Generic Substitution of Narrow Therapeutic Index Drugs
Note: This report, written in response to Resolution 526 (A-06), represents the medical/scientific literature on this subject as of June 2007.
Full Text
At the 2002 Annual Meeting, this Council presented a report on generic drugs, which included a detailed discussion of the generic substitution of narrow therapeutic index (NTI) drugs.1 The following report will provide an update of the earlier report with a focus on the evidence and the arguments surrounding the generic substitution of NTI drugs.
Methods
Previous reports of this Council on generic drugs were reviewed. Published studies from 2002 through February 2007 were identified through a MEDLINE search of English-language articles, using the MeSH terms, drugs, generic, and therapeutic equivalency. A total of 103 articles were identified. Additional articles were identified by a review of references cited in these publications. In addition, the Web sites of the Food and Drug Administration (FDA) and various medical specialty societies were accessed for articles relevant to NTI drugs.
AMA Policies [Editor's Note: The following reflects AMA policy at the time this report was written, June 2007.]
AMA Policy H-125.984 (AMA Policy Database) is the AMA’s primary policy on generic drugs, as follows:
“ The AMA believes that: (1) Physicians should be free to use either the generic or brand name in prescribing drugs for their patients, and physicians should supplement medical judgments with cost considerations in making this choice. (2) It should be recognized that generic drugs frequently can be less costly alternatives to brand-name products. (3) Substitution with Food and Drug Administration (FDA) "B"-rated generic drug products (ie, products with potential or known bioequivalence problems) should be prohibited by law, except when there is prior authorization from the prescribing physician. (4) Physicians should report serious adverse events that may be related to generic substitution, including the name, dosage form, and the manufacturer, to the FDA’s MedWatch program. (5) The FDA, in conjunction with the AMA and the United States Pharmacopoeia, should explore ways to more effectively inform physicians about the bioequivalence of generic drugs, including decisional criteria used to determine the bioequivalence of individual products. (6) The FDA should fund or conduct additional research in order to identify the optimum methodology to determine bioequivalence, including the concept of individual bioequivalence, between pharmaceutically equivalent drug products (ie, products that contain the same active ingredient(s), are of the same dosage form, route of administration, and are identical in strength). (7) The Congress should provide adequate resources to the FDA to continue to support an effective generic drug approval process. (CSA Rep. 6, A-02)”
AMA Policy H-115.974 also is relevant to generic substitution and the dispensing of generic drug products, as follows:
“ The AMA recommends (1) That when a physician desires to prescribe a brand name drug product, he or she do so by designating the brand name drug product and the phrase "Do Not Substitute" (or comparable phrase or designation, as required by state law or regulation) on the prescription; and when a physician desires to prescribe a generic drug product, he or she do so by designating the USAN-assigned generic name of the drug on the prescription. (2) That, except where the prescribing physician has indicated otherwise, the pharmacist should include the following information on the label affixed to the container in which a prescription drug is dispensed: in the absence of product substitution, (a) the brand and generic name of the drug dispensed; (b) the strength, if more than one strength of drug is marketed; (c) the quantity dispensed; and (d) the name of the manufacturer or distributor. (3) When generic substitution occurs: (a) the generic name (or, when applicable, the brand name of the generic substitute ["branded" generic name]) of the drug dispensed; (b) the strength, if more than one strength of drug is marketed; (c) the quantity dispensed; (d) the manufacturer or distributor; and (e) either the phrase "generic for [brand name prescribed]" or the phrase "substituted for [brand name prescribed]." (4) When a prescription for a generic drug product is refilled (eg, for a patient with a chronic disease), changing the manufacturer or distributor should be discouraged to avoid confusion for the patient; when this is not possible, the dispensing pharmacist should satisfy the following conditions: (a) orally explain to the patient that the generic drug product being dispensed is from a different manufacturer or distributor and, if possible (eg, for solid oral dosage forms), visually show the product being dispensed to the patient; (b) replace the name of the prior generic drug manufacturer or distributor on the label affixed to the prescription drug container with the name of the new generic drug manufacturer or distributor and, show this to the patient; (c) affix to the primary label an auxiliary (sticker) label that states, "This is the same medication you have been getting. Color, size, or shape may appear different"; and (d) place a notation on the prescription record that contains the name of the new generic drug manufacturer or distributor and the date the product was dispensed. (BOT Rep. 1, A-95; Amended: CSA Rep. 2, I-99; Modified Res. 512, I-00; Reaffirmed: CSA Rep. 6, A-02)”
