Original Investigation | January 2014
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`http://archinte.jamanetwork.com/article.aspx?articleid=1761922
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`FREE
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`1,2
`Thomas J. Moore, AB ; Curt D. Furberg, MD, PhD
`Institute for Safe Medication Practices, Alexandria, Virginia
`Department of Epidemiology and Biostatistics, The George Washington
`University School of Public Health and Health Services, Washington, DC
`Division of Public Health Sciences, Wake Forest School of Medicine, Winston-
`Salem, North Carolina
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`3
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`JAMA Intern Med. 2014;174(1):90-95.
`doi:10.1001/jamainternmed.2013.11813.
`
`Importance The US Food and Drug Administration (FDA) has advanced
`multiple proposals to promote biomedical innovation by making new drugs
`available more quickly but with shorter, smaller, and more selective clinical
`trials and less rigorous end points.
`
`Objective To inform the debate about appropriate standards, we studied the
`development times, clinical testing, postmarket follow-up, and safety risks for
`the new drugs approved by the FDA in 2008, when most provisions of current
`law, regulation, and policies were in effect.
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`Design Descriptive study of the drugs classified as new molecular entities
`using preapproval FDA evaluation documents, agency drug information
`databases, prescribing information, and other primary data sources.
`
`Main Outcomes and Measures Comparison of drugs that received standard
`review and those deemed sufficiently innovative to receive expedited review
`with regard to clinical development and FDA review time, the size and duration
`of efficacy trials, safety issues, and postmarket follow-up.
`
`Results In 2008, the FDA approved 20 therapeutic drugs, 8 with expedited
`review and 12 with standard review. The expedited drugs took a median of 5.1
`years (range, 1.6-10.6 years) of clinical development to obtain marketing
`approval compared with 7.5 years (range, 4.7-19.4 years) for the standard
`review drugs (P = .05). The expedited drugs were tested for efficacy in a median
`of 104 patients receiving the active drug (range, 23-599), compared with a
`median of 580 patients (range, 75-1207) for standard review drugs (P = .003).
`Nonclinical testing showed that 6 therapeutic drugs were animal carcinogens, 5
`were in vitro mutagens, and 14 were animal teratogens. Other safety concerns
`resulted in 5 Boxed Warnings; 8 drugs required risk management plans. The
`FDA required 85 postmarket commitments. By 2013, 5 drugs acquired a new
`or expanded Boxed Warning; 26 of 85 (31%) of the postmarketing study
`commitments had been fulfilled, and 8 (9%) had been submitted for agency
`review.
`
`Conclusions and Relevance For new drugs approved by the FDA in 2008,
`those that received expedited review were approved more rapidly than those
`that received standard review. However, considerably fewer patients were
`studied prior to approval, and many safety questions remained unanswered. By
`2013, many postmarketing studies had not been completed.
`
`In 1962, the US Congress required as a condition of approval that the benefits
`of any new drug be proven with substantial evidence from controlled clinical
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`1
`trials conducted by persons qualified by training and experience. The Food,
`Drug, and Cosmetic (FDC) Act amendments further required that safety be
`1
`demonstrated “by all means applicable.”
`
`In 2013, these requirements largely survive, although US Food and Drug
`Administration (FDA) approvals are controlled by scores of amendments,
`regulations, and guidance documents that specify the testing required for drugs
`intended for “the diagnosis, cure, mitigation, treatment or prevention of
`2
`disease.”
`
`One group of FDC Act amendments relates to the speed and conditions under
`which the FDA assesses applications for new drugs. These set review
`deadlines including “priority reviews” for drugs representing a significant
`therapeutic advance and “fast-track reviews” for drugs that fill unmet needs for
`3
`treatment of serious illnesses.
`
`A second group of changes provides for exceptions to the standards for
`evidence from clinical trials. The requirement that 2 clinical trials of a drug
`demonstrate a beneficial effect may be waived, and data from a single trial may
`1
`be sufficient. Under “accelerated approval,” data from a single trial and with a
`surrogate end point thought to predict a beneficial effect are sufficient, but
`3
`further studies to confirm benefit are required after marketing approval. An
`FDA guidance adopted an international regulatory harmonization guideline that
`sets minimum standards for testing drugs intended for long-term or open-ended
`4
`use at 300 patients observed for 1 year or more without a comparison group.
