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Ethical Considerations In Bioequivalence Studies

Usama Jamshaid

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EthicsEthics means: Moral principles that govern

a person's behavior or the conducting of an activity.

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Bioavailability Bioavailability means the rate and extent to which

the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.

In case of IV administration, bioavailability is almost 100% but when a drug is administered orally, bioavailability is decreased.

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BioequivalenceTwo products are bioequivalent if they are pharmaceutically equivalent the bioavailable concentrations following

administration are same and giving the same effect

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Ethical Guidelines for Research with Humans

One set of guidelines specifically developed to guide research conducted by educational researchers is the AERA Guidelines.

The AERA is the largest professional association

in the field of education, and is also known as the American Educational Research Association.

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Basic Ethical Principles 1. Respect for Persons 2. Beneficence 3. Justice

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Essential Parameters 1. Informed Consent 2. Assessment of Risks and Benefits 3. Selection of Subjects

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Study Design

In order to reduce variability a cross over design usually is the first choice.Other designs or methods may be chosen in specific situations, but should be fully justified in the protocol and final study report.The subjects should be allocated to treatment sequences in a randomized order.

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Selection of subjects Subjects could belong to both sexes; however, the risk to women of

childbearing potential should be considered on an individual basis. In general, 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 for suitability by means of clinical laboratory tests, an extensive review of medical history, and a comprehensive medical examination.

Subjects should preferably be nonsmokers and without a history of alcohol or drug abuse. If moderate smokers are included (less than 10 cigarettes per day) they should be identified as such and the consequences for the study results should be discussed.

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If the purpose of the bioequivalence study is to address specific questions such as investigation of differences in bioavailability in different subsets of the population or drug/drug interactions the selection criteria and the statistical analysis should be adjusted accordingly.

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Inclusion of Volunteers If the investigated active substance is known to

have adverse effects or risks then it is considered unacceptable for healthy volunteers, it may be necessary to use patients instead under suitable precautions and supervision.

In this case the applicant should justify the alternative.

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Informed Consent This is the process of providing the research participants

with information enables them to make an informed decision as to whether they want to participate in the research study.

State the purpose of the research and describe the procedures to be followed.

Describe any potential risks or discomforts the participant may encounter.

Describe any potential benefits from participation.

Describe extent to which results will be kept confidential.

Give a list of names the participants may contact with any questions they have.  

State that participant is voluntary and that they are free to withdraw from the study at any time.

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Informed Consent with Minors as Research Participants

Consent must be obtained from parents or guardians.

Assent must also be obtained from minors who are old enough or have enough intellectual capacity to say they are willing to participate.

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DeceptionProviding false information to the participant

about the nature and/or purpose of the study

It is discouraged by the AERA, but not disallowed in all It is discouraged by the AERA, but not disallowed in all cases. cases.

Sometimes deception is required in order to conduct a valid Sometimes deception is required in order to conduct a valid research study. The researcher must justify the use of research study. The researcher must justify the use of deceptiondeception..

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Freedom to Withdraw Participants must be informed that they

are free to withdraw from the study at any time without penalty.

If you have a power relationship with the participants you must be extra careful to make sure that they really do feel free to withdraw.

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Protection from Mental and Physical Harm

This is the most fundamental ethical issue confronting the researcher.

Educational research generally poses minimal risk to participants.

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Elements of a Bioavailability/Bioequivalence Study Protocol

I. Title

  A. Principal investigator (study director)

  B. Project/protocol number and date

II. Study objective

III. Study design

  A. Design

  B. Drug products

    1. Test product(s)

    2. Reference product

  C. Dosage regimen

  D. Sample collection schedule

  E. Housing/confinement

  F. Fasting/meals schedule

  G. Analytical methods

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Elements of a Bioavailability Study Protocol

IV. Study population

  A. Subjects

  B. Subject selection

    1. Medical history

    2. Physical examination

    3. Laboratory tests

  C. Inclusion/exclusion criteria

    1. Inclusion criteria

    2. Exclusion criteria

  D. Restrictions/prohibitions

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Elements of a Bioavailability Study Protocol

V. Clinical procedures

  A. Dosage and drug administration

  B. Biological sampling schedule and handling procedures

  C. Activity of subjects

VI. Ethical considerations

  A. Basic principles

  B. Institutional review board

  C. Informed consent

  D. Indications for subject withdrawal

  E. Adverse reactions and emergency procedures

VII. Facilities

VIII. Data analysis

  A. Analytical validation procedure

  B. Statistical treatment of data

IX. Drug accountability

X. Appendix

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Institutional Review Board

This is a board consisting of professionals and lay people who review research proposals to insure that the researcher will adhere to ethical standards in the conduct of the research.

Researchers must submit a Research Protocol to the IRB for review

Three of the most important categories of review are exempt studies, expedited review, and full board review

Much educational research falls in the exempt category because the study involves no or minimal risk

Studies with children, prisoners, and fetal participants are never exempt

Even if your study ultimately falls in the exempt category, it is still essential that you follow the ethical guidelines

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There are three ways, and three ways only, to encourage participation ethically (Senese 1997):

Anonymity: Keep promises anonymous. After identifying your sample try to forget taking

names or other identification. Reassure people not to go to media.

Confidentiality: Use confidentiality if you cannot guarantee

anonymity. It requires that you guarantee that no one will be

individually identified in any way by you.

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o Informed Consent:

Be honest and fair with your subjects.

Tell them every thing about your research.

Subjects should not have any pressure to participate in your research.

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Ethical Principles 1. It is the duty of the health care professionals to promote and

safeguard the health of the people. 2. The Declaration of Geneva of the World Medical Association binds

the health care professionals with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A health care professional shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient."

3. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.

4. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society.

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5. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality.

6. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens.

7. Medical research is subject to ethical standards that promote respect for

all human beings and protect their health and rights. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress.

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8. Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.

9. The subjects must be volunteers and informed

participants in the research project.

10. When obtaining informed consent for the research project the health care professional should be particularly cautious if the subject is in a dependent relationship with the investigator or may consent under duress.

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11. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law.

12. When a subject is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative.

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References Applied Biopharmaceutics & Pharmacokinetics, 5th Edition, Leon

Shargel, Susanna Wu-Pong, Andrew B.C. Yu Concepts In Clinical Pharmacokinetics - 4th Ed. (2005) ,Joseph T.

DiPiro Pharm.D., William J. Spruill Pharm.D., FASHP, William E. Wade Pharm.D., FASHP, Robert A. Blouin Pharm.D.

Abernethy DR, Azarnoff DL: Pharmacokinetic investigations in elderly patients. Clinical and ethical considerations. Clin Pharmacokinet 19:89–93, 1990 [PMID: 2379383] .

Malaysian guidelines for the conduct of bioavailability and bioequivalence studies, September 2000, Ministry of Health, Malaysia.

The Code of Ethics of the American Educational Research Association (AERA) , February 2011.

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THANK YOUTHANK YOU

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