Good clinical practices-drug discovery

1. Dr. Dhruva Kumar Sharma
Department of Pharmacology
SMU/SMIMS
Saturday, the 19th Of July, 2014

2. Evolution of Good Clinical
Practices:
An overview
2

3. PROTOCOL
• Nazi war crimes
• Tuskegee syphilis trial
• Thalidomide disaster
• Jews chronic disease trial
• Neuremberg trial code
• Declaration of helsinki
• Belmonte report
• ICH/GCP Guidelines
3

4. Good Clinical Practice (GCP): Meaning
4
 Good Clinical Practice (GCP) is an international
ethical and scientific quality standard for designing,
conducting, recording and reporting trials that involve the
participation of human subjects.
 Compliance with this standard provides public
assurance that the rights, safety and well-being of trial
subjects are protected, consistent with the principles that
have their origin in the Declaration of Helsinki, and that
the clinical trial data are credible.

5. • The objective of this ICH GCP Guideline is to
provide a unified standard for the European
Union (EU), Japan and the United States to
facilitate the mutual acceptance of clinical
data by the regulatory authorities in these
jurisdictions.
5

6. History
Why Do We Need Guidelines?
Why Are We Regulated?

7. Nazi Medical War Crimes:
during World War II
• Experiments conducted by Nazi physicians
during World War II were unprecedented in
their scope and the degree of harm and
suffering to which human beings were
subjected
• Typically, the experiments resulted in
death, disfigurement or permanent disability,
and as such are considered as examples
of medical torture

8. Nazi Medical War Crimes
"Medical experiments" were performed on
thousands of concentration camp
prisoners and included deadly studies and
tortures such as-
 Injecting people with gasoline and live
viruses
 Immersing people in ice water
 Forcing people to ingest poisons

9. 9
Incisions made by
medical personnel
that were purposely
infected with bacteria,
dirt, and slivers of
glass

10. Victim of a tuberculosis medical
experiment
10

11. Prisoner in a compression chamber
11
An experiment to
determine
altitudes at which
aircraft crews
could survive
without oxygen

12. Immersing people in ice water
• With the intent of discovering
means to prevent and treat
hypothermia.
• 280 to 300 victims
• One study forced subjects to
endure a tank of ice water for up
to five hours.
12

13. • In 1946, an American
military tribunal opened
criminal proceedings
against 23 leading German
physicians : Doctors' Trial
• Sixteen of the doctors were
found guilty
• Seven were sentenced to
death
• Development of
the Nuremberg
Code of medical ethics
13
THE DOCTORS TRIAL

14. The Tuskegee Syphilis Study
• Research participants was the long-term study of
black males conducted at Tuskegee, Alabama by the
United States Public Health Service.
• (1930s-1970) - examination of the natural history of
untreated syphilis
• More than 400 African-American men with syphilis
participated
• The men were recruited without informed consent
and, in fact, were misinformed that some of the
procedures done in the interest of the research (e.g.,
spinal taps) were actually "special free treatment."

15. The Tuskegee Syphilis Study
• In the 1940s, penicillin was found to be effective in the
treatment of syphilis.
• The study continued, however, and the men were neither
informed of nor treated with the antibiotic.
• The first accounts of this study appeared in the national
press in 1972.
• Belmont report 1978 (Ethical Principles and guidelines
for the protection of human subjects of research)-
Tuskegee syphilis study

16. The Jewish Chronic Disease Hospital
Study
• In 1963, studies were undertaken at New York's Jewish
Chronic Disease Hospital to understand whether the
body's inability to reject cancer cells was due to cancer or
debilitation.
• Previous studies had indicated that healthy persons
reject cancer cells promptly, and the researchers
allegedly believed that the debilitated patients would
also reject the cancers but at a substantially slower rate
compared to healthy participants.

17. The Jewish Chronic Disease Hospital
Study
• Further, patients were not told that they
would receive cancer cells, because the
researchers felt it would unnecessarily
frighten them
• It was found that the study had not been
presented to the hospital's research
committee and that the physicians
responsible for the patients' care had not
been consulted.
• The researchers were found guilty of fraud,
deceit, and unprofessional conduct.

18. The Willowbrook Study
• Institutionalized children, as participants in research
is demonstrated in a series of studies conducted
from 1963 through 1966 at the Willowbrook State
School, a New York institution for "mentally
defective" children.
• In order to gain an understanding of the natural
history of infectious hepatitis under controlled
circumstances, newly admitted children were
deliberately infected with the hepatitis virus.
• In some cases, parents found they were unable to
admit their children to Willowbrook unless they
agreed to their child’s participation in the studies.

