Pharmacokinetics

The Journal of Clinical Pharmacology

Bioequivalence Study Designs for Generic Solid 53(12) 1252–1260
© 2013, The American College of
Oral Anticancer Drug Products: Scientific and Clinical Pharmacology
DOI: 10.1002/jcph.163
Regulatory Considerations

Paramjeet Kaur, PhD, Chandra S. Chaurasia, PhD, Barbara M. Davit, PhD, JD,
and Dale P. Conner, PharmD

Abstract
The demonstration of bioequivalence (BE) between the test and reference products is an integral part of generic drug approval process. A sound BE
study design is pivotal to the successful demonstration of BE of generic drugs to their corresponding reference listed drug product. Generally, BE of
systemically acting oral dosage forms is demonstrated in a crossover, single‐dose in vivo study in healthy subjects. The determination of BE of solid oral
anticancer drug products is associated with its own unique challenges due to the serious safety risks involved. Unlike typical BE study in healthy subjects,
the safety issues often necessitate conducting BE studies in cancer patients. Such BE studies of an anticancer drug should be conducted without disturbing
the patients’ therapeutic dosing regimen. Attributes such as drug permeability and solubility, pharmacokinetics, dosing regimen, and approved
therapeutic indication(s) are considered in the BE study design of solid anticancer drug products. To streamline the drug approval process, the Division of
Bioequivalence posts the Bioequivalence Recommendations for Specific Products guidances on the FDA public website. The objective of this article is to
illustrate the scientific and regulatory considerations in the design of BE studies for generic solid oral anticancer drug products through examples.

Keywords
anticancer, bioequivalence, generics, guidances, pharmacokinetics

In the United States, cancer is the second most common
cause of death, accounting for nearly one‐fourth of all
deaths.1 Traditionally, the parenteral route of administra-
tion has been the standard in oncologic treatment. With the
increase in the number of available solid oral anticancer
dosage formulations, use of the oral route is increasing
mainly because of practical convenience such as, ease of
administration and reduced ambulatory care visits.2,3
As of April 2013, the United States Food and Drug
Administration (U.S. FDA) has approved 51 innovator
oral anticancer drugs (Table 1) through the New Drug
Application (NDA) pathway.4–7 The Drug Price Compe-
tition and Patent Restoration Act (Hatch–Waxman
Amendment) of 1984 created section 505(j) of the Federal
Food, Drug, and Cosmetic Act, which established the
current Abbreviated New Drug Application (ANDA)
approval process.8 To date, the FDA has approved generic
equivalents for a total of 14 innovator oral anticancer
drugs under the provision of 505(j). The difficulties
associated with conducting BE studies may partly be the
reason for the limited number of generic solid oral
anticancer drug products.
BE as defined in the U.S. Code of Federal Regulations
(21 C.F.R. Part 320.1), refers to the absence of a
significant difference in the rate and extent to which the
active ingredient or active moiety in pharmaceutical
equivalents or pharmaceutical alternatives becomes
available at the site of drug action when administered at
the same molar dose under similar conditions in an
appropriately designed study.9 Generally, the BE of a
systemically acting generic oral dosage form and its
corresponding reference listed drug product (reference) is
demonstrated in single‐dose, two‐way crossover in vivo
BE studies in healthy subjects, with measurement of active
ingredient or active moiety in an appropriate biological
fluid, commonly blood plasma. The maximum plasma
drug concentration (Cmax) and area under the plasma
concentration versus time curve (AUC) are used as an
index of the rate and extent of drug absorption,
respectively. The test and reference products are consid-
ered to be bioequivalent if the 90% confidence interval
(CI) of the geometric mean test/reference ratio of Cmax
and AUC fall within the limits of 80–125%.10,11 The
determination of BE of solid oral anticancer drug products
is associated with its own unique challenges due to the
Division of Bioequivalence, Office of Generic Drugs, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration, Rock-
ville, MD, USA
Submitted for publication 8 May 2013; accepted 13 August 2013.
Corresponding Author:
Paramjeet Kaur, Division of Bioequivalence, Office of Generic Drugs,
Center for Drug Evaluation and Research, U.S. Food and Drug
Administration, Rockville, MD 20852, USA
Email: paramjeet.kaur@fda.hhs.gov
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Kaur et al 1253

Table 1. FDA Approved Oral Anticancer Drug Products4–7

Generic
Oral Cytotoxic Year Original Equivalent
Brand (United States Dosage Agent NDA Approved Available
Adopted Name) Form (Yes/No) by FDA (Yes/No) FDA Approved Indication(s) From Product Labeling

