According to the World Health Organization (WHO), cancer is the leading cause of death worldwide, accounting for nearly 10 million deaths in 2020 (1). In addition, GLOBACAN estimated 19.3 million new cancer cases and almost 10 million cancer deaths in 2020 with breast, lung, colon, rectum, and prostate cancers being the most common cancer types (2). It is important to ensure that anticancer treatments are available to patients to improve their quality of life and reduce cancer-related hospital expenses and death. However, most cancer treatments are expensive and not available to all patients giving way to increasing interest in the concept of ‘generic’ oncology drugs. The Food and Drug Administration (FDA) approved 16 new cancer drugs and 5 generic cancer drugs in 2021 (3). Oncology bioequivalence clinical studies are an important part of cancer clinical trials. These studies help to determine if a drug or treatment is safe and effective for a particular cancer patient. They also provide valuable data about the efficacy of the drug or treatment for future patients. Oncology bioequivalence clinical studies can be used to determine the safety, efficacy, and side effects of various treatments for different types of cancers. These studies are essential in helping doctors make informed decisions about which treatments will be most effective for their patients.Generic drugs are medications created to be the same as an already marketed brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use (4). Patent expiration and loss of marketing exclusivity of the brand-name or innovator drug molecules allow manufacturers to produce generics. The Drug Price Competition and Patent Term Restoration Act or the Hatch-Waxman Act 1984 established several practices to facilitate the development and marketing of generic medications. The global generics market was worth $390 billion in 2020 and is projected to reach $574 billion by 2030 (5). In the U.S., 9 of 10 prescriptions filled are for generic drugs. Although generic medications contain the same active ingredient as brand-name medicines, they may differ in inactive ingredients or excipients and can differ in appearance. However, these differences should not affect the performance, safety, or effectiveness of the generic.

1. Oncology Bioequivalence Clinical Studies
Table of Contents
​ 1)What are generic drugs and why are they so important?
​ 2)How are generics approved?
​ 3)What are bioequivalence (BE) studies?
​ 4)Considerations for Bioequivalence studies for Oncologic treatments
​ 5)References

2. According to the World Health Organization (WHO), cancer is the leading
cause of death worldwide, accounting for nearly 10 million deaths in 2020
(1). In addition, GLOBACAN estimated 19.3 million new cancer cases
and almost 10 million cancer deaths in 2020 with breast, lung, colon,
rectum, and prostate cancers being the most common cancer types (2). It
is important to ensure that anticancer treatments are available to patients
to improve their quality of life and reduce cancer-related hospital
expenses and death. However, most cancer treatments are expensive
and not available to all patients giving way to increasing interest in the
concept of ‘generic’ oncology drugs. The Food and Drug Administration
(FDA) approved 16 new cancer drugs and 5 generic cancer drugs in
2021 (3).
Oncology bioequivalence clinical studies are an important part of cancer clinical
trials. These studies help to determine if a drug or treatment is safe and effective for
a particular cancer patient. They also provide valuable data about the efficacy of the
drug or treatment for future patients. Oncology bioequivalence clinical studies can be
used to determine the safety, efficacy, and side effects of various treatments for
different types of cancers. These studies are essential in helping doctors make
informed decisions about which treatments will be most effective for their patients.
What are generic drugs and why are they so
important?
Generic drugs are medications created to be the same as an already
marketed brand-name drug in dosage form, safety, strength, route of
administration, quality, performance characteristics, and intended use (4).
Patent expiration and loss of marketing exclusivity of the brand-name or
innovator drug molecules allow manufacturers to produce generics. The
Drug Price Competition and Patent Term Restoration Act or the
Hatch-Waxman Act 1984 established several practices to facilitate the
development and marketing of generic medications. The global generics
market was worth $390 billion in 2020 and is projected to reach $574
billion by 2030 (5). In the U.S., 9 of 10 prescriptions filled are for generic
drugs. Although generic medications contain the same active ingredient
as brand-name medicines, they may differ in inactive ingredients or
excipients and can differ in appearance. However, these differences
should not affect the performance, safety, or effectiveness of the generic.

3. The reason for the relatively lower cost of generics compared to
brand-name medications is that they do not require extensive nonclinical
(animal) and clinical studies. Since the manufacturers of generics save a
lot of time and resources, generics are priced considerably lower than
brand-name drugs. The lower cost of generics makes them affordable,
and accessible to patients allowing for increased patient adherence,
particularly in cases of chronic diseases. Generic drugs play an important
role in healthcare due to their affordability and accessibility. Clinical
research organizations (CROs) work to ensure that generic medications
meet the same standards of safety and efficacy as their branded
counterparts. This helps to ensure that patients receive the best possible
care while reducing overall healthcare costs.
How are generics approved?
The FDA approves generics via the Abbreviated New Drug Application
(ANDA) pathway also known as the 505(j) pathway. Generic applications
are termed ‘abbreviated’ as they do not require extensive nonclinical and
clinical studies to demonstrate safety and effectiveness. However, to be
marketed generics must demonstrate that they are ‘therapeutically
equivalent’ to brand-name medications. Therapeutic equivalence implies
pharmaceutical equivalence (same active pharmaceutical ingredient
(API)) and bioequivalence. Two products are considered bioequivalent
when they are equal in the rate and extent to which the API becomes
available at the site(s) of action. Bioequivalence testing is the most critical
requirement of ANDAs. Several oncologic drugs such as monoclonal
antibodies and interferons are biologicals with complex structures.
Biologicals do not have generic equivalents as their structures can differ
slightly based on the manufacturing process and starting materials. The
so-called generic counterparts of biologicals are known as biosimilars or
follow-on biologicals and require extensive bioequivalence testing in
addition to tests for safety and immunogenicity.

