Deficiencies of the FDA in evaluating Generic formulations: Addressing narrow therapeutic index drugs

American Journal of Law and Medicine

Volumn 38, Issue 4, 2012, Pages 667-689

  Hottinger, Michelle ^a   Liang, Bryan A ^a,b  

^a CALIFORNIA WESTERN SCHOOL OF LAW   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMFEBUTAMONE; ANTICOAGULANT AGENT; ANTICONVULSIVE AGENT; ANTIDEPRESSANT AGENT; GENERIC DRUG; WARFARIN;

ARTICLE; CHEMISTRY; DRUG APPROVAL; FOOD AND DRUG ADMINISTRATION; HUMAN; LEGAL ASPECT; THERAPEUTIC EQUIVALENCE; UNITED STATES;

ANTICOAGULANTS; ANTICONVULSANTS; ANTIDEPRESSIVE AGENTS, SECOND-GENERATION; BUPROPION; CHEMISTRY, PHARMACEUTICAL; DRUG APPROVAL; DRUGS, GENERIC; HUMANS; THERAPEUTIC EQUIVALENCY; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION; WARFARIN;

MLCS; MLOWN;

EID: 84874991854     PISSN: 00988588     EISSN: None     Source Type: Journal    
DOI: 10.1177/009885881203800403     Document Type: Article

References (87)

1. CTR. FOR DRUG EVALUATION & RESEARCH, FDA, GENERIC DRUGS 7, available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ SmallBusinessAssistance/ucml2 7615.pdf (last visited Feb. 7, 2011).
2. See id.; Facts About Generic Drugs, FDA, http://www.fda.gov/drugs/ resourcesforyou/consumers/buyingusingmedicinesafelb/understandinggenericdrugs/ ucm 167991.htm (last visited Sept. 19, 2012).
3. Akula Thukaram Bapuji et al., Bioequivalence Testing-Industry Perspective, 2 J. BIOEQUIVALENCE & Bioavailability 98, 98 (2010);
4. see also Generic Drugs; Questions and Answers, FDA, http://www.fda.gov/ Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucmlOO 100.htm (last updated Aug. 24, 2011) (stating that "[according to the Congressional Budget Office, generic drugs save consumers an estimated $8 to $10 billion a year at retail pharmacies").
5. See AM. MED. ASSOC., SUMMARIES AND RECOMMENDATIONS OF COUNCIL ON SCIENTIFIC AFFAIRS REPORTS 13-14 (2002) (stating that in 2000, generic drugs accounted for approximately 42% of all prescriptions at the retail level in the United States);
6. Lewis Krauskopf & Bill Berkrot, Generics to Cut U. S. Drugs Bill by $70 Billion, REUTERS, Nov. 8, 2010, available at http://www.reuters.com/ assests/print?aid=ustre6a73xj-20101108 (explaining that generic prescriptions are expected to take over 85% of the prescriptions market as soon as 2014);
7. Bioequivalence, GENERIC PHARMACEUTICAL ASS'N, http://www.gphaonline.org/ issues/bioequivalence (last visited Jan. 7, 2011) (finding that in 2005, generic drugs accounted for 56% of all prescriptions dispensed in the United States. This number rose to 75% in 2010 and is estimated at 77% in 2011).
8. The Patient Protection and Affordable Care Act, in an effort to close the donut hole on Medicare Part D drugs, covers more brand name drugs than ever before. The efforts to close the donut hole are an exception to the overall trend of increasing generic drug use to reduce healthcare costs. See Medicare Beneficiary Savings and the Affordable Care Act, HEALTHCARE. GOV, http://www.healthcare.gov/law/resources/reports/affordablecareact.html (last visited June 23, 2012). 1 Covered brand name drugs were discounted by manufacturers by 50% starting in 2011, with the ! remaining costs to be subsidized by up to 25% by 2020. Id. Generic drugs were also discounted 7% in 2011 and will rise up to 75% in 2020. Id. Indirectly, healthcare reform encourages generic use by passing the cost of healthcare onto Medicaid. Id. Individual states have laws that encourage generic drug use over brand drugs to varying degrees.
