Andrx and AstraZeneca until the appeal is decided beis still unresolved. Even if Andrx cause we were confident that wins, AstraZeneca could appeal. the court decisions will be upT h e decision to launch the held," a spokeswoman for Genegeneric version will depend on va Pharmaceuticals tells C&EN. the strength of the ruling in faLast month, GSK filed another SPECIAL vor of Andrx and how difficult lawsuit claiming that the generREPORT it would be for AstraZeneca to ic companies are using a stolen overturn it, says Gale A. Blackburn, direcstrain of bacteria to make their generic vertor of investor relations at Andrx. sions ofAugmentin (C&EN, Sept. 2, page 10). "The most recent allegations of GlaxoA notable exception at present is the SmithKline are unfounded," the spokesat-risk launch of amoxicillin clavulanate woman says. potassium by Geneva Pharmaceuticals, an affiliate of Novartis Generics. In July, the In the future, more generic companies company began shipping the drug, which might follow Geneva Pharmaceuticals' is a generic version of the GSK antibiotic example. The beauty of the automatic stay
F^
FINE & BIOCHEMICALS
N-Acetylneuraminic acid
N-Glycolylneuraminic acid
(Sialic acid, Lactaminic acid, NANA)
CAS #131-48-6 Molecular Formula: C i t H ; N O i HO
CAS #1113-83-3 Molecular Formula: C H NO
OH ?H
HO Hir~~/ 110
O
/
COOH
HO R-COCH OH
FW: 309.3 Synthetic Research Quantities / Bulk Quantities High Purity Most competitive price
FW: 325.3 Synthetic Custom synthesis
-
- J
N-Acetylneuraminic acid methyl ester
CAS #50998-13-5 Molecular Formula: C H NO
yumsm
Shenzhen QiuSuo Biotech Co., L t d . TEL: 0086-755-26617258 FAX: 0086-755-26617258 http://www.asbiotech.com E-mail:
[email protected] FW: 323.3 Synthetic Custom synthesis
56
C&EN
/
SEPTEMBER
CPHI Paris 2002 BOOTH # S94-01, HALL 3B
23,
2002
is that it is an iron-clad guarantee that generic entry prior to patent expiration is delayed, because without FDA approval, entry is impossible. For this reason, brand companies fiercely protect their current ability to extend stays from 30 months to as long as possible. GENERICS ALSO maybe delayed getting to the market when the generic company that first files a Paragraph IVANDAagrees to "park" its right to 180 days of marketing exclusivity in exchange for compensation from the innovator company The FTC study found several cases of settlement agreements in which an innovator company paid a generic company to delay launch of its product for a specified period or until the patents expire. Payments to generic applicants ranged from $1.7 million to $132.5 million. And times between the agreement date and patent expirations ranged from four months to 10 years. In FTC's view, some ofthese agreements violate antitrust laws, and in those cases the agency takes legal action against the parties involved. For example, in April 2001, F T C sued Schering-Plough, Upsher-Smith Laboratories (Minneapolis), and American Home Products (AHP, now called Wyeth) for entering into anticompetitive agreements related to K-Dur 20, Schering-Plough's prescription potassium chloride supplement, whose patent protection expires in September 2006. In August 1995, Upsher-Smith filed a Paragraph IVANDA for a generic version. In December 1995, A H P also filed a Paragraph IV ANDA. Schering-Plough promptly sued both, but it settled with Upsher-Smith in 1997 and with AHP in 1998. Upsher-Smith agreed to delay launching its generic product until September 2001 in exchange for $60 million. AHP agreed to delay its generic version until January 2004 in exchange for $15 million. FTC sued, charging that the agreements "are unreasonable restraints of trade and that the companies have conspired to monopolize the market for potassium chloride supplements." T h e companies responded that the payments were license fees for other products licensed by Schering-Plough from the two companies. Last February, AHP settled with FTC. The settlement prohibits AHP from entering into agreements that involve payments to generic companies to delay launch of their products, among other things. But lastJune, an administrative court dismissed the cases against Schering-Plough and Upsher-Smith. FTC is appealing that ruling. HTTP://PUBS. ACS.ORG/CEN
GLOSSARY
