Generic drug approval: A US perspective

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Copyright 2011 Informa UK Limited Not for Sale or Commercial DistributionUnauthorized use prohibited. Authorised users can download, display, view and print a single copy for personal useCurrent Medical Research & Opinion Vol. 27, No. 3, 2011, 5415450300-7995 Article ST-0103.R1/548374doi:10.1185/03007995.2010.548374 All rights reserved: reproduction in whole or part not permittedBrief reviewGeneric drug approval: A US perspectiveB.P. NagoriV. MathurS. GargLachoo Memorial College of Science and Technology(Pharmacy Wing), Jodhpur, Rajasthan, IndiaAddress for correspondence:Vipin Mathur, Lachoo Memorial College of Scienceand Technology (Pharmacy Wing), Sector A,Shastri Nagar, Jodhpur 342003, Rajasthan, India.Tel./Fax: 91 29 12 43 18 20;mathur_vipin@rediffmail.comKey words:Brand name drug Generic drug HatchWaxmanAct Patent US FDAAccepted: 13 December 2010; published online: 11 January 2011Citation: Curr Med Res Opin 2011; 27:54145AbstractObjective:Generic drugs are identical or bioequivalent versions of the brand name drugs. They are the economicalternative of the costlier brand name drugs. This article presents a general overview of the procedure andregulatory aspects relating to generic drug approval in the US.Methods:A computerized search was conducted to find literature on generic drug approval in the US. The literaturewas searched using the following key words: generic drug, brand name drug, HatchWaxman Act, MedicareAct, NDA, ANDA, CTD and exclusivity.Findings:The search results were filtered for the literature describing and analyzing the procedure and regulatoryprovisions for generic drug approval in the US. After the screening total 19 applicable literature remained.Conclusion:In the US standardized procedures for the recognition of generic drugs have been laid down under the DrugPrice Competition and Patent Term Restoration Act, 1984 (the HatchWaxman Act). Provisions of this Actsuch as patent challenge, patent term extension and data exclusivity have created profound effects on theapproval, sale and distribution of the pharmaceuticals in the US. The HatchWaxman Act is an excellentpiece of legislation that takes care of the rights of both the brand name and generic drug companies. Thisarticle presents only an overview of generic drug approvals and for all practical purposes official resourcesshould be referred.IntroductionAccording to the US Food and Drug Administration (US FDA) generic drugs1are the drugs identical or bioequivalent to brand name drugs (innovators prod-uct) in active ingredient, dosage form, safety, strength, route of administration,quality, performance characteristics and intended use. Although generic drugsare chemically identical to their branded counterparts, they are typically sold atsubstantially lower prices than the brand name drugs2. This is principally due tothe fact that development of brand name drugs requires substantially highinvestments in terms of time and money (approximately 1012 years and100500 million dollars) in drug discovery and product development. Instead,generic manufacturers do not incur the price of costlier clinical trials and canmanufacture bioequivalent versions of the brand name drugs by doing reverse-engineering of the known drug molecules.After the innovators patent expiry any generic firms may enter in the marketand start selling copies of the original branded drug. Under the HatchWaxmanAct provisions, generic drugs can be launched even before the innovatorspatent expiry. The entry of generics into the market lead to price competitionand the monopoly of brand name drugs comes to an end. The availability of! 2011 Informa UK Ltd Generic drug approval Nagori et al. 541Curr Med Res Opin Downloaded from by University of Maastricht on 07/03/14For personal use only.generic products generates market competition that inturn leads to lowering of prices of both the brand nameand generic drug products.This article highlights the basic facts relating to genericand brand name drugs. A general overview of the USFDAs generic drug approval process and related regulatoryprovisions is provided to gain the basic understanding ofthe subject area.The information presented in this article was collectedfrom various online databases between 2009, April and2010, September. Searches were mainly conducted onUS Food and Drug Administration (US FDA) andUnited States Patent and Trademark Office (USPTO)websites. Google search engine was also used for onlinesearching for this purpose. Search terms used were genericdrug, brand name drug, HatchWaxman Act, MedicareAct, NDA, ANDA, CTD and exclusivity. The down-loaded literature was screened and the most relevant arti-cles, i.e. those describing and analyzing the procedure andregulatory provisions for generic drug approval