9. See Recent Medicaid Prescription Drug Laws, 2001-2012, Nat'l Conf. OF State legs., http://www.ncsl.org/issues-research/health/medicaidpharmaceutical- laws-and-policies.aspx (last visited June 27, 2012);
10. Medicaid Preferred Drug Lists for Mental Health and Substance Abuse, NAT'L CONF. OF STATE LEGS., http://www.ncsl.org/documents/health/PDL-2-2012.pdf (last visited Sept. 9, 2012) (showing a chart of differing state laws regarding preferred drug lists).
11. See Lynda Welage et al., Understanding the Scientific Issues Embedded in the Generic Drug Approval Process, 41 J. AM. PHARMACEUTICAL ASSOC. 856, 856 (2001);
12. see also Gregory M. Peterson, Generic Substitution: A Need for Clarification, 71 BRIT. J. CLINICAL PHARMACOLOGY, 966, 966 (2011) (stating that the debate is often fueled intentionally by the pharmaceutical industry).
13. See Hege S. Blix et al., Drugs with Narrow Therapeutic Index as Indicators in the Risk Management of Hospitalised Patients, 8 PHARMACY PRAC. 50, 50 (2010);
14. Stuart T. Haines, Substituting Warfarin Products: What's the Source of the Problem?, 45 ANNALS PHARMACOTHERAPY 807, 807 (2011).
15. See generally Mikko Yamada & Timothy Welty, Generic Substitution of j Antiepileptic Drugs: A Systematic Review of Prospective and Retrospective Studies, 45 ANNALS PHARMACOTHERAPY 1406 (2011) (finding that several retrospective studies imply a lack of BE while the prospective studies find few significant differences in pharmacokinetic measures).
16. Eugen Trinka et al., Requirements for Generic Antiepileptic Medicines: A Clinical Perspective, 258 J. NEUROLOGY 2128, 2130-31 (2011).
17. Pub. L. No. 75-717, 52 Stat. 1040 (1938)
18. (codified as amended at 21 U. S. C. §§ 301-399d (2006)).
19. Russell Katz, FDA: Evidentiary Standards for Drug Development and Approval, 1 J. AM. Soc'y Experimental NeuroTherapeutics 307, 307 (2004).
20. See Alexander Nasr et al., Unapproved Drugs in the United States and the Food and Drug Administration, 28 ADVANCES THERAPY 842, 846-47 (2011).
21. Pub. L. No. 98-417, 98 Stat. 1585 (1984)
22. (codified as amended at 15 U. S. C. §§ 68b-68c, 70b (2006);
23. U. S. C. §§ 301, 355, 360cc (2006);
24. U. S. C. § 2201 (2006);
25. U. S. C. §§ 156, 271, 282 (2006)).
26. AM. MED. ASSOC., supra note 4, at 3; see also Welage et al., supra note 7, at 857.
27. AM. MED. ASSOC., supra note 4, at 2.
28. 21 C. F. R. § 320.1 (e) (2012) (elaborating on the definition of BE);
29. see CTR. FOR DRUG EVALUATION & RESEARCH, GUIDANCE FOR INDUSTRY: STATISTICAL APPROACHES TO ESTABLISHING BIOEQUIVALENCE (2001) [hereinafter CDER], available at http://www.fda.gov/downloads/Drugs/⋯/GuidancesAicm070244. pdf (an active moiety is the part of the drug molecule responsible for the physiological or pharmacological action of the drug substance).
30. See Meir Bialer & Kamal K. Midha, Generic Products of Antiepileptics Drugs: A Perspective on Bioequivalence and Interchangeability, 51 EPILEPSIA 941, 942 (2010).
31. Barbara M. Davit et al., Comparing Generic and Innovator Drug: A Review of 12 Years of Bioequivalence Data from the United States Food and Drug Administration, 43 ANNALS PHARMACOTHERAPY 1583, 1585 (2009);
32. Robert H. Howland, Evaluating the Bioavailability and Bioequivalence of Generic Medications, 48 J. PSYCHOSOCIAL NURSING & MENTAL HEALTH SERVCES 13, 14 (2010).
33. Malachy O. Columb & Jan M. Lutz, Bioequivalence and Non-Inferiority Trials, 20 CURRENT ANAESTHESIA & CRITICAL CARE 98, 99 (2009).