`
`A third group of changes mandates additional requirements, including
`postapproval testing of drugs in a pediatric population, legally binding
`requirements for postmarketing studies, restricted distribution for some
`high-risk drugs, and a requirement for manufacturers to develop plans to
`5,6
`identify and manage drug risks.
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`Under the Obama Administration, the FDA may also change the testing
`requirements for many drugs prior to approval; the stated rationales are
`promoting innovation and reducing the time and cost of discovering new drugs.
`Recent reports and initiatives include a White House report on “Propelling
`7
`Innovation in Drug Discovery, Development, and Evaluation,” an FDA program
`8
`to promote biomedical innovation, a proposed “Alternative Development
`9
`Pathway” to permit shorter, smaller trials of new drugs for serious illnesses, a
`draft guidance for “enriched trials,” which are conducted in a subset of patients
`10
`where the benefits of a drug can be more readily demonstrated,
` and reduced
`11
`efficacy standards for drugs for Alzheimer disease.
`
`To inform the debate about the appropriate standards for testing new drugs, we
`studied the development times, clinical testing, postmarket follow-up, and
`safety risks for the new drugs approved by the FDA in 2008, when most
`provisions of current law, regulation, and policies were in effect.
`
`Because this study relied on publicly available documents previously reviewed
`for public release by the FDA, institutional review board approval was not
`obtained.
`
`We studied new molecular entities, which the FDA defines as new active
`pharmaceutical ingredients that were not previously marketed in the United
`States. We did not study changes to existing drugs, such as different salts,
`esters, or dosage forms or new medical uses (indications).
`
`We assessed drug testing and approval through the following primary data
`sources: Drugs@FDA database for FDA Approved Drug Products (for
`12
`preapproval testing reviews),
` the DailyMed Current Medication Information
`13
`web site (for the current prescribing information),
` and the FDA database
`Postmarket Requirements and Commitments to evaluate completion of
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`12
` Through the
`postmarketing studies required as a condition of approval.
`Freedom of Information Act, we also obtained the date human testing was
`authorized in the original Investigational New Drug (IND) application, as well as
`supplementary data about completed postmarketing studies. We used data
`from the National Prescription Audit for 2013 conducted by IMS Health Inc to
`assess utilization of outpatient drugs.
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`End point definitions were as follows: total development time was the years
`between FDA approval of the initial IND to begin human testing for the
`indication that was eventually approved and the date of marketing approval.
`Information on preclinical development time was not available. Total FDA
`review time was the months between submission of the original New Drug
`Application (NDA) and marketing approval. Food and Drug Administration
`review time included time needed to respond to requests by the agency for
`additional information or requirements to conduct additional studies. Exposed
`patients in efficacy trials was defined as the number of patients receiving the
`active drug in clinical trials described in the Clinical Studies section of the
`original approved label. The total number of patients exposed to the active drug
`was obtained from the safety summary in the FDA Medical Review of the drug.
`Carcinogen, teratogen, and mutagen signals were defined as any reported
`abnormalities listed in the Nonclinical Toxicology section of the approved label.
`A drug could account for a safety signal in 1 or more of these 3 independent
`categories. Postmarketing commitments were additional studies specifically
`listed in the FDA letter of NDA approval or were found in the postmarketing
`commitments database. Expedited approval was 1 or more of the following:
`priority review, fast-track review, or accelerated approval. Orphan drug status
`provides tax and patent exclusivity for drugs for rare diseases; such drugs do
`14,15
`not automatically qualify for expedited approval.
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`New drugs were classified as outpatient drugs normally dispensed from the
`pharmacy or inpatient drugs administered in physicians’ offices, hospitals or
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`other medical facilities, or diagnostic tests. We excluded diagnostic tests from
`most analyses because their testing requirements substantially differ from the
`requirements for drugs. Drugs were designated as intended for short-term use if
`the expected therapy period was 6 months or less and for open-ended use if the
`expected length of treatment could be more than 6 months.
