E-drug: generic substitution
---------------------------------------------
WARNING: LONG MESSAGE
I have copied the following from a recent posting on Medscape under the fair
use rules because of recent discussion re generics.
I guess that the conclusions only apply to the USA but may be of interest
elsewhere.
NOTE: To view the article with Web enhancements, go to:
http://www.medscape.com/SMA/SMJ/2001/v94.n01/smj9401.03.hend/smj9401.0
3.hend-01.html.
Generic Substitution: Issues for Problematic Drugs
James D. Henderson, PhD, RPh, Richard H. Esham, MD, Department of Physician
Assistant Studies, College of Allied Health Professions, and the Division of
General Internal Medicine and Geriatrics, University of South Alabama
College of Medicine, Mobile.
[South Med J 94(1):16-21, 2001. � 2001 Southern Medical Association]
Abstract
The methodology and criteria for bioequivalence testing have been firmly
established by the Food and Drug Administration (FDA). For certain drugs
with a narrow therapeutic index (eg, digoxin, levothyroxine, warfarin),
generic substitution may not be advisable or even allowable, depending on
the substitution laws of individual states. Digoxin and levothyroxine
tablets are examples of drugs for which no New Drug Applications (NDAs)
currently exist. However, commercially available generic products for both
of these drugs have not been determined by the FDA to be therapeutically
equivalent to the innovator products. Generic versions of warfarin have been
approved by the FDA as being therapeutically equivalent to the innovator
products, as have generic versions of the rescue inhaler albuterol. Yet,
misinformation and myths persist regarding the adequacy and proven
reliability of the FDA's determination of bioequivalence for these products.
Introduction
Since the passage of the Drug Price Competition and Patent Term Restoration
Act in 1984, commonly known as the Waxman-Hatch Act, a virtual
explosion has occurred in the number of Abbreviated New Drug
Applications (ANDAs)
submitted to the FDA from generic drug sponsors seeking approval for generic
drugs.[1] In 1980, the FDA first published a list of approved drugs,
consisting of innovator drugs approved through the NDA process and the
generic products considered by the FDA to be therapeutically equivalent to
these innovator products. The Waxman-Hatch Act mandated that the FDA
continue to publish this list of Approved Drug Products With Therapeutic
Equivalence Evaluations, referred to as the Orange Book.[2] As of September
1999, a total of 9,939 approved drugs were listed, with 6,923 of these as
multisource products, including innovator products and their therapeutically
equivalent generic versions. With so many generic drugs available,
practitioners should be aware of some drugs for which generic substitution
is either not advisable or is the subject of current controversy. In this
article, we describe certain drugs and conditions in which authorization of
generic substitution is either controversial or should not occur.
Background
Table 1 shows the system used by the FDA for rating the therapeutic
equivalence of approved drugs, Drugs that are solid oral dosage forms
(suspensions, capsules, tablets) and have been determined by the FDA to be
therapeutically equivalent are rated "AA" or "AB." If drugs are rated to be
therapeutically equivalent, then they may be generically substituted for
each other with the assurance of efficacy and safety. The procedures used by
the FDA for approval of generic drugs have been described and
recommendations made regarding generic substitution.[3-6] However,
there are widely used and significant drugs for which the
appropriateness of generic
substitution should be examined. Four such drugs are described in this paper.
Digoxin
Digoxin in tablet form is not listed in the Orange Book, since this is a
"grandfathered" dosage form of digoxin.[7] Since the tablet formulation of
digoxin was established in clinical use before passage of the Federal Food,
Drug, and Cosmetic Act of 1938, generic versions of digoxin tablets may be
marketed without an approved ANDA. Data showing bioequivalence of generic
digoxin tablet products to the innovator product Lanoxin are generally not
available or forthcoming, so that comparable rate and extent of absorption
between generic products and Lanoxin brand tablets, or between different
generic products, is not ensured.[8] Seventeen generic digoxin tablets (0.25
mg) have been listed as currently marketed, though some of these may be
marketed by suppliers or distributors of another manufacturer's product.[9]
Without pharmacokinetic data to verify the bioequivalence of these products
to Lanoxin, the clinical responses (both therapeutic and toxic) from these
generic products compared with Lanoxin are unpredictable. This inability to
guarantee therapeutic equivalence to a reference product opposes the entire
premise of generic substitution: the practitioner should expect the same
responses (no more, no less) from a therapeutically equivalent generic
product. Consequently, generic substitution is not advised. Use of a generic
digoxin product as initial therapy may result in lower or higher than
expected bioavailability, requiring additional monitoring and dosage
adjustment, and ultimately increasing costs of therapy far above the cost
savings from a less expensive generic product.
