CONTINUING

MEDICAL EDUCATION

Generic drugs in dermatology

Part I
Michael Payette, MD, MBA, and Jane M. Grant-Kels, MD Farmington, Connecticut

CME INSTRUCTIONS
The following is a journal-based CME activity presented by the American Academy of Dermatology and is made up of four phases: 1. Reading of the CME Information (delineated below) 2. Reading of the Source Article 3. Achievement of a 70% or higher on the online Case-based Post Test 4. Completion of the Journal CME Evaluation CME INFORMATION AND DISCLOSURES Statement of Need: The American Academy of Dermatology bases its CME activities on the Academys core curriculum, identied professional practice gaps, the educational needs which underlie these gaps, and emerging clinical research ndings. Learners should reect upon clinical and scientic information presented in the article and determine the need for further study. Target Audience: Dermatologists and others involved in the delivery of dermatologic care. Accreditation The American Academy of Dermatology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation The American Academy of Dermatology designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AAD Recognized Credit This journal-based CME activity is recognized by the American Academy of Dermatology for 1 AAD CME Credit and may be used toward the American Academy of Dermatologys Continuing Medical Education Award. Disclaimer: The American Academy of Dermatology is not responsible for statements made by the author(s). Statements or opinions expressed in this activity reect the views of the author(s) and do not reect the ofcial policy of the American Academy of Dermatology. The information provided in this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to the diagnostic, management and treatment options of a specic patients medical condition. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of this journal-based CME activity have reported no relevant nancial relationships with commercial interest(s). Authors The authors of this journal-based CME activity have reported no relevant nancial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant nancial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant nancial relationships with commercial interest(s). Resolution of Conflicts of Interest In accordance with the ACCME Standards for Commercial Support of CME, the American Academy of Dermatology has implemented mechanisms, prior to the planning and implementation of this Journal-based CME activity, to identify and mitigate conicts of interest for all individuals in a position to control the content of this Journal-based CME activity. Learning Objectives After completing this learning activity, participants should be able to dene key historical events and legislative milestones over the past century that have shaped the present day generic drug industry; dene standards of bioequivalence and the limitations inherent in bioequivalence; and access available treatment equivalent codes in the FDAs Orange Book. Date of release: March 2012 Expiration date: March 2015 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2011.11.944 Technical requirements: American Academy of Dermatology: d Supported browsers: FireFox (3 and higher), Google Chrome (5 and higher), Internet Explorer (7 and higher), Safari (5 and higher), Opera (10 and higher). d JavaScript needs to be enabled. Elsevier: Technical Requirements This website can be viewed on a PC or Mac. We recommend a minimum of: d PC: Windows NT, Windows 2000, Windows ME, or Windows XP d Mac: OS X d 128MB RAM d Processor speed of 500MHz or higher d 800x600 color monitor d Video or graphics card d Sound card and speakers Provider Contact Information: American Academy of Dermatology Phone: Toll-free: (866) 503-SKIN (7546); International: (847) 240-1280 Fax: (847) 240-1859 Mail: P.O. Box 4014; Schaumburg, IL 60168 Confidentiality Statement: American Academy of Dermatology: POLICY ON PRIVACY AND CONFIDENTIALITY Privacy Policy - The American Academy of Dermatology (the Academy) is committed to maintaining the privacy of the personal information of visitors to its sites. Our policies are designed to disclose the information collected and how it will be used. This policy applies solely to the information provided while visiting this website. The terms of the privacy policy do not govern personal information furnished through any means other than this website (such as by telephone or mail). E-mail Addresses and Other Personal Information - Personal information such as postal and e-mail address may be used internally for maintaining member records, marketing purposes, and alerting customers or members of additional services available. Phone numbers may also be used by the Academy when questions about products or services ordered arise. 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The Academy does not collect personal information from anyone it knows is under the age of 13. Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/privacy policy Copyright statement: 2011 by the American Academy of Dermatology, Inc.

