Transcript nonclinical laboratory study

GLP and GCP
Chapters 6 & 7
Fundamentals of US Regulatory Affairs
7th Edition
Good Laboratory Practice (GLP)
Regulations
Chapter 6
Objectives
• Review the history and purpose of GLP
regulations
• Learn the key GLP regulation components
• Examine the implications of noncompliance
History of GLPs (Why?)
Two Famous Examples of FDA Inspections of Toxicology Studies
• G.D. Searle and Company
–
–
–
–
–
–
Questionable test data
Sloppy work
Untrained personnel
Poor data collection
Poor analysis
Poor review and reporting practices
• Industrial Bio-Test Laboratories (IBT)
–
–
–
–
–
Scientific misconduct
Fabrication of Data
Replacement of dead animals with healthy ones
Changes in the Interpretation of Histopathology Slides
Changes in Report Conclusions to make them look more favorable
• Still goes on today!!!
Introduction
• The FDA requires manufactures of human drugs,
biopharmaceuticals and biological products, animal drugs,
medical devices, electronic and food additives to demonstrate
the safety of their products prior to use in humans or in the
case of animals , prior to use in the indicated species (for the rest
of this review, - the manufacturer of … will be referred to as ‘drugs’)
• Compliance with 21 CFR Part 58 – the Good Laboratory
Practice (GLP) regulation is intended to assure the quality and
integrity of the safety data used to support the application s
for research or marketing permits for FDA regulated products.
• GLP Compliance allows for accurate reconstruction of the
conduct of a nonclinical study based on quality record keeping
and reporting.
GLP Regulations Vary with Agencies and Nations
• FDA - FD&C Act 1938 and 21CFR58
– FDA is currently revising and updating
• US EPA – TSCA (40CFR792) and FIFRA (40CFR160)
– Applies to chemical substances, mixtures, pesticides
• OECD (North America, Europe and Asia) – ‘EU Requirements’
– Similar to FDA GLPs but includes EPA compounds
• MHLW (Japanese FDA)
– Similar to FDA GLPs
• Mutual Recognition Agreement
– US FDA, EU and Japanese FDA generally accept each others GLPs (report should
state that it meets all 3 agency GLPs)
– However they do not accept Chinese GLPs
• FDA, EPA and MHLW GLPs are regulations and required
by law, OECD GLPs are voluntary
– Requirements for all 3 should be met in the Toxicology and Safety
Pharmacology reports
GLPs prevent Fraud
• GLPs were designed to ensure data quality and to reduce
fraud by requiring specific documentation be kept
regarding several key areas including:
–
–
–
–
–
–
–
–
Laboratory staff
Facilities and Operations
Equipment
Test and Control Articles
Protocol
Conduct of study (what happened)
Quality Assurance
Achieving of data, records and specimens
• Specific Retention Time required for all for the above for
marketed drugs (different for discontinued drugs).
Definition of a Study (1/4)
• A ‘nonclinical laboratory study’ means in vivo or in
vitro experiments in which test articles are studied
prospectively in test systems under laboratory
conditions to determine their safety (not in the clinical
trials or field trials in animals) .