4. What are bioequivalence (BE) studies?
Bioequivalence (BE) studies compare the in vivo rate and extent of drug
absorption of the brand-name medication (or reference-listed drug (RLD))
and the proposed generic product. Typical studies are done in a 2*2
two-sequence, two-period, two-treatment crossover design in both the
fasted and fed states in healthy volunteers. Comparison of
pharmacokinetic endpoints such as the area under the curve (AUC) and
maximal drug concentration (Cmax) are mostly used. Two products are
bioequivalent when the 90% confidence interval for the test/reference
ratio of Cmax and AUC falls within 80-125%. The FDA has developed
product-specific recommendations for BE studies for several drugs
including oncologic agents. Bioequivalence clinical trials( Bioequivalence
(BE) studies)assess the safety and effectiveness of generic drugs. These
studies compare the bioavailability of a generic drug to its reference drug
in order to demonstrate that they are equivalent in terms of their
absorption, distribution, metabolism, and excretion.

5. Considerations for Bioequivalence studies for
Oncologic treatments
The following factors need to be considered when designing a BE study
for oncologic safety keeping patient safety the utmost priority.
● Study design
Most BE studies are designed to be crossover studies in which the RLD
and proposed generic product are administered to the same participant in
a two-period, two-sequence pattern following randomization. Although the
crossover design helps eliminate intra-subject variability as the subjects
serve as their own control and reduces the number of subjects required

6. for the study, crossover designs are not suitable for drugs that have long
half-lives due to carryover effects that can affect the next treatment. In
these cases, parallel designs should be considered in which subjects in
the RLD and generic treatment groups are matched for various
demographic characteristics.
● Population
Unlike BE studies for most drugs that include healthy participants, cancer
patients need to be included in BE studies for oncologic agents. This is
because of safety concerns and the cytotoxicity of cancer drugs. Finding
enough patients with similar cancer staging or diagnosis may be difficult
for BE studies because of strict inclusion/exclusion criteria. Recruitment
of patients using registries is recommended to meet target patient
enrolment goals. In cases where the oncologic agent is non-cytotoxic
healthy volunteers may be considered.
● Gender
In cases where BE studies are performed in healthy volunteers, it is
necessary to ensure that the anticancer agent does not cause other
undesirable side effects such as birth defects or teratogenicity. In certain
cases, it may be recommended to include only male participants in the
BE studies.
● Dosing
In BE studies done on cancer patients, it is important to ensure that the
regular treatment schedule of the patient is unaffected. The anticancer
agent should be administered at the same dose and schedule as done
routinely so as not to affect the patient’s treatment response. Although
the highest dose level of the drug is recommended for BE studies this
may not be feasible for oncologic agents as the patient’s normal dose
may not be the highest dose strength.

7. ● Biopharmaceutics Classification System (BCS) biowaivers
The BCS classifies drugs based on their solubility and permeability
characteristics into four classes: I, II, III, and IV. Biowaivers for BE studies
may be permitted for BCS Class I drugs that have a high solubility and
high permeability as these drugs dissolve and are absorbed rapidly
following oral administration. Due to safety concerns with oncologic
agents, these compounds may not be exempt from BE studies even if
they fall into the BCS Class I category as they are cytotoxic. In these
cases, additional studies may be required, and an Investigation New
Drug (IND) application may be necessary prior to conducting BE studies.
● Narrow therapeutic index
Most oncologic agents have a narrow therapeutic index meaning that
they have the potential to cause dose-limiting adverse effects at or near
doses required to achieve the desired therapeutic effect. In such cases,
the bioequivalence criteria of 90% CI with 80-125% may be insufficient.
The European Medicines Agency (EMA), Health Canada, and the FDA
have proposed to tighten the limits to 90-111.1% according to
within-subject variability in response and perform replicate studies.
Bioequivalence studies form the basis for approval of generic products as
well as approval of products following manufacturing or post-approval
changes. These studies are especially critical for oncologic agents that
have safety concerns and therefore should be performed with utmost
care to ensure the availability of affordable medications allowing for
improved patient adherence.
References
● Cancer (who.int)

8. ● Global Cancer Statistics 2020: GLOBOCAN Estimates of
Incidence and Mortality Worldwide for 36 Cancers in 185
Countries – PubMed (nih.gov)
● 2021 First Generic Drug Approvals | FDA
● Generic Drugs: Questions & Answers | FDA
● Generic drug market growth: insights to 2030
(europeanpharmaceuticalreview.com)