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The cost of health care in the United States is increasing. In order to help control these rising costs, all parties involved in the delivery of health care, including dermatologists, need to be part of the solution of ethically reducing the cost of delivery of care. One potential means of meeting this goal is to increase the use of generic medications in daily practice. Generic medications can offer equally efcacious therapy at signicantly lower prices, which can translate into large scale savings for the individual patient, the payer, and the overall health care system. Herein we provide an overview of new drug development, review the history of the generic drug industry, describe how generic drugs are approved by the US Food and Drug Administration, and dene the concepts of bioequivalence and therapeutic equivalence. In part II, we explore various factors impacting generic drug use, provide cost analyses of dermatologic brand name and generic drugs, and review data addressing potential differences in the effectiveness of brand name versus generic drugs in dermatology. The cost of brand name and generic medications is highly variable by pharmacy, state, and payer. We used one source (www.drugstore.com) as an example and for consistency across all medications discussed herein. Prices included here may not reflect actual retail prices across the United States. ( J Am Acad Dermatol 2012;66:343.e1-8.) Key words: bioequivalence; brand name medication; cost effectiveness; drug; generic medication; therapeutic equivalence.

With health care reform OVERVIEW OF NEW CAPSULE SUMMARY DRUG DEVELOPMENT looming, dermatologists need Key points to be part of the solution of Several key Congressional Acts, such as d Only 21% of drugs that ethically reducing the cost of the HatcheWaxman Act of 1984, have begin human testing get delivery of care. Using availshaped the current generic drug approved able equally efcacious industry. d Although patents procheaper medications is one Generic medications must demonstrate vide 20 years of monoppotential technique for bioequivalence to obtain approval by oly from the date of achieving this goal. Although the US Food and Drug Administration. drug application, the we all want to be part of the actual period of exclusolution and not the problem, The Orange Book is a list of multisource sivity is much shorter many of us wonder how products that contains therapeutic d There are numerous much potential savings exists equivalence codes for generic problems with the US through generic substitution medications. patent system and whether the generic drugs are in fact equally efAs with other new products, new pharmaceutical cacious to the branded drugs we have come to trust drugs are developed under patents, which protect the and rely upon. If the cheaper generic drugs are not investment in a drugs development by giving a as effective, there will likely be more visits to the pharmaceutical company the sole right to sell the dermatologist and no zero sum gain to the costs of drug while the patent is in effect.1 Patents on new health care delivery. In addition, patient morbidity drug products are rational for several reasons. may also be extended. Herein we provide an Patents reward an inventors creativity, encourage overview of new drug development, review the innovation, and justify investment in expensive and history of the generic drug industry, describe how risky research; only 21% of drugs that begin human generic drugs are approved by the US Food and testing ever get approved,2,3 at an average producDrug Administration (FDA), and dene the tion cost of more than $1 billion per drug.4,5 In the concepts of bioequivalence and therapeutic United States, patents officially provide innovators equivalence.
d d d

From the Department of Dermatology, University of Connecticut Health Center. Funding sources: None. Reprint requests: Michael Payette, MD, MBA, Chief Dermatology Resident, University of Connecticut Health Center, Department

of Dermatology, MC6231, 263 Farmington Ave, Farmington, CT 06032. E-mail: payette@resident.uchc.edu. 0190-9622/$36.00