Levothyroxine
Levothyroxine sodium tablets are also currently not listed in the Orange
Book. In the words of the FDA, "Levothyroxine sodium was first introduced
into the market before 1962 without an approved NDA, apparently in the
belief that it was not a new drug."[10] The lack of bioequivalence data of
generic preparations to the two major brand name products Synthroid and
Levothroid has been noted, along with the adoption in 1984 of United States
Pharmacopoeia (USP) guidelines for potency of levothyroxine sodium
tablets.[11] However, between 1987 and 1994, a total of 58 adverse drug
experience reports with levothyroxine sodium tablets were received by the
FDA, with 47 of the incidences apparently related to subpotency and 9
incidences related to superpotency.[10] These adverse events were caused not
only by switching product brands, but also by inconsistencies in
bioavailability between different lots from the same source.[10]
Bioequivalence issues regarding levothyroxine sodium tablets were
highlighted when the results of a bioequivalence study comparing the
innovator product Synthroid with several generic brands finally appeared in
the literature.[12] The study sponsor (the marketer of Synthroid) attempted
to prevent publication of these results, which claimed bioequivalence of
Synthroid to three other levothyroxine sodium products. After publication of
these study results, advertisements appeared in journals and trade magazines
advocating the substitution of other brand-name levothyroxine sodium
products (eg, Levothroid, Levoxyl) for Synthroid. In addition, statements
were made such as "Feel comfortable using Levothroid, Levoxyl, or Synthroid
in hypothyroid patients. These three are bioequivalent...even though they're
not AB-rated."[13]
Several points should be considered before routinely switching marketed
brands of levothyroxine sodium tablets (at least 24 products for the 0.1 mg
tablet are listed).[9] First, although the conclusions stated in the
peer-reviewed bioequivalence study cited appear to be generally accepted,
the results of this study were not subjected to the scrutiny of the FDA
review process. In view of significant stability and potency problems, the
FDA has issued a Federal Register notice stating that (1) orally
administered levothyroxine sodium products are now considered new drugs, and
(2) manufacturers who intend to continue marketing these products must
submit an NDA within 3 years to obtain approval.[10] Recently, the FDA
extended this deadline for an additional year.[14] Second, the impression
that all levothyroxine sodium tablet formulations are likely to be
bioequivalent is not currently supported with FDA-substantiated
bioequivalence data; routine substitution of these products for refills of
existing prescriptions is not advisable until FDA review is complete. Third,
practitioners must always comply with the substitution laws in their
individual states. If a statute mandates substitution of a therapeutically
equivalent or bioequivalent product, reliance upon data reported in the
scientific literature may not always guarantee these requirements will be
satisfied.
Warfarin Sodium
Three approved generic versions of warfarin sodium tablets (seven strengths)
are currently listed in the Orange Book. Before approval of these generic
warfarin sodium products, several states either enacted or were considering
legislation to require pharmacists to obtain prescriber and patient approval
for generic substitution of drugs with a narrow therapeutic index
(NTI).[15,16] In response, the FDA issued a position statement.[17] The
FDA's position is clear with regard to the issue of tightening confidence
intervals (CIs) and changing study designs for bioequivalence determinations
of NTI drugs: "To date, we have not seen data to support such proposed
changes."[17] In addition, Benet has stated: "I believe that the present
requirements to prove bioequivalence, at least in the United States and
Canada, are already so difficult and constrained that there is no
possibility, even for narrow therapeutic index drugs, that dosage forms
meeting the criteria could lead to therapeutic problems."[18] Benet notes
that drugs approved through the NDA process with NTIs, by definition, must
have low intrasubject variability. Otherwise, patients would have cycles of
toxicity and lack of efficacy, and therapeutic drug monitoring would be
useless.[19] The low intrasubject variability associated with NTI drugs
ensures that patient response to a specific drug should be consistent, and
the statistical criteria required by the FDA for bioequivalence appear more
than adequate for confidence in generic substitution. This is especially
true in light of the notable absence of data that prove otherwise. For the
most part, the arguments against generic substitution of NTI drugs appear to
be based on economic considerations.
