1. Clinical Trial Regulations
P.Olliaro
Nov04

2. Clinical Trials: a Phase of Product Development

3. R&D ATTRITION RATES < discovery > <pre-clinical>

5. TOTAL Discovery + Development 115-240 million
(including cost of failure)
DISCOVERY
PRE-DEVELOPMENT
REGULATORY
REVIEW
DEVELOPMENT
MARKETING
PRE-CLINICAL
CLINICAL
PHARMACEUTICAL
Bulk active synthesis
Analytical development preformulation
Formulation development
Pharmacology
PK & metabolism
Toxicology
Clinical trial packaging
post-IND tox
Bioanalytical sample analysis
Phase I
Phase II
Phase III
Validation, QC analysis
Commercial packaging
Long-term stability
IND
filing
NDA $
million $
million $
million $
million $
million
Cost of TB New drug - Source: GATB webpage

6. R&D OPPORTUNITY NEW TOOL NEED DEPLOYMENT IMPLEMENTATION INTELLIGENCE,
SURVEILLANCE
R&D
OPPORTUNITY
NEW TOOL
NEED
DEPLOYMENT
IMPLEMENTATION
MONITORING
& EVALUATION
“OPERATIONAL
RESEARCH”

7. Capacities & capabilities for sustained, durable clinical research
GCP, GCLP requirements
First In
Humans
Registration
Policy,
Practice
Discovery
& Pre-clinical
Research
Regulatory
Clinical studies
(Phase I, II, III)
Post-
registration
studies to
inform policy
Capacities & capabilities
for sustained, durable clinical research
in Developing Countries

8. The Critical Path of a Clinical Trial
Planning
Protocol • CRF
Regulatory and
Ethical Approval
Trial Documents • Materials
Select
Investigators
Initial Visits
Site Assessments
Patient Recruitment
Periodic Monitoring
Study Termination
Data Data Statistical Final
Entry Clean-up Analysis Report
*START
*END

9. Special features
Mission: provide affordable, adapted public health priority products
Corollary: provide data in support of registration, policy & practice; availability of quality product
Context: developing country capacities & capabilities

10. GCPs (& GCLPs) ICH Guidelines

11. Good Clinical Practice
Guidelines established to ensure clinical research is consistently performed to high ethical and scientific standards
Primary considerations are to:
protect the rights and safety of clinical subjects
ensure quality and integrity of data
In the next slide I have attempted to simplify that rather long definition. GCP is nothing else but guidelines, established to ensure that clinical research is consistently performed according to high ethical and scientific standards.
There are 2 primary considerations in the definition of GCP, and these are: to protect the rights and safety of clinical subjects, and ensure the quality and integrity of data.

12. What is GCP ? Good Clinical Practice
A standard for
the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that
provides assurance that the data and reported results are credible and accurate, and that
the rights, integrity and confidentiality of trial subjects are protected.
Ref: ICH Harmonized Tripartite Guideline for Good Clinical Practice (1.24), 1997

13. For what/whom? GCP Applies to All Research
All sponsors: private, government, university, industry
All study designs: RCTs, double-blind, open-label, comparator, etc
All study phases: Phase I to IV
All investigational products: new drugs, new indications, biomedical device, new methodology, new surgical techniques, etc
Ref:

14. Why GCPs? Historical events

15. Why GCPs? Historical events

16. Continuing Development of GCP Guidelines
USA( FDA GCP Regulations)
Protection of human subjects:Informed consent; Standards for IRB
Guidelines for monitoring of Clinical Investigations – 1988
EU: Good Clinical Practice for Trials on Medicinal Products in the European Community
Japan: Good Clinical Practice, GCP Manual
WHO: Guidelines for GCP for trials on Pharmaceutical Products
Other refinements of the regulations

17. GCP is a process, not a book
Sponsor
The standard
[Show the CFR & ICH guidelines book.]
GCP is a very dynamic process:
For you, because as you work you should keep learning how to better apply the principles
For the standard, because it evolves as the international community and the Federal government adopt practices that demand increasing quality
For the investigator, because they continuously learn how to improve the quality of clinical trials, and help their staff to do the same
Investigator