Types of GLP Studies (2/4)
• Contract Research Organization or In-house
Studies:
–
–
–
–
–
–
Acute, Subchronic, Chronic Studies
Carcinogenicity and Genotoxicity Studies
Development and Reproductive Toxicology Studies
Dermal/Eye/Venous/Muscle Irritation Studies
Immunogenicity/Antigenicity Studies
Bioanalytical Studies of Samples from Dose Groups of Study
Animals (Pharmacokinetics/Toxicokinetics)
– Validation of analytical methods for GLP studies (TK and
formulation analysis)
– Safety Pharmacology Studies (Cardiovascular, Respiratory and
CNS)
External Types of Studies (3/4)
• Laboratories that analyze samples that are
generated by GLP studies, they do not conduct
the study (can be separate from the laboratory that conducts the in
life study):
–
–
–
–
–
–
Clinical Chemistry
Hematology
Urinalysis
Histology and Pathology
Toxicokinetics
Validation of analytical methods for GLP studies (TK and
formulation analysis)
– Immunogenicity Assays
Types of Studies Not Covered by GLP (4/4)
•
•
•
•
•
Basic Research (Primary and Secondary Pharmacology)
Proof of Concept Studies
Exploratory Pharmacokinetic Studies (DMPK)
Dose-Range Finding Studies (Toxicology)
Primary Pharmacodynamic Studies
• Analytical Quality Control Testing for Clinical and
Commercial Studies
• Stability Testing of Clinical and Commercial Products
• Studies using Human Studies
• Field Trials in Animals
FDA GLP Subparts and Sections of 21CFR58 (1/10)
(Subpart A – General Provisions)
Subpart A 58.1– Scope
58.3 Definitions
58.10 Applicability to Studies performed under Grants and Contracts
58.10 Inspection of a testing facility
Subpart A 58.3: Definitions
–
–
–
–
–
Act
Test Article
Control Article
Nonclinical Laboratory Study
Applications for Research or
Marketing Permit
• IND / NDA / BLA
• Notice of Claimed Investigational
Exemptions for a New Animal Drug /
New Animal Drug Application
• Application for Premarket Approval
of a Medical Device / Product
Development Protocol for a Medical
Device
–
–
–
–
–
–
–
–
–
–
–
Sponsor
Testing Facilities
Person
Test System
Specimen
Raw Data
Quality Assurance Unit
Study Director
Batch
Study Initiation Date
Study Completion Date
FDA GLP Subparts and Sections of 21CFR58 (2/10)
(Subpart A – General Provisions)
• Subpart A: 58.10 Application to Studies Performed
under Grants and Contracts
– Applies to CROs to perform all or part of a nonclinical
laboratory study submitted to the FDA as part of an
application
• Sponsor is responsible to tell the CRO the studies are GLP
• Protocol includes a statement about the regulatory standards
under which the study will be conducted (FDA, OECD, EPA, MHLW)
• Implied that the site should be inspected (audited) by the sponsor
if never inspected by the FDA
FDA GLP Subparts and Sections of 21CFR58 (3/10)
(Subpart B – Organization and Personal)
• 58.29 - Personnel (Job Descriptions / Training Records)
• 58.31 - Testing Facility Management
–
–
–
–
Responsible for approving a test facilities Standard Operating Procedures (SOPs)
Assigning a Study Director prior to initiation of study and replacing as necessary
Responsible for Test and Control Articles
Make sure the study complies with GLP
• 58.33 - Study Director
– Overall responsibility for the study’s design, conduct, reporting and compliance
with GLPs and SOPs
– Document and assess all circumstances and if their impact on the study and
corrective actions
– Not the principle investigator/ contributing scientist if the study is conducted over
different sites
• 58.35 - Quality Assurance Unit
•
•
•
•
Responsible for ensuring that studies are conducted in accordance with GLPs
Is independent of the study
Maintain a master schedule of GLP studies and inspect the CRO accoding to the schedule as defined
by SOPs to insure GLP compliance
Responsibility – Audit everything - see Subpart A 58.3
FDA GLP Subparts and Sections of 21CFR58 (4/10)
(Subpart C - Facilities)
Think SOPs!
