Ethics in Clinical Research The patient rights Clinical

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Ethics in Clinical ResearchThe patient rights
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Clinical trials the ABC
What is informed consent? What is IRB?
What is a clinical trial? How is a drug approved
for testing? Who is a research subject? Who can
be in a clinical trial?
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What is a Clinical Trial?

• A clinical trial tests the effects of a
  medication, medical treatment, or device on a
  group of volunteers. Clinical trials are an
  important step in making new medications
  available. They measure the drug's ability to
  treat a condition, its safety and possible side
  effects.

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How is a Drug Approved for Testing?

• The U.S. Food and Drug Administration (FDA)
  typically must authorize a drug company's
  proposal to conduct clinical trials. Drug
  companies must do years of laboratory research
  before they can begin testing medicines in
  humans.

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Who Can Be in a Clinical Trial?

• People with the condition being studied as well
  as healthy people can volunteer to participate in
  a trial. There are strict requirements that
  specify which trials involve healthy volunteers
  and which trials involve patients with the
  condition being studied.

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Who Can Be in a Clinical Trial?

• Each trial has specific requirements such as age,
  sex, or medical condition for participants.
• The physician conducting the trial must review
  each volunteer's medical history and the trial
  requirements to determine who can participate.
• Known risks and discomforts will be explained by
  the trial physician prior to participating in the
  trial.
• In addition to the known risks, there may be
  unknown risks such as medication side effects
  involved in participating in a clinical trial.
• Trial procedures, risks, and benefits are
  explained to volunteers during the informed
  consent process.

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The research subject

• A research subject is any object or phenomenon
  that is observed for purposes of research.
• In survey research and opinion polling, the
  subject is often called a respondent.
• In human subject research, one highly important
  topic is informed consent and human subject
  protection.
• There are many guidelines, all to insure that the
  subject is clearly informed of what the study
  will be, their participation, any possible
  consequences, that they can quit any time without
  consequences, who to contact with questions, and
  so forth.
• All research involving human subjects should
  include aspects of human subject protection.

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What is Informed Consent?

• Informed consent is the process designed to give
  volunteers the information that they need to
  decide about participating in a clinical trial.
• This process allows the volunteer to ask
  questions and to exchange information freely with
  the clinical investigator.
• The clinical investigator is responsible for
  ensuring that informed consent is obtained from
  each research volunteer before that person
  participates in the research trial.

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History of Experiments on Humans

• Human experimentation and research ethics evolved
  over time.
• Much of the time, the subjects of human
  experimentation were prisoners, slaves, family
  members, or the experimenter him/herself.

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Who is the Institutional Review Board ?

• The IRB is a group of healthcare professionals
  and members of the local community which must
  review and approve a clinical trial before it
  begins.
• The IRB reviews trial activities because its
  primary responsibility is to protect the safety
  and rights of the trial participants.
• The purpose of an IRB review is to assure, both
  in advance and by periodic review, that
  appropriate steps are taken to protect the rights
  and welfare of humans participating as subjects
  in a research study.

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Institutional review Board IRB

• To accomplish their purpose, IRBs review research
  protocols and related materials (e.g., informed
  consent documents and investigator brochures) to
  ensure protection of the rights and welfare of
  human subjects of research.
• The chief objectives of every IRB protocol review
  are to assess the scientific merit of the
  research and its methods, to promote fully
  informed and voluntary participation by
  prospective subjects who are themselves capable
  of making such choices (or, if that is not
  possible, informed permission given by a suitable
  proxy) and to maximize the safety of subjects
  once they are enrolled in the project.

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Progress in science and medicine is essential for
human advancement.

• Ethical values are essential in directing the
  application of scientific and medical advances.
• Moral progress requires that benefits of progress
  be shared more widely and equitably throughout
  the world.
• Scientific and medical progress should be
  inextricably linked to moral progress.

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Ethical Values

• Newer ethical values in research ethics
• Justice
• Fair access to participation in research studies
• Fairness in distribution of harms/benefits - long
  term as well as short-term
• Non-Exploitation of the vulnerable
• Coupling the research endeavor to improvements in
  health care through partnerships and improves
  overall standards of care in research
• Relevance of research to local needs - the
  importance of context
• Narrowing the 10 90 gap by reshaping the
  research agenda
• Cultural and linguistic sensitivity in obtaining
  informed consent
• Solidarity and interdependence - acknowledging
  and facing global threats
• Addressing deteriorating global health
• Focusing on re-emerging and new infectious
  diseases
• Global health information equity

• Long-standing ethical values in research ethics
• Do not harm
• Minimization of risk
• Protection of the vulnerable
• Respect for dignity of patients/ subjects
• Informed consent
• Protection of confidentiality
• Freedom to withdraw
• Justice
• Compensation for injury
• Appropriate remuneration for participation

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The Declaration of Helsinki

• Declaration of Helsinki was developed by the
  World Medical Association (WMA), as a set of
  ethical principles for the medical community
  regarding human experimenting.
• It is widely regarded as the cornerstone document
  of human research ethics (WMA 2000, Bošnjak 2001,
  Tyebkhan 2003), although it is not a legally
  binding instrument in international law.
• It draws its authority from the degree to which
  it has been codified in, or influenced national
  or regional legislation and regulations (Human
  and Fluss 2001).
• However codes and guidelines impact on practice
  in both symbolic and instrumental roles. Its role
  was described by a Brazilian forum in 2000 in
  these words "Even though the Declaration of
  Helsinki is the responsibility of the World
  Medical Association, the document should be
  considered the property of all humanity" (Human
  and Fluss 2001).

