General Principles for Meeting Regulatory Responsibilities

Terry VandenBosch, RN, PhD, CIP, CCRP Senior Research Compliance Associate Office of Human Research Compliance Review University of Michigan June 1, 2010

Todays Discussion
Describe Best Research Practices (BRP) and Good Clinical Practices (GCP) Compare GCP requirements for FDA regulated studies and regulatory requirements for non-FDA regulated studies Identify common sense principles for implementing best practices and GCP in clinical studies

What is Best Practice

Experience-based Evidence-based? Effective and efficient practices to meet
1) ethical principles 2) federal regulations & guidance 4) state laws & practice acts 5) university policies and procedures 6) any applicable study SOPs

Best Practices = Responsible Research Practices

Ultimate Goal: Responsible Research Practices

The University of Michigan is committed to the highest standards of ethical behavior by faculty, staff, and students engaged in the conduct and administration of research and other scholarly activity.

UM Provost Policy Statement on Academic and Research Integrity

Ethical Principles & Best Practices

Ethical principles inform decision-making and basis for federal regulations and guidance Past abuses stimulate use of Best Practices
Nuremburg Tuskegee syphilis study Willowbrook retarded children hepatitis study

Are these ethical lapses and abuses all in the past?

Nicole Wan (healthy volunteer- died), 1996 Jesse Gelsinger (ineligible-died), 1999 Ellen Roche (healthy volunteer-died), 2001 Inadequate monitoring with overdose of pediatric subjectsPfizer FDA warning letter, April 9, 2010

Ethical Principles-Belmont
Belmont Report 1979
Summarized ethical principals identified by National Commission for the Protection of Human Subjects Prompted by the Tuskegee Syphilis Experiment and the Willowbrook hepatitis study 3 basic ethical principles:
(1) Respect for persons (2) Beneficence (3) Justice
The Tuskegee Study Group were invited to receive "special treatment", which was actually a diagnostic lumbar puncture Peter Buxtun, PHS venereal disease investigator, the Tuskegee whistleblower

Respect for Persons

Ethical convictions
Acknowledge autonomy of the individual Protect those with diminished autonomy

Applying the principle

Informed consent
The elements of informed consent Information, comprehension, voluntary

Vulnerable populations

Beneficence
Ethical convictions
Do no harm Maximize possible benefits Minimize possible harms

Applying the principle

Investigator & IRB

Minimize risks Weigh risks and benefits When appropriate, a plan to monitor and ensure safety

Justice
Ethical Convictions
Fairness in distribution of burdens and benefits of research participation

Applying the principle

Investigator-subject selection IRB asks Is the selection of subjects equitable?

Regulations
Regulations developed in response to egregious, harmful research conduct Developed on ethical principles Congressional legislation signed into law by President Laws interpreted in CFR (Code of Federal Regulations) by responsible federal agency CFR regulations detail how law is implemented Noncompliance with CFR may result in criminal prosecution, fines, sanctions or debarment from research

Regulations (contd)
Regulations are not specific Regulations dont address everything that is important in the protection of human subjects
No regulations address decision-making capacity of possible subjects

Regulations MUST be met

Federal Guidance and Information Sheets

Published by federal agencies to provide more information or to recommend best practices Interprets application of regulations Current thinking NOT legally binding FDA An alternative approach may be used if such approach satisfies the requirements of the applicable statue, regulations, or both Guidance should be met

University of Michigan Policies and Procedures

Standard Practice Guide
Approved by Regents Section 303, http://spg.umich.edu/section/303

Human Research Protection Program (HRPP) Operations Manual

http://www.hrpp.umich.edu/om/

IRB Guidance & SOPs

See IRB websites

What is GCP
A type of Best Practice term coined by the International Conference on Harmonization (ICH) and used by FDA Refers to FDA regulations, guidance and notices for Drugs, Devices & Biologics
FDA assures the safety and efficacy of pharmaceuticals, biologics, and medical devices on the market in the U.S.A.

What entities covered by FDA GCP?

IRB Investigator Research Sponsor

NIH- Scientific and ethical standards of human subject research

ICH E6 International Conference on Harmonization

Multi-national body, USA, EU & Japan, est. 1989 Meets periodically to resolve different technical requirements for drug registration
Goal: Create guidelines and standards for conducting clinical trials allowing sponsors to generate a single set of data to meet submission requirements of the three regions

Originally based on ethical principles from the Declaration of Helsinki-1964 with revisions Adopted as guidance for drugs/biologics by FDA in 1997 Also used by FDA in reference to devices

ICH-E6 GCP Definition

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 = Quality Data the Rights, Integrity, and Confidentiality of Trial Subjects are Protected = Ethics Adopted as guidance by FDA in 1997

FDA Regulations and ICH Guidelines

Companies that wish to have study data accepted by the regulatory agencies in the US, EU, and/or Japan need to follow the ICH guideline. Differences between FDA Regulations and ICH GCP Guidelines:
ICH Guideline states general principles is more prescriptive than regulations e.g., 21 CFR 50 requires signature and date of subject while ICH E6 says one should also have the signature of the investigator.