34. A two-way crossover study is one where two groups receive separate drugs, and then after a period of no drugs, each group is given the other's drug. See generally Shashank Patel et al., Single-dose, Two-way Crossover, Bioequivalence Study of Mycophenolate Mofetil 500 mg Tablet Under Fasting Conditions in Healthy Male Subjects, 33 CLINICAL THERAPEUTICS 378 (2011) (describing a two-way crossover study to determine BE of mycophenolate). This limits variation of subjects as a cause of BE or non-BE findings.
35. See AM. MED. ASSOC., REPORT 2 OF THE COUNCIL ON SCIENCE AND PUBLIC HEALTH (A-07) 1-2 (2007).
36. See id. at 1585; see also Bialer & Midha, supra note 26, at 942 (finding that variation in bioavailability of up to 10% may occur). The 90% confidence intervals for the ratio "of each pharmacokinetic variable must lie between 0.80 and 1.25." Gregory M. Peterson, Generic Substitution: A Need for Clarification, 71 BRIT. J. CLINICAL PHARMACOLOGY 966, 966 (2011). This range is an indication of certainty of the study results and does not mean that the average observed Cmax and AUC ratios or plasma concentrations can vary by this range. Id. Products usually must vary by less than 10% to satisfy the 90% Cl required for BE. See id.
37. See Eugen Trinka et al., Requirements for Generic Antiepileptic Medicines: A Clinical Perspective, 258 J. NEUROLOGY 2128, 2129 (2011);
38. see also Uwe Christians et al., Bioequivalence Testing of Immunosuppressants: Concepts and Misconceptions, 77 KIDNEY INT'L 51, 51 (2010).
39. Gregory L. Krauss et al., Assessing Bioequivalence of Generic Antiepilepsy Drugs, 70 ANNALS NEUROLOGY 221, 223-24 (2011) (stating that Cmax values varied by 15 to 25% in 11% of studies);
40. see also Mubarak Al Ameri et al., Generic and Therapeutic Substitutions: Are They Always Ethical in Their Own Terms?, 32 PHARMACY WORLD & SCI. 691, 693 (2010) (citing that in Sweden between 1972 and 1996, the increase in the generic market share was associated with the increase in the number of reported side effects in seven of the fifteen medicines studied).
41. See id.; see also 21 C. F. R. §320.1 (2012).
42. See FDA Considering Tighter Controls on Generics, GENERICS & BIOSIMILARS INITIATIVE (July 1, 2011), http://www.gabionline.net/Generics/News/ FDA-considering-tighter-controls-on-generics/(highlight)/ FDA%20CONSIDERING%20TIGHTER%20CONTROLS%200N%20GENERICS.
43. See Bioequivalence, supra note 4;
44. see also J. J. Gagne et al., Refilling and Switching of Antiepileptic Drugs and Seizure-Related Events, 88 CLINICAL PHARMACOLOGY & THERAPEUTICS 345, 349-50 (2010).
45. All generic, multisource drug markets should be bioequivalent and therapeutically equivalent to a single standard reference listed drug (RLD). See Akula Thukaram Bapuji et al., Bioequivalence Testing-Industry Perspective, 2 J. BIOEQUIVALVENCE & BIOAVAILABILITY 98, 99 (2010). This will help avoid significant variations among generic drugs and brand name drugs. Id. Selecting a RLD product is a constant challenge to industry. Id.
46. See Donald Birkett, Generics-Equal or Not?, 26 AUSTL. PRESCRIBER 85, 86 (2003).
47. See Mark E. Arnold, Implications of Differences in Bioanalytical Regulations Between Canada, USA and South America, 3 BIOANALYSIS, 253, 253, 257 (2011).
48. Raman Sankar et al., Understanding Therapeutic Equivalence in Epilepsy, 15 CNS SPECTRUM 112, 117 (2010).
49. see also Fads about Current Good Manufacturing Practices, FDA, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucml69105.htm (last updated June 25, 2009).
50. FDA Ensures Equivalence of Generic Drugs, FDA (Aug. 2002), http://www.fda.gov/Drugs/EmergencyPreparedness/BioterrorismandDrugPreparedness/ ucml34444.htm (quoting Gary Buehler, Director of FDA's Office of Generic Drugs) ("The standards for quality are the same for brand name and generic products.").
51. Christine L. Fitzgerald & Mercedes P. Jacobson, Generic Substitution of Levetiracetam Resulting in Increased Incidence of Breakthrough Seizures, 45 ANNALS PHARMACOTHERAPY 1, 4 (2011).