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WORLD MEDICAL ASSOCIATION DECLARATION OF
HELSINKI Ethical Principles for Medical Research
Involving Human Subjects

• Adopted by the 18th WMA General Assembly,
  Helsinki, Finland, June 1964, and
• Amended by the 29th WMA General Assembly, Tokyo,
  Japan, October 1975
• 35th WMA General Assembly, Venice, Italy, October
  1983
• 41st WMA General Assembly, Hong Kong, September
  1989.
• 48th WMA General Assembly, Somerset West,
  Republic of South Africa, October 1996 and the
• 52nd WMA General Assembly, Edinburgh, Scotland,
  October 2000
• Note of Clarification on Paragraph 29 added by
  the WMA General Assembly, Washington 2002
• Note of Clarification on Paragraph 30 added by
  the WMA General Assembly, Tokyo 2004

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THE IMPACT OF THE DECLARATION ON SOCIETY

• Some of the wisest words on this critically
  important aspect have been written by Justice
  M.N. Venkatachaliah, a former Chief Justice of
  India, in his Foreword to the 2000 Indian
  Guidelines referred to above
• Genome-mapping, Genetic Recombinant Engineering,
  Assisted Reproductive technology, Stem-Cell
  Research, Human cloning, etc. have opened up
  hitherto unimagined vistas in the practical
  application of Biomedical Technologies for the
  benefit of the mankind.
• Biomedical Research is perched on the threshold
  of a bold and brave new world. Crucial to its
  management is the ability of the scientists and
  the society to handle these forces of change.
• Correspondingly, as in all frontier-line
  researches, our ignorance of the areas of the yet
  unknown might, paradoxically, expand with the
  expansion of our knowledge.
• Biomedical Research has acquired dimensions which
  are at once exciting and awesome.It raises some
  delicate and difficult issues of ethics which
  need to be addressed with sensitivity to human
  values and with great circumspection.
• While research which promises to mankind the
  great blessings of Science should not be stifled
  by too restrictive an approach, however, great
  care should be taken to ensure that something
  does not go out of hand. Therefore, any system of
  ethical guidelines on research needs to be
  cognizant of, and informed by, a sensitive
  balance of the risks and benefits.

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Landmarks in protection of human subjects in
clinical trials

• Nuremberg Code
• Belmont Report
• CIOMS
• Declaration of Geneva
• International Conference on Harmonisation of
  Technical Requirements for Registration of
  Pharmaceuticals for Human Use
• Informed consent
• Medical ethics
• Clinical trial
• Code of Federal Regulations

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International Conference on Harmonization (ICH)

• The International Conference on Harmonization of
  Technical Requirements for Registration of
  Pharmaceuticals for Human Use (ICH) is a project
  that brings together the regulatory authorities
  of Europe, Japan and the US and experts from the
  pharmaceutical industry in the three regions to
  discuss scientific and technical aspects of
  pharmaceutical product registration.
• The purpose of ICH is to reduce or obviate the
  need to duplicate the testing carried out during
  the research and development of new medicines by
  recommending ways to achieve greater
  harmonization in the interpretation and
  application of technical guidelines and
  requirements for product registration.
• Seven parties that represent the regulatory
  bodies and the research-based industries of the
  founding members are responsible for the decision
  making process the European Commission, the
  European Medicines Agency (EMEA), the European
  Federation of Pharmaceutical Industries and
  Associations (EFPIA), the Ministry of Health,
  Labor and Welfare, the Japan Pharmaceutical
  Manufacturers Association (JPMA), the Food and
  Drug Administration (FDA), and the Pharmaceutical
  Research and Manufacturers of America (PhRMA).

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GCP

• Good Clinical Practice is an international
  quality standard that is provided by
  International Conference on Harmonisation (ICH),
  an international body that defines standards,
  which governments can transpose into regulations
  for clinical trials involving human subjects.
• Good Clinical Practice guidelines include
  protection of human rights as a subject in
  clinical trial. It also provides assurance of the
  safety and efficacy of the newly developed
  compounds.
• Good Clinical Practice Guidelines include
  standards on how clinical trials should be
  conducted, define the roles and responsibilities
  of clinical trial sponsors, clinical research
  investigators, and monitors. In the
  pharmaceutical industry monitors are often called
  Clinical Research Associates.