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with 20 years of monopoly from the date of application. After taking into consideration the need for clinical trials once the patent is approved and before the drug is released to the market for general use, the actual period of exclusivity ranges from 12 to 15.4 years, but may be as little as 4 to 5 years.2,4 When patents or other periods of exclusivity expire, manufacturers can apply to the FDA to sell generic versions of drugs. Since the 1990s, there has been a decline in the number of innovator products developed, specically fundamentally new molecular entities. Although the reasons for this decline are unclear, several inherent problems and conicts of interest with the current US patent system may to be blame. First, in order to recover high research costs, the monopoly patent system decreases consumer access to the higher priced innovative products.2,6 For example, consider the innovator drug Stelara (ustekinumab; Centocor Ortho Biotech, Horsham, PA), a novel interleukin (IL)-12 and IL-23 inhibitor. Assuming the average wholesale price of the brand name product is $5595.60 per 45-mg/0.5-mL vial,7 the annual cost for the first year of treatment for an individual who weighs less than 100 kg would be $25,826, and each additional year would be $22,382. The cost is doubled for individuals weighing more than 100 kg. Second, market demand instead of actual health needs drives research priorities.2 Psoriasis medications are examples of drugs being developed to meet market demand, and the potential revenues are indeed substantial: Enbrel (etanercept) earned $3.3 billion in sales in 2009 and $1.1 billion in 2008.8 According to the National Psoriasis Foundation, more than 30 medications are currently in phase II or III trials (12 topical, 13 oral, and 7 injectables).9 Excluding drugs for the treatment of psoriasis, however, most drugs that are relatively exclusive to dermatology earn less than $50 million annually.8 Third, overall investment in research and development (R&D) is too low relative to high profits, and more revenue is allocated to other expenses; average allocations for the 10 largest pharmaceutical companies are 13.7% for R&D, 34.4% for marketing and administrative costs, 29.4% for manufacturing costs, and 23.6% for pretax profits.2,6 Fourth, the patent system unfairly discriminates against US patients, employers, and taxpayers. Because there are fewer price restrictions in the United States, American health care payers experience higher drug prices compared to payers in other developed countries and end up contributing more than 60% of global pharmaceutical profits.2 Lastly, even without patent monopolies, the payment system for drugs is suboptimal, with more than two-thirds of drug

expenditures coming from private insurance and government, thereby skewing market incentives and prohibiting traditional economic analysis.2 Aside from issues with the current US patent system, there are other likely contributors to the overall decline in new innovator drug products, including the following: emphasis on producing drugs to treat chronic disease, search for drugs that have potential sales of $1 billion or more (blockbuster drugs), increasing size and expense of clinical trials, difculty in patient recruitment and retention, increased government regulation, and insufcient returns on expensive discovery technologies.2 With regard to new molecular entities in dermatology, low economic potential, high riskebenefit relationship, absence of surrogate end points, and inadequate understanding of basic pathophysiologic mechanisms of skin disease are additional contributing factors. In the 10-year period between 1999 and 2009, of the 268 new molecular entities developed, only five exclusive to dermatology were approved by the FDA: Levulan-Kerastick (DUSA Pharmaceuticals), Solage (Stiefel, a GlaxoSmithKline company), Bexarotene (Eisai), Elidel (Novartis), and Stelara (Johnson & Johnson).8

HISTORY OF GENERIC DRUGS Key point

d

There are several key historical Congressional Acts regarding generic drug regulation

Unlike with innovator drug products, the regulations applying to the development of generic drugs are different and in part stem from the history of generic drug development. Historically, generic drug manufacturing companies were allowed to formulate, produce, and sell their generic products without needing to submit safety or efcacy data to the FDA.10 In 1937, after 107 people died after ingesting elixir of sulfanilamide, which contained the poisonous solvent diethylene glycol, Congress was prompted to pass the Federal Food, Drug, and Cosmetic (FDC) Act of 1938 which, among other provisions, created a new system of drug regulation by requiring drug manufacturers to show that new drugs were safe.10,11 However, the law did not require manufacturers to show that new drugs were also effective. In fact, as long as new drugs were generally regarded as safe (GRAS) by qualified experts or the drugs were identical, related, or similar (IRS) to an already approved drug, the new drug could be marketed without FDA approval.12 Consequently, between 1938 and 1962, thousands of unapproved generic drugs were marketed to the American public because they were either GRAS or IRS drugs, and