Defining The Terms Of The Hatch-Waxman Act ANDA, Abbreviated New Drug Application, is the process of obtaining approval to market a generic drug. An ANDA contains information demonstrating that the generic drug is bioequivalent to the brand-name product and certification that the generic drug does not infringe on any patent for the brand-name product listed in the Orange Book or certification that the listed patents are invalid. Bioequivalence is the Food & Drug Administration requirement that the active ingredient of a generic drug be absorbed into the body and metabolized in approximately the same amount over approximately the same period as the active ingredient of the innovator drug. Bioequivalence is demonstrated in two ways. Dissolution testing determines if the generic drug product dissolves in approximately the same amount of time
as the innovator product. Blood-level testing is done by giving the generic drug product to humans and measuring how much of the drug enters the bloodstream, how fast it does so, and how Long it takes to leave the body. Generic drug (multisource pharmaceutical) is a pharmaceutical preparation that is essentially similar to an original product, involves an active ingredient that is no longer protected by patent, is approved for sale by a simplified registration, and is sold under a common name with little, if any, promotion. NDA, New Drug Application, is the process of obtaining approval from FDA to market a new drug. 180-day exclusivity is the marketing exclusivity granted to the first applicant
Orange Book is the common name of "Approved Drug Products with Therapeutic Equivalence Evaluations," the FDA publication that lists, among others, patents protecting the active ingredient, formulation, and method of use of a drug product. Paragraph IV certification is a declaration that a patent listed in the Orange Book is invalid or will not be infringed by the generic drug in an ANDA. 30-month stay is the automatic prohibition of FDA action on an ANDA with a Paragraph IV certification if the brandname company files a patent infringement suit against the generic applicant within 45 days.
Metal flotating Reagents Rubber Assistants Corriosion-inhibitors Perfume and Flavour
Businel jfcope: ISO9002 CertifiedliCpmpany
Sodium Isopropyl Xanthate
AC Blowing Agent
Tetramethylurea
(methyl-alp^a-gluc9p^anoside)
Dithiophosphates
Dimethyl Disulfide (DMDS)
Dimethyl-5-Sulfoisophthalate Sodium Salt
n, n-Dimethyl Amino AcetfC|Acid
Thionocarbamates
Rubber Vulcanized Agent DCP
2-Chlorobenzothiazole
Castor Oil BP80~/\
Frothers (Terpineol, Aliphatic Alcohol)
Rubber Accelerator Agent Series
2-Amino-6-methylbenzothiazole
Cold-pfe'ssed Castor'Oil
'"f ,' l
Sodium Carboxymethyl Cellulose
Rubber Antioxidant Series
l,2,3lknzotriazole,
Oxalic Acid
2,6 - Di-Tert-Butyl para-Cresol
Tolytriazole and Tolytriazole sodium salt
Succinic Acid and esters
Ethylene Thiourea
Disodium Sebacate
Chlorinated Paraffin
Diphenyl Thiourea
liquid/solid/granular
Glutaric Anhydride Bronopol UV Stabilizers Benzophenone / Benzophenone 4 Nicotanic acid
Dioctyl Sebajcate
Chlorinated Polyethylene
Hexamine
Vinyl trimethoxysilane
Dibutyl Sebacate
Tributyl Phosphate
Dimethyl Sulfoxide (DMSO)
Vinyl triethoxysilane
Tri-Isobutyl Phosphate
Dimethyl Sulfide (DMS)
Vinyl trichlorosilane
Sebacic acid
Triethyl Phosphate
Para-Cresol
E|unethyl Adipate
Chlorinated Paraffin 70% solid
Diphenyl Oxide
DiisoprBpylAdip'ate
Zinc Borate. 3.5H20
Aromatic Petroleum Resin C9
Diphenyl Methane
Zinc Phosphate
Coumarone Resin
2-Mercaptobenzotriazole
Trimejlitic Anhydride
Decabromodiphenyl Oxide
Poly Aluminium Chloride (PAC)
Triethylene Tetramine Hexamethylene -Phosphonic Acid
Titanyl Sulfate
Itaconic Acid
Piperonal
Trichloroisocynuric Acid
Choline Chloride
Sodium Antimonate
Raspberry Ketone
Rubber crosslinking agent BIPB
Sodium Pyroantimonate
Dimethyl Carbonate
Bis (2-ethylhexyl) Phosphoric Acid
Isopropyl phenyl diphenyl Phosphate (IPPP)
Diphenyl Carbonate
Copper-8-Hydroxyquinoline
Tricresyl Phosphate (TCP)
Tung Oil
P-tert Butyl Benzoic Acid
Triphenyl Phosphate (TPPa)
Hydrogenated Castor Oil
Potassium Hydrogen Tartrate (Cream of Tartar) FCC
Gama-aminopropyl triethoxysilane
Triphenyl Phosphite (TPPi)
12-Hydroxystearic Acid
Diethyl Hydroxylamine
Tris (2-chloroethyl) Phosphate (TCEP)
Propylene Carbonate
Organic Silicon
Tris (l-chloro-2-propyl) Phosphate (TCPP)
Sulfolane
Aluminium powder
Dimethyl,Sebacate
f
that files an ANDA with Paragraph IV certification.