Afinitor® (Everolimus) Tablet No 2009 No Neuroendocrine tumors of pancreatic origin, renal cell
carcinoma, breast cancer, renal angiomyolipoma with
tuberous sclerosis complex (TSC), subependymal giant cell
astrocytoma (SEGA) with TSC
Alkeran® (Melphalan) Tablet Yes 1964 No Multiple myeloma and epithelial carcinoma of the ovary
Arimidex® (Anastrozole) Tablet No 1995 Yes Breast cancer
Aromasin® (Exemestane) Tablet No 1999 Yes Breast cancer
Bosulif® (Bosutinib) Tablet No 2012 No Chronic, accelerated, or blast phase Philadelphia
chromosome‐positive (Phþ) chronic myelogenous
leukemia (CML)
Casodex® (Bicalutamide) Tablet No 1995 Yes Prostate cancer
Caprelsa® (Vandetanib) Tablet No 2011 No Medullary thyroid cancer
CeeNU® (Lomustine) Capsule Yes 1976 No Brain tumors, Hodgkin’s disease
Cometriq® (cabozantinib) Capsule No 2012 No Medullary thyroid cancer
Cytoxan® (Cyclophosphamide) Tablet Yes 1959 Yes Malignant lymphomas, Hodgkin’s disease, multiple myeloma,
leukemia’s, mycosis fungoides, neuroblastoma, ovarian
cancer, retinoblastoma, breast cancer, nephrotic
syndrome
Hydrea® (Hydroxyurea) Capsule Yes 1967 Yes Melanoma, myelocytic leukemia, ovarian cancer, primary
squamous cell carcinomas of the head and neck
Emcyt® (Estramustine) Capsule Yes 1981 No Prostate cancer
Eulexin® (Flutamide) Capsule No 1989 Yes Prostate cancer
Erivedge® (Vismodegib) Capsule No 2012 No Basal cell carcinoma
Fareston® (Toremifene) Tablet No 1997 No Breast cancer
Femara® (Letrozole) Tablet No 1997 Yes Breast cancer
Gleevec® (Imatinib) Tablet No 2003 No Phþ chronic myeloid leukemia, gastrointestinal stromal
tumors
Hexalen® (Altretamine) Capsule Yes 1990 No Ovarian cancer
Hycamtin® (Topotecan) Capsule Yes 2007 No Small cell lung cancer
Iclusig® (Ponatinib) Tablet No 2012 No Chronic myeloid leukemia, Phþ ALL
Inlyta® (Axitinib) Tablet No 2012 No Advanced renal cell carcinoma
Leukeran® (Chlorambucil) Tablet Yes 1957 No Chronic lymphatic leukemia, malignant lymphomas
Lysodren® (Mitotane) Tablet Yes 1970 No Adrenal cortical carcinoma
Matulane® (Procarbazine) Capsule Yes 1969 No Hodgkin’s disease
Megace® (Megestrol) Tablet Yes 1971 Yes Carcinoma of the breast or endometrium
Myleran® (Busulfan) Tablet Yes 1954 No Chronic myelogenous leukemia
Nexavar® (Sorafenib) Tablet No 2005 No Hepatocellular and renal cell carcinoma
Nilandron® (Nilutamide) Tablet No 1999 No Prostate cancer
Nolvadex® (Tamoxifen) Tablet No 1977 Yes Breast cancer, ductal carcinoma in situ
Pomalyst® (Pomalidomide) Capsule No 2013 No Multiple myleoma
Purinethol® (Mercaptopurine) Tablet Yes 1953 Yes Acute lymphatic leukemia
Revlimid® (Lenalidomide) Capsule No 2005 No Multiple myeloma, myelodysplastic syndromes
Trexall® (Methotrexate)a Tablet Yes 2001 Yes Neoplastic diseases, psoriasis, rheumatoid arthritis
Sprycel® (Dasatinib) Tablet No 2006 No Chronic myeloid leukemia, Phþ CML, Phþ acute
lymphoblastic leukemia
Stivarga® (Regorafenib) Tablet No 2012 No Metastatic colorectal cancer, gastrointestinal stromal tumor
Sutent® (Sunitinib) Capsule No 2006 No Gastrointestinal stromal tumor, renal cell carcinoma,
pancreatic neuroendocrine tumors
Tabloid® (Thioguanine) Tablet Yes 1966 No Acute nonlymphocytic leukemias, chronic myelogenous
leukemia
Tarceva® (Erlotinib) Tablet No 2004 No Non‐small cell lung cancer, pancreatic cancer
Targretin® (Bexarotene) Capsule No 1999 No Cutaneous manifestations of cutaneous T‐cell lymphoma
Tasigna® (Nilotinib) Capsule No 2007 No Phþ CML
Temodar® (Temozolomide) Capsule Yes 1999 Yes Glioblastoma multiforme, refractory anaplastic astrocytoma
Thalomid® (Thalidomide) Capsule No 1998 No Multiple myeloma, erythema nodosum leprosum

(Continued)
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1254 The Journal of Clinical Pharmacology / Vol 53 No 12 (2013)

