2. Bio-equivalence
Bioequivalence is the property of two dosage forms or active
ingredients with similar blood concentration levels that produce the
same effect at the site of physiologic activity.
3. Bio-Equivalence Studies
Bio-equivalence studies are done for:
Comparison the bioavailability of generic drug products to the
brand name product.
To check that the bioequivalent drugs have same systemic
bioavailability will have same predictable drug response.
To monitor the pharmacokinetic and pharmacodynamic parameters
after the administration of tested drugs.
For intervention study to examine effects e.g Food and concomitant
medication.
4. Types of Bio-equivalence Studies
In vivo
1. Oral immediate release product with systemic action.
2. Non-Oral immediate release product.
3. Modified release product with systemic action.
In vitro
1. The drug product can be differ only in strength, must follow the
conditions like:
a) Same ratio between active compounds and excipients.
b) Same qualitative composition.
c) Pharmacokinetics linear.
5. 1. Should meet all the requirements like:
a) Solution or solubilized form.
b) Topical administration.
c) Oral administration.
d) By inhalation as a gas or vapor.
6. Assessment of Bio-equivalence
BE studies are generally recommended by using the following
endpoints:
Pharmacokinetic studies
Pharmacodynamic studies
Comparative Clinical studies
In vitro dissolution studies
7. Pharmacokinetics method to assess BE
The two major pharmacokinetic methods used to assess BE are:
1. Plasma level-time studies
2. Urinary excretion studies
8. Design of Bio-Equivalence Studies
The basic design is determined by:
The nature of reference material and dose form to be tested.
The availability of analytical method.
Scientific questions to be answered.
Benefit-risk and ethical consideration with regard to testing in
humans. For some drugs, FDA offers general guidelines for
conducting these studies.
9. ETHICS
Ethics are a personal code of conduct based on respect for one's
self, others and surroundings and is governed by the principles or
assumptions underpinning the way individuals or organizations
ought to conduct themselves.
Research ethics involves the application of fundamental ethical
principles to research activities which include the design and
implementation of research, respect towards society and others,
the use of resources and research outputs, scientific misconduct
and the regulation of research.
10. Ethical Consideration
Guidelines are specifically developed to guide researchers to conduct
bioequivalence studies by following international and national forums;
1. Declaration of Helsinki 1964 (Revised on 1975, 1983, 1989, 1996,
2000, and 2008)
2. World Health Organization (WHO; Technical Report Series # 996,
2016)
3. Drug Regulatory of Pakistan (DRAP; Guideline For Industry On
Investigation Of Bio-equivalence (BE) / Bioavailability (BA)
Studies For Multisource Generic Drug Products, 1st Edition, 2021)
4. Institutional Review Boards (IRB)/ Independent Ethics Committee
(IEC)
11. DRAP Statement regarding BA/BE
All research involving human subjects should be conducted in
accordance with the ethical principles contained in the current
version of the Declaration of Helsinki, including respect for persons,
beneficence (“maximize benefits and minimize harms and wrongs”)
and non-maleficence (“do no harm”), as defined by the International
Ethical Guidelines for Biomedical Research Involving Human
Subjects issued by the Council for International Organizations of
Medical Sciences (CIOMS), including rules/ regulations issued by
DRAP.
12. Basic Ethical Principles:
Respect for persons
Beneficence
Justice
Essential Parameters:
Informed Consent
Assessment of risks and benefits
Selection of subjects
13. Subject Selection
Subjects could be both male/female, however the risks should be
considered.
Subjects should be between 18-55 years old , capable of giving
informed consent and of weight within the normal range or Body
Mass Index (BMI) of 18-30.
They should be screened by clinical laboratory testing , medical
history and a comprehensive medical examination.
Subjects should be non-smoker and without a history of drug abuse
and alcohol.
14. Inclusion/Withdrawl of Volunteers
If the investigational active substance have adverse effects/risks
then it will be unacceptable for healthy volunteers, its necessary to
use patients under precautions and supervision.
Alternatives should be given.
15. Informed Consent
Process of providing research participants with information enables
them to make an informed decision whether they want to participate
in studies.
State the purpose and procedure of these studies
Potential risks/discomforts the participants may encounter.
Extents to which results will be confidential.
Potential benefits from participation.
List of names of other participants for their comfort.
Participants are free to withdraw from the study at any time.
Consents must be obtained from parents/guardians and must also
obtained from minors, old enough/have enough capacity to show
willingness for participation
16. Deception
Providing false information to the participants about the nature or
purpose of studies.
Although its discouraged by the AREA but not disallowed in all cases.
Sometimes deception is required in order to conduct a valid
research study. The researcher must justify the use of deception.
17. Protection From Mental and Physical
Harm
It’s the most fundamental ethical issue, must be followed by the
researchers
These studies generally poses minimal risk to participants although
state of stress, anxiety, and irritability documented in subjects.
18. Institutional Review Board (IRB)
Institutional review boards (IRB), also known as independent ethics
committees (IEC) in the European Union, are formally designated
independent bodies that safeguard the rights, safety, and well-being of all
human subjects involved in a trial.
The IRB has the authority to approve, require modifications prior to giving
a favorable opinion, disapprove, or terminate/suspend any prior approval
of the research.
IRBs are composed of medical and nonmedical members that have no
conflicting interest with the BE. Regulations require IRBs to have a
diverse membership, which can be in terms of race, gender, cultural
background, and community members. The recommended composition
of an IRB includes at least five members, with at least one whose primary
area of interest is in a nonscientific area, and at least one member who is
independent of the institution or trial site. Nonmembers with expertise in
special areas may be invited. The investigator may attend an IRB
19. Adverse reactions and Emergency
procedures
Adverse Events (Adverse event means any untoward medical
occurrence associated with the use of a drug in humans, whether
or not considered drug related.)
Suspect adverse reactions
Adverse Reactions (An adverse reaction means any adverse event
caused by a drug. Adverse reactions are a subset of all suspected
adverse reactions where there is reason to conclude that the drug
caused the event.)
Unexpected
Serious
Life Threatening
* 21 Code for Federal Regulation 312/320 USA