Commentaries debating the suitability of generic warfarin products have
focused on the results from reports of clinical studies with generic
warfarin and the content uniformity requirements for warfarin sodium
tablets.[20,21] As indicated in a letter addressing these issues, no
convincing and substantiated scientific data have been published showing
bioinequivalence of generic warfarin products or product failure of these
products in clinical studies.[22] Recently, an evidence-based medicine
approach was used to compare the results reported with Coumadin and a
generic warfarin product in clinical studies.[23] No significant differences
were found in the international normalized ratio (INR), number of dosage
changes to adjust INR in range, or number of hospitalizations or incidences
of bleeding between the reference and generic warfarin products. Physicians
may sometimes encounter difficulties in maintaining stabilized INR in
patients anticoagulated with warfarin, since "multiple drug interactions and
patient variables affect warfarin levels and create difficulty in achieving
consistently therapeutic INR values."[24] However, factors such as diet,
concurrent illnesses, interacting drugs, and noncompliance are intersubject
variables that are unrelated to the bioequivalence issue.[25] For crossover
studies using log-transformed data, "it is largely the within-subject
distribution of values [intrasubject variability] that determines the
validity and efficiency of the standard parametric methods of analysis."[26]
For NTI drugs such as warfarin, intrasubject variability, by definition, is
low and the available clinical data indicate that lack of bioequivalence
does not appear to be the explanation for problems experienced during
warfarin therapy.
Another article introduces the concept of "switchability," that is, the
substitution of one approved generic product for another generic
product.[27] Bioequivalence studies submitted to the FDA through an ANDA are
conducted by comparing data from the proposed generic product and a
reference product. The reference product is selected by the FDA and is
typically the innovator or pioneer product that was originally introduced
into the market. Suppose approved generic product A differed from the
reference product in at least one parameter (eg, mean area-under-the-curve
[AUC] values) by +4%, and that approved generic product B differed from the
reference product by -4%. The net difference of generic products A and B
would then be 8%; could this magnitude of difference result in
bioinequivalence and lack of equivalent therapeutic response for an NTI
drug?
No data were presented from any clinical studies that could support the
contention that switchability for NTI drugs is problematic. Rather, phrases
such as "...with NTI drugs, small variations in bioavailability can
potentially pose problems" and conceptual arguments are used to suggest the
need for special bioequivalence criteria to be applied to NTI drugs.[27]
Reference is made to the FDA's draft guidance for population and individual
bioequivalence studies, which proposes the use of reference scaling
(essentially, modifying the bioequivalence criteria to account for the
variability of the reference product) for NTI drugs, regardless of the
intrasubject variability of the reference product.[28] Since NTI drugs have
low intrasubject variability as discussed, this approach would likely result
in narrower CI requirements. However, as noted by Benet "...tightened
bioequivalence intervals [for NTI drugs] can be readily met with a
reasonable number of subjects."[19]
Finally, a recent report further confirms the bioequivalence of generic
warfarin to the innovator product.[29] More than 100 subjects anticoagulated
with Coumadin were switched to a generic warfarin product for 8 weeks in a
nonrandomized comparative clinical observational study. The overall
conclusion was that the variability in INR in patients receiving generic
warfarin was not statistically significant from that seen in the control
group receiving Coumadin. These investigators identified associated factors
not related to the product change in subjects whose INR varied by >1.0 from
baseline. This further emphasizes the critical role of interpatient factors
(physical activity, dietary vitamin K, noncompliance, drug interactions,
congestive heart failure, diarrhea, alcohol consumption) affecting the
anticoagulant response with warfarin.
Albuterol Metered-Dose Inhalers
Four approved generic versions of albuterol metered-dose inhalers are
currently listed in the Orange Book as therapeutically equivalent (AB-rated)
to the reference product Ventolin. The Proventil product is rated BN, or not
therapeutically equivalent to Ventolin or the four generic products. For
products administered by metered-dose inhalation and intended for local
therapeutic effects, the typical pharmacokinetic methods (Table 2) for
evaluating bioequivalence cannot be used. Rather, an approach based on acute
pharmacodynamic response (forced expiratory volume in 1 second, FEV1) was
proposed, with asthmatic patients as subjects.[5] The statistical criteria
and appropriate CIs for bioequivalence determination are not as rigidly
defined for pharmacodynamic methods as for pharmacokinetic methods.
Consequently, variability in patient response may be of slightly greater
concern, since albuterol metered-dose inhalers are used as "rescue inhalers"
for nocturnal asthma attacks (even though they are not considered NTI
drugs). However, the FDA is satisfied that these products will produce
equivalent therapeutic responses.