in the US,were selected for the study.Generic drugs: some basic factsGeneric drugs are copies of brand name drugs and haveexactly the same dosage, intended use, side effects, route ofadministration, risks, safety and strength as the original orthe brand name drug. Generic medicines comply with thesame strict standards of quality, safety and efficacy as orig-inal pharmaceutical products and are intended to produceexactly the same pharmacological effects as those of theirbrand name counterparts3.The US FDA requires that generic drugs be as safe andeffective as brand name drugs. Many people mistakenlythink that generic drugs have low quality, safety and effec-tiveness since they are cheaper than the brand name drugs.In fact the US FDA applies same standards for assessing thequality, safety and efficacy of both the generic and brandname drugs. So, it is only a myth that generic drugs aremanufactured with poorer quality facilities or are inferiorin quality to brand name drugs.Another common misbelief is that generic drugs takelonger to work4. In fact the US FDA requires that genericdrugs work as fast and as effectively as the originalbrand name products. Generic drugs have same onset ofaction, mechanism of action and release profile as thebrand drugs.Difference between generic and brandname drugsBrand name drugs are the Reference Listed Drugs (RLD)developed by the innovator drug companies. They aretermed RLD since their names are listed in theApproved Drug Products with Therapeutic Equivalence(Orange Book) listing on the US FDA database. Genericdrugs are approved subsequently that have been provedidentical or bioequivalent to a RLD.Brand name drugs are sold under a trade name chosenby the manufacturer, usually on the basis that it can beeasily recognized, pronounced and remembered by healthprofessionals and patients5. Whereas, a generic drug nameis the official medical name of the active pharmaceuticalingredient of the medicine.A branded drug is approved by the US FDA after thecomplete set of preclinical and clinical testing data estab-lishing quality, safety and efficacy of the drug product isprovided by the company through a New DrugApplication (NDA). The US FDA does not require thecomplete set of preclinical and clinical data for givingapproval to a generic drug. A generic drug is approvedchiefly on the basis of its bioequivalence to the brandname drug.A generic drug may contain different color, flavor orcombinations of inactive ingredients than the brandeddrug since the US Trademark law does not allow the gen-eric drugs to look exactly like the brand name prepara-tion6. But the US FDA ensures that any such changesshall not affect the products quality and the generic drugshall perform in the same manner as the brand name drug.The HatchWaxman ActThe principal law that governs generic drug approval inthe US is the Drug Price Competition and Patent TermRestoration Act, 1984 (the HatchWaxman Act). TheAct provides an expedited US FDA drug approval programfor speedy generic drugs entry in the market.Significant changes were made in the Federal FoodDrugs and Cosmetics Act 1930 through the HatchWaxman Act in 1984 and a streamlined regulatory sub-mission process known as an Abbreviated New DrugApplication (ANDA) was introduced for the approval ofgeneric drugs. Through ANDA a generic manufacturerprovides the US FDA with documentation of therapeuticequivalence to a corresponding branded product.This Act introduced two sets of changes in the druglegislation. First, it eliminated the duplicative testingrequirements necessary to obtain approval for a genericcopy of a previously approved innovator drug (Title I ofthe HatchWaxman Act). Second, the Act establishedpatent-term extensions for innovator drugs (Title II ofthe HatchWaxman Act).The two parts of the law intend to strike a careful bal-ance between encouraging competition, and research andinnovation7.Current Medical Research & Opinion Volume 27, Number 3 March 2011542 Generic drug approval Nagori et al. ! 2011 Informa UK LtdCurr Med Res Opin Downloaded from by University of Maastricht on 07/03/14For personal use only.Title I of the HatchWaxman ActThe Act created an abbreviated process for the approval ofgeneric copies of innovator drugs8. The HatchWaxmanAct requires manufacturers of generic drugs to conductclinical tests demonstrating bioequivalence with a brandname drug and file an Abbreviated New Drug Application(ANDA). Under the HatchWaxman provision a genericdrug manufacturer is allowed to conduct drug testingrequired for the regulatory submission even before theexpiry of the innovators patent. It is noteworthy thatbefore the HatchWaxman Act, clinical tests conductedby generic manufacturers before the innovators patentexpiration constituted patent infringement.Under the HatchWaxman Act, a list of innovatorspatents is published by the US FDA that the innovatorbelieves would be infringed if a generic drug were marketedbefore the expiration of these patents. This list is publishedin the database of Approved Drug Products withTherapeutic Equivalence (Orange Book). An ANDAapplicant must certify its intent with regard to each ofthe innovators listed patents associated with the genericdrug it seeks to market. One of the following four certifi-cations shall be made9:(i) Paragraph I Certification: It certifies that patentinformation has not been filed in connection withthe NDA referred in the application.