Table 1. Continued

Generic
Oral Cytotoxic Year Original Equivalent
Brand (United States Dosage Agent NDA Approved Available
Adopted Name) Form (Yes/No) by FDA (Yes/No) FDA Approved Indication(s) From Product Labeling
®
Tykerb (Lapatinib) Tablet No 2007 No Breast cancer
Vepesid® (Etoposide) Capsule Yes 1986 Yes Small cell lung cancer
Vesanoid® (Tretinoin) Capsule No 1995 Yes Acute promyelocytic leukemia
Votrient® (Pazopanib) Tablet Yes 2009 No Renal cell carcinoma, soft tissue sarcoma
Xalkori® (Crizotinib) Capsule No 2011 No Non‐small cell lung cancer
Xeloda® (Capecitabine) Tablet Yes 1998 No Colon cancer, colorectal cancer, breast cancer
Xtandi® (Enzalutamide) Capsule No 2012 No Metastatic castration‐resistant prostate cancer
Zelboraf® (Vemurafenib) Tablet No 2011 No Melanoma with BRAFV600E mutation
Zolinza® (Vorinostat) Capsule Yes 2006 No Cutaneous manifestations in patients with cutaneous T‐cell
lymphoma
Zytiga® (Abiraterone) Tablet No 2011 No Prostate cancer

a
Approved through ANDA pathway.

serious safety risks involved. Unlike typical BE studies in
healthy subjects, the safety issues often necessitate
conducting BE studies in cancer patients. BE studies
conducted in a patient population have their own
limitations. The limitations in the recruitment of patients
for BE studies are due to (a) specific cancer patients
needed, and (b) stricter inclusion/exclusion criteria. The
various scientific and regulatory factors taken into
consideration while designing BE studies for solid oral
anticancer drug products are discussed below.
Scientific and Regulatory Considerations
for Bioequivalence Study Design
The FDA publication Approved Drug Products with
Therapeutic Equivalence Evaluations (Orange Book)
identifies the products that have been designated as
reference listed drugs (RLDs) for BE comparators for
generic drug products. For an ANDA to be approved, the
generic drug manufacturers must show that the proposed
generic drug product is both pharmaceutically equivalent
and bioequivalent to its corresponding RLD. Two products
are considered to be pharmaceutically equivalent if they
contain the same active ingredient in the same dosage form
and meet compendial or other applicable standards.9 As
mentioned above, the documentation of BE of systemically
acting oral drug products is generally established through
in vivo BE studies, and two products are considered to be
bioequivalent if the 90% CI for the geometric mean ratios
of AUC and Cmax is within limits of 80–125%.
The BE studies for systemically acting oral drug
products are usually conducted in normal healthy
subjects.10 However, due to the safety issues associated
with anticancer drugs, it is often necessary to conduct BE
studies in the target patient population. While designing in
vivo BE studies for solid oral anticancer drug products, the
following factors should be considered12:
 Possibility of waiving the in vivo bioequiva-
lence study requirements (grant a biowaiver)
under the Biopharmaceutics Classification
System (BCS) if the drug substance and
product meet certain criteria;
 Safety in healthy subjects at the recommended
BE study dose;
 Approved therapeutic indication and intended
patient population;
 Dosing regimen in the patient population and
guidelines for therapy;
 PK parameters such as, half‐life, time to reach
steady‐state, and intrasubject variability;
 Feasibility of conducting BE study using a
particular strength; and
 Cytotoxicity, which requires the submission
of an Investigational New Drug Application
(IND) prior to the conduct of the BE studies—
See 21 CFR 320.31(a)(3).
Figures 1 and 2 are graphical depictions, “decision trees”,
covering the above factors in the design of a BE study of
a solid oral dosage form of an anticancer drug. The
following examples discuss the rationale for a specific BE
study design.
Bioequivalence Based on the BCS Concept
The BCS is a scientific framework to classify drug
substances according to their aqueous solubility and
intestinal permeability.13 A drug substance can be
classified into the following four classes using the BCS,
based on their solubility and permeability.
Class I: High solubility, high permeability.
Class II: Low solubility, high permeability.
Class III: High solubility, low permeability.
Class IV: Low solubility, low permeability.
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Kaur et al 1255

Figure 1. Decision tree to design bioequivalence study for solid oral anticancer drug products.