Discussion
The fundamental principles underlying the concept of bioequivalence and the
process of generic substitution can be summarized as follows:
Generic substitution is based on the premise of therapeutic equivalence;
that is, the generic product will produce the exact same clinical effects
(both therapeutic and toxic) as the reference product when administered
under the same conditions in the same dosage in the same patient.
When authorizing generic substitution, the practitioner expects therapeutic
equivalence between the generic product and the reference product;
therefore, no dosage adjustment or additional monitoring should be required
(above and beyond that which would normally occur with the reference
product).
Products that are bioequivalent will be therapeutically equivalent.
Bioequivalence is assessed by comparison of bioavailability parameters
(Table 2).
It is apparent that the key step in this process is the determination of
bioequivalence; the following discussion describes the development of the
FDA's criteria for bioequivalence.
The science of bioequivalence testing originated in the early 1970s from the
necessity for regulatory guidelines that could be used to declare drug
products to be bioequivalent. Originally, it was believed that orally
administered products (suspensions, capsules, tablets) whose average
bioavailability parameters differed by less than 20% should be
therapeutically equivalent. The shortcomings of this approach were
immediately evident, since such a criterion would theoretically allow the
parameters of generic product A to differ from the reference (innovator)
product by +20%, while allowing the parameters of generic product B to
differ from the reference product by -20%. The net difference between the
two generic products A and B would then be as much as 40% and, therefore,
beyond the limits of therapeutic equivalence as originally conceived. To
correct for this deficiency, the FDA adopted the "power" approach in the
early 1980s. This method tested the null hypothesis (H0) that the generic
and reference products were identical, and it evaluated the power of the
bioequivalence study to detect a 20% difference between the means of the
parameters. If the differences between the mean values of parameters for the
two products were not statistically significant (P > .05), and the study
power was at least 80%, the products were declared bioequivalent.
However, the power approach had a major flaw because it tested the
assumption of identical performance from products that were already known
not to be identical. Clearly, the formulations of the reference and generic
products are not identical, and differences in the extent and rate of
gastrointestinal absorption are expected to occur. Therefore, it was
concluded that the statistical test of no difference between the products
was not the proper bioequivalence assessment. In 1986, the FDA adopted the
currently used decision rule, which tests the more relevant alternative
hypothesis (H1). This approach asks: (1) how great are the differences
between the generic and reference products? and (2) more specifically, are
these differences within limits that would still guarantee bioequivalence
and therefore therapeutic equivalence? The determination of bioequivalence
using this approach is termed "average bioequivalence."[30]
The statistical method for the average bioequivalence assessment is termed
the "two 1-sided tests" procedure. Typically, the data from a single-dose,
2-way crossover bioavailability study are analyzed using a complex
statistical model that allows evaluation of the least squares means of the
bioavailability parameters and their standard errors. These results are then
used to construct the 90% CI for the differences in parameter means. A 90%
CI is used, since a 5% statistical error is allowed at both the upper and
the lower limits; therefore, the total error is 10%, generating the 90% CI.
When the current rule was adopted in 1986, if both the upper and lower
limits of the CI were within 20% of the reference mean (80% to 120%), the
generic product was declared bioequivalent to the reference product. In
1992, the FDA issued a guidance in which the use of log-transformed data and
an upper limit of 125% were adopted. These criteria remain the current rule
for bioequivalence decisions.[26]
A recent article underscores the misinformation that persists regarding the
FDA criteria for generic drug approval. The article states: "Only 17% of 396
physicians were aware that FDA allows the rate and extent of absorption of a
generic drug product to depart from those of the brand-name version by up to
25%. . ."[31] "The determination of average bioequivalence is made by
calculating the 90% confidence interval (CI) for the difference between
generic and reference products and by requiring that the entire CI lie
completely within the lower and upper limits which define bioequivalence.
