care research community

Overview of Good Clinical Practice

Donna W. Dorozinsky, RN, MSN, CCRC teach

Welcome

• Please silence cell phones • Please limit exits and entrances 2

Course Objectives

• Discuss the purpose and various sponsors of clinical research • Discuss the evolution of Good Clinical Practice and the importance of it in today’s research environment.

• Discuss the general principles of Good Clinical Practice including ICH Guidelines, Title 45 and 21 CFR, Parts 11, 50, 54, 56, 312 and 314 • Identify the sponsor, investigator and monitor responsibilities in conduct of FDA regulated studies.

The Clinical Research Process

• Clinical trials are a principled partnership between the clinical investigator and industry – Provide an avenue for providing cutting edge health care to your patients.

– Provide a scientific and ethical pathway for new product development.

– Create public awareness of the clinical research process.

The Clinical Research Process

• Industry, in collaboration with clinical investigators, develops diagnostic, therapeutic, and preventative products to better serve the health care community.

– The clinical investigator plays an important role by conducting • Clinical trials to further profile the new product by testing the safety and efficacy in a diversified patient population • Safety and efficacy testing involving patients • Conducting translational research

Clinical trial: What does it mean?

Trials to evaluate the effectiveness and safety of medications or medical devices by monitoring their effects on large groups of people.

Who are the players?

• Sponsor • NIH • CRO • SMO • Clinical Investigator • Institutional Review Board

The Sponsor

• Individual, group or company that takes responsibility for the design, management and financing of the study.

– Investigator-sponsored research – Commercial organization • Biotech company • Pharmaceutical company – Federally funded (NIH) • The responsibilities of the sponsor can be retained by the original party or transferred to another organization such as a Clinical Research Organization (CRO).

National Institutes of Health

• Department of Health and Human Services • Funds research, conducts studies, and funds multicenter national studies • Composed of 27 Institutes and Centers • NIH annually invests over $28 billion in medical research through competitive grants • 10% research is conducted at NIH in Bethesda, Maryland • Examples – National Cancer Institute

NIH Impacting Health Care

• Death rates from heart disease and stroke fell by 40% and 51%, respectively, between 1975 and 2000. • The overall five-year survival rate for childhood cancers rose to nearly 80% during the 1990s from under 60% in the 1970s. • The number of AIDS-related deaths fell by about 70% between 1995 and 2001. • Sudden infant death syndrome rates fell by more than 50% between 1994 and 2000. • Infectious diseases—such as rubella, whooping cough, and pneumococcal pneumonia —that once killed and disabled millions of people are now prevented by vaccines. • Quality of life for 19 million Americans suffering with depression has improved as a result of more effective medication and psychotherapy.

NIH Medical Discoveries

• The sequencing of the human genome • Bioterrorism research • Aggressively pursue ways to make effective vaccines for deadly diseases like HIV/AIDS, tuberculosis, malaria, and potential agents of bioterrorism. • Progress in understanding the immune system may lead to new ways to treat and cure diabetes, arthritis, asthma and allergies. • New, more precise ways to treat cancer are emerging, such as drugs that zero in on abnormal proteins in cancer cells. • Novel research methods are being developed that can identify the causes of outbreaks, such as Severe Acute Respiratory Syndrome (SARS), in weeks rather than months or years.

CRO

• Sponsor delegates specific responsibilities to the CRO • Accountability remains with the original sponsor. • A CRO that assumes a sponsor obligation is required to comply with the local regulatory requirements • Examples

Site Management Organization (SMO)

• Individual, a network of individuals or an organization that sub-contracts clinical trial responsibilities from a CRO. – Contract negotiations with the trial institution – IRB approval – Patient recruitment – Patient follow-up – Informed consent form (ICF) translation into vernacular languages – Site initiation and trial close-out operations – Trial-related documents archival and maintenance – Reporting Serious Adverse Events to the CRO and the IRB/IEC

Clinical Investigator

• Ensures that an investigation is conducted according to: – the signed investigator statement, – the investigational protocol – applicable regulations; • Protects the rights, safety, and welfare of subjects under the investigator's care • Responsible for the control of drugs under investigation.

IRB

• A group of scientists, doctors, clergy, and consumers • Designed to protect study participants. • Review and must approve the consent, protocol and any other information that is given or seen by the subject.

• Confirm that the trial is well designed, does not involve undue risks, and includes safeguards for subjects

What regulates this entire process?

•

The Federal Food, Drug and Cosmetic Act (505(a))

– “…evidence consisting of adequate and well-controlled clinical investigations, by experts (education, training, and experience) to show the drug has the effect it claims.” • 21 CFR 314.126

Good Clinical Practice

• What is it?

• A collection of regulations, guidelines, and accepted quality research practices which define the standards and procedures for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials.

GCP Applicability

• All phases of clinical research • All aspects of clinical research – Ethical conduct – Study conduct – SOPs – Processing of data – Archiving of records – Quality assurance – Staff training

History of GCP

• 1902 Biologics Act • 1906 Food and Drug Act • 1937 Elixir of Sulfanilamide Tragedy • 1938 Food, Drug, and Cosmetics Act • 1962 Thalidomide Tragedy • 1962 Kefauver-Harris Amendments • 1965 Declaration of Helsinki • 1977 FDA Bioresearch Monitoring Program

History of GCP

• 1981 Informed Consent and IRB Regulations • 1987 Regulations covering clinical investigator and sponsor obligations • 1997 ICH GCP guidelines • Computerized Systems Used in Clinical Investigations, May 2007 • Protecting the Rights, Safety and Welfare of Study Subjects-Supervisory Responsibilities of Investigators, May 2007 • FDAA, 2008

Common Elements of GCP

• Human subject protection • Informed Consent • Investigator obligations • Sponsor obligations • Monitor obligations • Documentation/data handling/statistics • Record keeping/archival • Quality Assurance

Good Clinical Practice

Sponsor Regulatory Agency Clinical Investigator IRB/IEC Subject

Mission of FDA Good Clinical Practice Program

• Focal point within FDA for Good Clinical Practice issues • Coordinates FDA policies • Contributes to leadership and direction through participation in FDA's Human Subject Protection/Bioresearch Monitoring Council • Coordinates FDA's Bioresearch Monitoring program with respect to clinical trials, working together with FDA's Office of Regulatory Affairs (ORA) • Contributes to international Good Clinical Practice harmonization activities • Plans and conducts training and outreach programs • Serves as a liaison with the HHS Office for Human Research Protection (OHRP) and other stakeholders of GCP

Office for Good Clinical Practice (OGCP)

• Established to be watchdog for GCP in clinical trials • Committed to Quality Assurance in clinical trials • “Quality assurance and quality improvement should become the prevailing themes in clinical research.”