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therefore were not considered new drugs.10 After thalidomide was found to have caused birth defects in thousands of babies in the 1950s and early 1960s, Congress passed the KefauvereHarris Drug Amendment of 1962, which required drug manufacturers to prove to the FDA through preclinical laboratory and animal testing, and well controlled clinical trials, that new drugs including new generic drugs were not only safe but also effective before being made commercially available to the public.11 In 1966, as part of the Drug Efficacy Study Implementation (DESI) Review, the FDA joined with the National Academy of Sciences/National Research Council to evaluate the effectiveness of more than 4000 IRS drugs that had been approved between 1938 and 1962 on the basis of safety alone; only 20% were deemed effective for their intended use (DESI drugs).11,12 Interestingly, nearly 50 years after the DESI review began, the project remains unfinished and there are still an unknown number of unapproved drugs on the market; the Prescription Drug Wrap-Up Program is designed to address these remaining unapproved drugs.12

THE HATCHeWAXMAN ACT OF 1984 Key points

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The HatcheWaxman Act of 1984 significantly changed generic drug regulation Abbreviated new drug applications accelerate generic drug approval A process for litigation between brand and generic manufacturers exists

In the 1970s and early 1980s, as the cost of brand name drugs began to increase, the impetus for substituting less costly generic drugs similarly increased. In 1984, Congress passed the Drug Price Competition and Patent Term Restoration Act, more commonly known as the HatcheWaxman Act, which accelerated the availability of generic drugs by allowing the FDA to approve applications to market generic versions of innovator drugs without repeating the extensive research (including clinical trials) initially performed to prove that the innovator drugs were safe and effective.11 Generic drug makers were allowed to file abbreviated new drug applications (ANDAs) for previously approved innovator drugs, decreasing not only the time to new drug approval but also the expense, because ANDAs only required a limited set of data for approval (see Approval of Generic Drugs below). Within 2 years of the HatcheWaxman Act, nearly 1000 new generic drugs were approved by the FDA,13 and instead of the estimated $1 billion cost to bring a branded drug to market, research and development costs associated with new generic drugs were

typically only in the $1 to $2 million range.5 Moreover, the HatcheWaxman Act eliminated the previous patent term extension that existed by providing that the production, use, or sale of a patented invention was no longer an infringing act as long as the activities were reasonably related to obtaining FDA approval.14 This reform enabled generic drug makers to have a generic substitution for an innovator drug available to consumers the day after the innovator drug patent expired. Before the HatcheWaxman Act, only 35% of leading innovator drugs that were no longer patent protected had generic equivalents, compared to the majority by the late 1990s.5 Aside from prescription drugs, several over the counter (OTC) drugs must also obtain FDA approval before becoming commercially available. The dermatologic OTC drugs chlorhexidine gluconate and minoxidil are examples.12 One class of drugs not eligible for abbreviated approval under the HatcheWaxman Act, however, is the biologics. Instead, the Biologics Price Competition and Innovation Act of 2009, a component of the Patient Protection and Affordable Care Act, provides an abbreviated pathway for the approval of generic biologic drugs, referred to as biosimilars.5 In addition to regulating generic drug approval, the HatcheWaxman Act outlined a process to resolve patent disputes between manufacturers of generic and brand name drugs. After 1984, generic drug manufacturers were given an incentive to challenge innovator drug patents because the rst company to le an ANDA was given 180 days of exclusive marketing of their generic drug, allowing the company a period of very competitive pricing.14,15 Generic companies are only required to claim that their drug product will not infringe on any existing patents. However, if a patent infringement claim is subsequently filed by the innovator company against the generic manufacturer within 45 days of the noninfringement claim, then the FDA cannot approve the generic drug for at least 30 months or until the resulting litigation is resolved.15 This obviously creates a great deal of incentive for a brand name manufacturer, because it can delay the arrival of a generic drug competitor to the market by years. To further secure their competitive edge, brand name manufacturers now carry an average of 10 patents per drug, compared to only two 15 years ago.15 Brand name manufacturers can also protect their products by creating reformulations that use different delivery systems (which can then be patented) and by introducing their own generic medication to compete with the generic drug manufacturer that initially challenged the patent (which can be sold during the 180-day exclusive period and therefore reduce incentives for companies to challenge