i-
Guanidine carbonate Hydroxy Ethylidene Diphosphonic Acid Amino Trimethylene Phosphonic Acid Aminated and Methylated Polyacrylamine
Sodium dichloroisocynurate Anthracite Filter Material Maltol Ethyl Maltol Potassium Sodium Tartrate
SINOCHEM LIAONING IMP. & EXP. CORP.
HTTP://PUBS.ACS.ORG/CEN
C&EN / SEPTEMBER
23, 2002
57
• pPmtmmaKKm^s^Sm^-:
IIIIIIS
RICHMAN CHEMICAL INC. XTTRIUMB
xl
LABORATORIES
XTTRIUM LABORATORIES Your Quality Source for
CHLORHEXIDINE
is looking for a challenge! Bring us your toughest custom projects. We specialize in: • Metabolites •» Reference standards • Competitor's products • Multi-step organic syntheses • Mg to kg scale • Process development m Custom distillation • Custom drying m cGMP available With processPoint, our state of the art, web based interactive technology, we can save you time, money and headaches.
Drug Master File Available Xttrium Laboratories, Inc. 415 W. Pershing Road Chicago, Illinois 60609 Tel: (773)268-5800 (800)587-3721 Fax: (773)924-6002 www.xttrium.com
ipj§itll
Bf§§8 m§§§§
FAR Research, Inc. & King's Research, Inc.
Custom Chemical Manufacturing Kilos to Tons Specializing in: Low Temperature Chemistry (-90°C up to 1500 Gallons) Wiped Film Evaporation Organosilane Chemistry • Acetylene Chemistry • Grignard Chemistry • Isothiocyanates • Bromination Cyanate Esters • Boronic Acids Manufacturers of: Cyanogen Bromide Vinyl Bromide • Imidazoles Triethylamine Trihydrofluoride and other HF Base Complexes Visit us at CPhI, Hall 1, Booth B106 Plant Site: FAR Research, Inc./King's Research, Inc. 2210 Wilhelmina Court, NE • Palm Bay, FL 32905 • USA Tel: 321-723-6160* Fax: 321-723-8753 e-mail:
[email protected] or
[email protected] website: www.far-research.com or www.kingsresearch.com European Sales Office: Protex International 6 Rue Barbes B.P. 177 • 92305 Levallois, Paris • France ^^^Tel^0)4n41400-Fax^(l)^
HI
msn
f\
For further information: www.richmanchemical.com email:
[email protected] Ph: 215-628-2946; Fax: 215-628-4262
Contract Manufacturing&Research From Flask to cGMP Production Products:Anticancer agents, Antibiotics etc.
stferdan
Carboplatine Conjugated Estrogens Cyproterone Acetate GalanthamineHbr Gemcitabine Gestodene
Isotretinoin Levocetirizine Oxaliplatin Terbinafine HCL Tibolone Tretinoin • Ethyl Bromodifluorace Acetate • 2-doexy-2,2-difluoro-D-erythropentof uranous-1 -ulose-3,5-dibenzoate
Custom Synthesis
/Manufacturing
Hande Industry & Trade Hlodings Ltd. 4F,Yiqiangju Bidg.,Yitian Rd., Shenzhen, P.R.China TEL: 86-755-83823906,83825563 FAX: 86-755-83826866
[email protected] ^www.handepharm.com