Currently, these limits are 80-125% of the reference product mean value
using data after logarithmic transformation."[6] Using these statistical
criteria, it is difficult for any generic product whose mean arithmetic
bioavailability parameters differ by more than 10% from the reference to
meet the CI requirements, and it is virtually impossible to meet the CI
requirements if the differences approach 20%. "A generic product that truly
differs by -20%/+25% or more from the innovator product with respect to one
or more pharmacokinetic parameters would actually have less than a 5% chance
of being approved."[2] An FDA study showed that the mean difference for AUC
values between test and reference products was 3.5% in the 2-year period
following the Waxman-Hatch Act, and that 80% of the absolute differences
between generic products approved since 1984 and the corresponding innovator
products were within 5%.[32]
Conclusion
The FDA has issued a statement to medical organizations and state boards of
pharmacy in response to certain groups who have raised the issue of generic
substitution of NTI products.[17] Two of the most important points are that
(1) to date, there are no documented examples of failure of a generic drug
due to bioequivalence determination; and (2) products declared as
bioequivalent should not require any additional clinical testing or
monitoring. For the three NTI drugs discussed, we support the substitution
of AB-rated generic versions of warfarin sodium tablets, recommend against
generic substitution for Lanoxin brand tablets, and advise caution against
generic substitution of levothyroxine sodium tablets until the FDA declares
these products to be AB-rated to the corresponding reference products.
Finally, we recommend substitution of AB-rated generic versions of albuterol
metered-dose inhalers.
On August 22, 2000, the FDA approved the first NDA for an oral levothyroxine
sodium product, Unithroid (Jerome Stevens Pharmaceuticals, Bohemia, NY).
Reprint requests to James D. Henderson, PhD, RPh, University of South
Alabama, Department of Physician Assistant Studies, SHAC 4410, 1504
Springhill Ave, Mobile, AL 36604.
Table 1. Therapeutic Equivalence Codes[2]
Rating Comments
A Drug products that FDA considers to be therapeutically equivalent to other
pharmaceutically equivalent products because either there are no known or
suspected bioequivalence problems, or bioequivalence problems have been
resolved with in vivo or in vitro data confirming bioequivalence
AA Products in conventional dosage forms not presenting bioequivalence
problems
AB Products meeting necessary bioequivalence requirements
AN Solutions and powders for aerosolization
AO Injectable oil solutions
AP Injectable aqueous solutions and, in certain instances, intravenous
nonaqueous solutions
B Drug products that FDA, at present, considers not to be therapeutically
equivalent to other pharmaceutically equivalent drug products
BC Extended release dosage forms (capsules, injectables, and tablets)
BD Active ingredients and dosage forms with documented bioequivalence
problems
BE Delayed-release oral dosage forms
BN Products in aerosol-nebulizer drug delivery systems
BP Active ingredients and dosage forms with potential bioequivalence
problems
BR Suppositories or enemas that deliver drugs for systemic absorption
BS Products having drug standard deficiencies
BT Topical products with bioequivalence issues
BX Drug products for which data are insufficient to determine therapeutic
equivalence
B Drug products requiring further FDA investigation and review to determine
therapeutic equivalence
FDA = Food and Drug Administration.
Table 2. Bioavailability Parameters for Assessment of Bioequivalence
Parameter Measurement
Area under the curve (AUC) Total area enclosed by the plasma
concentration-time curve; measures the amount of drug reaching the systemic
circulation and is directly proportional to the amount of drug absorbed
Peak concentration (CMAX) Maximum drug concentration observed in the plasma;
value is dependent on specific sampling times after dosing
Peak time (TMAX) Time after dosing at which the maximum drug concentration
is observed; value is dependent on specific sampling times
AUC is determined by collecting serial blood samples at designated times
after subjects have received the drug formulation (innovator or generic).
Times of collection are based on knowledge of the drug's pharmacokinetic
behavior such that a sufficient number of data points are obtained that
define the absorption phase (from time = 0 to time = TMAX) and the
elimination phase (from time = TMAX to a time point representing at least 3
elimination half-lives, allowing estimation of the elimination rate
constant). AUC is calculated using the "trapezoidal rule." Each pair of
consecutive data points (eg, c1, t1 and c2, t2) is used to form a trapezoid
from which the area is calculated with the geometric formula for a
trapezoid. These areas are summed to give the total AUC, referred to as the
AUC0-t. An additional measurement of AUC extrapolated to infinity (AUCinf)
is obtained by adding the term clast/kel to AUC0-t, where clast is the last
measured concentration and kel is the estimated elimination rate constant.
Both parameters AUC0-t and AUCinf are termed "model-independent" or
"noncompartmental," since they are not affected by the specific
pharmacokinetic model for the drug's entry and passage from the body.
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regards,
Peter
Dr Peter Mansfield
Director, MaLAM (Medical Lobby for Appropriate Marketing)
peter.mansfield@flinders.edu.au
www.malam.asn.au
PO Box 172 Daw Pk SA 5041 Australia
ph/fax +61 8 8374 2245
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