• 58.41 – General
• 58.43 – Animal Care Facilities
• 58.45 – Animal Supply Facilities
• 58.47 – Facilities for handling test and control articles
• 58.49 – Laboratory Operation Areas
• 58.51 - Specimen and Data Storage Facilities
FDA GLP Subparts and Sections of 21CFR58 (5/10)
(Subpart D - Equipment)
• 58.81 – Equipment Design
– Computer systems are not covered under GLPs but are
included in an FDA inspection and must insure the quality
and integrity of the study
– 21CFR11 – Electronic Records and Electronic Signatures
established the criteria the FDA uses for electronic records,
electronic signatures and hand written signatures executed
to electronic records to be trustworthy
• 58.63 Maintenance and Calibration of Equipment
– SOPs establish the maintenance and the frequency of
calibration of all equipment (scales to air handelers)
FDA GLP Subparts and Sections of 21CFR58 (6/10)
(Subpart E – Test Facility Operation)
• 58.81 – Standard Operating Procedures (SOPs)
– Intended to ensure that laboratory procedures ad processes are
consistently performed by all individuals in the facility
– Must be available to all staff anywhere in the facility
– Mandatory review of all SOPs as needed by Facility Management
– The protocol describes ‘what’ needs to be done, SOPs describe ‘how’
– All deviations from SOPs need to be documented in the records and
report by the study director and the impact on the study assessed
– If specific instructions in the protocol are differnet than the SOP, then
this is a deviation of the SOP and needs to be documented
• 58.83 – Reagents and Solutions
• 58.90 - Animal Care
FDA GLP Subparts and Sections of 21CFR58 (7/10)
(Subpart F – Test and Control Articles)
• 58.105 – Test and Control Article Description
– Test article - is any food additive, color additive, drug,
biopharmaceutical, biologic product, medical device or electronic
prodict intended for human use
– Control article – any article other than the test article intended to be
used as a control in the study
– GLPs require the characterization, stability testing sample retention
and inventory of test and control articles
• 58. 107 – Test and Control Article Handling
– Requires the CRO to document the proper storage, handling,
distribution, identification, receipt and distribution of the article,
showing the ‘chain of custody’ (think SOPs)
• 58.113 – Mixtures of Articles with Carriers
– Analytical methods to demonstrate the article is consistently mixed
with the carrier (usually sampling from the top, middle and bottom of
the mixture is sufficient.
FDA GLP Subparts and Sections of 21CFR58 (8/10)
(Subpart G – Protocol for and Conduct of a Nonclinical Study)
• 58.120 – Protocol
– A formal plan of the study
• 58.130 – Conduct of a Nonclinical Laboratory Study
– The execution, changes to and deviations during the study
need to be documented and the impact assessed and
recorded.
– All records in ink and any changes require initials and date
of the change. General a single line through the data.
FDA GLP Subparts and Sections of 21CFR58 (9/10)
(Subpart J – Records and Reports)
• 58.185 – Reporting of Nonclinical Laboratory Results
– Standard list of what is in the final report
– FDA inspections of reports follow the Compliance Program
7348.808.
– GLP statement not required but implicitly required, covered
under 21CFR312.23(a)(8)(b)(iii) Investigational New Application
and 314.50 (d)(2)(v) Application for FRA approval to market a
New Drug
• 58.190 – Storage and Retrieval of Records and Data
– Establishment of an Archive and Archivist for the storage of all
raw data, documentation, protocols, specimens, and interim /
final reports and kept in a secure storage area in accordance
with 58.195
• 58.195 – Retention of Records
FDA GLP Subparts and Sections of 21CFR58 (10/10)
(Subpart K – Disqualification of Testing Facilities)
• 58.200 - Purpose
• 58.202 – Ground for disqualification
• 58.204 – Notice of and opportunity for hearing on
proposed disqualification
• 58.206 – Final Order of Disqualification
• 58.210 – Actions upon Disqualification
• 58.213 – Public disclosure of information regarding
disqualification
• 58.215 – Alternatives or additional action to disqualification
• 58.217 – Suspension or termination of a testong facility by
a sponsor
• 58.219 – Reinstatement of a disqualified testing facility
Proposed Changes to GLP
• In December of 2010 the FDA issued a public
request for comments on proposed revisions
to the GLPs
FDA Inspection of GLP Laboratories and the
Consequence of Noncompliance
• All laboratories in the USA can be inspected by
the FDA. The FDA needs to request foreign
laboratories to conduct GLP inspections.
• Bioresearch Monitoring Program (BIMO) to
address both domestic and international
inspections of nonclinical laboratories operating
under US GLPs (Compliance Program Guidance
7348.808)
• 483s (Inspection Observations) Warning Letters
Consent Agreements Disqualifications
Good Clinical Practice (GCP)
Chapter 7
Objectives
• Overview of GCP for drugs and devices
• Overview of clinical trial monitoring
responsibilities
• Differences between HIPAA: FDA’s Common Rile
and HHS Privacy Rule
• Overview of Drug and Device Regulations
• Distinguish Clinical Trial Requirements at the
State and Federal Level
• Provide Regulator Compliance Guidance
Laws, Regulations and Guidelines
• Lots of them - CFRs, Guidances, ICH (Chapter references 67 of
them)
• GCP are international ethical and scientific quality standards used
for designing, conducting, monitoring, auditing, analyzing,
recording and reporting clinical trials involving participation of
human subjects.