A drug substance is considered highly soluble when the
highest dose strength is soluble in 250 mL or less of
aqueous media over the pH range of 1–7.5, and highly
permeable when the extent of absorption is 90%.13 Data
supporting high permeability and high solubility of the
drug substance may be used for a biowaiver request of in
vivo biostudies for rapidly dissolving (>85% in 30 mi-
nutes) immediate‐release (IR) solid oral dosage forms.13 If
the ANDA applicant satisfactorily demonstrates that the
drug substance is highly soluble and highly permeable,

1256
Figure 2. Decision tree to enroll/drop patients from bioequivalence study for solid oral anticancer drug products.
and the ANDA IR drug product is also rapidly dissolving,
then the drug can be designated as BCS Class I.
Biowaivers can be granted for BCS Class I drugs except
for narrow therapeutic range drugs and the drug product
designed to be absorbed in the oral cavity (e.g., sublingual
or buccal tablets).13
In requesting a BCS‐based biowaiver, each applicant
should submit its own solubility, permeability, and
dissolution data. In support of the permeability determi-
nation, information available in the approved labeling of
the reference product may be used. Peer‐reviewed articles
are generally not acceptable sources of pivotal informa-
tion because they usually do not contain the necessary
details of the testing for the Agency to make a judgment
regarding the quality of the study. In some cases,
however, the Agency will use information published in
the scientific literature as supportive of a BCS designa-
tion. Once the BCS‐based biowaiver is granted for a
particular product, there is no need to conduct in vivo BE
studies. Notably, each BCS biowaiver is product‐
specific. A BCS‐biowaiver applies only for that IR solid
oral drug product for which the biowaiver was sought and
granted.
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The Journal of Clinical Pharmacology / Vol 53 No 12 (2013)
Bioequivalence Recommendations for a Non‐Cytotoxic
Anticancer Drug
For IR drug products which are not BCS Class I, BE must
be demonstrated by in vivo BE studies. Most often, in vivo
studies in support of bioequivalence of an anticancer drug
product are conducted in the target patient population due
to the serious toxicity of the drug substance. For
noncytotoxic anticancer solid oral formulations, healthy
subjects may be used, although not frequently. The
decision to use healthy normal subjects is based on the
safety evaluation of the recommended BE study dose
when administered orally. Bexarotene IR capsules is an
example of such a drug product. Bexarotene is a
noncytotoxic drug approved for the treatment of cutaneous
T‐cell lymphoma.14,15 For in vivo BE testing of generic
bexarotene IR capsules, the FDA recommends a single
dose crossover study in carefully screened healthy male
subjects at a dose of 75 mg.16 The use of healthy male
subjects in BE study at the recommended dose was based
upon several observations.
The Approval Summary for Targretin® (bexarotene)
Capsules presents data from an in vivo drug–drug
interaction study in human subjects.17 The Targretin®