19. The Willowbrook Study
This controversial case raised important
questions about the adequacy and
freedom of consent, inadequate disclosure
of the child's risk of later developing
chronic liver disease

20. The Milgram Study
• The ‘teachers’ were instructed to give the ‘learners’
electrical shocks in response to incorrect answers on
verbally given ‘tests’.
• Participants were deceived as to the nature of the
study, being told it was to test new teaching-learning
techniques.

21. Thalidomide tragedy
• Thalidomide was a widely used drug in the
late 1950s and early 1960s for the
treatment of nausea in pregnant women
• It became apparent in the 1960s that
thalidomide treatment resulted in severe
birth defects in thousands of children.
21

22. • Within a few years of
the widespread use of
thalidomide in
Europe, Australia, and
Japan, approximately
10,000 children were
born with
phocomelia, leading
to the ban of
thalidomide in most
countries in 1961
22

23. • The thalidomide tragedy marked a turning
point in toxicity testing, as it prompted
United States and international regulatory
agencies to develop systematic toxicity
testing protocols
• The thalidomide tragedy also brought into
sharp focus the importance of rigorous and
relevant testing of pharmaceuticals prior
to their introduction into the market place
(Kelsey, 1988).
23
Thalidomide tragedy

24. Nuremberg Code-1947
• On April 17, 1947, United States Counsel for War Crimes
came out with six points defining “legitimate research”.
• The verdict of August 19 reiterated almost all of these
points in a section entitled "Permissible Medical
Experiments" and revised the original six points into ten.
• Subsequently, the ten points became known as the
"Nuremberg Code."
24

25. Codes and Guidelines
 Nuremberg Code (1947).
 W.M.A’s Declaration of Helsinki (1964).
• Belmont Report (USA) (1979)-Tuskegee syphilis study
 Council for International Organizations of Medical Sciences
(CIOMS) 1993.
 International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human
Use (ICH), in 1996, Guideline on Good Clinical Practice,E6
(GCP).

26. Nuremberg Code (1947)
Voluntary and Informed consent-absolutely essential.
Anticipate scientific benefits, Useful.
Animal experimentation first.
Avoid physical and mental suffering.
Benefits outweigh risks.
No intentional death or disability.
Protection from harm.
Subject free to withdraw.
Qualified investigators.
Investigator will stop if harm occurs.

27. THE DECLARATION OF HELSINKI-1964

28.  Is an international standard for the conduct of clinical
research adopted by International Conference on
Harmonization(ICH) Good Clinical Practice standards.
 A global ethical standard for medical research and was
approved at the WMA General Assembly by a majority vote
of 75%.
 It is the mission of the clinical research professionals to
safeguard the health of the people.
THE DECLARATION OF HELSINKI-1964

29. Historical Overview:-
Its origin has been found in the Nazi Disaster and has
undergone several modifications.
Prior to 1947 Nuremberg Code, there was no
accepted code of conduct governing the ethical
aspects of human research.

30. World Medical Association
 It is an international organization of physicians,
established on September 17, 1947.
 First general Assembly of WMA was held in Paris,
France.
 Mission:- Serve humanity by endeavoring to achieve the
highest international standards in medical education,
science, ethics and health care for all peoples of the world.

31. Declaration of Helsinki 1964
 Adapted from Nuremberg
Code by the World Medical
Association (WMA).
 First adopted in Helsinki,
Finland, 1964

32. WORLD MEDICAL ASSOCIATION DECLARATION OF
HELSINKI- 2008
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
 53th WMA General Assembly,
Washington 2002 (Note of
Clarification on paragraph 29
added)
 55th WMA General Assembly,
Tokyo 2004 (Note of Clarification
on Paragraph 30 added)
 59th WMA General Assembly,
Seoul, October 2008

33. Seven Ethical Pillars of Clinical
Research
 AUTONOMY
 BENEFICENCE
 NON – MALFEASANCE
 FIDELITY
 TRUTHFULNESS
 CONFIDENTIALITY
 JUSTICE

34. Declaration of Helsinki
Autonomy
Consent
Para 20 The subjects must be volunteers and
informed participants in the research project.
Para 22 freely-given informed consent,
preferably in writing .