• Compliance insures the public that the study subject’s rights, safety
and well-being are protected and consistent with the ethical
principles originating in the Declaration of Helsinki
• Primary Objectives:
– Protect human subjects during clinical trials
– Protect patients who might receive an approved product in the future.
Clinical Trials Conduct and GCPs
• GCPs are covered in the US by 21CFR, Guidances, laws, regulations
at the state and federal levels and cover
– Clinical Trial Responsibility
– Institutional Review Boards
– Investigator Obligations
• US Agencies with GCP regulations include:
–
–
–
–
DHHS – Office of Research Integrity
FDA – 21CFR 11, 50, 54, 56, 58, 312 and 314
NIH – Office for Human Research Protections
Office of Human Subjects Research and Department of Clinical
Bioethics
– National Human Genome Research Institute
• International - ICH E6: Guidelines for Good Clinical Practice
• EU - EMA - Clinical Directive (2001/20/EC)
GCPs primarily apply to the IND
• The submission of an IND is required prior to
conducting a human clinical trail in the US for an
unapproved new drug or a new use for a marketed
drug. Key personnel are defined by 21 CFR 50 and 312.
– Sponsor: a person who initiates a clinical investigation but
does not conduct the investigation
– CRO: a person or corporation or agency acting as an
independent contractor for the sponsor and who assumes
one of more of the sponsor’s obligations
– Sponsor-Investigator: an individual who both initiates and
actually conducts, alone or with others, a clinical
investigation
Clinical Trials Responsibilities
Sponsors Obligations
Primary Responsibility -Focus on the clinical study’s ethical,
scientific and regulatory obligations
•
•
•
•
•
to protect each study subject’s
rights, safety and welfare
Ensure the proposed clinical trail is
adequately supported by
nonclinical and clinical information
on the investigational product
Ensure all clinical trial study
personnel are adequately qualified
and trained
Ensure the protocol is approved by
the IRB or Independent Ethics
Committee (IEC)
Ensure all decisions made on behalf
of study subjects are made by a
qualified physician
•
•
•
•
•
•
•
Ensure all clinical tasks are
performed by qualified personnel
Ensure all clinical trials information
is recorded
Ensure all informed consents are
obtained and freely given
Ensure the confidentiality records
are protected
Ensure the investigational product
is prepared under cGMPs
Ensure quality systems are in place
and have been implemented
Report unanticipated adverse
events
Institutional Review Board (IRB) Obligations
The IRB [IEC, Ethics Committee, Independent Research Committee
(IRC) or Research Ethics Board (ERB)] protects the rights and welfare of
human subjects in clinical trials (21CFR56). Each trial (domestic or
foreign) must get IRB approval prior to commencement of the trial
• Ensure risks to subjects are minimized and reasonable in relation to
anticipated benefits
• Ensure patient selection is as equitable as possible relative to
demographics and the clinical trial’s purpose
• Review of protocol, informed consent form (ICF), and Investigator’s
Brochure (IB)
• Ensure a pediatric clinical trial is conducted according to
regulations
• Provide initial and continuing review of the ongoing clinical trial at
different intervals
• Request more information if required
• Approve, disapprove and/or terminate a trial
Investigator Obligations
Primary Responsibility is to ensure the rights, safety and welfare of the
study subjects
• Follow the protocol and its specific procedures
• Ensure the trial’s proper conduct at the sites under their authority
are in compliance with the signed agreement. The investigational
plan, the protocol and all applicable FDA and other government
regulations
• Prepare timely and accurate reports to the IRB, sponsor, medical
monitor and FDA if acceptable
• Maintain accurate records
• Control the investigational new drug product
• Ensure that patients sign the ICF before the study procedures begin
• Maintain appropriate and scheduled communication with the
study sponsor, medical monitor and IRB
HIPPA
(Health Insurance Portability and Accountability Act Privacy Rule)
• For the use and disclosure of protected health
information for research purposes
• Established in 1996 and states the minimum
federal requirements for protecting the privacy of
individually identifiable health information.