Generic Drug Use and Costs
Generic drugs accounted for 56% of all prescriptions dispensed in the United States in 2005, but this represented less than 13% of every dollar spent on prescription drugs. The average retail price of a prescription for a generic drug was $29.82 versus $101.71 for a brand name drug.2 Thus, the use of generic drugs provides an opportunity to substantially reduce spending on pharmaceuticals. For this reason, the Medicare Part D outpatient prescription drug program strongly encourages the use of generic drugs whenever possible, and the Centers for Medicare and Medicaid Services (CMS) reported that 61% of Part D prescriptions dispensed in the third quarter of 2006 were for generic drugs.3
Approval of Generic Drug Products
CSA Report 6 (A-02) provided an extensive discussion of this subject,1 and the following is a synopsis of that discussion to provide context for the current report. Generic drug products are approved in the United States via the Abbreviated New Drug Application (ANDA) process. Generic products approved under an ANDA must be “pharmaceutical equivalents” (ie, have the same active ingredient[s], route of administration, dosage form, and strength) of the reference drug (brand name innovator) product. They must also be “bioequivalent” and the manufacturer must supply other basic technical information related to manufacturing of the product that is normally required of any New Drug Application (NDA).1,4
Bioequivalence is defined as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents…becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”4,5 The FDA currently uses an “average bioequivalence” approach, which involves a comparison of means. For immediate-release oral dosage forms, the standard average bioequivalence determination employs a single-dose, two-way crossover study, typically conducted in a limited number of healthy volunteers (usually 24 to 36 adults). For drugs with long half-lives, parallel design studies may be used. Both the rate and extent of absorption are evaluated. The former includes the maximum plasma concentration (Cmax) and the time required to achieve this value (Tmax). The extent of absorption is measured by the area under the plasma concentration-time curve (AUC). Results are analyzed according to whether the generic product (test), when substituted for the brand name product (reference), is significantly less bioavailable, and alternatively, whether the brand name product, when substituted for a generic product, is significantly less bioavailable (the two 1-sided tests). The core of the bioequivalence concept is an “absence of a significant difference.” A difference of ›20% is viewed by the FDA as significant. By convention, all data are expressed as a ratio of the average response (AUC and Cmax) for test/reference, so the limit expressed in the second analysis is 125% (reciprocal of 80%). Tests are carried out using an analysis of variance and calculating a 90% confidence interval (CI) for the average of each pharmacokinetic parameter, which must be entirely within the 80% to 125% boundaries.1,4,5
The FDA considers generic drug products to be “therapeutically equivalent” to brand name innovator products if they meet the criteria outlined above, even though other characteristics of the product (eg, shape, color, excipients) may be different. Generic drug products that the FDA considers to be therapeutically equivalent to brand name innovator products are “A-rated,” and those that are not therapeutically equivalent are “B-rated.” These are the first letters of therapeutic equivalence evaluation codes for all drug products listed in the FDA’s publication, Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).4 A second letter follows the “A” or “B” rating and provides additional information on the basis for the FDA’s evaluation. For example, most orally administered generic drug products that are therapeutically equivalent are designated with the code “AB,” which means that actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence.4
Concerns have been raised as to whether assessment of bioequivalence assures therapeutic equivalence, and numerous case reports have appeared in the medical literature suggesting problems temporally related to generic substitutions with a number of “A-rated” products.1 However, the FDA has investigated numerous reports of potential generic product inequivalence, and the Agency has claimed it cannot document a single example of therapeutic failure when an FDA-designated therapeutically equivalent product was substituted for its reference (brand name innovator) product.1,6 The FDA also has conducted two large surveys to quantify the differences between generic and brand name products. The first, conducted on 224 bioequivalence studies submitted in approved applications during 1985 and 1986, found an average difference in AUC measures between reference and generic products of 3.5%.7 The second, involving 127 bioequivalence studies submitted in 1997 found average differences of 3.47% for AUC and 4.29% for Cmax.8 Finally, it is important to emphasize that when the formulation of a brand name innovator drug product is changed by its manufacturer, not an infrequent occurrence, the identical bioequivalence tests are performed to show therapeutic equivalence.1