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patents).15 Finally, brand name manufacturers can delay market entry of a competing generic drug by paying the generic manufacturer to settle the patent litigation, often referred to as pay-for-delay or reverse payment settlements.5,15 According to the Federal Trade Commission (FTC), there were 19 such settlements in the 2009 fiscal year, which on average delayed the market entry of a generic drug by 17 months; by January of 2010, these settlements were protecting at least $20 billion in sales of branded drugs from competition with lower cost generic medications.5

APPROVAL OF GENERIC DRUGS AND BIOEQUIVALENCE Key points

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Generic drugs must demonstrate bioequivalence for US Food and Drug Administration approval There are different methods for establishing bioequivalence Abbreviated new drug applications accelerate generic drug approval

To gain FDA approval, an ANDA submitted by a drug manufacturer must show that its generic drug product has the same therapeutic effect as its corresponding reference product, which is usually the innovator drug product but may be another generic drug product in cases in which the innovator drug product has been withdrawn.14,16 This means that, relative to a reference product, generic drugs must have the same use indication; contain identical amounts of the same active ingredients (inactive ingredients, also known as excipients, may vary); be identical in strength, dosage form, and route of administration; meet the same batch requirements for identity, strength, purity, and quality; be adequately labeled; be manufactured under the same strict standards of the FDAs good manufacturing practice regulations required for innovator products; and be bioequivalent.1,16 Bioequivalence, as dened by the FDA, is the rate and extent of absorption of the test drug does not show a signicant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or the extent of absorption of the test drug does not show a signicant difference from the extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the reference drug in

the rate of absorption of the drug is intentional, is reected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.17 Mathematically, the parameters used for systemic medications are the maximal plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC). Two products are considered bioequivalent if the 90% confidence intervals (CIs) of the geometric mean response for both pharmacokinetic parameters (ie, generic/ innovator Cmax and AUC ratios) of the two formulations falls between 80% and 125%.16,18 When the confidence intervals for both AUC and Cmax are within the 80% to 125% range, the mean results for two drugs rarely differ by more than 5%13; this has been confirmed in several studies that have reviewed large numbers of previously approved generic drug applications.19-21 Bioequivalence calculated this way is defined as average bioequivalence.16 For dichotomous end points in a study population, such as treatment success or cure rates, the 90% CI range is -20% to 20% for the difference between the test and reference product.13 For topical, locally acting medications, pharmacodynamic or clinical endpoint studies in humans, instead of pharmacokinetic studies, are the preferred method for establishing bioequivalence.13 Although less involved than innovator drug development, these trials can still be lengthy and expensive, making alternative or surrogate tests for showing bioequivalence ideal.22 At present, the only surrogate pharmacodynamic study approved by the FDA for evaluating bioequivalence in dermatologic medications is the McKenzieeStoughton Vasoconstriction Assay for topical corticosteroids. In this test, chromametry is used to measure blanching, which correlates with significant vasoconstriction and in turn drug potency.23 The results have been used to distinguish vehicle-related differences between various steroid formulations.24-27 This assay is the method of choice for evaluating bioequivalence of generic versions of topical steroids. Other surrogate methods, including in vitro, dermatopharmacokinetic (DPK), dermal microdialysis, and near infrared spectroscopy (NIR), are under consideration as potential tests for establishing bioequivalence for topical products. Procedural details and limitations of these methodologies are discussed elsewhere.22,28 The FDA also recognizes two modied bioequivalence criteria. The rst is dened as population bioequivalence and is a measure of the equality of the distribution of generic and reference product bioavailability across a population of subjects (ie, measures variation between individuals and is the

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criterion relevant to a patient being started on a new drug).18,29-31 The second is individual bioequivalence and is a measure of the equality of the distribution of generic and reference product bioavailability within an individual subject (ie, measures variation within an individual and is the criterion relevant to a patient being switched from one formulation to another).18,29-31 Of the three types of bioequivalence, individual bioequivalence is considered the most accurate, followed by population bioequivalence and then average bioequivalence, although average bioequivalence is still the primarily used calculation.18