52. see also Francesco Dentali et al., Brand Name Versus Generic Warfarin: A Systemic Review of the Literature, 31 PHARMACOTHERAPY 386 (2011) (discussing anticoagulant drugs);
53. Review of Therapeutic Equivalence Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg, FDA (Sept. 18, 2009), http://www.fda.gov/AboutFDA/ CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucml53270.htm (discussing antidepressant drugs).
54. AEDs are NTI drugs that require careful titration of each individual patient to achieve the effective dose resulting in no breakthrough seizures.' See Mei Sheng Duh et al., The Economic Implications of Generic Substitution of Antiepileptic Drugs: A Review of Recent Evidence, 10 PHARMACOTHERAPY 2317, 2320 (2009). About half of newly diagnosed epilepsy patients can gain control of their seizures through their first treatment. Id. at 2320-21. Another 20% of patients can gain control of their seizures after a change in treatment drugs. Id. at 2321. Control of occasional seizures cannot be obtained by the remaining 30% of patients seeking treatment. Id. Patients that are fortunate enough to achieve stability of their epilepsy may require polytreatment, consisting of multiple medications added to monotherapy to achieve optimal treatment. Id.
55. see also Josemir Sander et al., Generic Substitution of Antiepilelptic Drugs, 10 NEUROTHERAPY 1887, 1887 (2010) (stating that "[d]espite optimum treatment", epilepsy is associated with a 20 to 30% refractory rate with current treatments).
56. Sander et al., supra note 82, at 1894 (explaining that patients may be confused by the change in product appearance leading to discontinuity in treatment). Note also that such changes may represent significant challenges in biologic drug, "biosimilar", or follow on biologic formulations, including immunogenicity reactions. See, e.g., Bryan A. Liang & Tim Mackey, Emerging Patient Safety Issues Under Healthcare Reform: Follow On Biologies and Immunogenicity, 7 THERAPEUTICS and CLIN, RISK MANAG. 483 (2011).
57. Differences in excipients, packaging, and labeling can be expected but not relevant to therapeutic quality. This may cause patient confusion. The formulation stability may also slightly vary. See Sander et al., supra note 82, at 1889. Several other European organizations from Germany, Italy, and Sweden recommend not switching from brand-named AEDs to generics. See Trinka et al., supra note 11, at 2129. In Pliva, Inc. v. Mensing, the Court held that generic manufacturers are unable to independently change their labels, even if dangerous side effects are known. Pliva, Inc. v. Mensing, 131 S. Ct. 2567, 2570 (2011). Generic drugs must have identical labels to brand name drugs according to federal law. See id. at 2572 (holding that federal drug regulations regarding generic drug manufacturers directly conflict with state laws and thus pre-empt the state claims);
58. see also 21 U. S. C. § 355 (j) (4) (g) (2006).
59. Sameer R. Ghate et al., Hemorrhagic and Thrombotic Events Associated with Generic Substitution of Warfarin in Paitients with Atrial Firbrillation: A Retrospective Analysis, 45 ANNALS PHARMACOTHERAPY 701, 701 (2011).
60. In a study of warfarin and Coumadin, the generic showed small but significant decreases in INR, but no differences in morbidity or mortality. See Aaron S. Kesselheim et al., Clinical Equivalence of Generic and Brand-Name Drugs Used in Cardiovascular Disease, A Systemic Review and Meta-Analysis, 300 JAMA 2514, 2523-24 (2008). Increased risk potential should be monitored 1 more closely. Id. The authors found the differences generally to be insignificant. See id.;
61. see also Todd Neale, Generic Cardiovascular Drugs Measure Up to Brand-Name Counterparts, MEDPAGE TODAY (Dec. 2, 2008), http://www.medpagetoday. com/Cardiology/MyocardialInfarction/11984.
62. A citizens' petition can be filed if a drug raises questions of quality. See Citizen Petition, GENERIC PHARMACEUTICAL ASSOC., http://www.gphaonline.org/ issues/citizen-petitions (last visited July 8, 2012). Brand name drug companies have a long history of filing Citizen Petitions in an attempt to prolong the time in which generic drugs can enter the market. Id. Nearly three quarters of petitions in 2008 were found to have no merit and were consequently dismissed. Id. In response, the FDA Revitalization Act of 2007 aims to curb such abuses by forcing the FDA to respond to petitions within six months. Id. This is costly, but enables generic drugs to enter the market with less delay.