Kaur et al
(bexarotene) Capsules New Drug Application (NDA)
applicant conducted a crossover in vivo study in 24
healthy subjects between 18 and 65 years using
bexarotene as two single 400 mg/m2 doses.18 This dose
was reported to lower serum thyroid‐stimulating hormone
(TSH) levels, free T3, and free T4 levels in healthy
subjects.19 However, the declined TSH levels were
reversible and dose proportional.15,20 Data from the
literature and clinical studies conducted by the NDA
applicant and posted in the Approval Summary indicate
that a single dose of 75 mg in a crossover BE study in a
carefully screened population of healthy male subjects is
unlikely to pose serious risks.
In this case, FDA’s draft Bioequivalence Recommen-
dations for Specific Products for Bexarotene Capsules
(Bexarotene BE draft Guidance) recommends including
males only in the BE evaluation. This is an exception to
recommendations in the FDA’s General BA/BE guid-
ance10 that in vivo BE studies be conducted in individuals
representative of the general population, taking into
account age, sex, and race. It is recommended that if the
drug product is intended for use in both sexes, the sponsor
attempt to include similar proportions of males and
females in the study with a few exceptions. However, in
the case of bexarotene capsules, only males should be used
in BE studies due to the following safety reasons.
The FDA does not recommend using females in
bexarotene BE studies because bexarotene is labeled as a
Pregnancy Category X drug. The FDA approved
Targretin® (bexarotene) Capsules labeling contains a
black‐boxed warning about birth defects in humans.
Bexarotene is reported to cause congenital anomalies, fetal
harm, and developmental mortality. The approved
labeling for Targretin® (bexarotene) Capsules indicates
that bexarotene when administered orally to pregnant rats
caused incomplete ossification, cleft palate, depressed eye
bulge/microphthalmia, small ears, and developmental
mortality. Consequently, females should not be used in
the in vivo BE study. In addition, the Targretin® labeling
carries specific language about pregnancy risk counsel-
ing.15 In addition to recommending exclusion of females
in BE studies, the draft bexarotene BE recommendations
state that, before initiating the BE study, formal pregnancy
counseling for male subjects regarding the risk to their
female partners as is stated in product labeling should be
provided.16
BE Recommendations for Cytotoxic Anticancer Drugs
For cytotoxic anticancer products which are not in BCS
Class I, a BE study must be conducted in an appropriate
patient population after the submission and acceptance of
an IND. A BE study design of a drug involving a patient
population must be designed to fit into the established
therapeutic dosing regimen for the patients. Thus, only
patients should be enrolled in the BE program if they are
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1257
already receiving the drug in a dosage suitable for the BE
study as part of their normal treatment.
Generally, single‐dose pharmacokinetic studies are
preferred to demonstrate BE between the generic and
reference drug products due mainly to single‐dose studies
being more sensitive in detecting formulation differences
compared to multiple‐dose steady‐state studies. However,
due to the patient’s therapeutic dosing regimen and a
drug’s pharmacokinetic properties, a single‐dose cross-
over design may not be feasible. A rational approach to
recommend a single‐dose or steady‐state BE study design
for solid oral cytotoxic anticancer drug products is
discussed below.
Single dose bioequivalence studies. A single‐dose BE
study is recommended whenever it is feasible to
incorporate this design into the patients’ normal multi‐
dose therapeutic regimen without interrupting the dosing
regimen, as depicted in Figure 1. An example is the
cytotoxic drug mercaptopurine IR tablet, which is
indicated for maintenance therapy of acute lymphatic
leukemia as part of a combination regimen. Mercaptopu-
rine is a potent drug that should not be used unless a
diagnosis of acute lymphatic leukemia has been adequate-
ly established.21 The FDA’s final bioequivalence recom-
mendations for this drug product suggest a single‐dose,
two‐way crossover BE study in patients receiving
mercaptopurine in a stable regimen using the same dosage
unit (multiples of the 50 mg strength).22
As specified in the approved labeling of the RLD
Purinethol®, IR mercaptopurine is given once daily based
on body weight and has a plasma half‐life of 47 minutes in
adults.21 Based on t1/2 of <1 hour, 99% of drug is expected
to be eliminated in approximately 7 hours, that is, prior to
administration of the drug on next day. Thus, the complete
pharmacokinetic profile for mercaptopurine can be
captured within the 24‐hour dosing interval. Due to
relatively short half‐life of mercaptopurine as compared to
the dosing interval, a determination of its pharmacokinetic
profile in the middle of a clinical dosing regimen
approximates the pharmacokinetic profile following a
single‐dose. An advantage of such a study design is
continuation of the patient’s multiple dose therapeutic
regimen without any interruption in the normal dosing
schedule.
Mercaptopurine therapy often includes daily oral
mercaptopurine and weekly oral methotrexate regimen.
The pharmacological effects of methotrexate may poten-
tially affect the pharmacokinetics of mercaptopurine
differently on different days.23,24 Therefore, the FDA
recommends that the two periods of the BE study of
mercaptopurine tablets be conducted at weekly intervals
within the daily dosing regimen of mercaptopurine, using
the same time interval between methotrexate and study
drug administration for each period. Mercaptopurine is
available in only one strength as 50 mg tablets. Thus, the