Office for Good Clinical Practice (OGCP)

• In Clinical trials, you should strive for – Building quality upfront – Assuring Quality throughout – Developing the capacity for continuous quality improvement now and in the future • Quality Assurance is the cornerstone of success in GCP

Office for Good Clinical Practice (OGCP)

• Why do we need QA in Clinical Trials?

– More studies, more sites, and more volunteers at each site – Expansion and fluidity of the clinical investigators pool – New players in new roles (CROs, SMOs) – New technologies (Electronic record keeping) – More participation by vulnerable subjects – Global expansion

What Defines U.S. GCPs?

• Food & Drug Administration’s Code of Federal regulations • FDA Guidelines • Other sources • International Conference on Harmonisation Good Clinical Practice: Guideline (ICH/GCP) • Hippocratic oath/Nurse Practice Act, etc.

FDA Regulations

• Electronic Records – 21 CFR, part 11 • Protection of Human Subjects – 21 CFR, part 50 • Financial Disclosure – 21 CFR, part 54 • Institutional Review Boards – 21 CFR, part 56 • Investigational New Drug Applications – 21 CFR, part 312 • Application for FDA Approval to Market a New Drug or an Antibiotic Drug – 21 CFR, part 314

21 CFR, Part 11

21 CFR, Part 11

• Went into effect August 1997 • Establishes the FDA’s requirements for electronic records and electronic signatures • Applies to records in electronic format that are created, modified, maintained, archived, retrieved, or transmitted under any records requirements in FDA regulations.

21 CFR, Part 11

• The regulation applies to source documents which are – Created in hard copy then entered into a computerized system – Created by direct entry by a person into a computerized system – Created automatically by a computerized system.

21 CFR, Part 50

• Applies to all clinical investigations regulated by the FDA • No investigator may involve a human being as a subject in research unless the investigator has obtained informed consent • Details exceptions to informed consent • Details 8 elements of informed consent • IC must be documented using a written document of IC.

• Subpart D details the additional safeguards for children.

21 CFR, Part 54 Financial Disclosure

• Purpose: To ensure that financial interests and arrangements of the clinical investigators are identified and disclosed.

• Applies to drugs, biologics and devices • Intent is to make the agency aware of payment arrangements between commercial sponsors and investigators that could lead to inadvertent bias • FDA will give closer scrutiny to studies where investigators have reportable financial interests or arrangements

21 CFR, Part 54 Financial Disclosure

• Applicant must completely and accurately disclose or certify information concerning the financial interests of a clinical investigator who is not a full-time or part-time employee of the sponsor for each covered clinical study. • Reporting Requirements – Compensation affected by the outcome of clinical studies – Significant equity interest in the sponsor of a covered study – Proprietary interest in the tested product

21 CFR, Part 56 Investigational Review Boards

• Composition, operation, and responsibility of an Institutional Review Board (IRB) that reviews clinical investigations regulated by the Food and Drug Administration • Clinical investigation which must meet the requirements for submission to the FDA can not be initiated unless that investigation has been reviewed and approved by, and remains subject to continuing review by, an IRB • Membership must have at least 5 members – Diversity in race, gender – One individual who is Scientist – One individual who is a non-scientist – One member not affiliated with the institution

21 CFR, Part 56 Investigational Review Boards

• Requires that IRB follows detailed written procedures • Requires review of documents at convened meetings • Allows for expedited review for situations with minimal risk

21 CFR, Part 312 Investigational New Drug Application

• Details procedures and requirements for the use of investigational new drugs • Allows you to ship drugs that have not been approved by the FDA for the purposes of conducting a clinical trial.

• Drug must be labeled with "Caution: New Drug--Limited by Federal (or United States) law to investigational use." • FDA's primary objectives in reviewing an IND are, – To assure the safety and rights of subjects, – In Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety.

21 CFR, Part 312 Investigational New Drug Application

• Sponsor submits IND when conducting a study with a drug that is regulated by part 312 • Focus of the initial IND submission is on the general investigational plan and the protocols for specific human studies • Amendments contain new or revised protocols build logically on previous submissions and include additional information • Annual reports to the IND report the status of studies being conducted under the IND and update the general investigational plan for the coming year.

21 CFR, Part 314 Application to Market a New Drug

• Applications to the FDA to review and approve a new drug to market.

• Establishes an efficient and thorough drug review process in order to: – (a) Facilitate the approval of drugs shown to be safe and effective; and – (b) ensure the disapproval of drugs not shown to be safe and effective.

FDA Guidelines

• FDA Information Sheets • FDA Guidelines for Monitoring of Clinical Investigations • Guidance for IRBs, Investigators, and Sponsors • FDA compliance Program Guidance Manuals • FDA Compliance Policy Guidelines • FDA Guidelines for the Preparation of IND Products • www.fda.gov

ICH/Good Clinical Practice

• What is it?

An international, ethical, and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects.

ICH/Good Clinical Practice

• Goals: – Identify and reduce differences in technical requirements for drug development among regulatory agencies – Ensure worldwide acceptability of data – Improve the quality of research – Protection of research subjects

ICH/Good Clinical Practice

• History: – Initiated in 1990 with focus on Safety, Quality and Efficacy.

– Agreement between US, Europe and Japan to take action on harmonization – Primarily concerned with studies conducted in United States, Japan, and the European Union • As a result of the need for better quality in clinical trials the ICH GCP guideline was developed.