Generic Substitution of Narrow Therapeutic Index Drugs
Therapeutic Equivalence Considerations. There is no universally accepted definition of an NTI drug. The FDA prefers to use the term “narrow therapeutic range,” but notes that “narrow therapeutic index” is more commonly used. In its most recent Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations, the FDA defines narrow therapeutic range drug products “as containing certain drug substances subject to therapeutic drug concentration or pharmacodynamic monitoring, and/or where product labeling indicates a narrow therapeutic range designation.” Examples cited by the FDA include: digoxin, lithium, phenytoin, theophylline, and warfarin. While the FDA Guidance recommends that sponsors (manufacturers) consider additional testing and/or controls to ensure the quality of narrow therapeutic range drug products, the Guidance recommends that “the traditional bioequivalence limit of 80 and 125 percent for non-narrow therapeutic range drugs remain unchanged for the bioavailability measures (AUC and Cmax) of narrow therapeutic range drugs.”5
As discussed in CSA Report 6 (A-02), surveys and guidelines confirm that some physicians remain concerned about the potential therapeutic inequivalence of generic NTI products, including antiepileptic drugs, antiarrhythmics, warfarin, and cyclosporine.1 These include current position statements of the: 1) American Academy of Neurology that: a) opposes generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician’s approval; and b) opposes prior authorization requirements by public and private formularies for anticonvulsant drugs in the treatment of epilepsy9; and 2) American Association of Clinical Endocrinologists, The Endocrine Society, and the American Thyroid Association (joint statement) that: a) raises concerns with the FDA’s method for determining bioequivalence for generic levothyroxine products; and b) recommends that physicians not substitute levothyroxine drug products.10 the AMA also has a policy directive (D-125.991) that urges the FDA to re-examine its bioequivalence standards for levothyroxine.
CSA Report 6 (A-02) contained a detailed discussion of both the evidence and the arguments surrounding the generic substitution of NTI drugs, including antiepileptic drugs, antiarrhythmic drugs, warfarin, and cyclosporine.1 The current report briefly reviews the more recent (since 2002), but limited published studies that were conducted in the United States.
Antiepileptic Drugs. Based on a retrospective review of approximately 200 medical records of patients with seizures who had been mandated to switch from Dilantin Kapseals to an “AB-rated” generic phenytoin product (Mylan Pharmaceuticals) in State of Minnesota health plans without physician notification, eight adult patients were identified whose seizures increased such that they were switched back to the brand name product. Mean total phenytoin serum concentration on brand was 17.7 + 5.3 mg/L, decreased to 12.5 + 2.7 mg/L on generic, and increased to 17.8 + 3.9 mg/L after brand was re-introduced. Unbound phenytoin serum concentrations decreased in each of the eight patients when switched to generic. This small observational study had obvious limitations, however.11
Antiarrhythmic Drugs. A retrospective chart review was performed on 138 patients with cardiac arrhythmias in a Veterans Administration (VA) Medical Center who were taking a stable dose of amiodarone before and after switching from Cordarone, the brand name innovator product, to an “AB-rated” generic product (Pacerone from Upsher-Smith Laboratories). For 77 patients who took each product at the same dose, steady-state plasma concentrations of amiodarone and its active metabolite, desethylamiodarone (DEA), did not differ among the two drug products. However, after substitution with the generic product, 11 patients experienced a large change of >100% in amiodarone concentrations. Because of limitations in the study design, it could not be definitively concluded that these changes were due to the change in drug formulation. Plasma concentrations of the active metabolite DEA were very stable after the switch, and no patient developed new clinical evidence of toxicity. The authors concluded that it is possible to switch amiodarone products with minimal risk to the vast majority of patients. Monitoring of drug concentrations in plasma is warranted.12
Warfarin. An anticoagulation clinic associated with an HMO collected data on 182 patients eight months prior to and 10 months after the substitution of an “AB-rated” generic warfarin product (Barr Laboratories) for Coumadin (brand name innovator product) for the following endpoints: (1) international normalized ratio (INR) control; (2) frequency of INR monitoring; (3) number of dose changes; and (4) rate of thrombotic and hemorrhagic events. No differences were found in any endpoint. The authors concluded that generic substitution of warfarin could be done safely without the need for additional monitoring.13