63. Ghate et al., supra note 109, at 709-10. Studies from the 1980s at Boston City Hospital indicated that after a routine substitution of Panwarfarin in place of brand name Coumadin, a number of patients began to experience wide fluctuation in their prothrombin times. See Haines, supra note 8, at 807. In response to this issue, the hospital did a retrospective study and found that 93% of patients that received Panwarfarin had a prothrombin time outside their target range. Id. Patients that switched were twice as likely to have prothrombin target times above the goal. Id. Also, patients that switched cost more due to increased clinical visits. Id. The estimated cost was $14, 000 more than the nonswitching group, which far exceeds any cost savings gained by switching to generic. Id. However, this study was done in the 1980s and involved fifteen patients who switched to the generic. This study is neither large nor recent enough to give current accurate information. Through the 1990s, as more generic warfarin products became available, pharmacy literature began to report suspicions that generics were not bioequivalent despite meeting FDA standards. Id. at 808. A 210-patient study by the Group Health Cooperative of Puget Sound found that patients who voluntarily switched to generics found no increased likelihood of increased change in INR. Id. Another study by the Barnes-Jewish Hospital Blood Thinner Clinic supported the finding that no differences between generic and brand named exist. Id. Kaiser examined 2300 patient records and found no evidence of failed generic warfarin-the only known prospective, randomized, controlled, and blinded clinical study failed to find substantial differences in patient response to a generic switch. Id. Several studies have proven that generic and brand warfarin are the same, but all the randomized controlled trials were very small, making them inadequate in detecting differences in products. Id. These retrospective studies may also be important for what they did not measure. For example, over-the-counter drugs that may affect the risk of hemorrhagic and thrombotic events are not captured in the database of warfarin users. See Barry L. Carter, Letter to the Editor, Equivalence of Generic and Brand-Name Drugs for Cardiovascular Disease, 301 JAMA 1654 (2009) (finding that many of the systemic reviews do not consider the effects of repeated formulation substitution over time among a branded drug and its generics).
64. Bupropion is the active ingredient of Wellbutrin, a commonly prescribed antidepressant. Several pharmaceutical alternatives have been developed, as well as generics for each alternative. See Mei-Ling Chen et al., Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified-Release Products: Workshop Summary Report, 40 EUR. J. PHARMACEUTICAL SCI. 148, 149 (2010);
65. see also Robert H. Howland, When Is a "Generic" Medication Not Really a Generic?, 27 J. PSYCHOSOCIAL NURSING & MENTAL HEALTH SERVICES 13 (2010).
66. Review of Therapeutic Equivalence Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg, supra note 80; see also Jacqueline Stenson, Report Questions Generic Antidepressant, NBC NEWS (Oct. 12, 2007), www.msnbc.msn. com/id/21142869/#.trgv2bzfk29.
67. Review of Therapeutic Equivalence Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg, supra note 80.
68. Generic Drug Equality Questioned: The People's Pharmacy, THE PEOPLE'S PHARMACY (Oct. 12, 2007), http://www.peoplespharmacy.eom/2007/l 0/12/generic-drug-eq/.
69. see also Drug Tests: Wellbutrin vs. Generic Bupropion, CONSUMERLAB, www.consumerlab.com/howtested/wellbutrin-vs-Generic-Bupropion/Wellbutrin/ (last visited Oct. 17, 2012).
70. Review of Therapeutic Equivalence Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg, supra note 80 (finding that if 10, 000 persons switched from the brand name product to the generic product, then 500 to 800 people would be expected to experience a worsening of symptoms even if there was no change in drugs, as this is the natural course of the disease).
71. See ram, Comment to Generic Drug Equality Questioned, supra note 127 (Oct. 12, 2007, 11:14 AM) ("I too take Wellbutrin XL 300 mg and was switched from brand name to Teva's generic version by my pharmacy/health plan. I experienced a huge spike in depression that had been well controlled on brand name Wellbutrin for several years previously. Normally I have no problems taking generics, but with these findings, and my increase in depression this last year, I have to question the efficacy of Teva's version of Wellbutrin XL.");
72. see also Melissa, Comment to Generic Drug Equality Questioned, supra note 127 (Oct, 12, 2007 1:48 PM) ("I thought I might be imagining things when 1 switched from name brand Wellbutrin to generic Wellbutrin and began having depression symptoms. I was on 300 mg daily and though [sic] that maybe it was time to up the dosage or switch to another antidepressant when it didn't seem to work anymore. 1 suspected the generic drug might be the problem so a [sic] asked for a month's supply of the name brand and felt better almost instantly. I'm glad to know that this issue is being looked at.").