1258
BE study is recommended in patients receiving their own
dosing regimen using multiples of the 50 mg strength.22
Unlike a typical BE study in healthy subjects, dosage
and dosing regimen impose additional challenges in the
BE study design of a cytotoxic anticancer drug. Generally,
for multiple strength products, the highest strength of
innovator drug product is listed as the RLD in the Orange
Book, with some exceptions, mainly due to safety
reasons.10 With studies in patients for anticancer drugs,
use of the highest dosage strength is not always practical,
since many patients usual dose is not the same as highest
dosage strength. In this case a proportionally similar lower
strength is usually recommended for BE studies. This is
the case for topotecan capsules, which are indicated for
treatment of relapsed small lung cancer. The RLD
Hycamtin® (topotecan) Capsules approved labeling
recommends a topotecan capsule dose of 2.3 mg/m2/day
once daily for 5 consecutive days repeated every
21 days.25 The RLD Hycamtin® (topotecan) Capsules is
available in two strengths, 0.25 and 1 mg, with the 1 mg
strength recommended in the Orange Book as the strength
on which BE studies should be conducted.5 However,
based on topotecan dose of 2.3 mg/m2, it is not possible to
enroll an adequate number of patients with a wide range of
body surface area receiving different topotecan doses as
multiples of the 1 mg strength. Therefore, the in vivo BE
study is recommended in patients receiving their own
topotecan dosing regimen using multiples of the 0.25 mg
capsules.26 Enrollment of patients whose dosing regimen
requires combination of 0.25 and 1 mg is not recom-
mended as BE studies usually compare a single strength of
generic drug product with that of the reference product.
Based on a reported mean terminal t1/2 of 3–6 hours and
therapeutic regimen, the most appropriate study design for
topotecan is a single‐dose, two‐way crossover BE study
incorporated into the patient’s multiple‐dose therapeutic
regimen.25,26 For a two‐way crossover BE study in
patients, there is higher possibility of pharmacokinetic
variability if the study periods are completed in two or
more treatment cycles—due to possible changes in the
disease state potentially altering absorption, distribution,
metabolism, and elimination of the drug—than in one
treatment cycle. Due to a relatively short half‐life of
topotecan, the test and reference products may be dosed on
2 consecutive days of a treatment cycle.26 The feasibility
of completing BE study over a 2‐day period should also
take into account the frequency and volume of blood
samples that can be withdrawn from the cancer patients.
The completion of the BE trial in one treatment cycle
minimizes the effect of high pharmacokinetic variability
noted above. If a change in therapeutic regimen is
warranted during different study periods, the patient
should be dropped from BE study to avoid any potential
variability in pharmacokinetic parameters due to a change
in the dosing regimen during the study periods.26
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The Journal of Clinical Pharmacology / Vol 53 No 12 (2013)
Multiple‐dose bioequivalence studies. Multiple‐dose
studies are necessary in patients, whenever it is not
feasible to incorporate the single‐dose BE study design in
the patients’ multiple‐dose therapy without interrupting
the treatment regimen. Recommendations for a multiple‐
dose, steady‐state BE study are explained using the
examples of etoposide capsules and pazopanib tablets.
Etoposide capsules are indicated for the first‐line
treatment of small lung cancer, in combination with other
approved chemotherapeutic agents. In small lung cancer,
the recommended dose of Vepesid® (etoposide) Capsules
is two times the intravenous dose (which generally ranges
from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5
days), rounded to the nearest 50 mg. The elimination t1/2 of
etoposide ranges from 4 to 11 hours.27 Considering the
upper range of t1/2 and the dosing regimen, a multiple‐dose
steady‐state crossover BE study is recommended for
etoposide to avoid any interruption in the patients’
therapeutic regimen.28 The test or reference product
should be given once daily starting from days 1 to 5 of a
treatment cycle, with pharmacokinetic sampling begin-
ning on day 5 (the final dose) of each period. The patients
should be switched to receive the other treatment in Period
II. Based on a treatment cycle of 4 or 5 days, and the t1/2 of
etoposide, the two periods of the BE study must be
completed in two consecutive cycles. Therefore, it is
recommended that patients, who are already receiving
etoposide and expected to receive at least two additional
treatment cycles at the same dose, be enrolled in the BE
study.28
As noted above, typically the BE study design for most
orally administrated dosage forms is a two‐way crossover.
In this design, each patient serves his/her own control that
reduces inter‐subject variability, thus requiring smaller
number of subjects compared to a parallel BE study
design.29 However, such a design may become impractical
for long half‐life drugs due to time required to achieve
steady‐state and adequately characterize the pharmacoki-
netic profile. In this case, using a parallel rather a crossover
BE study design is recommended.10,30 An example of
such a drug product is pazopanib tablets, which is
indicated for the treatment of patients with advanced renal
cell carcinoma and advanced soft tissues sarcoma who
have received prior chemotherapy. Pazopanib tablet is
available in the 200 mg strength. The RLD Votrient®
(pazopanib) Tablets approved labeling recommends a
starting dose of 800 mg once daily without food (at least
1 hour before or 2 hours after a meal). Pazopanib has a
mean t1/2 of 30.9 hours after administration of the
recommended dose of 800 mg.31 The FDA’s draft
bioequivalence recommendations for this drug product
suggest a parallel or crossover steady‐state BE study in
advanced renal cell carcinoma patients for whom
pazopanib is indicated, who are already receiving
pazopanib tablets in standard therapy, and who are