(ii) Paragraph II Certification: It certifies that a patentcovering the NDA has expired.The FDA may approve immediately an ANDA containingany of the paragraph I or II certifications.(iii) Paragraph III Certification: Under paragraph III cer-tification the ANDA approval is sought after thelisted patent is expired. The FDA may approve theANDA only after such patent expiration.(iv) Paragraph IV Certification: It certifies that a listedpatent is either invalid or will not be infringed by thegeneric drug for which the ANDA applicant seeksapproval.When an ANDA is filed under Paragraph IV certificationtwo additional provisions of the HatchWaxman Act areimplicated10 viz. (i) 30-Month Stay Provision, and (ii)180-Day Market Exclusivity. Both of these provisionsrelate to the US FDAs approval of an ANDA.The 30-month stay provisionFiling of an ANDA under paragraph IV certification isconsidered to be an act of infringement for which thebrand name company can sue the ANDA applicant. Inthe case of paragraph IV filing the ANDA applicant isrequired to notify the patent owner of its intent to requestmarket approval before the patent expiry. The patentowner in such case may bring a patent infringement suitagainst the ANDA applicant within 45 days of receivingthe notification. As a result of such infringement suit theUS FDA is prohibited from approving the generic drug inquestion for 30 months or until the time the patent isfound to be invalid or not infringed. On the contrary, ifthe court holds that the patent is valid or would beinfringed by the proposed generic product then the USFDA will not approve the ANDA until the patent expires.If a suit is not filed within 45 days, the US FDA canapprove the ANDA as soon as all the regulatory require-ments are fulfilled. The 30-month stay provision serves toprovide incentives to the brand name drug manufacturersby delaying competition at least by 30 months.The 180-day market exclusivityThe HatchWaxman Act rewards the generic manufac-turer who files first ANDA under Paragraph IV certifica-tion and challenges one or more patents associated withthe Reference Listed Drug (RLD). This reward consists of a180-day generic drug market exclusivity period awarded bythe US FDA to the generic applicant who files first ANDAunder Paragraph IV certification11. During this exclusivityperiod the US FDA may not approve any other ANDA forthe same drug product. This results in creating monopolyfor such manufacturer in the generic drug market byrestricting competition for 180 days.Title II of the HatchWaxman ActPatents have a limited term of 20 years from the date offirst filing of the patent application. However, the effectivepatent term is frequently less than 20 years because patentsare often obtained before products are actually marketed.Further, any delays from the US FDA in granting approvalto the drug products can adversely affect the effectivepatent term. Title II of the HatchWaxman Act12 con-tains provisions for extending the term of a pharmaceuticalpatent to reflect regulatory delays encountered in obtain-ing marketing approval by the US FDA. This is called aspatent term restoration program. Under this program theterm of one patent can be extended per product for a max-imum of 5 years. In all cases, the total patent life with thepatent extension cannot exceed 14 years from the prod-ucts approval date.The Medicare Act 2003The Medicare Prescription Drug, Improvement, andModernization Act of 2003 implemented significantchanges to the HatchWaxman Amendments. The Actclosed some legal loopholes that delayed generic drugapproval13. Among the most noteworthy changes, theAct provides for new causes of action for the generic appli-cant, outlines events that trigger the generic applicantsCurrent Medical Research & Opinion Volume 27, Number 3 March 2011! 