`
`Both investigators jointly determined whether a drug was intended for
`outpatient or inpatient use and for short-term or open-ended use. Medical uses
`and risks for specific drugs were taken from each drug’s 2012 prescribing
`information.
`
`The data were analyzed with the R Package for Statistical Computing
`(http://www.r-project.org). For study variables, we calculated the mean,
`median, and range and compared the means of continuous variables with the
`Welch 2-sample t test.
`
`In 2008, the FDA approved 24 new drugs—10 inpatient drugs, 10 outpatient
`drugs, and 4 diagnostic tests. Characteristics of the inpatient and outpatient
`drugs are given in Table 1. The drugs included 3 cancer treatments and 3
`drugs targeting opioid receptors. Several drugs were variants of products
`already available: desvenlafaxine (Prestiq; Pfizer Inc) is an active metabolite of
`the antidepressant venlafaxine (Effexor; Pfizer Inc); fospropofol (Lusedra; Eisai
`Inc) is a prodrug of the anesthetic propofol (Diprivan; Abraxis); certolizumab
`(Cimzia; UCB Inc) was the fourth approved anti–tumor necrosis factor
`biological product, and fesoterodine (Toviaz; Pfizer Inc) shares an active
`metabolite with tolterodine (Detrol; Pfizer Inc) as a treatment for overactive
`bladder.
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`Table 1. New Drugs Approved by the Food and Drug Administration in 2008a
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`View Large | Save Table | Download Slide (.ppt) | View in Article Context
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`Among the new drugs were 7 orphan drugs for rare diseases that received
`favorable tax treatment and increased patent exclusivity under the FDC Act.
`Rufinamide (Banzel; Eisai Inc) was approved for Lennox-Gastaut syndrome, a
`form of epilepsy with a patient population numbering in the hundreds. Also
`approved were 2 orphan drugs for second-line use in immune
`thrombocytopenic purpura, with an estimated population of 16 000, and
`tetrabenazine (Xenazine; Lundbeck Inc), a monoamine oxidase (MAO) depletor
`for Huntington chorea, a subset of uncertain size of approximately 18 000
`patients with Huntington disease. Overall, 6 of 8 drugs deemed innovative
`enough to qualify for expedited approval were for small patient populations.
`
`Among the 20 therapeutic drugs, a median of 6.5 years (range, 1.6-19.4 years)
`elapsed from FDA authorization to initiate testing in humans to market
`approval. The FDA approval process, including time for manufacturers to
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`provide additional information, lasted a median of 10.9 months (range, 4.1-36.4
`months) and accounted for 14.1% of total development time.
`
`Both development and approval times differed among the 12 standard review
`drugs and the 8 drugs with 1 or more forms of expedited approval (8 priority
`reviews, 3 fast-track, and 2 accelerated approvals; 3 drugs were part of more
`than 1 expedited category). The expedited pathway drugs took a median of 5.1
`years (range, 1.6-10.6 years) to obtain marketing approval compared with 7.5
`years for the standard review drugs (range, 4.7-19.4 years) (P = .05). Food and
`Drug Administration review times were shorter for expedited pathway drugs
`compared with the standard review group, a median of 7.7 months (range,
`4.1-35.2 months) for expedited drugs, compared with 13.2 months (range,
`9.5-36.4 months) for standard reviews, although the mean differences were not
`significant (P = .15).
`
`In the controlled trials that were conducted to establish substantial evidence of
`benefit, the drugs were tested in a median of 352 patients (range, 23-1207) for
`the active drug; the size of the control groups varied. These data are given in
`Table 2. The expedited pathway drugs were tested in a median of 104 patients
`for the active drug (range, 23-599); the standard review drugs were tested in a
`median of 580 patients (range, 75-1207). The difference in the mean number of
`patients was significant (P = .003).
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`Table 2. Testing and Characteristics of Outpatient and Inpatient Drugs, 2008
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`View Large | Save Table | Download Slide (.ppt) | View in Article Context
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`Overall, 5 of 20 drugs (25%) were tested for efficacy in a single trial, 11 of 20
`(55%) had 2 efficacy trials, and 4 drugs were tested in more than 2. None of the
`8 expedited pathway drugs were tested in more than 2 trials; 3 were approved
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`on the basis of a single efficacy trial.