– 1997 Publication of Document E6 providing guidelines that describe the responsibilities and expectations of all participants in the conduct of clinical trials, – Adopted by FDA as guidance document

International Conference on Harmonization (ICH)

• E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting • E9 Statistical Principals for Clinical Trials • E11 Clinical Investigation of Medicinal Products in Pediatric Population • E14 The Clinical Evaluation of QT/QTc Interval Prolongation and Pro-arrhythmia Potential for Non-Anti-arrhythmic Drugs

ICH/Good Clinical Practice

• General Points of Document E6 – Protocol development – Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and approval – Informed consent processes – Study conducted according to protocol – Data recording, handling, storage – Investigational drug accountability/control – Adverse experience reporting – Procedures to ensure quality of trial and data

ICH/Good Clinical Practice

• ICH Guidelines cover the following topics: – Institutional Review Board (IRB)/Independent Ethics Committee (IEC) – Investigator – Sponsor – Protocol

ICH/Good Clinical Practice

– Investigator’s Brochure (IB) – Essential documents for the conduct of a clinical trial

Institutional Review Board (IRB)/Independent Ethics Committee (IEC)

• Primary function is to safeguard the rights, safety, and well-being of all trial subjects, especially vulnerable subjects • Local IRB vs Central IRB

Investigator Responsibilities – Ethical Principles

• Medical management of study subjects • Qualifications • Adequate Resources • Medical Care of Trial Subjects • Communication with IRB/IEC • Compliance with Protocol • Investigational Product • Informed Consent • Patient records/case report forms

Investigator Responsibilities

• Records and Reports • Progress Reports • Safety Reporting • Premature termination/suspension of trial • Final Report

Sponsor Responsibilities

• Medical expertise – Investigator’s Brochure • Study design • Trial management, • Data management – Data Handling, Recordkeeping, and Independent Data Monitoring Committee – Supervise conduct of study – Data handling and verification

Sponsor Responsibilities

• Investigator selection • Confirmation of review by IRB/IEC • Safety reporting • Record management

Sponsor Responsibilities

• Audit – Evaluate trial conduct is in compliance with protocol, GCP and SOP • Monitoring – Purpose: insure rights of subjects are protected, data are accurate, complete and verifiable, trial conducted to GCP – Selection/Qualifications of Monitor

Sponsor Responsibilities

• Quality Assurance/Quality Control – SOPs regarding trial conduct • Registration of clinical trials • Contract Research Organization – Sponsor may transfer all trial responsibilities to a CRO – CRO must implement QA/QC – All sponsor responsibilities transfer to CRO

Monitoring Responsibilities

• Main line of communication • Verify investigator qualifications • Monitor handling of investigational product • Verify adherence to protocol • Informed consent • Manage study regulatory documents on behalf of the sponsor • Ensure site training is provided • Provide Monitoring Report

Protocol and Amendments

• Should include – General Information – Background Information – Trial Objectives and Purpose – Trial Design – Selection/Withdrawal of subjects – Treatment of Subjects – Assessment of Efficacy – Assessment of Safety – Statistics

Investigator’s Brochure

• Compilation of the clinical and nonclinical data on the investigational drug.

• Needs to reviewed at least annually and revised as necessary • As per GCP, relevant new information may be so important that it should be communicated to the investigators before it is included in a revised IB – IND safety updates • Copy provided to IRB.

KEYS to GCP

• Follow – The regulations – The protocol – The SOPs – Guidelines • If it’s not documented, it didn’t happen!

• Must be able to recreate CRF data from source documents

Links

• • • • • • • E6 Consolidated Guidance for Good Clinical Practice – http://www.fda.gov/cder/guidance/959fnl.pdf#search='fda%20E6 ‘ FDA 21 CFR, Part 50 – http://www.access.gpo.gov/nara/cfr/waisidx_00/21cfr50_00.html

FDA 21 CFR, part 54 – http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=54 FDA 21 CFR, part 56 – http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=56 FDA 21 CFR, part 312 – http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312 FDA 21 CFR, part 314 – http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314 NIH – http://www.nih.gov/about/NIHoverview.html

care research community

Role of the Principal Investigator

Donna W. Dorozinsky, RN, MSN, CCRC teach

Objectives

• Describe the Investigator responsibilities as defined by the FDA and ICH • Discuss the practical elements necessary to remain in regulatory and ethical compliance with all aspects of the clinical trial process • Discuss the additional responsibilities of the Investigator in Investigator initiated research.

GCP and the and the Investigator

• To ensure the integrity of clinical research data • To provide adequate safeguards to ensure the protection of human subjects • To ensure that the highest standard of ethical conduct is preserved • To address all applicable regulatory requirements

Expectations

• What does the FDA expect of you?

– Manage the clinical trial – Conduct the protocol – Collect quality data – Investigational article accountability

Expectations

• What does the FDA expect of you?

– Manage the clinical trial • Responsibility, authority, accountability, delegation, and documentation – Conduct the protocol • Who did what?

• Who obtained informed consent?

• Who determined participant eligibility?

• Who corresponded with the IRB?

• Who identified, reported and followed-up on AEs?

Expectations

• What does the FDA expect of you?

– Quality data • Who maintained study files?

• Who collected the data?

• Who completed the case report forms?

• What source documents are used to validate and support data submitted to FDA?

– Investigational article accountability • Where was the investigational drug stored?

• Who dispensed the drug?

• Who can account for the investigational drug?

Statement of Investigator

Your commitments Form FDA 1572

DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION

STATEMENT OF INVESTIGATOR

(TITLE 21, CODE OF FEDERAL REGULATIONS (CFR) PART 312)

(See instructions on reverse side.) 1. NAME AND ADDRESS OF INVESTIGATOR Form Approved: OMB No. 0910-0014. Expiration Date: January 31, 2006.

See OMB Statement on Reverse.

NOTE: No investigator may participate in an investigation until he/she provides the sponsor with a completed, signed Statement of Investigator, Form FDA 1572 (21 CFR 312.53(c)). 2. EDUCATION, TRAINING, AND EXPERIENCE THAT QUALIFIES THE INVESTIGATOR AS AN EXPERT IN THE CLINICAL INVESTIGATION OF THE DRUG FOR THE USE UNDER INVESTIGATION. ONE OF THE FOLLOWING IS ATTACHED.