35. Declaration of Helsinki
Para 5 well-being of the human subject should
take precedence over the interests of science
and society.
Beneficence

36. Declaration of Helsinki
Para 16
• Preceded by careful assessment of
predictable risks and burdens
• Attempt to avoid any act or treatment
plan that would harm the patient
Non Malfeasance

37. Declaration of Helsinki
Para 11
Medical research involving human subjects must be based
on generally accepted scientific principles, thorough
knowledge of the scientific literature and on adequate
laboratory and, where appropriate, animal
experimentation.
Para 15
Conducted only by clinically competent medical person.
Fidelity – duty of care

38. Declaration of Helsinki
Para 27
Both authors & investigators are obliged to
preserve the accuracy of the results. Negative
as well as positive results should be published
Truthfulness - Honesty

39. Declaration of Helsinki
Para 21
Every precaution should be taken to
respect the privacy of the subject, the
confidentiality of the patient's information
Confidentiality

40. Declaration of Helsinki
Para 30
Every patient entered into the study should be assured of
access to the best proven prophylactic, diagnostic and
therapeutic methods identified by the study.
Para 9
Research Investigators should be aware of the ethical,
legal and regulatory requirements for research on human
subjects
Para 17
Physicians should cease any investigation if the risks
outweigh the potential benefits
Justice

41. DECLARATION OF HELSINKI :-
Basic Principles
1. Conform to accepted scientific principles.
2. Design formulated in experimental protocol, reviewed by IEC.
3. Conducted by qualified and trained persons.
4. Importance in proportion to inherent risk.
5. Assessment of risks vs. benefits.
6. Safeguard subject’s integrity (privacy).
7. Abstain unless hazards are predictable.
8. Preserve accuracy when publishing.
9. Adequately inform or right to withdraw.
10. Obtain true informed consent in writing.
11. Reliance on legal guardian.
12. State compliance with Declaration.

42. Ethical Principles and Guidelines for the
Protection of Human Subjects of Research
• Tuskegee Syphilis Study (1932–1972)
• Named the Belmont Report, for
the Belmont Conference Center, where the
National Commission met when first
drafting the report
42
Belmont Report: 1979

43. Belmont Report: 1979
Three ethical principles related to research on human
subjects:
1. Respect for Persons
2. Beneficence: "Do no harm" while maximizing benefits
for research project and minimizing risks to the research
subjects
3. Justice: ensuring reasonable, non-exploitative, and
well-considered procedures are administered

44. Overview of
ICH GCP

45. What is ICH?
• The International Conference on
Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for
Human Use (ICH)- is unique in bringing
together the regulatory authorities and
pharmaceutical industry of Europe, Japan
and the US to discuss scientific and
technical aspects of drug registration.
45

46. What is ICH?
• Since its inception in 1990, ICH has
gradually evolved
• ICH's mission is to ensure that safe,
effective, and high quality medicines are
developed and registered in the most
resource-efficient manner

47. How did it evolve?
The need to harmonize
• Public disasters, serious fraud and abuse of
human rights.
• Trials of War criminals-Nuremberg code
1949
• Thalidomide- Declaration of Helsinki 1964
• Belmont report 1978 (Ethical Principles and guidelines
for the protection of human subjects of research)-Tuskegee syphilis
study

48. History
1962 US FDA IND Guidelines
1964 Declaration of Helsinki
1968 Committee on Safety of Medicines, uk
1978 GCP, US FDA
1991 GCP, Europe
1996 ICH GCP
1997 ICH GCP Guideline

49. When did it begin?
• Ist conf. in 1990 in Brussels
3 regions participated
• Representatives from
Industry
Academia
Ministry of
health

50. ICH parties
6 parties
• EU
• EFPIA European federation of pharmaceutical industries’ associations
• MHLW Ministry of health, Labor and welfare, Japan
• JPMA Japan Pharmaceuticals manufacturers Association
• US FDA
• PhRMA
• Observers : WHO, TPP(canada)
• International federation of Pharmaceutical manufacturer’s
association

51. Key objective
• To discuss and define the minimum
standards for the development and
registration of investigational products

52. The result?
Many guidelines made
• Most important- ICH GCP guidelines
• Evolved in several steps
• Consolidated guideline ICH E6 Sept 1997

53. ICH Guidelines: examples
• Efficacy:
– clinical trials etc
• Safety:
– pharmacovigilance, adverse drug reaction
reporting
• Quality:
– raw materials, impurities, residual solvents etc
• Multidisciplinary:
– common technical document, electronic
submission, coding systems

54. What is GCP?
A standard for the design, conduct,
performance, monitoring ,auditing,
recording, analyses and reporting of
clinical trials that provide assurance that
the data and the reported results are
credible, accurate and that the rights,
integrity and confidentiality of trial
subjects are protected.