A nonprofit, group model HMO began a system-wide conversion of patients from Coumadin to an “AB-rated” generic warfarin product (Barr Laboratories). A retrospective study was done on 2,299 patients who had been taking warfarin for at least 180 days and who had received uninterrupted oral anticoagulation therapy during the 90 days before and 90 days after switching to generic warfarin. The primary endpoint was the calculated amount of time each patient’s INR values were within the patient-specific target INR range in the 90 days before and after the switch. Data also were collected on adverse events and medical resource utilization, and a pharmacoeconomic analysis was performed. The overall difference in calculated time INR values was below (22.6% before vs. 26.1% after switch, p=0.0001) and within (65.9% before vs. 63.3% after switch, p=0.0002) the therapeutic INR range was statistically but not clinically significant. Only 28% of patients experienced a change in therapeutic INR control of 10% or less, 33.1% experienced INR control that improved by greater than 10%, and 38.9% experienced INR control that worsened by more than 10%. The INR control varied by greater than 50% after product conversion in 13% of patients. Whether this variability in anticoagulation response was directly attributable to generic substitution or simply reflects the inherent variability associated with warfarin therapy could not be determined. No statistically significant difference was noted in the number of nonfatal anticoagulation-related adverse events after generic substitution, and the proportion of patients who actually experienced adverse events was small. However, the study design prevented analysis of adverse events that necessitated withdrawal of patients from the study. The difference in total treatment costs associated with brand name and generic warfarin was $3,128/100 person-years in favor of the generic product. The authors concluded that most patients were successfully switched from brand name to generic warfarin. The authors also recommended that additional INR monitoring should occur in the days and weeks after generic substitution of warfarin products.14
Cyclosporine. An open-label, three-period design, multicenter study was performed in 50 renal transplant recipients taking stable doses of Neoral, the brand name innovator cyclosporine product. Patients continued on their Neoral regimen during period I (days 1-14), switched to the same dosage of an “AB-rated” generic cyclosporine product (Gengraf from Abbott Laboratories) during period II (days 15-28), and switched back to the same dosage of Neoral during period III (days 29-35). Twelve-hour pharmacokinetic evaluations (maximum observed blood concentration [Cmax], concentration before dosing [Ctrough], time to maximum observed concentration [Tmax], and area under the blood concentration-vs.-time curve [AUC]) occurred on days 1, 14, 15, 28, and 29. Predose Ctrough samples also were evaluated on days 7, 21, and 35; laboratory and safety parameters also were evaluated. The pharmacokinetics of the generic drug product (Cmax, Tmax, Ctrough, and AUC) were indistinguishable from the Neoral values in these stable renal transplant patients, and the bioequivalent capsules were interchangeable with respect to Cmax, Ctrough, and AUC at steady state and also on conversion from one capsule formulation to another. The 90% confidence intervals for the generic vs. Neoral comparison at steady state (day 28 vs. day 14) were 0.95 to 1.03 for AUC and 0.92 to 1.04 for Cmax. Trough concentrations remained consistent throughout the study with no need for dosage adjustment in any patient, and no differences in adverse events were observed. The authors concluded that the “AB-rated” generic drug product was interchangeable with Neoral in stable renal transplant patients.15
Forty-one patients receiving follow-up care at a renal transplant clinic in the VA healthcare system were switched from Neoral to an “AB-rated” generic cyclosporine product (Gengraf from Abbott Laboratories) based on a 1:1 dosing equivalency. Steady state cyclosporine trough concentrations were obtained both prior to and following the generic substitution. Patients also were monitored for changes in serum creatinine, hospitalization, cyclosporine toxicity, graft rejection, and need for further adjustment in cyclosporine regimen. No differences in cyclosporine trough concentrations or serum creatinine were observed following the Neoral to generic conversion. There were no reports of cyclosporine toxicity, no episodes of graft rejection, and no need for further dosage adjustment related to generic substitution. The authors concluded that the “AB-rated” generic drug product was interchangeable with Neoral in these renal transplant patients.16