• Define how Protected Health Information (PHI)
can be used in clinical trials
– Health status, health care, payment history, name,
address, phone/fax number date of birth email
address, SS#
Common Rule
Federal Policy for the Protection of Human Subjects
• Codified under 45CFR46, subpart A and 21CFR
50 and 56.
• Consent to participate in the research study as
a whole not simply for the research use or
disclosure of protected health information
GCP’s for Device Trials
(cover under medical devices)
• Are different than drugs
• ICH E6 states that an FDA form 1572 must be
submitted for a drug trial
• It does not have to be submitted in a medical device
trail, however, the sponsor should provide the
elements listed under 21CFR812.43*c) to the
investigator and the principle investigator (PI) should
sign this Investigator Agreement prior to commencing
a device clinical trial.
• ISO - Internal Standard 13155:2011, Clinical
investigation of Medical Devices for Human Subjects –
Good Clinical Practice applies
Clinical Trial Regulations
• Designed to ensure that clinical trial subjects are
protected from harm, that the subjects’ rights are
protected and that the trial’s scientific integrity is
assured. They require:
–
–
–
–
A strong, effective and efficient regulatory framework
Willingness of investigators to participate and comply
Adequate site/research infrastructure
Willingness of patients to participate and comply
• Differ between drugs and Devices
• Differ at the Federal and State Level
Federal Clinical Trial Requirements - Differences
Regulation
Drugs
Devices
IND/IDA
21CFR 312
21CFR 812
IND/IDE Application Process
21CFR 312.23
21CFR 812.20 and 812.25, 27
Form FDA 1571
21CFR 312.23(a)(1)
Form FDA 1572
21CFR 312.53(c)
Foreign Clinical Trials not conducted under
an IND
21CFR 312.120
Legal Representation
21CFR 321.52
Labeling
21CFR 312.6
21CFR 812.5
Responsibilities of Sponsors and
Investigators
21CFR 312 subpart D
21CFR 812 subpart C and E
Records and Reports
21CFR 312, 57, 58, 62, 64, 68
21CFR 812.140 and 150
Safety Reporting
21CFR 312.32
21CFR 803
Bioavability and Bioequivalence
Requirements
21CFR 320
Quality System Regulations
21CFR 812 .43(c) not required for
devices
21CFR 820
Clinical Trial Regulations Applicable to IND and IDA
Regulation
Source
Electronic Records; Electronic Records
21CFR11
Protection of Human Subjects (Informed
Consent)
21CFR50
Financial Disclosure by Clinical
Investigators
21CFR54
IRBs
21CFR56
Form FDA 3674 (Certification)
Food and Drug Administration
Amendment Act of 2007
HIPPA
Privacy Act
HIPPA
Pediatric Clinical Trials
21CFR50 Subpart D – Additional
safeguards for Children in Clinical
Investigations
State Clinical Trial Requirement
• Compliance with individual state clinical trial
regulations is one of the most difficult
compliance issues for a sponsor as state
requirements may differ form federal
regulations.
• Same holds true for international clinical
programs
“Need legal advice for different states
or countries”
State Clinical Trials Insurance Requirements
• About half of the state legislatures have
passed clinical trial legislation and /or
instituted special agreements requiring health
plans to pay the cost of routine medical care
for study subjects
• Table 7-4 lists individual states
Compliance Issues
Clinical Trial Regulatory Compliance
• Most noncompliance in clinical trial research is due to
clinical trial or protocol misconduct
• The investigator, the sponsor, the institution and the
IRB are responsible for subject safety
• Enforcement:
– DHHS(45CFR46) - noncompliance reported to IRB,
Institutional officials and agency
– FDA (21CFR56.120-124)
• IRB must report to the agency
• Has enforcement authority [Office of Regulatory Affairs
(Bioresearch Monitoring (BIMO)) that does onsite inspections and
audits]
– NIH
Financial Disclosure
• Anyone submitting a marketing application to
the FDA must also submit lists of participating
clinical investigators who conducted clinical
trials and certify and/or disclose certain
financial arrangements
Pharmacovigilance in Clinical Trials
• Sponsors are required to review all
information pertaining to the safety of an IND
from any domestic or foreign sources.
• An IRB is also required to continue to review
the study at set intervals to assure the
protection of human subjects’ rights and
welfare.