55. Why is it needed?
• To ensure the rights, safety and well being
of the trial subjects are protected
• Ensure the credibility of clinical trial data

56. The ICH GCP guideline
• Provide a unified standard for the EU, Japan and
USA regions to facilitate mutual acceptance of
clinical trial data by the regulatory authorities in
these regions.
• 8 sections

57. ICH GCP guideline
1. Glossary
Common language for
investigators/sponsors/ethics committees
2.Principles of Good Clinical Practice
13 tenets of ICH GCP
3.Requirements for IRB/IEC
Roles responsibilities and composition

58. ICH GCP guideline
4.Responsibilities of the investigator
5.Responsibilities of the sponsor
6.Requirements for clinical trial protocol and
protocol amendments
7.Responsibility of the sponsor in the
development of investigator’s brochure.
8.Essential documents

59. Principles of ICH GCP
• Ethical conduct as per
Declaration of Helsinki
GCP
Regulatory Requirements
 Risk- Benefit
Primary concern- Subject

60. Principles of ICH GCP
• Supportive data
• Protocol
Scientifically sound, clear, detailed
• Ethical Clearance
Study to be conducted in compliance
to the protocol which has received EC
approval

61. Principles of ICH GCP
• Subject Care
Medical decisions responsibility of
qualified physician
• Qualified staff
By education, training, experience in their
area of responsibility
• Informed Consent

62. Principles of ICH GCP
• Clinical Trial data
Recorded, handled and stored to enable
accurate reporting, interpretation and
verification
• Confidentiality

63. Principles of ICH GCP
• Investigational Product
Manufactured, handled and stored as per
GMP

64. Principles of ICH GCP
• Quality Assurance
Systems and procedures to ensure the
Quality of every aspect of the trial

65. Indian GCP guidelines
• Released in Dec 2001(Developed by CDCSO
and endorsed by DCGI)
• In general, in line with ICH GCP
• Has Revised Schedule Y (Jan 2005)
addressed discrepancies?

66. • SAFEGUARD PUBLIC HEALTH
• ASSURE CONSUMER PROTECTION STANDARDS
• FACILITATE AVAILABILITY OF SAFE AND EFFECTIVE
PRODUCTS
• ELIMINATE INCONSISTENT STANDARDS
INTERNATIONALLY
• FACILITATE MUTUAL ACCEPTANCE OF DATA FROM
CLINICAL TRIALS
GOALS OF INTERNATIONAL HARMONIZATION OF
REGULATORY REQUIREMENTS

67. Study Documentation
During the study
The investigator must keep:
– Source documents
• Medical records (including access to computer
records)
• Laboratory reports
• ECGs, X-rays, etc.
• Any other medical records, reports or notes
(hospital admissions and discharges)
– A subject identification list
– Copies of all study related documentation

68. Medical Records
• In particular, they should contain notes on:
– Sufficient information to support subject eligibility
– This should be well documented (signed and dated)
– Subject’s participation in the study
– Dates of visits
– Procedures, investigations done
– Observations, diagnoses
– Medications taken (including study medication)
– Adverse events
– Completion or withdrawal (reason) from the study

69. Study Documentation
After the study
The sponsor needs from the
investigator:
– Final drug accountability records
– All used and unused supplies and
medication
– All required documents completed

70. Conclusion
70
Thanks.....
“When a doctor [goes] wrong, he is
the first of criminals. He has nerve
and he has knowledge.”
- Sherlock Holmes

71. References:
 http://www.wma.net/e/policy/b3.htm
 www.hhs.gov/ohrp/humansubjects/guidance/belmont.ht
ml
 www.hhs.gov/ohrp/references/nurcode.html
 www.icmr.nic.in/guidelines/GCLP
 www.cdsco.nic.in/
 www.ub.edu/recerca/Bioetica/doc/Declaracio_Helsinki_2
013
 www.jewishvirtuallibrary.org/jsource/Holocaust/nazi_exp
eriments
 www.ich.org/fileadmin/Public_Web.../ICH.../E6_R1__Guid
eline