CURRICULUM VITAE OTHER STATEMENT OF QUALIFICATIONS 3. NAME AND ADDRESS OF ANY MEDICAL SCHOOL, HOSPITAL OR OTHER RESEARCH FACILITY WHERE THE CLINICAL INVESTIGATION(S) WILL BE CONDUCTED.

4. NAME AND ADDRESS OF ANY CLINICAL LABORATORY FACILITIES TO BE USED IN THE STUDY.

5. NAME AND ADDRESS OF THE INSTITUTIONAL REVIEW BOARD (IRB) THAT IS RESPONSIBLE FOR REVIEW AND APPROVAL OF THE STUDY(IES).

6. NAMES OF THE SUBINVESTIGATORS

(e.g., research fellows, residents, associates)

WHO WILL BE ASSISTING THE INVESTIGATOR IN THE CONDUCT OF THE INVESTIGATION(S).

7. NAME AND CODE NUMBER, IF ANY, OF THE PROTOCOL(S) IN THE IND FOR THE STUDY(IES) TO BE CONDUCTED BY THE INVESTIGATOR.

8.

ATTACH THE FOLLOWING CLINICAL PROTOCOL INFORMATION: FOR PHASE 1 INVESTIGATIONS, A GENERAL OUTLINE OF THE PLANNED INVESTIGATION INCLUDING THE ESTIMATED DURATION OF THE STUDY AND THE MAXIMUM NUMBER OF SUBJECTS THAT WILL BE INVOLVED.

FOR PHASE 2 OR 3 INVESTIGATIONS, AN OUTLINE OF THE STUDY PROTOCOL INCLUDING AN APPROXIMATION OF THE NUMBER OF DRUG AND THE NUMBER TO BE EMPLOYED AS CONTROLS, IF ANY; THE CLINICAL USES TO BE SUBJECTS TO BE TREATED WITH THE INVESTIGATED; CHARACTERISTICS OF SUBJECTS BY AGE, SEX, AND CONDITION; THE KIND OF CLINICAL OBSERVATIONS AND OR A DESCRIPTION OF CASE REPORT FORMS TO BE USED.

LABORATORY TESTS TO BE CONDUCTED; THE ESTIMATED DURATION OF THE STUDY; AND COPIES 9.

COMMITMENTS: I agree to conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, rights, or welfare of subjects.

I agree to personally conduct or supervise the described investigation(s).

I agree to inform any patients, or any persons used as controls, that the drugs are being used for investigational purposes and I will ensure that the requirements relating to obtaining informed consent in 21 CFR Part 50 and institutional review board (IRB) review and approval in 21 CFR Part 56 are met.

I agree to report to the sponsor adverse experiences that occur in the course of the investigation(s) in accordance with 21 CFR 312.64.

I have read and understand the information in the investigator’s brochure, including the potential risks and side effects of the drug.

I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.

I agree to maintain adequate and accurate records in accordance with 21 CFR 312.62 and to make those records available for inspection in accordance with 21 CFR 312.68.

I will ensure that an IRB that complies with the requirements of 21 CFR Part 56 will be responsible for the initial and continuing review and approval of the clinical investigation. I also agree to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risks to human subjects or others. Additionally, I will not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.

I agree to comply with all other requirements regarding the obligations of clinical investigators and all other pertinent requirements in 21 CFR Part 312.

INSTRUCTIONS FOR COMPLETING FORM FDA 1572 STATEMENT OF INVESTIGATOR:

1.

2.

3.

4.

5.

Complete all sections. Attach a separate page if additional space is needed.

Attach curriculum vitae or other statement of qualifications as described in Section 2.

Attach protocol outline as described in Section 8.

Sign and date below.

FORWARD THE COMPLETED FORM AND ATTACHMENTS TO THE SPONSOR. The sponsor will incorporate into an Investigational New Drug Application (IND).

10.

SIGNATURE OF INVESTIGATOR this information along with other technical data 11.

DATE

(WARNING:

A willfully false statement is a criminal offense. U.S.C. Title 18, Sec. 1001.) Public reporting burden for this collection of information is estimated to average 100 hours per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to: Food and Drug Administration CBER (HFM-99) 1401 Rockville Pike Rockville, MD 20852-1448 Food and Drug Administration CDER (HFD-94) 12229 Wilkins Avenue Rockville, MD 20852 "An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number."

Investigator Responsibilities FDA Form 1572

I.

• Protocol compliance. Agree to… – conduct of the trial according to the Protocol.

– Personally supervise the study – Inform subjects of drugs that are being used for investigational purposes – Ensure all clinic staff fully understand and follow the protocol – Implement changes to the protocol only after written consent of sponsor, IRB and regulatory agencies.

– Report AEs – Read and understand the IB – Maintain records – Comply with 21 CFR Parts 56 and 312

Investigator Responsibilities

• Medical management of trial participants • To provide information to the participant regarding nature of the investigation • To provide adequate medical care for the The participant during the trial • To ensure welfare and safety of the participant se during the trial are • To provide appropriate medical care and follow-up procedures at the conclusion of the trial not ordi nar

Translation Into Practice

• Answer subject questions • Medical care takes priority over the protocol • Safety comes first • Follow events to resolution • Communication with PCP • Subject access to PI

Investigator Responsibilities

• Staff and Facilities • To ensure that there is adequate staff to support the study, that they are familiar with the trial protocol and the standards of Good Clinical Practices • To ensure adequate facilities and equipment • To use certified laboratories with validated assay methodology

Translation Into Practice

• Study Coordinator • Facilities and Equipment – Secured storage of IP and study files – Evidence of equipment maintenance • Validated assays

Investigator Responsibilities

• Adequate Resources – Potential for recruiting adequate number of qualified subjects.

– Sufficient time to properly conduct study – Adequate staff and resources – Ensure all staff involved in conduct of study have been properly trained

Translation Into Practice

• Available

qualifying

patients • Research is time consuming • Are your coordinators carrying too many studies?