`
`Among the smallest efficacy trials were those for 2 orphan drugs; rilonacept
`(Arcalyst; Regeneron Pharmaceuticals Inc), an interleukin-1 blocker, was tested
`in 23 patients receiving the active drug, and tetrabenazine, an MAO depletor,
`was tested in 54 patients receiving the active drug. Three drugs had more 1000
`patients in efficacy trials—desvenlafaxine with 1207 patients, fesoterodine with
`1120 patients, and alvimopan (Entereg; Cubist Pharmaceuticals Inc) with 1096
`patients.
`
`The total number of patients exposed to an active drug during testing includes
`clinical pharmacology studies, uncontrolled studies, and other specialized
`studies. For the expedited drugs, a median of 626 patients (range, 313-1161)
`were exposed, compared with 2133 (range, 430-4110) for standard review
`drugs. The difference was also significant (P < .001).
`
`The 20 drugs had a wide spectrum of known safety issues at time of approval
`including Stevens-Johnson syndrome (romiplostim [Nplate; Amgen Inc]), abuse
`liability (tapentadol [Nucynta; Johnson & Johnson]), lacosamide (Vimpat; UCB
`Inc), serious opportunistic infections (certolizumab), severe fetal harm
`(bendamustine [Treanda; Cephalon Inc]), suicidality (desvenlafaxine,
`lacosamide, and tetrabenazine), medically significant cytopenia (certolizumab),
`and serious hepatotoxicity (eltrombopag [Promacta; GlaxoSmithKline]). At time
`of approval, the drugs had 1 or more of the following safety risk indicators: 5 of
`20 drugs had a Boxed Warning indicating a significant safety risk, 8 drugs
`required special risk management plans, and 8 had a warning or
`contraindication for hypersensitivity.
`
`The risks of cancer and birth defects for new drugs are assessed prior to
`approval in animal and in vitro studies, with uncertainties about how the results
`might apply to humans. In these nonhuman studies, 6 drugs had signals for
`animal carcinogenicity, 5 were mutagens in vitro or in animals, and 14 were
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`animal teratogens (Table 2). Pediatric studies are not required prior to approval,
`and were waived for 9 drugs, deferred for 1, and required after approval for 10.
`Specific unanswered questions were outlined in required postapproval studies.
`Overall, the FDA required 85 postmarketing studies for 19 of the 20 drugs.
`Silodosin (Rapaflo; Actavis Pharma Inc), a treatment for benign prostatic
`hyperplasia, had no required postapproval studies; the FDA, however, required
`enhanced postmarket surveillance of serious hepatic events. None of the trials
`conducted prior to approval assessed the efficacy of the drug beyond 24 weeks,
`including those for medications intended for open-ended use. After approval,
`the FDA required the collection of efficacy data beyond 24 weeks for
`desvenlafaxine and bendamustine.
`
`As of January 2013, all 20 drugs were still marketed; 3 of the 10 outpatient
`drugs were on an IMS Health list of the 400 most frequently dispensed
`outpatient drugs: the antidepressant desvenlafaxine (ranked 223 with 825 000
`dispensed outpatient prescriptions in the first quarter of 2013), and the opioid
`tapentadol (ranked 384 with 241 000 prescriptions), and the topical
`difluprednate (Durezol; Alcon Laboratories Inc) (ranked 392 with 227 000
`prescriptions). Of these 3 drugs, only difluprednate had received expedited
`approval. Both drugs granted accelerated approval (etravirine [Intelence;
`Johnson & Johnson] and eltrombopag [Promacta]) were granted full approval
`after completing 2 confirmatory studies that were ongoing at the time of initial
`approval.