LIMITATIONS OF BIOEQUIVALENCE Key points

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Bioequivalence studies are small and not reflective of target populations Bioequivalence studies are performed using single doses of medications Excipient compounds can vary between bioequivalent products

Bioequivalence is associated with certain potential limitations. First, bioequivalence studies are generally two-treatment crossover studies involving a small number of patients, usually ranging from 24 to 36 patients but with an FDA-recommended minimum of 12 patients.16,32 The study participants themselves are a homogeneous group of healthy 18- to 55-year-old adult male volunteers of normal height and weight who do not take any concurrent medications, do not smoke, and receive a controlled diet.18,33 While the use of normal, healthy subjects does reduce the probability that any bioinequivalence could be related to changes in the disease process over time rather than differences in drug formulation, it is important to realize that the drug pharmacokinetic properties in healthy individuals may not accurately predict the pharmacokinetic properties in patient subgroups because of patient variables including disease comorbidities, concurrent medications, differences in first-pass metabolism, varied diets, gastrointestinal variations (ie, gastric pH, blood flow, and bacterial flora) and even placebo and nocebo (ie, negative reactions not related to a drug) responses.13,34-37 This risk is even greater in the elderly population, in which agerelated physiologic changes that affect drug absorption, metabolism, and excretion may exist, but could be missed in younger healthier populations.18,38 Second, bioequivalence studies are usually performed using single doses of drugs because single-dose studies are generally more sensitive at measuring the release of the active metabolite from a drug product into the circulation than multidose

studies.18,32 Predicted effects from multidose administration are then extrapolated from the single-dose data. The maintenance of a steady state in the circulation and consequent therapeutic benefit, however, typically requires higher drug concentrations than can be achieved through single dosing.18,39 Moreover, simply increasing the amount of a single-dose drug to achieve higher concentrations will not necessarily address this limitation, and also increases the risk for adverse events.18,39 Single-dose studies also may not accurately predict effects from accumulation of active metabolites that can occur with more frequent dosing.39 Third, apparent inert or inactive compounds in the generic drug product that could affect factors like drug absorption, distribution, metabolism, and excretion at steady state may not be detected after single dosing.39 A particularly good example of an inert compound would be the salt used in a medication. Because most drugs are weak organic acids or weak organic bases, they can exist as different salt forms, and each salt is a chemical entity with distinct biologic and chemical properties that could affect clinical efficacy and safety.40 Other excipients designed to serve as preservatives, binders, or carriers of the active drug are often also different from the innovator product. Although these compounds are usually ones that have been used in other approved drugs with identical routes of administration in the same amount and daily exposure, and for which data exist indicating that use of these different compounds will not alter a products safety and effectiveness, their unique combination in a particular drug is apt to affect that products overall pharamacokinetics.13 Inactive ingredients and their highest concentrations in FDAapproved products can be found in the Inactive Ingredient for Approved Drug Products listing.13,41 Finally, there are other factors that are not included in establishing bioequivalence. For example, genetic polymorphism in drug metabolizing enzymes, which could potentially lead to signicant variations in drug metabolism, and enteric coatings on generic drugs, which may impact the rate and extent of drug absorption, are not evaluated in routine studies of bioequivalence.18

THE ORANGE BOOK Key point

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The Orange Book is a list of multisource products

As of December 2010, a total of 13,838 prescription drugs were listed as marketed in the FDAs Approved Drug Products with Therapeutic Equivalence Evaluations (commonly known as the

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Orange Book), of which 11,267 (81.4%) were listed as multisource products, denoting that one or more generic versions are also marketed.17,42 In the Orange Book, the FDA identifies drugs that are therapeutically equivalent to reference listed drugs (RLDs), meaning that a particular drug can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the reference listed drug. The FDA has identified in the Prescription Drug Product and OTC Drug Product Lists the RLDs to which the bioequivalence of applicants products are compared. Drug products are considered to be therapeutically equivalent only if they are pharmaceutical equivalents (ie, they have the same active ingredients, dosage form, route of administration, and strength) and are assigned the same therapeutic equivalence codes by the FDA.17 The FDAs Additions/Deletions for Prescription and OTC Drug Product Lists is a supplement that is generated monthly by the FDA and is meant to be used in conjunction with the most current Cumulative Supplement and Orange Book.