Kaur et al
tolerating a stable dosing regimen of 800 mg/day (4 mg 
200 mg).32 In the BE study, the test or reference product
should be given orally without food (at least 1 hour before
or 2 hours after a meal) per FDA approved Votrient®
(pazopanib) Tablets labeling. If a patient’s current dose
cannot be given using multiples of the 200 mg strength, the
patient must be excluded from the BE study. No change in
the dose and dosage regimen is recommended for the
purpose of BE study.32
Bio Investigational New Drug Application Requirements
for Anticancer Drugs
The submission of a Bio Investigational New Drug
Application (BioIND) is required by regulation (Title 21
of the Code of Federal Regulations, Part 320.31) prior to
the conduct of a BE study for anticancer generic drug
products in the following cases:
 The drug product under investigation is
cytotoxic (e.g., mercaptopurine and topote-
can). Cytotoxic drugs act by damaging cells
which are in the process of division, either
killing them, or preventing their division.33
Cytotoxic drugs may damage not only cancer
cells, but also normal and healthy tissues.34
 The drug product is co‐administered with a
cytotoxic drug product. For example submis-
sion of BioIND is required prior to conduct of
a BE study for lapatinib tablets. Although
lapatinib is not cytotoxic, it is co‐administered
with capecitabine, which is a prodrug of 5‐
fluorouracil, which is cytotoxic.35
Ethical Considerations
Ethical considerations for conducting the BE studies in
patients must be considered in any study design. Only the
patients for whom drug therapy is indicated and who are
already receiving the drug should be included into the BE
study. Due to safety risks associated with interruption and/
or change in therapeutic regimen, no changes in dose,
dosage regimen, or combination therapy should be made
for the purpose of the BE study in cancer patients. It is
recommended that ANDA applicants refer to the warn-
ings, contraindications, precautions and incidence of
adverse reactions in the FDA‐approved labeling and/or
Risk Evaluation and Mitigation Strategies (REMS) if one
exists and follow the approved labeling recommendations
closely for subject inclusion and exclusion criteria.
Conclusions
Many challenges are encountered when designing and
conducting BE studies of solid oral anticancer drug
15524604, 2013, 12, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.163 by Infotrieve, Wiley Online Library on [27/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1259
products. As illustrated in the above examples, BE study
designs for solid oral anticancer drug products are
recommended after careful consideration of various
scientific, regulatory, and safety issues. These recom-
mendations are posted as Bioequivalence Recommen-
dations for Specific Products guidances on the FDA
website to help generic drug manufacturers understand
the BE study recommendations in order to meet
regulatory requirements. As of April 2013, the FDA
has posted 36 Bioequivalence Recommendations for
Specific Products guidances for solid oral anticancer
drug products. This article has illustrated the various
factors that are considered in designing BE studies for
generic versions of solid oral anticancer drug products.
We hope that this publication will help generic drug
manufacturers to understand the rationale behind BE
study design recommendations for solid oral anticancer
drugs.
Acknowledgments
This project was supported in part by FDA Commissioner’s
Fellowship and also in part by an appointment to the ORISE
Research Participation Program at the Center for Drug
Evaluation and Research administered by the Oak Ridge
Institute for Science and Education through an agreement
between the U.S. Department of Energy and CDER. The authors
would also like to thank Hoainhon T. Nguyen, M.S. (Deputy
Director, Division of Bioequivalence I) and Ethan Stier, Ph.D.
(Deputy Director, Division of Bioequivalence II) for their
suggestions during the development of Bioequivalence Rec-
ommendations for Specific Products guidances. Support
provided by LCDR Duong Nhu, Pharm.D., Project Manager,
DB II in preparation of this manuscript is also gratefully
acknowledged.
Disclosure
This article reflects the views of the authors and should not
be construed to represent FDA’s views or policies.
References
1. American Cancer Society. Cancer Facts and Figures 2013.
http://www.cancer.org/acs/groups/content/epidemiologysurveilance/
documents/document/acspc‐036845.pdf. Accessed March 02, 2013.
2. Oral Chemotherapy Drug Coverage Mandated Benefit Sunrise
Review. Washington State Department of Health Publication
Number 631‐014; December 2010. http://www.doh.wa.gov/
portals/1/Documents/Pubs/631014.pdf. Accessed March 02, 2013.
3. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral
versus intravenous palliative chemotherapy. J Clin Oncol.
1997;15:110–115.
4. U.S. Food and Drug Administration Approved Drugs for Oncology.
http://www.centerwatch.com/drug‐information/fda‐approvals/drug‐
areas.aspx?AreaID¼12. Accessed April 26, 2013.
5. Approved Products with Therapeutic Equivalence Evaluations. 31st
edition. Washington, DC: US Department of Health and Human