18. ICH - International Conference on Harmonization

19. ICH Guidelines: 4 major categories
Q: "Quality" Topics = chemical & pharmaceutical Quality Assurance. E.g: Q1 Stability Testing, Q3 Impurity Testing
S: "Safety" Topics = in vitro & in vivo pre-clinical studies. E.g : S1 Carcinogenicity Testing, S2 Genotoxicity Testing
E: "Efficacy" Topics = clinical studies in human subject. E.g : E4 Dose Response Studies, E6 Good Clinical Practices. (NB: Clinical Safety Data Management is also classified as an "Efficacy" topic - E2)
M: "Multidisciplinary" Topics = cross-cutting
M1: Medical Terminology (MedDRA)
M2: Electronic Standards for Transmission of Regulatory Information (ESTRI)
M3: Timing of Pre-clinical Studies in Relation to Clinical Trials
M4: The Common Technical Document (CTD)
M5: Data Elements and Standards for Drug Dictionaries  

20. ICH Harmonized Tripartite Guidelines for Good Clinical Practice (ICH-GCP)
Joint initiative by regulators and industry from three regions - US, EU & Japan.
A framework for pharmaceutical companies and investigators to conduct clinical trials
According to similar rules and regulations
Conforming to high ethical and scientific standards.
The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a joint regulatory/industry project to improve, through harmonization, the efficiency of the process for developing and registering new medicinal products in Europe, Japan and the United States, in order to make these products available to patients with a minimum of delay.
The six parties to ICH represent the regulatory bodies and research-based industry in the three regions, Europe, Japan and the USA, where the vast majority of new medicines are currently developed.
The ICH process has achieved success because it is based on scientific consensus developed between industry and regulatory experts and because of the commitment of the regulatory parties to implement the ICH tripartite, harmonized guidelines and recommendations.
The Fourth International Conference on Harmonization (ICH 4) Brussels, July 1997, marks the completion of the first phase of ICH activities in which significant progress has been made towards the goal of reducing duplication in the process for developing new medicinal products and submitting technical data for registration.
The next slide presents what should be the Pfizer mantra for doing clinical research…

21. ICH-GCP – Harmonized Tripartite Guidelines - Whom?
Founder members:
European Union: EC + EFPIA (European Federation of Pharmaceutical Industries’ Associations)
Japan: Ministry of Health & Welfare + JPMA ( Japan Pharmaceutical Manufacturers Association)
USA: FDA + PhRMA (Pharmaceutical Research and Manufacturers of America)
Harmonization of regulatory requirements was pioneered by the European Community, in the 1980s, as the EC (now the European Union) moved towards the development of a single market for pharmaceuticals. The success achieved in Europe demonstrated that harmonization was feasible. At the same time there were bilateral discussions between Europe, Japan and the US on possibilities for harmonization. It was, however, at the WHO Conference of Drug Regulatory Authorities (ICDRA), in Paris, in 1989, that specific plans for action began to materialize. Soon afterwards, the authorities approached IFPMA to discuss a joint regulatory-industry initiative on international harmonization, and ICH was conceived.
The birth of ICH took place at a meeting in April 1990, hosted by the EFPIA in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the USA met, primarily, to plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH.
The ICH Steering Committee which was established at that meeting has since met at least twice a year, with the location rotating between the three regions.

22. ICH-GCP - When? Introduced in 1996
November 1991
Development of tripartite GCP agreement
ICH 2
October 1993
Review of progress toward harmonization in areas of:
efficacy
safety
quality assurance
Update status of:
tripartite agreement
progress toward harmonization
ICH 3
November 1995
The Topics selected for discussion in the three Workshops at ICH 1, particularly those for Quality and Safety were very broad in their scope. Whilst ICH 1 was clearly a successful Conference, it was evident that the harmonization Topics would need to be more focused, with a clearly defined, and realistic objective. Thus most of the eleven ICH 1 Topics (identified simply as "Quality T1-T3", "Safety T1-T4 and "Efficacy T1-T4") were subsequently sub-divided and given the ICH Codes which are more familiar today.
At least one Topic has come "full circle" since ICH 1. The single Quality Topic Specifications was divided into topics on Analytical Validation (Q2) and Impurities (Q3) and these were further sub-divided and developed into harmonized guidelines. Once these tasks were substantially complete, it was agreed, at ICH 3, that work should re-commence on a consolidated guidance for setting specifications for new drugs and products (Q6).
The broad Safety Topic from the first Conference, Toxicity Testing Programme was also broken down into more manageable elements which have resulted in harmonized guidelines. Other Topics were put "on hold" but have since been re-visited, such as Safety Testing for Biotechnology Products and the Timing of Toxicity Studies in Relation to Clinical Trials.
* 1996
ICH 4
July 1997
Review and update of the implementation and impact of the ICH GCP Guideline

