Clinical Trial Regulations
P.Olliaro
Nov04
Clinical Trials: a Phase of Product Development
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12
53
11
10
100
1000va
lidat
ed id
ea
lead
cand
idate
IND/p
hase
I
phas
e II
phas
e III
NDA
ADME40%
Toxicity20%
Efficacy40%
ADME33%
Toxicity34%
Efficacy33%
ADME12%
Toxicity38%
Efficacy50%
< discovery > <pre-clinical> < clinical >
R&D ATTRITION RATESR&D ATTRITION RATES
OVERVIEW OF THE R&D PROCESS
0
25
50
75
100S
uc
ce
ss
ra
te %
DISCOVERY
PRE-DEVELOPMENT REGULATORYREVIEW
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
INDfiling
NDAfiling$ 4.9-5.3
million $ 9.9-26.6 million
$ 5.3-8.0 million
$ 76-115 million
$ 40-125 million
TOTAL Discovery + Development 115-240 million(including cost of failure)
Cost of TB New drug - Source: GATB webpage
NEED
OPPORTUNITY
NEW TOOL
DEPLOYMENTIMPLEMENTATION
INTELLIGENCE,SURVEILLANCE R&D
“OPERATIONALRESEARCH”
MONITORING& EVALUATION
Regulatory Clinical studies (Phase I, II, III)
First In Humans
Discovery& Pre-clinicalResearch
Registration
Post- registration studies to inform policy
Policy,Practice
Capacities & capabilitiesfor sustained, durable clinical research
in Developing Countries
GCP, GCLP requirements
The Critical Path of a Clinical Trial
*START *END
Data Data Statistical FinalEntry Clean-up Analysis ReportData Data Statistical FinalEntry Clean-up Analysis Report
Study Termination
Periodic Monitoring
Patient Recruitment
Site Assessments
Planning
Protocol • CRF
Regulatory andEthical Approval
Trial Documents • Materials
Select Investigators
Initial Visits
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
GCPs (& GCLPs)ICH Guidelines
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
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
Ref: www.ifpma.org
www.fda.gov
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
Why GCPs? Historical eventsEvent Year Reaction
Publication of a book (“The Jungle” by Upton Sinclair) exposing the unsanitary conditions in Chicago slaughterhouses
1906 Pure Food and Drug Act: created the Food & Drug Administration Every product needed to be
accurately labeled Did not require testing for either
safety or efficacy More than 100 children die after taking Strep-Elixir (sulfanilamide and diethyleneglycol)
1938 Federal Food, Drug & Cosmetic Act required that drugs be tested for safety
Nazi Experiments conducted without consent of
participants caused unnecessary pain,
suffering and death absence of benefits for the
participants lack of adequate scientific
rationale
1948 Nuremberg Code – to prevent atrocities from happening again subject participation must be
voluntary physical or mental suffering or
damage is not acceptable subject has the right to withdraw
from the study at any time experiments must be supported
by strong science
Why GCPs? Historical eventsEvent Year Reaction
Children are born with phocomelia eventually linked to the
administration of Thalidomide to mothers for the treatment of morning sickness
Thalidomide had been tested in 300 individuals with no side effects
1962 Kefauver-Harris Amendment passed by the U.S. Congress experiments must be supported
by strong scientific material required evidence of efficacy
before approval evidence of safety before
testing in humans gave protection to humans in
research active review of test data before
approval 1964 Helsinki Declaration - Adopted by
the 18th World Medical Assembly (latest version 2000, Edinburgh, Scotland): Justice (Fair distribution of
burdens and benefits) Beneficence (Maximize benefit,
minimize harm) Non-maleficence (“Do no harm”) Respect (Autonomy, protect the
vulnerable)
Continuing Development ofGCP Guidelines USA( FDA GCP Regulations)
Protection of human subjects:Informed consent; Standards for IRB - 1981
Guidelines for monitoring of Clinical Investigations – 1988 EU: Good Clinical Practice for Trials on Medicinal
Products in the European Community - 1991 Japan: Good Clinical Practice, GCP Manual - 1991 WHO: Guidelines for GCP for trials on
Pharmaceutical Products - 1994
GCP is a process, not a book
Th
e st
and
ard
Investigator
Sponsor
ICH - International Conference on Harmonization
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
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.
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)
ICH-GCP - When? Introduced in 1996
ICH 1November 1991
ICH 2October 1993
ICH 3November 1995
Development of tripartite GCP agreement
Update status of:• tripartite agreement• progress toward harmonization
Review of progress toward harmonization in areas of:• efficacy• safety• quality assurance
ICH 4July 1997
Review and update of the implementation and impact of the ICH GCP Guideline
* 1996
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.
ICH-GCP - GoalsBenefits Reduce rising cost of health care Reduce escalating R&D costs Minimize delay in making new treatments available to
patientsGoals Decrease country-to-country differences in guidelines Decrease differences between regulatory authoritiesGoals are designed to: Streamline drug development and regulatory process Increase efficiency of clinical research and enforcement of GCP guidelines
GCPs: roles of sponsor, investigators, monitor
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
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
Monitor
Audit/ Inspection
Archiving
Patient Follow-up
Annual/Safety Rep.
DocumentationDocumentation
Report SAEs
Ability to conduct
Pre-trial Data
Regulatory
Protocol
Informed Consent
Drug Control
CRF
GCP– role of Sponsor
SPONSOR
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
Investigator
ICH sections E6 4.1 - 4.13 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
Investigator Qualifications
Appropriate education and training, with evidence there of (e.g. CV, certificate/diploma)
Experience and respect in therapeutic field of study
Publication recordReputation and IntegrityAdequacy and quality of staffAccess to and adequate number of patients for
the study
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
QUALITY CONTROL:
PERMIT MONITORING, AUDITING AND INSPECTIONS Sponsor: Section 5.1.1. 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 4.1.4 ICH GCP “The investigator/institution should permit monitoring and
auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).”
Investigator Responsibilities
Investigator Responsibilities
Documentation “If it is not written, it did not happen” Document what happened and well as what did
NOT happenAssure direct access to records
Submit progress reports to IRB/ECPromptly report all SAEs to sponsor and
IRB/EC (if required)Report all Adverse Events and lab
abnormalities to sponsor
Failure to follow the protocol ,
70
Falsification, 67
Informed Consent Issues
, 55
Inadequate Records, 25
Qualifications of persons
performing physicals , 27
Failure to report adverse events
, 40
Failure to get IRB approval,
report changes , 20
Failure to follow FDA regulations
, 13
Misconduct at Investigational Sitesn = 118, SW Woollen, FDA’s OGCP, 2001
GCP – Role of Investigator
Monitor
Audit/ Inspection
Archiving
Patient Follow-up
Annual/Safety Rep.
DocumentationDocumentation
Report SAEs
Ability to conduct
Resources
Medical Care
Ethics Approval
Informed Consent
Drug Control
Protocol AdherenceINVESTIGATOR
Safety in clinical trials
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
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.
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.
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
IEC / IRB:Independent Ethics Committees/ Institutional Review Boards
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.
Ref: Applied Clinical Trials Vol 6, No 12, Dec 1997
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
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.
IEC/IRBComposition 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
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
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
Informed Consent in Clinical Trials
Informed Consent
E6 Guideline for Good Clinical Practice: Section 4.8.1 - 4.8.15
“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.”
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”
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
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
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
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
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
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
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
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
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
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)
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