2011 Informa UK Ltd Generic drug approval Nagori et al. 543Curr Med Res Opin Downloaded from by University of Maastricht on 07/03/14For personal use only.180-day market exclusivity and restricts branded drugmanufacturers to one 30-month stay per product to resolveinfringement disputes involving patents listed in theOrange Book.The US FDAS generic drug approvalprocessFor taking marketing approval of a generic drug in the USthe applicant is required to submit an Abbreviated NewDrug Application (ANDA) to the US FDA. Generic drugapplications are called abbreviated because they generallydo not include preclinical (animal toxicity study) and clin-ical (human trial) data to establish safety and effectivenessof the drug14. Instead, the generic applicant is required toscientifically demonstrate that their generic product is bio-equivalent (performs in the same manner) to theReference Listed Drug (RLD). Bioequivalence can bedemonstrated by measuring the rate and extent of absorp-tion (or bioavailability) of the generic drug and comparingit to that of the RLD in 24 to 36 healthy volunteers.Traditional and CTD formatsAn ANDA can be submitted to the US FDA in eithertraditional or in Common Technical Document (CTD)format15. The traditional ANDA format was developedby the US FDA to be used for submitting an applicationfor generic drug approval in the US. CTD is a commonformat of dossier for the registration of medicines thatcan be used across Europe, Japan and the United States.It is maintained by the International Conference onHarmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use (ICH).CTD significantly reduces time and resources for compil-ing applications for registration of drugs in all the ICHcountries. ICH allows for submitting CTD in electronicformat (eCTD) which has further eased the regulatory sub-mission and review process.CTD is divided into five modules: Administrativeinformation (Module 1); Summary (Module 2); Quality(Module 3); Preclinical study reports (Module 4); andClinical study reports (Module 5). While submitting a dos-sier for a generic drug in CTD format, Module 4 is usuallynot submitted since it contains preclinical trial data.Module 5 of an ANDA primarily contains bioequivalencedata. The US FDA strongly recommends all generic firmsto submit their ANDAs in the CTD format.NDA versus ANDA contentsAn abbreviated application (ANDA) differs from a fullapplication (NDA) mainly in the contents of preclinicaland clinical study data16. Full investigation reports of thepreclinical and clinical studies that establish the safety andefficacy of the drug product are not required to be repeatedin an ANDA. Instead, an ANDA provides only bioequiv-alence data of the generic and the brand name drug. Themain differences in the contents of NDA and ANDA arepresented in Table 1.QbD and QbR conceptsFollowing the global regulatory requirements the US FDAimplements the concept of Quality by Design (QbD) forevaluating Abbreviated New Drug Applications(ANDAs). QbD is based on the principle that qualitycan be planned and most quality crises and problemsrelate to the way in which quality was planned in thefirst place. QbD involves designing and developing formu-lations and manufacturing processes in such a way thatevery time products of predefined quality are produced17.To implement the QbD concept and to assure productquality, the US FDA has developed Question-basedReview (QbR) system for its Chemistry, Manufacturing,and Controls (CMC) evaluation of ANDAs. The QbRincorporates the most important scientific and regulatoryreview questions that focus on critical pharmaceuticalattributes essential for ensuring generic drug product qual-ity. The QbR not only provides a guide for reviewers toevaluate the product quality in an objective manner butalso it presents a transparent system of dossier review infront of the sponsors18.Comprehensive drug review processThe US FDA takes about 1524 months in the evaluationand review of an ANDA. The review is conducted by ateam of medical doctors, pharmacists, microbiologists,medicinal chemists, biopharmaceutical scientists, statisti-cians, field inspectors and other experts19. Under theANDA review the evaluators evaluate information con-cerning labeling and chemistry, manufacturing and con-trols (CMC) of the active pharmaceutical ingredient(s),excipients and the drug product. In addition, in vitroTable 1. NDA versus ANDA contents.S. No. NDA Contents forBrand Name DrugANDA Contents forGeneric Drug1. Chemistry Chemistry2. Manufacturing Manufacturing3. Controls Controls4. Labeling Labeling5. Testing Testing6. Preclinical (Animal) Studies Bioequivalence7. Clinical (Human) Studies8. BioavailabilityCurrent Medical Research & Opinion Volume 27, Number 3 March 2011544 Generic drug approval Nagori et al. ! 