23. ICH-GCP – Why?
Rapid increase in laws, regulations and guidelines for testing safety, quality and efficacy of new products
Different technical requirements by regulatory agencies, although fundamental guiding principals same
Industry becoming global
Duplication of time consuming & expensive testing.
The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a joint regulatory/industry project to improve, through harmonization, the efficiency of the process for developing and registering new medicinal products in Europe, Japan and the United States, in order to make these products available to patients with a minimum of delay.
The six parties to ICH represent the regulatory bodies and research-based industry in the three regions, Europe, Japan and the USA, where the vast majority of new medicines are currently developed.
The ICH process has achieved success because it is based on scientific consensus developed between industry and regulatory experts and because of the commitment of the regulatory parties to implement the ICH tripartite, harmonized guidelines and recommendations.
The Fourth International Conference on Harmonization (ICH 4) Brussels, July 1997, marks the completion of the first phase of ICH activities in which significant progress has been made towards the goal of reducing duplication in the process for developing new medicinal products and submitting technical data for registration.
The next slide presents what should be the Pfizer mantra for doing clinical research…

24. ICH-GCP - Goals Reduce rising cost of health care
Benefits
Reduce rising cost of health care
Reduce escalating R&D costs
Minimize delay in making new treatments available to patients
Goals
Decrease country-to-country differences in guidelines
Decrease differences between regulatory authorities
Goals are designed to:
Streamline drug development and regulatory process
Increase efficiency of clinical research and
enforcement of GCP guidelines
The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) was established in 1990 as a joint regulatory/industry project to improve, through harmonization, the efficiency of the process for developing and registering new medicinal products in Europe, Japan and the United States, in order to make these products available to patients with a minimum of delay.
The six parties to ICH represent the regulatory bodies and research-based industry in the three regions, Europe, Japan and the USA, where the vast majority of new medicines are currently developed.
The ICH process has achieved success because it is based on scientific consensus developed between industry and regulatory experts and because of the commitment of the regulatory parties to implement the ICH tripartite, harmonized guidelines and recommendations.
The Fourth International Conference on Harmonization (ICH 4) Brussels, July 1997, marks the completion of the first phase of ICH activities in which significant progress has been made towards the goal of reducing duplication in the process for developing new medicinal products and submitting technical data for registration.
The next slide presents what should be the Pfizer mantra for doing clinical research…

25. GCPs: roles of sponsor, investigators, monitor

26. Sponsor ICH sections E6 5.1-5.23
Definition: an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial
Medical expertise; Trial design; Allocation of duties and functions

27. Sponsor Responsibilities
Monitoring: SOPs
Trial Management, Data handling
Record Keeping
Investigator selection & support (adequacy of CI’s to comply with GCPs)
Provide insurance or indemnify CI; Trial subject compensation
Financing
Notification/Submission to Regulatory Authority
Confirmation of Review by IRB/IEC
Information on Investigational Product (IB)
Manufacturing, Packaging, Labelling & Coding
Supplying & Handling
Record access
QA and QC

28. GCP– role of Sponsor SPONSOR Ability to conduct Archiving
Pre-trial Data
Audit/ Inspection
Regulatory
SPONSOR
Monitor
Protocol
CRF
Patient Follow-up
Annual/Safety Rep.
Informed Consent
Documentation
Report SAEs
Drug Control

29. Monitor Selected by sponsor
Appropriately trained & familiar with GCPs, regulations, product, protocol, SOPs
Ensures that trial is conducted & documented properly
‘Communication link’ between sponsor & CI
On site monitoring visits pre-, during, post-trial
Verify compliance to procedures
Notifications, applications, submission, reports are accurate, complete, timely/dated
Identifies & corrects problems. Communicates deviations to investigator

30. Investigator
ICH sections E
A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals, the investigator is the responsible leader of the team and may be called the principal investigator” ICH Guideline for GCP 1.34

31. Investigator Qualifications
Appropriate education and training, with evidence there of (e.g. CV, certificate/diploma)
Experience and respect in therapeutic field of study
Publication record
Reputation and Integrity
Adequacy and quality of staff
Access to and adequate number of patients for the study

32. Investigator Responsibilities
(Contribute to) Understand & comply with protocol
Obtain ethical approval
Obtain inform consent
Ensure adequate medical care of trial subjects
Accountability & storage of investigational product
Ensure adequate resources (NB: capacities in DECs)
Appropriate supervision &/or delegation

33. Investigator Responsibilities
QUALITY CONTROL:
PERMIT MONITORING, AUDITING AND INSPECTIONS
Sponsor: Section ICH GCP
“The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data generated, documented, and reported in compliance with the protocol, GCP and the applicable regulatory requirements.”
Investigator: Section ICH GCP
“The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).”