• If your subjects need eye examinations do you have arrangements with an ophthalmologist?

Investigator Responsibilities

• Compliance with local regulations and institutional requirements • To obtain the review/approval of the IRB • To provide periodic study status reports to the IRB (at least annually) • To promptly inform the IRB / DSMB of significant safety issues (SAEs from site, IND Safety Reports for program) • Informed Consent

Translation Into Practice

• Communication with a duly constituted IRB – Local vs. Commercial – Annual update – Communicating IND safety updates to the IRB • Evaluating IND safety updates to determine need for adjustments to ICF • Process for identifying and reporting SAEs • Process for obtaining informed consent

Investigator Responsibilities

• Control of investigational drugs, vaccines, or devices (article) – To provide accountability system to address receipt, distribution, and return of all investigational supplies – To ensure that supplies are properly stored and accessible only to designated study staff – To ensure that investigational materials are used only according to protocol – To ensure that randomization procedures exist along with process for breaking the blind – May be delegated to a qualified individual – Explain correct use to the subject • Procedures for randomization and blinding

Translation Into Practice

• Process for receipt storage and return • Secure IP storage area that is monitored for temperature • Drug Accountability performed each time drug is dispensed • Establish procedure for maintaining randomization and breaking the blind

Investigator Responsibilities

• Patient records/case report forms

O C

• To provide complete and accurate data to the sponsor

U

• To maintain patient records to include history, prescribed

M

medication and investigational product(s), measurements,

E

exams, evaluations and adverse events

N

• To apply corrections to clinical research data according to

T

principles of good research practice (i.e., single-line delete,

A

date and initial)

T

• Correlation between the CRF and the source document

I O N

Translation Into Practice

D

• Patient records/case report forms

O C

• Complete and accurate data to the sponsor

U M

• Patient records that include history, measurements, exams, evaluations and adverse

E

events

N

• Access to in-patient records

T A

• QC of CRFs to source documents

T I O N

Translation Into Practice

• Regulatory Binder – IRB Communications – Protocol, ICF, Amendments – IB – FDA Form 1572 – Financial Disclosure – CVs – Site Signature Log – Delegation of Authority Log – Study Communications – Screening Log – Laboratory Reference Ranges – Site Visit Log – IP Accountability

Translation Into Practice

• Archive Essential Study Documents at end of study • Should be easy to retrieve documents • If you move your location, notify the sponsor

Investigator Responsibilities

• Safety Reporting – SAEs reported immediately to the sponsor – AE or laboratory abnormalities reported to the sponsor within the agreed timeline.

– Report deaths and all associated documentation to sponsor and IRB.

Translation Into Practice

• Assess for AEs at each visit • IB is the driver for determining SAEs – Key is “unexpected” • Report all adverse events –

you never know!

• All clinically significant laboratory or diagnostic results are AEs • Functioning under an assurance – Unexpected events – Unexpected problems

Investigator Responsibilities

• Compliance with the Protocol – Conduct the study as described in the protocol – No deviations without agreement from sponsor and IRB – Documentation of any unintentional deviations – Deviation for immediate hazard

Translation Into Practice

• Follow the protocol as it is written – Recipe versus Contract • Defined process for training staff involved in conduct of the trial • Do not implement a change in the protocol until you have received written IRB approval.

• Revision to ICF

Investigator Responsibilities

• Informed consent – Comply with all regulatory requirements and adhere to GCP – Revise ICF when new information becomes available – There should be no coercion of the subject to participate – Use non-technical language – Provide ample time for consenting – Copy of the signed and dated ICF

High Risk to Delegate

• Approval for study participation • Assignment of causality for adverse events (AE) • Physical examinations • Final review of CRFs

Protecting the Rights, Safety, and Welfare of Study Subjects – Supervisory Responsibilities of Investigators • Draft FDA Guidance, May 2007 • Responsibilities related to human subject protection and data integrity.

• Clarification of FDA expectations: – To supervise a clinical study where some study tasks are delegated – To protect rights, safety and welfare of study subjects.

Clinical Trials of Drugs

• Clarification of Investigator Responsibilities – Supervision of Conduct of the Study – Protecting the Rights, Safety and Welfare of Study Subjects

Supervision of Conduct of Study

• Appropriate delegation of tasks – Ensure that individuals to whom a task is delegated is qualified to perform the task.

– Generally related to tasks that are clinical or medical in nature.

– Historically in appropriate delegation of tasks.

Supervision of Conduct of Study

• Define adequate training – General familiarity with the protocol – Specific understanding of the details related to the tasks they will be performing – Awareness of regulatory requirements and acceptable standards – Competency – Informed of changes to protocol

Supervision of Conduct of Study

• Adequate Supervision – Routine meetings with staff to review trial progress and update staff – Routine meetings with the sponsor’s monitors – Procedure for • correcting problems identified by study personnel.

• documenting the performance of delegated tasks in a satisfactory manner.

• ensuring study is conducted in accordance with 21 CFR, Part 50.

• Ensuring that information in source documentation matches CRFs.

• dealing with data queries and discrepancies identified by the study monitor.

• Ensuring staff comply with protocol, AE assessment and reporting and other medical issues.

Supervision of Conduct of Study

• Oversight of other parties involved in the conduct of the study.

– Study staff not in direct employ of the investigator.

– Parties other than study staff (clinical laboratories

Protecting the Rights, Safety and Welfare of Study Subjects

• Provide a reasonable standard of medical care.

• Reasonable access to medical care by being available to subjects during the conduct of the trial at their site.

• Seek to minimize protocol violations which may be considered a failure to protect the rights, safety and welfare of subjects

Investigator Initiated Research

• Reasons Investigators choose to act as a sponsor – Scientific interest in a drug or product – An opportunity to contribute to clinical knowledge – A potential for publication of study results

Investigator Initiated Research

• Responsibilities – Writing the protocol and designing the Case Report Form – Monitoring the study and reviewing the source documents – Drug accountability – Submitting safety reports to the FDA – Complying with all applicable FDA regulations – IND submission

• ???