Why GCP?
Failures
Ethical Atrocities Preventable Research Deaths/Injury Scientific Fraud

Subject safety Public trust and support of research mission Assure valid data for evidence-based Health Care Drug development trajectory long, arduous, expensive (GCP assures safety and quality data) Useful products brought to market with known safety profile and effectiveness The better the GCP-the sooner the product is available for patients

Best Practices, GCP & Types of Studies

Investigator Initiated
May or may not be FDA regulated

NIH (HHS) supported

45 CFR 46

17 Federal agencies and the common rule

Part A of 45 CFR 46 e.g., Dept. of Energy, Dept. of Education

FDA Regulated
21 CFR 312 Drugs & Biologics 21 CFR 812 Devices 21 CFR 50 Protection of Human Subjects 21 CFR 56 Institutional Review Boards

Research Clinical Trials Best Practices and ICH E6 GCP

Both can be viewed as a series of key activities or practices
Order of activities may vary and may be simultaneous Multiple parties participate but PI remains accountable

Study scientific and ethical quality achieved by defining key study best practices and assuring oversight to implement them

Best Practices Key Activities

Obtain Informed consent Provide for Subject Safety & Medical Care Follow the IRB approved protocol or submit amendment to IRB Maintain Confidentiality Record keeping-Maintain accurate, current, organized records and submit reports Maintain communication with IRB Provide appropriate oversight of qualified staff FDA-Investigational Product Accountability FDA-Essential Documents Binder Additional areas
Conflict of interest Communication with sponsor (FDA) Shipping regulations

People and Paper Skills

Negotiation Communication Time management Record keeping Computer Organization Oversight of other research staff Detail-oriented Knowledge of regulations and their application Intimate knowledge of protocol

Informed Consent
Obtain Informed Consent

Informed Consent as a Process

Interpersonal communication skills assess subject understanding and motivation to participate Informed consent is freely given and is obtained from each subject prior to study participation The consent discussion is in language understandable to the participant or the representative and is done by a qualified person The consent process provides sufficient opportunity for the participant or the participants legally authorized representative to consider whether to participate The consent process minimizes the possibility of coercion or undue influence (Research is not the same as therapeutic txmt) The consent discussion is free of exculpatory language The IRB approved document without any changes and with the elements of informed consent is used Childrens assent & Parental Permission Adapted from AAHRPP, 2009

Informed Consent Monitoring

Privacy respected Voluntary Conducted as a process by PI Process follows the IRB approved protocol
Waiver of consent possible

Copy of consent given to subject Consent signed prior to any study procedures Re-consent completed and documented as appropriate 100% of consents used correct IRB approved version and were appropriately signed and dated

What does the public think?

Which one of the following do you think makes a greater contribution to mankind?
0.45 0.4 0.35 0.3 0.25 0.2 0.15 29% 40%

Percent

0.1 0.05 0
A person who gives blood

9%

10%

13%

A person who volunteers to take part in a clinical trail

A person who raises money for charity by running in a race

A person who donates an organ

Not sure/Refused

N=900

CISCRP/ODC Survey, 12/2006

It is a confusing time to be a subject-or to be thinking about becoming one

Moreno, 2001

Subject Safety
Provide for Subject Safety and Clinical Care

Adverse Events & Harms

.

Adverse event (AE) defined Prevent, monitor for, identify, provide immediate care for, track, analyze cause, report to IRB, may submit protocol amendment or changes to consent document & notify Sponsor (FDA) IRBMED Guidance and timetable for reporting AEs at http://med.umich.edu/irbmed/ae_orio/ae_report.htm Harms Physical Psychosocial Social Economic Legal Dignitary

What Can Result in Harms?

The protocol/treatment Side effects of drugs/biologics or adverse device effects NOT following the protocol NOT maintaining up-to-date records NOT maintaining communication with investigator and/or study sponsor Prevent harm Qualified person monitors overall study Monitor laboratory results and tests and treat as appropriate May withdraw subject from study Know emergency procedures for breaking a study blind Keep primary care provider in communication as appropriate AEs are graded by Seriousness Relatedness to the study Expected/Unexpected

The Protocol
Follow the Protocol or Amend it

The Tension in Research

The principal duty of a physician is to the well-being of the individual. The principal duty of society (social ethics) is to the greatest good for the greatest number of people. Research is protocol driven Clinicians often want to adapt the protocol for an individual

Know and Follow the Protocol

Changes to the protocol, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject. Read it
FDA-each person on study team signs it

Protocol Readily Available

No mix ups-Clearly label current version

Follow it
Prevent and track any protocol deviations
Notes to file-circumstances, CAPA Report to IRB and sponsor as applicable Amend protocol with IRB as needed

Follow randomization procedures If applicable, procedures follow data safety and monitoring plan (DSMP) submitted to IRB and funding agencies

Confidentiality
Maintain Confidentiality

Data Confidentiality & Security: Outcomes

Data maintained according to IRB approved protocol Access to confidential data is restricted Safe & secure storage
Dont share passwords!