Among 82 stable renal transplant patients being treated with Neoral on the renal transplant unit of a county medical center, 73 patients were switched to an “AB-rated” generic cyclosporine product (Gengraf from Abbott Laboratories) based on a 1:1 dosing equivalency. Nine patients remained on Neoral. Cyclosporine trough concentrations and serum creatinine concentrations were measured prior to and at two and four weeks following the generic substitution. Thirteen of 73 patients who switched to the generic drug required a dosage adjustment after the mean cyclosporine trough concentrations changed from 234 + 96 ng/ml at baseline to 289 + 102 ng/ml at two weeks. None of nine patients who remained on Neoral required a dosage adjustment. No significant differences in serum creatinine concentrations were observed in either group of patients. The authors recommended additional drug monitoring when there is generic substitution of cyclosporine.17
Clinical outcomes were compared for de novo kidney transplant recipients who received either Neoral (n=100) or an “AB-rated” generic cyclosporine product (Gengraf from Abbott Laboratories) (n=88) in a single-center, retrospective review. When compared to patients who received Neoral, patients who received the generic cyclosporine product were significantly more likely to have an acute rejection episode (39% vs. 25%, p=0.04), more likely to have a second rejection episode (13% vs. 4%, p=0.03), or to have received an antibody preparation to treat acute rejection (19% vs. 8%, p=0.02). Patients treated with the generic drug had a higher degree of intrapatient variability for cyclosporine trough concentrations as determined by % coefficient of variation (%CV) (p<0.05). The authors concluded that the incidence of acute rejection post-transplant was significantly higher in patients who received the generic drug when compared to Neoral, and they recommended that a larger, prospective controlled clinical trial be conducted to confirm their findings.18
Levothyroxine. No published studies on the generic substitution of levothyroxine in patients with hypothyroidism were found in the CSAPH’s search of the literature since 2002.
A potential concern regarding generic substitution of levothyroxine sodium is that there are four reference (brand name innovator) products, Unithroid, Synthroid, Levoxyl, and Levothroid, and three-character codes, AB1, AB2, AB3, and AB4, respectively, are assigned to each of these products in the FDA’s Orange Book. Generic drug products may be determined by the FDA to be therapeutically equivalent to one or more of these reference products, and the reference products, themselves, may be bioequivalent to one another. For example, Synthroid (AB1, AB2) is considered to be therapeutically equivalent to Unithroid, but not to Levoxyl and Levothroid. Generic levothyroxine sodium made by GenPharm (AB2, AB3) is considered to be therapeutically equivalent to Synthroid and Levoxyl, but not to Unithroid or Levothroid. On the other hand, generic levothyroxine sodium made by Mylan (AB1, AB2, AB3, AB4) is considered to be therapeutically equivalent to all four reference products, even though some reference products are not considered to be therapeutically equivalent to each other. Listings of levothyroxine sodium products consume 20 pages of the FDA’s Orange Book.4 This has the potential to result in considerable confusion regarding appropriate generic substitution among these products in the outpatient practice environment.10
Other Patient Safety Considerations. The frequency of medication errors and preventable medication-related injuries represents a very serious cause for concern. Medication errors can occur at any point in the medication use process and in any care setting.19 While the focus usually has been on errors caused by healthcare professionals, there is substantial evidence that patient errors also are important, whether they are due to non-adherence (non-compliance) with medication regimens,20 inappropriate use of medications,21 or an inability to understand simple information, such as prescription drug labels.22
In a report of this Council entitled, “Labeling of Prescription Drug Containers for Generic-Substituted Drugs” (CSA Report 2, I-99), it was recognized that the potential also exists for patient confusion when a generic drug is substituted for a brand name drug, or when a pharmacist changes the manufacturer of the generic drug during a refill. For example, the drug names (brand vs. generic) and/or the color, shape, and markings of solid oral dosage forms may be different.23 AMA Policy H-115.974 (see above) has two recommendations that are intended to minimize this problem. State generic substitution laws allow physicians to designate “Do Not Substitute” (or a comparable phrase or designation) on a prescription, thus allowing the physician to decide if a generic drug product can be substituted. AMA Policy H-115.974(1) recommends that physicians exercise this authority and clearly designate their preference when prescribing multisource drugs where alternative generic products are available. AMA Policy H-115.974(4) also discourages pharmacies from changing generic manufacturers when any generic prescription is refilled, and it lays out recommendations for pharmacists to educate patients if this cannot be avoided. Because of the potential for a disastrous outcome if there is a problem with the generic substitution of an NTI drug, these recommendations are especially applicable.