34. Investigator Responsibilities
Documentation
“If it is not written, it did not happen”
Document what happened and well as what did NOT happen
Assure direct access to records
Submit progress reports to IRB/EC
Promptly report all SAEs to sponsor and IRB/EC (if required)
Report all Adverse Events and lab abnormalities to sponsor
A useful tool for the Pfizer Team can be to provide a “Study calendar” – a tool to remind the investigators and personnel about key deliverables and pending actions (not our responsibility but a good practice)

35. Misconduct at Investigational Sites n = 118, SW Woollen, FDA’s OGCP, 2001

36. Misconduct at Investigational Sites
Failure to follow the protocol (70)
Falsification (67)
Informed Consent Issues (55)
Failure to report adverse events (40)
Qualifications of persons performing physicals (27)
Inadequate Records (25)
Failure to get IRB approval, report changes in research (20)
Failure to follow FDA regulations (13)
Charging for the test article (9)
Drug accountability (7)
No active IND (7)
Violations of GLP regs (7)
Misleading advertisements (5)
Blinding (3)
No 1572 (2)
Monitoring practices (2)
IRB shopping (1)
n = 118, Stan W. Woollen, FDA’s OGCP, 2001

37. GCP – Role of Investigator
Ability to conduct
Archiving
Resources
Audit/ Inspection
Medical Care
Monitor
Ethics Approval
INVESTIGATOR
Patient Follow-up
Protocol Adherence
Annual/Safety Rep.
Drug Control
This is a complex system of requirements – a systematic review of these aspects is useful both within the Pfizer team and with the site team
Documentation
Report SAEs
Informed Consent

38. Safety in clinical trials

39. Safety: definitions
Adverse Event (or Adverse Experience) = Any untoward medical occurrence in a patient or clinical investigation subject administered pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment
Adverse Drug Reaction (ADR) = All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reaction

40. Safety: definitions
Unexpected Adverse Drug Reaction = An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., IB for an unapproved investigational medicinal product)
Serious adverse event (experience) or reaction = any untoward medical occurrence that at any dose:
results in death,
is life-threatening (an event in which the patient was at risk of death at the time of the event; not an event which hypothetically might have caused death if it were more severe)
requires inpatient hospitalization or prolongation of existing hospitalization
results in persistent or significant disability/incapacity, or
is a congenital anomaly/birth defect.

41. Safety: definitions Severe DIFFERENT from Serious
Severe = Refers to the intensity (severity) of a specific event (minor, moderate, severe) and can be of relatively minor medical significance (e.g. severe headache).
Serious = Refers to the previous definition.
Based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning.
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

42. Safety Information and reporting : Sponsor’s obligations
Responsible for the ongoing safety evaluation
Promptly notify all concerned investigators & regulatory authorities of findings that could affect adversely the subjects safety
Adverse drug reaction reporting
Expedite the reporting to all investigators of all adverse drug reactions that are both serious and unexpected + regulatory requirements
CI  Monitor, Sponsor  IRB/EC; Health/Regulatory authorities; DSMC
Alert form: 24h; SAE Report Form: 5 wd’s

43. IEC / IRB: Independent Ethics Committees/ Institutional Review Boards
In accordance with the ICH-GCP guidelines, every clinical trial establishes procedures to ensure the review and the approval of the clinical research protocol, informed consent documents, and the suitability of the investigator by the IRB/IEC.
It is therefore, essential to understand the existence & composition, responsibilities and the requirements for the review of such research. 1

44. IEC / IRB: Independent Ethics Committees/ Institutional Review Boards
Any board, committee, or other group formally designated by an institution to
review,
approve the initiation of, and
conduct periodic review of,
biomedical research involving human subjects.
In accordance with the ICH-GCP guidelines, every clinical trial establishes procedures to ensure the review and the approval of the clinical research protocol, informed consent documents, and the suitability of the investigator by the IRB/IEC.
It is therefore, essential to understand the existence & composition, responsibilities and the requirements for the review of such research. 1

45. IEC / IRB
Independent body (a review board or a committee, institutional, regional, national or supranational)
Constituted of medical/scientific professionals and non-scientific professionals and non-scientific members,
Responsibility:
to protect the rights, safety and well-being of human subjects involved in a trial and
to provide public assurance of that protection by:
Reviewing and approving/providing favorable opinion on, trial protocol, suitability of the investigator(s), facilities,
And the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
Ref: Applied Clinical Trials Vol 6, No 12, Dec 1997