Questions

care research community

Human Subject Protection

Donna W. Dorozinsky, RN, MSN, CCRC teach

Course Objectives

• Discuss the history of human subject protection and the historical events impacting today’s current regulations.

• Identify the 8 elements of informed consent.

• Discuss the general requirements in obtaining informed consent.

• Discuss the IRB requirements and the contents of 21 CFR, Part 56.

• Discuss the HIPAA requirements as they relate to privacy in clinical research.

Human Subject Protection

• History of Human Subject Protection • Declaration of Helsinki • Belmont Report • Informed Consent • Institutional Review Boards

Historical Abuse of Subjects

• 1932: Tuskegee syphilis study – Designed to determine the natural history of untreated syphilis – 400 black men with syphilis were recruited without informed consent – Syphilis left untreated to determine course of disease – 100 men died, 40 wives infected, 19 children contracted disease at birth • World War II – Appalling experiments conducted on imprisoned ethnic groups by physicians

Human Subject Protection

• 1947: Nuremberg Code • 1962: Kefauver-Harris Amendment • 1964: Declaration of Helsinki • 1967: FDA required informed consent to be obtained in writing • 1974: National Research Act • 1979: Belmont report • 1981: Congress enacted 3 statutes that govern human subject protection

Declaration of Helsinki

• Research must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experiments.

• Follow a protocol which is reviewed by a “specially appointed independent committee for consideration, comment, and guidance” e.g. IRB • Conducted only by scientifically qualified persons; supervised by clinically competent medical person • Importance of the objective is in proportion to the risk to the subject • Predictable risks outweigh foreseeable benefits • Respect the privacy of the subject and safeguard his/her integrity

Declaration of Helsinki

• Each subject must give informed consent indicating they he/she is adequately informed of the study, benefits, hazards; they must be informed that he/she can decide not to participate or to withdraw from the study • If subject is incompetent, then informed consent must be obtained from the legal guardian.

• If the subject is a minor who can give consent, this should be obtained in addition to the legal guardian’s.

Belmont Report

• Objective is to provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects.

Belmont Report

• Covers 3 topics – Boundaries between practice and research – Basic ethical principles – Applications

Belmont Report

• Boundaries between practice and research –

Practice

: interventions to enhance the well-being of a patient with a reasonable expectation of success. To provide diagnosis and preventive treatment or therapy.

–

Research

: Activity designed to test a hypothesis, draw conclusions, and contribute to general knowledge. Formal protocol with an objective and set of procedures. Benefits are not always known.

– May be carried on together when the research is to evaluate the safety/efficacy of a new therapy.

– If there is any element of research, it needs to undergo review for the protection of human subjects, i.e. IRB review.

Belmont Report Basic Ethical Principles

Respect for Persons:    Individuals should be treated as autonomous agents Persons with diminished autonomy are entitled to protection Subjects must enter into the research voluntarily and with adequate information.

Beneficence  An obligation to improve a persons’ well being.

 Do not harm   Maximize possible benefits Minimize possible risks

Belmont Report Applications

Informed consent

:  People should have the opportunity to choose what shall or shall not happen to them.

 Contains 3 elements: information, comprehension, voluntariness 

Information

: subject must understand that research is neo necessary for their well being nor are the effects of the research fully known.



Comprehension

: The information provided to the subject must be in a language and at a level that he/she can understand. Investigators are responsible for making sure that a subject understands the information.



Voluntariness

: A consent is valid only if it is voluntarily given which means it is free of coercion and undue influence.

Belmont Report Applications

Assessment of Risks and Benefits

: – Risk: the possibility that harm may occur – Benefit: something positive related to well being.

– Risks to the subject should be outweighed by the sum of anticipated benefits to the subject and society

Selection of Subjects

: – Two levels of justice: individual and societal –

Individual justice

: Investigator must demonstrate fair procedures in selecting the subjects. –

Societal justice

: fair and equitable selection of subjects across economic, ethnic, and gender classes.

Informed Consent

Informed Consent

• Governing documents: – FDA 21 CFR 50: Protection of Human subjects – HHS 45 CFR 46: Protection of Human Subjects – FDA Information Sheet: Informed Consent Regulations – FDA Information Sheet: A Guide To Informed Consent Documents

Informed Consent

• “Informed consent is more than just a signature on a form, it is a process of information exchange that includes, recruitment materials, written materials, verbal instructions, question/answer sessions, and measure of subject understanding.”

Informed Consent

• “The consent document should be the basis for a meaningful exchange between the investigator and the subject.”

Ethical Standards of Informed Consent

• One of the biggest obligations facing everyone involved in developing new medicines and medical devices that use the human research subject is the consistent requirement of – Respect, compassion, understanding JAMA, 5/24/00, Vol 283, No. 20 “What makes Clinical Research Ethical?

Informed Consent

• Informed Consent Definition – 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

• Informed consent documents must meet the requirements of 21 CRF 50.20 and contain the information required by 21 CRF 50.25.

• IRBs have the ultimate authority for ensuring the adequacy of the information in the informed consent document.

Informed Consent

• General Requirements for Informed Consent: – No investigator may involve a human being as a subject in research unless informed consent is obtained.

– Sufficient opportunity must be give to the subject to decide whether or not to participate

Informed Consent

• General Requirements for Informed Consent: – Must minimize the possibility of coercion or undue influence – No informed consent may include any exculpatory language (release of responsibility).

Informed Consent

• Informed consent must be understandable – Technical and scientific terms must be adequately explained or simpler terms substituted.

– More understandable if the subject is referred to as “you” and the investigator as “I/we” – Subjects should not be asked to certify that they “fully understand” the study.

Informed Consent

• Informed consent must be understandable – Consent must not imply or state that the study is approved by the FDA – If subject population includes non-English specking subjects, a translated consent document should be prepared

Informed Consent

• Informed consent must be understandable – A person who understands English, but does not read and write can be consented by their “making their mark” on the document. – When consenting older children, it is recommended that there be two forms: an informed consent for the parent/guardian to sign as well as an assent document for the child to sign.

Can they read the consent form?

• 48% • Of American adults • Have low literacy • skills

Who are we protecting?