Conclusion
Generic drugs are significantly less expensive than brand name innovator drugs and provide an opportunity to reduce spending on pharmaceuticals in the United States. While physicians should be free to use either the generic or brand name in prescribing drugs for their patients, physicians should supplement medical judgments with cost considerations in making this choice (AMA Policy H-125.984).
As previously discussed in CSA Report 6 (A-02), the criteria used by the FDA to ensure bioequivalence among multisource drug products are widely misunderstood. These criteria do not allow for -20% to +25% difference in bioavailability between products. Rather, these parameters represent the statistical universe in which measures of variance must reside. In practice, the mean differences in pharmacokinetic parameters for most orally administered generic drug products are closer to 3% or 4%.1,7,8
The FDA is confident that its methodology for approving generic drugs, including NTI drugs, is adequate to establish therapeutic equivalence. The Agency has claimed it cannot document a single example of therapeutic failure when an FDA-designated therapeutically equivalent product was substituted for its reference (brand name innovator) product.1,6 Furthermore, the same criteria for bioequivalence are applied to brand name products when they undergo formulation changes. Like generic drugs, these reformulated brand name products are never tested in a clinical population.
While concerns still persist among some physicians about the therapeutic equivalence of generic NTI drugs to their brand name innovator products, scientific evidence to support these concerns either does not exist or is extremely weak. In large part, studies reviewed and cited in this report suggest “AB-rated” generic NTI drugs were bioequivalent to their brand name innovator products in patients with diseases for which the drugs are indicated. Theoretical assumptions of the possibility of inequivalence are not a sufficient basis for presuming its presence and acting on that assumption. Anecdotal reports are similarly unhelpful, since one is often unable to distinguish product failure from a natural change in disease process or patient response. Consistent with current AMA Policy H-120.984, however, physicians should continue to report serious adverse events that may be related to generic substitution to the FDA’s MedWatch program, and the FDA should continue to pursue research to ensure the methodology to determine bioequivalence is optimal.
Given the present evidence on the therapeutic equivalency of all FDA “A-rated” drugs, including those with a narrow therapeutic range, the prescribing physician should be able to decide whether a specific brand or generic drug product is most appropriate for the individual patient. Consistent with state laws, third-party payers should not substitute a generic for brand name drug unless it has been authorized by the prescribing physician. As stated in current AMA Policy H-115.994, when a prescription for a generic drug product is refilled (eg, for a patient with a chronic disease), changing the manufacturer should be discouraged, whenever possible, to avoid confusion for the patient.
For many drugs, especially those with a narrow therapeutic range, therapeutic drug concentration or pharmacodynamic monitoring is necessary to assure the desired clinical response. Such monitoring is necessary irrespective of whether the drug is a brand name or generic product.
In addition, patients must receive adequate education to be able to fully understand the nature and proper use of their medications. As described in current AMA Policy H-115.974, this should include appropriate education from the pharmacist if the generic drug manufacturer is changed when the prescription is refilled.
RECOMMENDATIONS
The following statements, recommended by the Council on Science and Public Health, were adopted by the AMA House of Delegates as AMA policy and directives at the 2007 AMA Annual Meeting:
-
The AMA reaffirms Policies H-125.984 and H-115.974. (Reaffirm Policy)
-
The AMA will inform the Centers for Medicare and Medicaid Services, America’s Health Insurance Plans, the Pharmaceutical Care Management Association, the National Association of Boards of Pharmacy, the National Association of Chain Drug Stores, the National Community Pharmacists Association, and the American Pharmacists Association about AMA Policies H-125.984 and H-115.974, and the AMA urges these payer and pharmacy organizations to support these AMA policies. (Directive)
CSAPH home page
Reports by topic
References (PDFs require Adobe® Reader®)
1. Generic drugs. Report 6 of the Council on Scientific Affairs. American Medical Association. (June)2002. Available at: http://www.ama-assn.org/ama/pub/category/15279.html. Accessed March 7, 2007.
2. Generic Pharmaceutical Association. Statistics. 2007. Available at: http://www.gphaonline.org/Content/NavigationMenu/AboutGenerics/
Statistics/default.htm. Accessed March 7, 2007.
3. Centers for Medicare and Medicaid Services. Part D performance data. 2007. Available at: http://www.cms.hhs.gov/PrescriptionDrugCovGenIn/
06_PerformanceData.asp. Accessed March 7, 2007.