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Overview of the guidance

• 1.9 When planning research in developing
  countries, researchers and sponsors may have to
  refer to
• International guidelines or conventions
• European Union Directives
• National laws or guidelines
• Regulations and guidelines for research sponsored
  by the pharmaceutical industry
• Guidelines produced by funding agencies
• Institutional guidelines
• Guidelines relating to a specific disease and
• Recommendations from advisory bodies.

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Guidance for Research in Developing countries

• World Medical Association (WMA 2000)
• Declaration of Helsinki as last revised in Oct
  2000
• Note of Clarification on Paragraph 29, Dec 2002
  Workgroup Report on the revision of Paragraph 30,
  Sep 2003 and
• Note of Clarification on Paragraph 30, October
  2004.
• Not legally binding, but referred to in other
  forms of guidance and regulations
• The Council for International Organizations of
  Medical
• Sciences (CIOMS) in collaboration with WHO (CIOMS
  2002)
• International Ethical Guidelines for Biomedical
  Research Involving Human Subjects, as last
  revised in Sep 2002.
• Not legally binding, but referred to in other
  forms of guidance and regulations

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Guidance for Research in Developing countries

• Council of Europe (CoE 2004)
• Additional Protocol to the Convention on Human
  Rights and Biomedicine concerning Biomedical
  Research, prepared by the Steering
• Committee on Bioethics (CDBI) of the Council of
  Europe adopted by the Committee of Ministers,
  June 2004. (A draft Protocol, approved by the
  CDBI in June 2003, was discussed during the
  Workshop in February 2004.)
• Legally binding if signed and ratified.
• European Council and European Parliament (Eurpean
  Union)(EU 2001)
• Directive 2001/20/EC of the European Parliament
  and of the Council on the approximation of the
  laws, regulations and administrative provisions
  of the Member States relating to implementation
  of good clinical practice in the conduct of
  clinical trials on medicinal products for human
  use, April 2001, adopted by Member States by May
  2003, brought into force May 2004.
• Incorporated into national law for EU Member
  States applies within the EU and for
  multi-center clinical trials taking place in
  Member States and other countries

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Guidance for Research in Developing countries

• The European Group on Ethics in Science and New
  Technologies (EGE 20030
• Its an advisory Opinion Nr 17 on the ethical
  aspects of clinical research in developing
  countries, published in Jan 2003.
• Nuffield Council on Bioethics (NCOB 2002)
• An advisory on the The ethics of research related
  to healthcare in developing countries, April
  2002.3
• Whereas the other documents listed earlier
  provide specific guidelines on externally
  sponsored research, this Report focuses on
  establishing an ethical framework for those
  conducting such research, and provides
  recommendations.

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Informed consent is a legal condition whereby a
person can be said to have given consent based
upon an appreciation understanding of the facts
and implications of an action.

• The individual needs to be in possession of
  relevant facts and also of his reasoning
  faculties, such as not being mentally retarded or
  mentally ill and without an impairment of
  judgment at the time of consenting. Such
  impairments might include illness, intoxication,
  insufficient sleep, and other health problems.
• Some acts cannot legally take place because of a
  lack of informed consent. In cases where an
  individual is considered unable to give informed
  consent, another person is generally authorized
  to give consent on their behalf. Examples of
  this include the parents or legal guardians of a
  child and caregivers for the mentally ill.
• In cases where an individual is provided limited
  facts, serious ethical issues may arise. Examples
  of this in a clinical trial in medical research
  are anticipated and prevented by an ethics
  committee or Institutional Review Board.

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Individual consent requiredNo research on a
person may be carried out without the informed,
free, express, specific and documented consent of
the person. Article 14
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Who should give consent?

• Provision of information Article 13 lists the
  information that should be addressed during the
  consent process Persons being asked to
  participate in a research project shall be given
  adequate information in a comprehensible
  formcovering the purpose, the overall plan and
  the possible risks and benefits of the research
  project
• i. of the nature, extent and duration of the
  procedures involved, in particular, details of
  any burden imposed by the research project
• ii. of available preventive, diagnostic and
  therapeutic procedures
• iii. of the arrangements for responding to
  adverse events or the concerns of research
  participants
• iv. of arrangements to ensure respect for private
  life and ensure the confidentiality of personal
  data
• v. of arrangements for access to information
  relevant to the participant arising from the
  research and to its overall results
• vi. of the arrangements for fair compensation in
  the case of damage
• vii. of any foreseen potential further uses,
  including commercial uses, of the research
  results, data or biological materials
• viii. of the source of funding of the research
  project. and their right to refuse consent or
  to withdraw at any time without being subject to
  any form of discrimination.Article 13

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Who should give consent?

• Recording consent
• Consent must be documented. Express consent may
  be either verbal or written as long as it is
  documented. Best practice demands that written
  consent be obtained, except in exceptional
  circumstances. Explanatory Report, paragraph
  79
• Inducements
• Details of all payments and rewards to be made in
  the context of the research project must be
  considered by the ethics committee. Appendix
  Information to be given to the ethics committee
• Other points
• Article 15 discusses protection of persons not
  able to consent to research Article 19 discusses
  research in emergency clinical situations, when a
  person is not in a state to give consent.