THERAPEUTIC EQUIVALENCE Key points

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Drugs are assigned therapeutic evaluation codes The vast majority of dermatologic generic drugs have an A therapeutic evaluation code and are considered therapeutically equivalent to their reference products

(tretinoin 0.025% gel). Stiefel GSKs and Medicis clindamycin phosphate/tretinoin 1.2%/0.025% topical gels (Veltin and Ziana, respectively) are also products with a B designation. A second letter is often included to provide additional information based on the FDAs evaluation, and in situations in which more than one reference listed drug of the same strength has been designated under the same heading, a number is added to the end of the therapeutic equivalence code. Atlantas Temovate and Temovate E, both of which are clobetasol propionate 0.05% topical creams, are designated AB1 and AB2, respectively. This system allows users to readily determine whether the FDA has evaluated a drug product as therapeutically equivalent to other pharmaceutically equivalent products.17 Of note, OTC drugs are not assigned therapeutic equivalence codes by the FDA. The online version of the Orange Book provides additional data when seeking information about generic substitution.43 Interestingly, in actual practice, nearly half of pharmacists do not refer to the Orange Book when dispensing generic medications, while most physicians do not even know that the Orange Book exists.13,44 Physician knowledge of bioequivalence is not much better; studies have shown that more than 80% of physicians cannot correctly identify FDA standards for bioequivalence.10
REFERENCES 1. US Department of Health and Human Services, Food and Drug Administration Web site. What are generic drugs? Available at: http://www.fda.gov/Drugs/ResourcesForYou/ Consumers/BuyingUsingMedicineSafely/UnderstandingGeneric Drugs/ucm144456.htm. Accessed April 4, 2011. 2. Barton JH, Emanuel EJ. The patents-based pharmaceutical development process: rationale, problems, and potential reforms. JAMA 2005;294:2075-82. 3. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003; 22:151-85. 4. DiMasi JA, Grabowski HG. The cost of biopharmaceutical R&D: is biotech different? Manage Decis Econ 2007;28:469-79. 5. US Department of Health and Human Services, Office of Science and Data Policy Web site. ASPE issue brief: expanding the use of generic drugs. Available at: http://aspe.hhs.gov/sp/ reports/2010/GenericDrugs/ib.pdf. Accessed April 12, 2011. 6. Scherer FM. The pharmaceutical industryprices and progress. N Engl J Med 2004;351:927-32. 7. CVS Caremark Web site. Specialty TrendsRx alert: Stelara (ustekinumab). Available at: https://www.caremark.com/portal/ asset/SpecialtyTrendsRxAlert_Stelara.pdf. Accessed April 21, 2011. 8. Eaglstein WH, Corcoran G. New drugs and new molecular entities in dermatology. Arch Dermatol 2011;147:568-72. 9. Naional Psoriasis Foundation/USA Web site. Drugs in development: drug pipeline. Available at: http://www.psoriasis.org/ NetCommunity/Page.aspx?pid=664. Accessed April 21, 2011. 10. Al-Jazairi AS, Bhareth S, Eqtefan IS, Al-Suwayeh SA. Brand and generic medications: are they interchangeable? Ann Saudi Med 2008;28:33-41.

The FDA places multisource drugs into two general categories, which are indicated by the rst letter in the therapeutic evaluation code. Drug products with an A designation are products that the FDA considers to be therapeutically equivalent to other pharmaceutically equivalent products (ie, drug products for which there are no known or suspected bioequivalence problems), or products in which actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence. Many of the commonly used generic topical and oral drugs used in dermatology have an A designation. Drug products with a B designation are products that the FDA considers not to be therapeutically equivalent to other pharmaceutically equivalent products (ie, drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence, often because of problems with specic dosage forms rather than with the active ingredients).17 An example of a generic drug with a B designation would be Mylans Avita

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