1260
Services, Public Health Service, Food and Drug Administration,
Center for Drug Evaluation and Research, Office of Pharmaceutical
Science, Office of Generic Drugs, 2009. http://www.fda.gov/
downloads/Drugs/DevelopmentApprovalProcess/UCM071436.pdf.
Accessed April 26, 2013.
6. U.S. National Library of Medicine. DailyMed™ Electronic Library.
http://dailymed.nlm.nih.gov/dailymed/about.cfm. Accessed April
26, 2013.
7. U.S. Food and Drug Administration Approved Drug Product Labels.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed
April 26, 2013.
8. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. 1998. Guidance for Industry: 180‐Day Generic Drug
Exclusivity Under the Hatch‐Waxman Amendments to the Federal
Food, Drug, and Cosmetic Act. Rockville: Food and Drug
Administration.
9. Code of Federal Regulations, Title 21, Part 320.1 (C), Revision
April 1, 2011.
10. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. 2003. Guidance for industry: Bioavailability and
bioequivalence studies for orally administered drug products—
General considerations. Rockville: Food and Drug Administration.
11. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. 2001. Guidance for industry: Statistical approaches
to establishing bioequivalence. Rockville: Food and Drug
Administration.
12. Kaur P, Chaurasia C, Davit B, Conner D. Scientific and regulatory
considerations for bioequivalence study design of solid oral
anticancer drug products. J Clin Pharmacol. 2011;51:1363.
Abstract: 119.
13. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. 2000. Guidance for industry: Waiver of in vivo
bioavailability and bioequivalence studies for immediate‐release
solid oral dosage forms based on a biopharmaceutics classification
system. Rockville: Food and Drug Administration.
14. Gniadecki R, Assaf C, Bagot M, et al. The optimal use of bexarotene
in cutaneous T‐cell lymphoma. Br J Dermatol. 2007;157:433–
440.
15. Eisai Inc., Woodcliff Lake, NJ 07677. Targretin® (bexarotene)
capsules label approved on May 16, 2011.
16. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. Guidance for Industry: Bioequivalence Recommendations
for Specific Products for Bexarotene Capsule. http://www.fda.
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM227413.pdf. Accessed January 13, 2013.
17. U.S. Food and Drug Administration. Approval Package for NDA
021055, Approval: December 29, 1999. http://www.accessdata.fda.
gov/drugsatfda_docs/nda/99/21055_Targretin_biopharmr.pdf. Ac-
cessed January 13, 2013.
18. Kuan H, Loewen G, Geiser R. Lack of effect of ketoconazole on the
pharmacokinetics of oral bexarotene in healthy subjects. Clin
Pharmacol Ther. 2005;77:P74. Abstract: PII‐89.
19. Golden WM, Weber KB, Hernandez TL, Sherman IS, Woodmansee
WW, Haugen BR. Single‐dose rexinoid rapidly and specifically
suppresses serum thyrotropin in normal subjects. J Clin Endocrinol
Metab. 2007;92(1):124–130.
15524604, 2013, 12, Downloaded from https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.163 by Infotrieve, Wiley Online Library on [27/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
The Journal of Clinical Pharmacology / Vol 53 No 12 (2013)
20. Farol LT, Hymes KB. Bexarotene: A clinical review. Expert Rev
Anticancer Ther. 2004;4:180–188.
21. Teva Pharmaceutical USA, Sellersville, PA 18960. Purinethol®
(mercaptopurine) tablets label approved on May 27, 2011.
22. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. Guidance for Industry: Bioequivalence Recommendations
for Specific Products for Mercaptopurine Tablet. http://www.fda.
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm088658.pdf. Accessed March 7, 2013.
23. Balis FM, Holcenberg JS, Zimm S, et al. The effect of methotrexate
on the bioavailability of oral 6‐mercaptopurine. Clin Pharmacol
Ther. 1987;41(4):384–387.
24. Innocenti F, Danesi R, Paolo AD, et al. Clinical and experimental
pharmacokinetic interaction between 6‐mercaptopurine and metho-
trexate. Cancer Chemother Pharmacol. 1996;37(5):409–414.
25. GlaxoSmithKline, Research Triangle Park, NC 27709. Hycamtin®
(topotecan) capsules label approved on October 07, 2011.
26. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. Guidance for Industry: Bioequivalence Recommendations
for Specific Products for Topotecan Capsule. http://www.fda.gov/
downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM249255.pdf. Accessed March 09, 2013.
27. U.S. National Library of Medicine. DailyMed™ Electronic Library.
Label for Etoposide Capsule. http://dailymed.nlm.nih.gov/dailymed/
lookup.cfm?setid¼508a418e‐985f‐4208‐9324‐2230655bb5c2. Ac-
cessed March 09, 2013.
28. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. Guidance for Industry: Bioequivalence Recommendations
for Specific Products for Etoposide Capsule. http://www.fda.
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM224208.pdf. Accessed March 09, 2013.
29. Rani S, Pargal A. Bioequivalence: An overview of statistical
concepts. Indian J Pharmacol. 2004;36:209–216.
30. Davit BM, Conner DP. 2004. Issues in bioequivalence and
development of generic drug products. In: Sahajwalla CG, editor.
New drug development: Regulatory paradigms for clinical
pharmacology and biopharmaceutics. New York: Marcel Dekker.
p 399–416.
31. GlaxoSmithKline, Research Triangle Park, NC 27709. Votrient®
(pazopanib) tablets label approved on November 15, 2012.
32. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. Guidance for Industry: Bioequivalence Recommendations
for Specific Products for Pazopanib Tablet. http://www.fda.
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM320017.pdf. Accessed June 14, 2013.
33. Luken J, Middleton J. 1995. Chemotherapy and the administration of
cytotoxic drugs into established lines. In: David J, editor. Cancer
care: Prevention, treatment and palliation. London, UK: Boundary
Row. p 77–112.
34. Ismael GFV, Rosa DD, Mano MS, et al. Novel cytotoxic drugs: Old
challenges, new solutions. Cancer Treat Rev. 2008;34(1):81–91.
35. U.S. Food and Drug Administration Center for Drug Evaluation and
Research. Guidance for Industry: Bioequivalence Recommendations
for Specific Products for Lapatinib Ditosylate Tablet. http://www.fda.
gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM212613.pdf. Accessed February 21, 2012.