4. Food and Drug Administration. Approved Drug Products with Therapeutic Equivalence Evaluations(27th edition). 2007. Available at: http://www.fda.gov/cder/orange/obannual.pdf
(PDF, 7.1 MB). Accessed March 7, 2007.
5. Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. (March) 2003. Available at: http://www.fda.gov/cder/guidance/5356fnl.pdf (PDF, 168 KB). Accessed March 7, 2007.
6. Letter from Jane E. Henney, MD, Commissioner, Food and Drug Administration to E. Ratcliffe Anderson, Jr., MD, Executive Vice President and Chief Executive Officer, American Medical Association. June 27, 2000.
7. Nightingale SL, Morrison JC. Generic drugs and the prescribing physician. JAMA. 1987;258:1200-1204.
8. Henney JE. Review of generic bioequivalence studies. JAMA. 1999;282:1995.
9. American Academy of Neurology. Position Statement on the Coverage of Anticonvulsant Drugs for the Treatment of Epilepsy. November, 2006.
10. American Association of Clinical Endocrinologists, The Endocrine Society, and American Thyroid Association. Joint Position Statement on the Use and Interchangeability of Thyroxine Products. 2007. Available at: http://www.aace.com/pub/pdf/guidelines/
AACE-TES-ATA-ThyroxineProducts.pdf (PDF, 59 KB). Accessed March 7, 2007.
11. Burkhardt RT, Leppik IE, Blesi K, et al. Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology. 2004;63:1494-1496.
12. Sauro SC, DeCarolis DD, Pierpont GL, Gornick CC. Comparison of plasma concentrations for two amiodarone products. Ann Pharmacother. 2002;36:1682-1685.
13. Milligan PE, Banet GA, Waterman AD, et al. Substitution of generic warfarin for Coumadin in an HMO setting. Ann Pharmacother. 2002;36:764-768.
14. Witt DM, Tillman DJ, Evans CM, et al. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy. 2003;23:360-368.
15. Roza A, Tomlanovich S, Merion R, et al. Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation. Transplantation. 2002;74:1013-1017.
16. Carnahan W, Cooper TY. Neoral-to-Gengraf conversion in renal transplant recipients. Transplant Proc. 2003;35:1308-1313.
17. Qazi YA, Forrest A, Tornatore K, Venuto RC. The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function. Clin Transplant. 2006;20:313-317.
18. Taber DJ, Baillie GM, Ashcraft EE, et al. Does bioequivalence between modified cyclosporine formulations translate into equal outcomes? Transplantation. 2005;80:1633-1635.
19. Institute of Medicine. Preventing Medication Errors. Washington, DC: National Academies Press; 2006.
20. Physician education of their patients about prescription medicines. Report 2 of the Council on Scientific Affairs. American Medical Association. (December)1998. Available at: http://www.ama-assn.org/ama/pub/category/13610.html. Accessed March 7, 2007.
21. Field TS, Mazor KM, Briesacher B, et al. Adverse drug events resulting from patient errors in older adults. J Am Geriatr Soc. 2007;55:271-276.
22. Davis TC, Wolf MS, Bass PF, et al. Literacy and misunderstanding prescription drug labels. Ann Intern Med. 2006;145:887-894.
23. Labeling of prescription drug containers for generic-substituted drugs. Report 2 of the Council on Scientific Affairs. American Medical Association. (December) 1999. Available at: http://www.ama-assn.org/ama/pub/category/13550.html. Accessed March 7, 2007.
Resolution 527, introduced by the Georgia Delegation at the 2006 Annual Meeting and referred to the Board of Trustees, asked:
That the American Medical Association (AMA) adopt a policy in support of the Centers for Medicare and Medicaid Services prohibiting any substitutions of a prescribed medication with a narrow therapeutic index with another manufacturer’s form of the same medication with a narrow therapeutic index on a Medicare Part D Prescription Plan chosen by the patient, without first submitting written notification of such change by the formulary to the patient and the prescribing physician; and
That the AMA request the Centers for Medicare and Medicaid Services produce guidelines prohibiting any substitution of physician prescribed medications with a narrow therapeutic index, as defined using the [Food and Drug Administration] requirements, from a certain manufacturer to any other manufacturer’s form of that medication on a Medicare Part D Prescription Plan, without first submitting written notification of such change by the formulary to the patient and the prescribing physician.
CSAPH home page
Reports by topic
Content provided by: CSAPH