Mobile device security for researchers at http://www.safecomputing.umich.edu/MDS UM Electronic data security Questions to Guide Research Protections at OHRCR website http://www.ohrcr.umich.edu/news/electronicdata. pdf

Implications for Confidentiality

Being notified only, with no re-consent or opt out process, before their information goes to a national database
47% completely unacceptable 20% somewhat unacceptable

No notification or re-consent at all, before their information is sent to a national database

54% completely unacceptable 16% somewhat unacceptable

How much do current and potential subjects want to be informed, give consent and maintain confidentiality of their data?

Record Keeping & Reports

Maintain Accurate, Current, Organized Records and Submit Reports

Study Files
Organized, accurate, up-to-date Direct/Indirect subject identifiers
Direct-subject identifiers stored with data Indirect-subject identifiers in key & not stored with data

Informed consent-stored with files? FDA-Complete, sign and submit FDA Form 1572 Work efficiently
Study schema of subject progress for complex procedures Checklist of forms completed

Maintain records for:

FDAtwo years after FDA approves NDA NIHthree years after study terminated HIPAA- six years after study terminated

ALCOA (FDA)
FDA Documentation Guidance A Attributable (who, when) L Legible (readable, pen, no white out, single line) C Contemporaneous (up-to-date) O Original (source document) A Accurate (verifiable with source)

Source Data and Documents (FDA)

All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification Source Document Definition
Original documents, data, and records, (e.g., ALL study records such as visits, CRF/Data Collection Forms, and, Subjective self-report instruments, hospital, clinical and office charts, laboratory notes, notes to file, subject diaries, checklists, pharmacy dispensing records, recorded data from automated instruments, XRays, digital records

Source Data
Generate and Keep source documents in original records May be using Electronic Data Capture (EDC)

The IRB
Maintain Communication with the IRB

IRB Communications and Submissions

Interact with IRB
Ask questions Get to know UM IRB contacts

Initial IRB submission and approval Ongoing oversight

AEs, protocol deviations, unanticipated problems, DSMC reports or safety officer reports, UM OHRCR report, new information that changes risk/benefit of study participation Continuing review

Terminate a study
Dont let it expire!

Study Oversight & Qualifications

Overall PI/Investigator Responsibilities

Ensure a study is conducted according to the protocol or study plan and applicable regulations
FDA Form 1572

Protect the rights, safety, and welfare of subjects under the investigators care FDA-Control drugs, biological products, and devices under investigation
FDA Guidance for Industry: Investigator Responsibilities, Oct 2009

Study Oversight by the PI/Investigator

Are individuals who are delegated study tasks qualified to perform them? Have individuals received training to the protocol and to the tasks? Oversight and involvement in ongoing conduct of the study Where reasonably possible, oversight of 3rd parties
Guidance for Industry: Investigator Responsibilities, Oct. 2009

Adequate Resources
Appropriate facilities Appropriate equipment
Correct equipment available Calibrated Preventive maintenance Study staff training

Proper laboratory facilities (FDA=CLIA certified)

Reference ranges for laboratory tests Details of analytical methods Quality assurance information

Delegating Tasks
The investigator should ensure that any individual to whom a task is delegated is qualified by education, training, and experience (and state licensure where relevant) to perform the delegated task The level of supervision should be appropriate to the staff, the nature of the trial, and the subject population.

Study logs & Oversight

Delegation log with study roles, tasks and dates worked on study Signature log with initials log Train to protocol Training log Stay up-to-date on subject and overall study progress
Regular staff meetings (FDA-take minutes)

Investigational Product (FDA)

Accountability for the Investigational Product

Investigational Product
Process investigational product
Receipt (shipping) and Dispensing Labeling Accountability to reconcile records for each tablet, compounded drug Secure storage of device & device return Return/Destroy drug as determined by sponsor Interface with Investigational Drug Services / Biomedical Engineering staff, as needed

Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP)

Essential Documents (FDA)

Maintain Study Binder

Binder Index
1. 2. 3. 4. 5. 6. 7. 8. 9. Contents Subject Logs and Lists Contact Logs and Monitoring Communications: General Protocol and Amendments Case Report Forms Investigator Information IRBMED Documents Laboratory Information