•Job applicants tested in 1998 - >33% lacked reading and mathematics skills for employment!

•Question?

•Do we expect these people to read and understand the consent form?

Elements of Informed Consent

1. Statement that the study involves research, explanation of the purposes of the research, expected duration of the subject’s participation, description of the procedures to be followed, identification of any procedures which are experimental.

Elements of Informed Consent

2. Description of any reasonably foreseeable risks or discomforts to the subject.

3. Description of any benefits to the subject or to others which may reasonably be expected from the research.

4. Disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

Elements of Informed Consent

5. Statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the FDA may inspect the records.

6. For research involving more than minimal risk, an explanations to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs.

Elements of Informed Consent

7. Explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights and whom to contact in the event of a research-related injury.

8. Statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits, that the subject may discontinue participation at any time without penalty.

Elements of Informed Consent

The following elements should be included if appropriate:  Statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.

 Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent.

Elements of Informed Consent

  Any additional costs to the subject that my result from participation in the study.

The consequences of a subjects’ decision to withdraw from the research and procedures for orderly termination of participation by the subject.

Elements of Informed Consent

  A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject.

The approximate number of subjects involved in the study.

The Consent Process

• The clinical investigator is responsible for ensuring that informed consent is obtained from each subject prior to their participating in the study. • FDA does not require that the investigator actually obtain the informed consent. May delegate it to appropriate individual who is knowledgeable about the research.

• The investigator retains ultimate accountability.

The Consent Process

• The subject should date & sign the document.

– Time of consent should be recorded.

• A copy of the consent form must be provided to the subject.

• A note is written in the progress notes confirming the consenting process.

• The signed consent form must be retained in the study records.

Informed Consent

• 2 types of forms – Written consent document that includes all the elements of informed consent required by 21 CFR 50.25. – Short form written consent stating that the required elements of informed consent have been presented orally.

Informed Consent Exceptions

• Both the investigator and a physician not participating in the investigation must certify in writing that the following conditions have been met.

– Subject is in a life threatening situation – Consent cannot be obtained from the subject – Insufficient time to obtain consent from the subject’s legal representative – No alternative treatment that would have an equal or greater chance of saving the patient is available – The test article is required to save the life of the subject.

Informed Consent Exceptions

• Documentation of both the investigator and independent physician must be submitted to the IRB within 5 working days.

■ Planned study that must be done in the emergency room in order to evaluate use of the test article in that setting.

 Limited to situations where intervention is life saving and there is not time to obtain consent.  Required FDA approval, IRB approval, and public disclosure.

Informed Consent Issues

• Disclosing information to subjects requires common sense.

– Too much information can be as bad as too little. – Too much can interfere with the subject’s ability to understand what is truly important.

– Need to provide enough information to make an educated decision.

Informed Consent Issues

• Poor comprehension of consent documents is usually a result of low readability and excessive length. – General population reads at a 6 repetition.

understanding.

short words.

th or 7 th grade level.

– Retention of information can be improved with – Using a variety of methods such as individualized discussion and visual aids may increase retention and – Improve readability by using short sentences and

Informed Consent Issues

• To demonstrate comprehension a subject must understand: – Their condition – The nature of the proposed treatment – Alternatives to treatment – Consequences of accepting or rejecting proposed treatment – Risks and benefits of various options

Informed Consent Issues

• Sufficient time must be given for the consent process.

– Sufficient time to read and digest the consent.

– Sufficient time to ask questions of staff.

– Sufficient time to consult with a friend or relative if appropriate.

– Sufficient time to reflect on his/her decision.

Informed Consent Issues

• Informed consent must be obtained prior to participation in the study.

– Prior to any specific exams or screening procedures specific to the study to determine eligibility.

– Prior to discontinuing any existing medications the subject is taking to meet inclusion/exclusion criteria. (wash-out period) – Procedures that are performed as part of the practice of medicine and which would be done regardless of the study, may be performed and the results used to determine eligibility.

Study Payment

• Payment for subjects is viewed as a recruitment incentive not a benefit.

• Financial incentives are generally used when benefits to the subject are remote or non-existent.

• Amount and schedule of payment should be presented to the IRB at the time on initial review.

• IRB should review the amount of payment and timing of payment to assure that they are not coercive or do not present undue influence.

Study Payment

• Payment should accrue as the study progresses.

• Payment may not be contingent upon the subject completing the entire study.

• Payment to subjects who withdraw may be made at the time they would have completed the study (or completed a phase of the study).

• Payment of a small proportion as an incentive for completion of the study is acceptable as long as it is not coercive.

• Payment details must be included in the informed consent.

Informed consent must be approached as a process rather than a distinct event in time.

Assess Competence to Consent

• Ability to Express a choice • Ability to Understand information about a trial • Ability to Reason with relevant information to understand a logical process of weighing options

What Can We Do?

• When obtaining consent ask yourself…..

• “Is the subject adequately informed to understand and comprehend the information in order to make a conscious decision to participate in a clinical research trial?”

What Can We Do?

• Reduce boilerplate language • Extended discussion about the trial • Multimedial presentations • Enhanced forms • “Test” of knowledge

The Ability to Understand the Informed Consent

• It is a function of: – Intelligence – Rationality – Maturity – Language • Ethically it is the investigator’s responsibility to ensure that the research subject has comprehended the information.

What Can We Do?

• Use less text and more graphics.

• Simplify language – use action verbs and direct statements • Read the FDA information sheets • Substitute long wordy sentences with tables or lists.

• Develop a list of lay terms • Make the form “EYE” friendly

Sample Phrases

All blood samples will be drawn from a forearm vein via an intravenous catheter contra lateral to the one used for drug administration in the case of the continuous infusion regimens.

We will need to take some blood from your arm for this study. We will insert a needle attached to a plastic tube in your forearm. A second needle with a plastic tube will be placed in your opposite arm

What Can We Do?

• How the document is laid out is just as important to readability and comprehension as the information it contains • Use a written or verbal post-consent evaluation to determine if the critical points were understood (must be IRB approved)

Informed Consent Questions??