73. Review of Therapeutic Equivalence Generic Bupropion XL 300 mg and Wellbutrin XL 300 mg, supra note 80.
74. David Maris, A Drug Recall That Should Frighten Us All About the FDA, FORBES (Oct. 10, 2012, 3:00 PM), http://www.forbes.com/sites/davidmaris/2012/10/ 10/fda-recall-points-to-serious-prob lems-at-the-fda/.
75. Id.; see also Daniel J. DeNoon, Teva's High-Dose Generic Wellbutrin XL Withdrawn, WebMD (Oct. 5, 2012), http://www.webmd.com/depression/news/20121005/ teva-high-dose-genericwellbutrin-xl-withdrawn.
76. A higher prevalence of side effects caused three patients to drop out of the study on the first day. Increased side effects could lead to poorer compliance of medical care. See Franck Chenu et al., Comparison of Pharmacokinetic Profiles of Brand-Name and Generic Formulations of Citalopram and Venlafaxine: A Crossover Study, 70 J. CLINICAL PSYCHIATRY 958, 965 (2009). Personal and familial suffering resulting from potential relapse may not be worth the immediate savings of generics. Id.
77. see also Therapeutic Research Ctr., State Regulations on Generic Substitution, PHARMACIST'S LETTER (2006), http://pharmacistsletter. therapeuticresearch.com/pl/ArticleDD.aspx7ni dchk=l&cs=&s=PL&pt= 2&segment=1186&dd=220901 (last updated Apr. 2009) (presenting a table of each state's policy).
78. See MINI-SENTINEL, http://mini-sentinel.org/ (last visited Sept. 24, 2012) (showing reports of pilot projects and progress).
79. This system aims to "help scientists better understand the potential safety issues associated with FDA-approved products." FDA's "Mini-Sentinel" Safety Pilot Program is Up and Running, Demonstrating Rapid Analysis of Medical Product Safety Questions, FDA, http://www.fda.gov/ downloads/Safety/FDAsSentinel Initiative/UCM268035.pdf (last visited Sept. 20, 2012). This system may offer great data and insight into issues associated with BE in the future.
80. James V. Hennessey, Presentation at the Meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology (July 26, 2011), available at https://www.aace.com/files/views/leg-reg-hennesseyjuly-2011.pdf.
81. See Vengelis Karalis et al., On the Leveling-off Properties of the New Bioequivalence Limits for Highly Variable Drugs of the EMA Guideline, 44 EUR. J. PHARMACEUTICAL SCI. 497, 498 (2011);
82. See GARY BEUHLER, FDA, HISTORY OF BIOEQUIVALENCE FOR CRITICAL DOSE DRUGS 69(2010), available at http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMater ials/Drugs/ AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM209319.pdf.
83. See YVETTE WAPLES & ELIZABETH M. TOPP, FDA, SUMMARY MINUTES OF THE ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE AND CLINICAL PHARMACOLOGY 1, 5(2011), available at http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM272111.pdf.
84. See FDA Considering Tighter Controls on Generics, supra note 51 (reporting that in an April 2010 meeting, the FDA advisory committee judged that current standards were not sufficient for critical dose drugs);
85. Kristina Fiore, FDA May Rein in Bioequivalence for Critical Dose Drugs, MEDPAGE TODAY (Oct. 23, 2010), http://www.medpagetoday.com/PublicHealthPolicy/ PublicHealth/22930;
86. EUR. MED. AGENCY, GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE 15(2008), available at http://www.ema.europa.eu/docs/en-GB/document-library/ Scientific-guideline/2009/09/WC500003011.pdf (acknowledging that NTI drugs may need a tighter interval and suggests narrowing the BE range to 90 to 111% in special cases of NTI drugs).
87. See EUR. Med. AGENCY, supra note 165, at 15.