2011 Informa UK LtdCurr Med Res Opin Downloaded from by University of Maastricht on 07/03/14For personal use only.dissolution data and in vivo bioequivalence data of thegeneric product is evaluated to examine whether the prod-uct performs in the same manner as the innovators drug.The final approval of the proposed product is extendedonly after FDAs team conduct an inspection of all thefacilities involved in the manufacturing, testing, packag-ing and control of the product and certifies that thesefacilities meet the set standards.ConclusionThe US legislation and FDAs procedure relating to thegeneric drug approval have faced significant changes withtime. The passage of the Drug Price Competition andPatent Term Restoration Act, 1984 (HatchWaxmanAmendments) was an important milestone in the USdrug regulation history. The Act laid down standardizedprocedures for the recognition of generic drugs in the US.The HatchWaxman Act presents an excellent way tobalance the rights of brand name and generic drug compa-nies. On one hand it provides incentives to the brandname drug company in the form of the 30-month stayand on the other hand generic companies that show inven-tive capabilities in the form of challenging the innovatorspatent are rewarded with 180-day market exclusivity.The Act simultaneously takes care of the public interestby providing high quality low cost generic medicines. TheUS FDAs QbD and QbR concepts ensure highest qualityproducts that meet global standards. This article presentsonly a general overview of the regulatory provisions relat-ing to the generic drug approval process in the US. Fordetailed and updated information the readers are advisedto refer the US governments official websites The US Food and Drug Administration. What Are Generic Drugs?. Silver Spring(MD): US Department of Health & Human Services, 2009. Available at: [Last accessed 12 May 2010]2. The US Food and Drug Administration. Generic Drugs: Questions and Answers.US Department of Health & Human Services, 2010. Available at: [Last accessed 12 May 2010]3. The US Food and Drug Administration. Facts and Myths about Generic Drugs.US Department of Health & Human Services, 2009. Available at: [Last accessed 12 May 2010]4. The US Food and Drug Administration. Generic Drugs: What You Need to Know.Silver Spring (MD): US Department of Health & Human Services,2009. Available at: [Last accessed 12May 2010]5. Nelson A. Difference Between Generic Drug And Branded Drugs.Sooperarticles. Available at: [Last accessed 9 January 2010]6. Depression and Bipolar Support Alliance. Generic and Brand Name Drugs:Understanding the Basics. Chicago, Illinois: Depression and Bipolar SupportAlliance, c2007. Available at:[Last accessed 23 August 2009]7. Dighe SV. A Review of the Safety of Generic Drugs. Transplant P. 1999;31:23S-24S8. The US Food and Drug Administration. Sec. 505. [21 USC x355] New Drugs.Silver Spring (MD): US Department of Health & Human Services,2009. Available at: [Last accessed 15 May 2010]9. IPpro Services (India) Pvt. Ltd. HatchWaxman Act and Paragraph IVLitigations. IPpro Inc., c2008. Available at: [Lastaccessed 19 June 2010]10. Schacht WH, Thomas JR. The HatchWaxman Act: Selected Patent-RelatedIssues. Washington DC: National Council for Science and The Environment,2002. Congressional Research Service Report RL31379. Available at: [Last accessed 12 April 2010]11. The US Food and Drug Administration. Guidance for Industry 180-Day GenericDrug Exclusivity under the HatchWaxman Amendments to the Federal Food,Drug, and Cosmetic Act. Silver Spring (MD): US Department of Health &Human Services, 1998. Available at: Information/Guidances/ucm079342.pdf [Lastaccessed 26 May 2010]12. United States Patent and Trademark Office. 35 USC 156 Extension of patentterm Patent Laws. Alexandria (VA): US Department of Commerce, 2008.Available at: [Last accessed 15 May 2010]13. The US Food and Drug Administration. Greater Access to Generic Drugs.Silver Spring (MD): US Department of Health & Human Services, 2010.Available at: [Last accessed 6 September 2010]14. Randall IV B, The US Drug Approval Process A Primer. Washington DC:National Council for Science and The Environment, 2002. CongressionalResearch Service Report RL30989. Available at: [Last accessed 20May 2010]15. Guidance for Industry (M4: Organization of the CTD). Silver Spring (MD): USDepartment of Health & Human Services, 2001. Available at: [Last accessed 26 May 2010]16. Raw AS et al. Regulatory considerations of pharmaceutical solid polymor-phism in Abbreviated New Drug Applications (ANDAs). Adv Drug Deliver Rev.2004;56:397-41417. The US Food and Drug Administration. Pharmaceutical Quality for the 21stCentury A Risk-Based Approach Progress Report. Silver Spring (MD): USDepartment of Health & Human Services, 2009. Available at: [Last accessed 6July 2010]18. Yu LX et al. US FDA question-based review for generic drugs: A new phar-maceutical quality assessment system. J Generic Medicines. 2007;4:239-4819. The US Food and Drug Administration. The FDAs Drug Review Process:Ensuring Drugs Are Safe and Effective. Silver Spring (MD): US Departmentof Health & Human Services, 2010. Available at: [Last accessed 20 April 2010]Current Medical Research & Opinion Volume 27, Number 3 March 2011! 2011 Informa UK Ltd Generic drug approval Nagori et al. 545Curr Med Res Opin Downloaded from by University of Maastricht on 07/03/14For personal use only.