46. IEC / IRB
The legal status, composition, function, operations, and regulatory requirements pertaining to IEC’s may differ among countries, but should allow the IEC to act in agreement with GCP as described in the ICH-GCP guideline.
Other names of such include: independent review board, institutional review board, independent ethics committee, institutional ethics committee, committee for the protection of human subjects.
Ref: Applied Clinical Trials Vol 6, No 12, Dec 1997

47. IEC/IRB Functions and Operations Composition
Heterogeneous: at least 5 members; ar least one member with primary area of interest in a non-scientific area; at least one member independent of the trial site
Without conflicting interest
Nonmembers (special expertise) may be invited ad hoc
Functions and Operations
Meetings: frequency, scheduling, notification, quorum, hierarchy, minutes
Procedures: submission requirements, confidentiality, majority vote, appeal, amendments
Reports 4

48. Criteria for Approval Suitability of investigator Qualifications
Experience
Time
Supporting staff
Available facilities
Suitability of protocol
Scientific efficiency
Justification of inconveniences and risks vs. Benefits
Equitable selection of subjects
Time provision
Monitoring the data
Confidentiality of subjects and data
Scientific efficiency:
the potential to reach sound conclusions with the smallest possible exposure of subjects.
Justification:
predictable risks/inconveniences weighed against anticipated benefits of the subjects and/or others. 8

49. Remember !
Inform subjects of any new relevant information as it becomes available
Consent should be in writing
Language used: non-technical and understandable by the subject
Provide sponsor with access to patient’s medical records
Provide patient with a copy of the signed and dated consent form
THE INFORMED CONSENT PROCESS IS BASED ON THE MINIMUM STANDARDS IMPOSED BY THE DECLARATION OF HELSINKI:
The following points are of special interest:
1. The subject should be told of new information when it becomes available
-revision of forms as new information comes as the study progresses
2. Consent should be in writing
-personally signed and dated by subject (or legally suitable rep)
3. Language use: non-technical and understandable by the subject
4. Inform patient that regulatory authorities, IEC/IRB, monitors, auditors will be granted access to one’s medical records for SDV.
5. Subject should receive a copy of the signed and dated consent form

50. Informed Consent in Clinical Trials

51. Informed Consent
E6 Guideline for Good Clinical Practice: Section
“A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.”

52. Informed Consent Process
Intended to:
Give a subject all the information he or she reasonably would want about a study
Ensure that the subject understands this information
Give the subject an opportunity to agree to participate
Permit the investigator and the subject to exchange information freely and to ask questions
Provide protection for “vulnerable subjects”

53. Informed Consent Must comply with GCPs/Declaration of Helsinki
Must be approved by IRB/EC and sponsor prior to use (govt approvals may also be required)
Subject must be fully informed of all pertinent aspects of the trial
Should be revised for new information
Subject must be informed of new information

54. Informed Consent Must be understandable to the subject
practical
nontechnical
in the subject’s language
May not cause subject to waive legal rights
Must provide ample time to consider
Investigator must answer questions

55. Informed Consent
Consent form must be signed and personally dated by the:
subject (or subject’s legally acceptable representative)
person who conducted the informed consent discussion
Subject should receive a copy of the signed informed consent form

56. Informed Consent
Subject’s legally acceptable representative can sign for subject if:
subject not able to read
subject not able to understand
emergency situations
If subject or legal representative are unable to read, an impartial witness must be present and must sign and date the ICF

57. Elements of the Informed Consent Form (ICF)
The trial involves research
The purpose of the trial and previous experience
Trial treatments and probability of random assignment to each
Trial procedures, including invasive procedures
Subject’s responsibilities

58. Elements of the Informed Consent Form (ICF)
Experimental aspects of the trial
Reasonably foreseeable risks or inconveniences
Reasonably expected benefits, if any
Alternative procedures or treatments
Compensation/treatment if injured
Anticipated payment and/or expenses

59. Elements of the Informed Consent Form (ICF)
Participation is voluntary
Access to records will be granted
Confidentiality of records
Subject will be informed of new information
Contact information
subject rights
safety information
general information about the study

60. Elements of the Informed Consent Form (ICF)
Circumstances for discontinuation
Expected duration of trial
Number of subjects in the trial (number of sites)
Copy of the Informed consent document to the subject

61. Informed Consent Vulnerable Subjects
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy, in case of refusal to participate.
- ICH-GCP 1.61

62. Informed Consent Vulnerable Subjects
Children
Persons under discipline (soldiers, army, police)
Laboratory assistants
Medical students
Ethnic minorities
Persons in nursing homes
Those mentally incapacitated (poor understanding)
Persons with incurable diseases or in emergency situations
Those economically disadvantaged (unemployed, impoverished, homeless, nomads, refugees)