Binder Index

(contd)

10. Equipment 11. Investigational Product Information 12. Investigational Product Accountability Records 13. Adverse Events/Effects 14. Investigator Meeting Documents 15. Regulatory Information 16. Study Reports 17. References 18. Contracts and Grants 19. Patient Data

Additional Best Practices

Conflict of Interest Disclosure Applies to all members of the study team Includes spouses and dependents May have a management plan FDA forms for financial disclosure from sponsor Communication with sponsor (FDA) Annual reports to sponsor Maintain ALL sponsor communications Letters, reports, emails, phone log, faxes Report AEs and unanticipated problems Report protocol deviations Monitoring log/visits

Shipping Regulations for Biologics

University personnel who ship infectious substances including patient (clinical) specimens, human-derived research materials, infectious micro-organisms, certain geneticallymodified organisms, etc. must complete a training program prior to shipping infectious or biological substances.
The Department of Occupational Safety and Environmental Health (OSEH) offers the IATA/DOT Shipping Infectious Substances Class on a monthly basis. More information and schedule can be found on the OSEH website www.oseh.umich.edu.

Those who complete training receive a training certificate which is valid for two years.

Overall
Legal or regulatory is not always adequate A personal commitment to integrity needs to be coupled with a firm understanding of Best Practices The public support of research rests on its trust of scientists, scholars and the institutions Individual actions can bolster trust and confidence or, unfortunately, undermine it as well

FDA GCP BIMO Program

Clinical Investigator Inspection Sponsor/Monitor/CRO Inspection Inspection programs allow the agency to

determine:
Adherence to applicable regulations Validity of studies in support of pending marketing applications Whether the rights and safety of subjects have been protected

FDA Common Investigator Deficiencies

Failure to follow the investigational plan & Protocol deviations (38%) Inadequate recordkeeping, source documentation, case hx, record retention (27%) Inadequate accountability for investigational product, shipping, handling, storage, labeling (10%) Inadequate subject protection-including informed consent (11%) and adverse event (8%) issues
Toth-Allen, J. APEC GCP Inspection Workshop, 2008

Most Common FDA Sponsor Deficiencies

Inadequate monitoring Failure to bring investigators into compliance Inadequate accountability for the investigational product

Selected Recent OHRP Noncompliance Determinations

Informed Consent Failure to obtain the legally effective informed consent of subjects or of the IRB to appropriately waive the requirements to obtain informed consent Failure to document informed consent or of the IRB to appropriately waive the requirements to document informed consent Failure to provide a copy of the informed consent document (ICD) to the subject or the subject's legally authorized representative Inadequate ICD for specific research/lack of basic elements Inadequate ICD for specific research/lack of additional elements ICD language too complex Exculpatory language in ICDs Enrollment procedures did not minimize possibility of coercion or undue influence

Selected Recent OHRP Noncompliance Determinations

Initial and continuing review
Research conducted without IRB review and/or approval IRB lacks sufficient information to make determinations required for approval of research Inadequate IRB review at convened meetings

IRB review of protocol changes

Changes to research initiated without IRB review and approval Inadequate IRB review and/or approval of protocol changes

IRB membership, expertise, staff support and workload IRB documentation, findings and procedures
OHRP, http://www.dhhs.gov/ohrp/compliance/findings.html#D20

Questions?

Resources
UM IRBMED & HBHS Workshops Join MICHR research coordinator email network Clinical Trials Network (Duke U)
Forms, education, etc. at https://www.ctnbestpractices.org

FDA Device Advice & training

http://www.fda.gov/medicaldevices/deviceregulationandguidance/default. htm

Virtual Regulatory Binder

http://www.partners.org/phsqi/vrb/files/index.htm

NIH-Office of Human Subject Research

http://ohsr.od.nih.gov/

OHRP Guidance documents

http://www.dhhs.gov/ohrp/policy/

ICH E6
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInf ormation/Guidances/ucm073122.pdf

ICH E6 Principles
Clinical Trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with applicable regulatory requirements. Foreseeable risks should be weighed against anticipated benefits for the individual and for society as a whole; a trial should only be initiated if anticipated benefits justify the risks. The rights, safety and well being of the trial subjects are the most important considerations and should prevail over interests of science and society. The non-clinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

ICH E6 Principles
Clinical trials should be scientifically sound, and described in a clear, detailed protocol. A trial should be conducted in compliance with the protocol and amendments that have received prior IRB approval. The medical care given to, and medical decisions made for subjects should always be the responsibility of a qualified physician. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). Freely given informed consent should be obtained from every subject prior to clinical trial participation.

ICH E6 Principles
All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol Systems with procedures that assure the quality of every aspect of the trial should be implemented.