`
`Substantial additional risks were discovered in the 4-year period after approval:
`5 drugs acquired a new or expanded Boxed Warning, bringing the total number
`of drugs with such warnings to 7; 1 drug had new contraindications; and 4
`drugs had additional warnings or precautions. Tapentadol, an opioid, had the
`most new risks, with 4 items in a new Boxed Warning, 3 new contraindications,
`and a more restricted indication. As of January 2013, 26 of 85 (31%) of the
`postmarket study commitments were fulfilled and another 8 (9%) had been
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`submitted for FDA review. The postmarket studies had original projected
`completion dates ranging from a few months to the year 2020 (dates were
`missing for 6 studies). Of the studies scheduled for completion by 2013, 34 of
`48 (71%) were completed or submitted. Additional postmarket study detail is
`given in Table 2.
`
`For new drugs approved by the FDA in 2008, those that received expedited
`review were approved more rapidly than those that received standard review.
`However, considerably fewer patients were studied prior to approval, and many
`safety questions remained unanswered. By 2013, many postmarketing studies
`had not been completed. As many safety questions were not answered prior to
`drug approval, some patients may have been exposed to safety risks that had
`not been well characterized.
`
`Among the 8 drugs deemed innovative, only 1 (difluprednate) ranked among
`the 400 most frequently dispensed outpatient drugs in 2013. However, 6 of the
`8 drugs deemed innovative were orphan drugs intended for small patient
`populations. Among the other 12 drugs, 3 were metabolites or prodrugs of
`existing drugs, and the FDA did not judge the remaining 9 as significant
`therapeutic advances.
`
`Our study has limitations. As the typical postmarket major regulatory safety
`16,17
`action occurs a median of 11 years after approval,
` our 4-year follow-up
`period could only capture some of the additional risks that are likely to be
`detected for the drugs approved in 2008. The year studied, 2008, was typical of
`drugs approved between 2008 and 2010 for 3 characteristics: number of new
`drugs, number of orphan drugs, and number of priority reviews.
`
`By definition, the FDA judged that all the drugs it approved in 2008 had benefits
`that outweighed the known risks; subsequent information about additional risks
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`has not led the FDA to remove any of the drugs from the market. The agency
`managed safety risks that became evident after approval with warnings and
`label changes.
`
`The testing of new drugs has shifted from a situation in which most testing was
`conducted prior to initial approval to a situation in which many innovative drugs
`are more rapidly approved after a small trial in a narrower patient population,
`with extensive additional testing conducted after approval. Our findings suggest
`that the shift has made it more difficult to balance the benefits and risks of new
`drugs. Further systematic assessment of the standards and procedures for
`testing new drugs is needed.
`
`Corresponding Author: Thomas J. Moore, AB, Institute for Safe Medication
`Practices, 101 N Columbus St, Ste 410, Alexandria, VA 22314
`(tmoore@ismp.org).
`
`Accepted for Publication: August 29, 2013.
`
`Published Online: October 28, 2013. doi:10.1001/jamainternmed.2013.11813.
`
`Author Contributions: Mr Moore had full access to all of the data in the study
`and takes responsibility for the integrity of the data and the accuracy of the data
`analysis.
`
`Study concept and design: Both authors.
`
`Acquisition of data: Moore.
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`Analysis and interpretation of data: Moore.
`
`Drafting of the manuscript: Moore.
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`Critical revision of the manuscript for important intellectual content: Both
`authors.
`
`Statistical analysis: Moore.
`
`Study supervision: Furberg.
`
`Conflict of Interest Disclosures: None reported.
`
`Disclaimer: This article is based in part on data obtained under license from
`the following IMS Health Incorporated information service: National Prescription
`Audit (Data, January-March 2013), IMS Health Incorporated. The statements,
`findings, conclusions, views, and opinions contained and expressed herein are
`not necessarily those of IMS Health Incorporated or any of its affiliated or
`subsidiary entities.
`
`1 21 USC §355. New drugs. www.gpo.gov/fdsys/pkg/USCODE-
`2010-title21/html/USCODE-2010-title21-chap9-subchapV-partA-
`sec355.htm. Accessed April 22, 2013.
`
`2 21 CFR §314.3. Applications for FDA approval to market a new drug:
`definitions. www.gpo.gov/fdsys/pkg/CFR-2003-title21-vol5/pdf
`/CFR-2003-title21-vol5-sec314-3.pdf. Accessed April 22, 2013.
`
`3 US Food and Drug Administration. Speeding access to important new
`therapies—fast track, accelerated approval and priority review.