Data Monitoring Committee (DMC)
• A group of individuals with relevant expertise
who regularly review accumulating data from
one or more ongoing clinical trials. The DMC
advises the sponsor regarding the ongoing
safety of enrolled and prospective study
subjects and the continuing validity and
scientific merit if the trial.
Clinical Trial Noncompliance
Common Issues
• Clinical Trail Monitoring Noncompliance Issues
–
–
–
–
–
–
–
–
–
–
Falsified Data
Plagiarism and falsified study results
False or misleading protocols
Failure to report Unanticipated AE
Implementing changes to the protocol or ICF without first submitting it to
the IRB
Commencing significant changes to a protocol without first submitting for
FDA approval
Enrolling a study subject who does not meet the inclusion criteria
Failure to withdraw study subjects who no longer meet inclusion criteria
or who meet one or more exclusion criteria
Failure to make timely reports to the IRB
Research conducted without IRB review
Investigator Noncompliance Issues
• Unreported changes to the protocol
• Misuse or nonuse of the Informed Consent
Form (ICF)
• Failure to submit protocols to the IRB in a
timely fashion
IRB Noncompliance Issues
• Inadequate research protocol review
• Failure to ensure that the ICF and process provide
sufficient information to allow prospective subjects to
make an informed decision as to whether to participate
in the research
• Failure to ensure that the research design includes
adequate data monitoring and any additional
safeguards necessary to protect the welfare of
particularly vulnerable patients
• Failure to conduct continuing review of research at
intervals appropriate to the degree of risk
• Failure to maintain adequate records of IRB business
• Insufficient information to make determinations
required for approval of research
IRB Noncompliance Issues (con’t)
• Inadequate review at convened meetings
• Inadequate continuing review
• Contingent approval of research with substantive changes
and no additional review by the convened IRB
• Failure to conduct continuing review at least once annually
• Meeting convened without quorum due to the absence if a
nonscientist
• Meeting convened without quorum due to a lack of a
majority
• Members with conflicting interest participated in IRB
review of research
Institutional Noncompliance Issues
• Failure to ensure that the IRB has the required
number of members and functions in
accordance with regulations
• Failure to ensure that the IRB receives
appropriate institutional support and staffing
• Failure to ensue that investigators meet their
obligations to the IRB
Regulatory Compliance Sanctions
At the DHS Level
• DHHS regulations di not specify administrative actions
for noncompliance other than the following
– Failure to comply with regulations can result in termination
or suspension of support for agency projects.
– Demonstrated inability to carry out IRB responsibilities in
accordance with DHHS regulations can be cause for
suspension or withdrawal of approval of an institution's
assurance
– ‘Systemic failure to abide by the terms and conditions or
an institution's assurance will result in withdrawal of
approval of the assurance.
Regulatory Compliance Sanctions
At the FDA Level
• Failure to comply with regulations in an FDA-regulated trail
can result in the assessment of both civil and criminal
penalties for clinical misconduct. (FDAAA 301(jj))
– Suspension of a clinical trial until resolution of the reason(s) for
misconduct
– Cancellation of clinical trial approval
– Rejection of IND or IDE application due to incomplete,
inadequate or fraudulent documentation
– Rejection of any publication that uses data from a noncompliant
clinical trial
– Disqualification of a clinical investigator from receiving
investigational drugs biologics and devices when an investigator
has repeatedly or deliberately violated regulations or has
submitted false information to the sponsor in a required report.
Clinical Trial Databases
(www.clinicaltirals.gov)
• FDAMA of 1997 requires sponsors of certain
key pharmaceutical and biologics clinical trials
to submitted limited data to the NIH’s clinical
trails database
• There are mandatory fields to complete
• Must be completed within 21 days of enrolling
the first patient
Pharmacovigilance Reporting
• Clinical Sponsors will be required to submit
annual development safety update report (US
and EU Annual Safety Reports)
– ICH E2F Draft Consensus Guideline: Development
Safety Update Report (Standard format)
– Report reviews and evaluates pertinent safety
information
IRB Registration
• IRB is required by FDA rules to supply:
– Contact Information
– Number of Active protocols involving FDA
regulated products reviewed during the last 12
months
– Description of the types of FRA-regulated
products involved in the protocols reviewed