`www.fda.gov/forconsumers/byaudience/forpatientadvocates
`/speedingaccesstoimportantnewtherapies/ucm128291.htm. Accessed
`September 20, 2013.
`
`4 International Conference on Harmonization. Guidance for industry: the
`extent of population exposure to assess clinical safety: for drugs
`intended for long-term treatment of non-life-threatening conditions.
`www.fda.gov/downloads/Drugs
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`/GuidanceComplianceRegulatoryInformation/Guidances/UCM073083.pdf.
`Accessed March 22, 2013.
`
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`5 21 USC §355c. Research into pediatric uses for drugs and biological
`products. www.gpo.gov/fdsys/pkg/USCODE-2012-title21
`/pdf/USCODE-2012-title21-chap9-subchapV-partA-sec355c.pdf.
`Accessed September 20, 2013.
`
`6 21 USC §355–1. Risk evaluation and mitigation strategies.
`www.gpo.gov/fdsys/pkg/USCODE-2012-title21/pdf/USCODE-
`2012-title21-chap9-subchapV-partA-sec355-1.pdf. Accessed
`September 20, 2013.
`
`7 President’s Council of Advisors on Science and Technology. Report to
`the President on Propelling Innovation in Drug Discovery, Development
`and Evaluation. Washington, DC: Executive Office of the President of
`the United States; September 1, 2012.
`
`8 US Food and Drug Administration. Driving Biomedical Innovation:
`Initiatives to Improve Products for Patients. October 2011.
`www.fda.gov/AboutFDA/ReportsManualsForms/Reports
`/ucm274333.htm. Accessed April 22, 2013.
`
`9 Creating an alternative approval pathway for certain drugs intended to
`address unmet need. Fed Regist. 2013;78(10):3005-3008.
`www.gpo.gov/fdsys/pkg/FR-2013-01-15/pdf/2013-00607.pdf. Accessed
`August 27, 2013.
`
`10 US Food and Drug Administration. Guidance for industry: enrichment
`strategies for clinical trials to support approval of human drugs and
`biological products: draft guidance. December 2012.
`www.fda.gov/downloads/Drugs
`/GuidanceComplianceRegulatoryInformation/Guidances
`/UCM332181.pdf. Accessed April 22, 2013.
`
`11 US Food and Drug Administration. Guidance for industry: Alzheimer’s
`disease: developing drugs for the treatment of early stage disease: draft
`guidance. February 2013. www.fda.gov/downloads/Drugs
`/GuidanceComplianceRegulatoryInformation/Guidances
`/UCM338287.pdf. Accessed April 22, 2013.
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`12 US Food and Drug Administration. Drug approvals and databases.
`www.fda.gov/Drugs/InformationOnDrugs/default.htm. Accessed April
`23, 2013.
`
`13 DailyMed Current Medication Information. US National Library of
`Medicine website. http://dailymed.nlm.nih.gov/dailymed/about.cfm.
`Accessed April 23, 2013.
`
`14 26 USC §45C. Clinical testing expenses for certain drugs for rare
`diseases or conditions. www.gpo.gov/fdsys/pkg/USCODE-2011-title26
`/pdf/USCODE-2011-title26-subtitleA-chap1-subchapA-partIV-subpartD-
`sec45C.pdf. Accessed August 27, 2013.
`
`15 21 USC §360cc. Protection for drugs for rare diseases or conditions.
`www.gpo.gov/fdsys/pkg/USCODE-2011-title21/pdf/USCODE-
`2011-title21-chap9-subchapV-partB-sec360cc.pdf. Accessed August
`27, 2013.
`
`16 Moore TJ, Singh S, Furberg CD. The FDA and new safety
`warnings. Arch Intern Med. 2012;172(1):78-80.
`PubMed | Link to Article
`
`17 Lester J, Neyarapally GA, Lipowski E, Graham CF, Hall M, Dal Pan
` G. Evaluation of FDA safety-related drug label changes in
`2010. Pharmacoepidemiol Drug Saf. 2013;22(3):302-305.
`PubMed | Link to Article
`Copyright ©2016 American Medical Association
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