Is getting the subject to sign a consent document all that is required by the regulations??

No!! The consent document is just a written summary of the information that should be provided to the subject

.

Informed Consent Questions??

May informed consent be obtained by telephone from a legal representative?

No. This does not satisfy the regulations. A document can be faxed to the representative. The discussion can be conducted by telephone and then the signed form can be faxed back.

Informed Consent Questions??

Does the copy of the consent form given to the subject have to be a signed copy?

No! This is encouraged but not mandatory. The purpose of this is to allow the subject to review the information with others as well as to serve as a continuing reference for them.

Informed Consent Questions??

Who should be present when the informed consent interview is conducted.

FDA does not require a third person or witness. The person who conducts the consent interview should be knowledgeable about the study and able to answer questions. Investigator may delegate responsibility to a person who has received appropriate training to perform this activity.

Informed Consent Questions??

When should study subjects be informed of changes in the study?

Those subjects who are enrolled and actively participating in the study should be informed of any changes if it may affect to their willingness to continue their participation in the study. FDA does not require reconsenting subjects that have completed their active participation or who are still actively participating but the change will not affect their participation.

IRBs

Sound Clinical Research Depends on Compliance with …

Good Clinical Science (Industry and Investigator) + Good Statistical Design (Industry and IRB) + Sound Ethical Conduct (IRB, Investigator, Industry)

What is an IRB?

• Knowledge and application of commitments, regulations, guidelines, state and local laws and standards of professional conduct • Knowledgeable about the care and protection of vulnerable population • An appreciation for doing the right thing

What is an IRB?

•

Under FDA Regulations (21 CFR 56 Subpart C) and (45 CFR 46 - Subpart A)

• An IRB is an appropriately constituted group that has been formally designated to review and monitor biomedical and behavioral research involving human subjects.

What is an IRB?

• An IRB has the authority to approve, require modifications (in order to secure approval), or disapprove search.

• An IRB is responsible for ensuring, in advance and by periodic review, that steps are taken to adequately protect the rights and welfare of human subjects.

Why an IRB?

• Knowledge and application of commitments, regulations, guidelines, state and local laws and standards of professional conduct • Knowledgeable about the care and protection of vulnerable population • An appreciation for doing the right thing.

Institutional Review Boards

• Membership – At least five members with varying backgrounds.

– Must consist of both men and women.

– May not be entirely of members of one profession.

– At least one member whose primary concerns are in a scientific area and one member in a non-scientific area.

– At least one member who is not otherwise affiliated with the institution.

Institutional Review Boards

• IRBs must: – Follow written procedures – Review research at convened meetings at which a majority of the members (quorum) is present including at least one member whose primary concerns are in nonscientific areas.

What is the Role of the IRB?

• Protect the rights and welfare of human research subjects.

• Answer three basic questions: 1. Should the study be done at all?

2. Do the benefits outweigh the probable risks and is this information adequately conveyed in the consent form?

3. How will the research subject be protected on an ongoing basis?

Institutional Review Boards

• Data submitted to IRB for review: – Protocol, protocol amendments – Informed consent form – Advertising and recruitment process – Information on the drug e.g. Investigator’s brochure – Information on the investigator e.g. CV

What is the Role of the IRB?

Criteria for IRB Approval

• Risks

v

Benefits • Risks minimized • Equitable selection • Informed consent • Investigator training relative to responsibilities • Documentation of informed consent • Monitoring of data • Privacy and confidentiality • Additional safeguards of all vulnerable populations

IRB Decisions

• Authority to make three possible decisions regarding studies: – Approved – Disapproved – Requires modifications to be approved • Notification of decisions must be made in writing to investigator.

• Continuing review of research must be done at a minimum of once per year.

The IRB “A collegial and cooperative relationship”

• Judge • Protector • Facilitator • Enforcer • Educator • Colleague • Partner

Institutional Review Boards

• The purpose of IRB review is to assure that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research.

• Risks to subjects are minimized • Risks to subjects are reasonable in relation to anticipated benefits • Selection of subjects is equitable • Informed consent will be sought • Research plan makes adequate provisions for monitoring the data collected to ensure the safety of subjects • Adequate provision to protect the privacy of subjects

Focusing on Continuing Review: Why?

• Has any significant and/or new information been made available since the study received last approval?

• Do the research subjects need different information with which to reconsider their continued participation • Is the study being conducted as approved?

• Did the IRB use the same review and approval process that it used to conduct the initial review?

Information required by the IRB for Continuing Review

• Enrollment and study start and stop • Adverse event information and follow-up where indicated • Study progress reports • Review of consent process and document changes. • Any new findings important to the subject’s safety • Unanticipated problems that pose a risk to the subject

Institutional Review Boards

• Expedited review: – Procedure to review and approve research without convening a meeting of the IRB.

– Used for minor changes in previously approved research.

– Review is done by the IRB chairperson or by one of the experienced members of the IRB – May not be disapproved by expedited review—only be full review.

HIPAA Requirements

What is HIPAA

• Health Insurance Portability and Accountability Act • Signed August, 1996 • Congress mandated that the Secretary of HHS adopt standards to facilitate the electronic exchange of health information • http://aspe.hhs.gov/admnsimp/

Who Must Comply with HIPAA?

• Health Plans, health care clearinghouses, and health care providers that transmit health information electronically in connection with defined HIPAA statute • Transmissions related to … – Health care claims – Health care payment or remittance advice – Coordination of benefits – Health clam status – Enrollment and disenrollment in a health plan, – Eligibility for health plan – Health plan premium payments – Referral certification and authorization – First report of injury – Health claims attachments – Other transactions

What is a Covered Entity

• Employees of a covered entity (hospital, etc), then they must comply with regulation.

• Function independent of a covered entity (i.e. physician who is not employee of the hospital), they must meet all of the requirements independent of the institution.

What about Researchers

• Research is not a covered function, however….

• If the research involves either – the provision of health care by a covered entity – Retention of medical records or biological samples by a covered entity • ….then disclosure of information or clinical trial data for research purposes must comply with the Privacy Rule

Penalty for Non-Compliance

• Civil monetary penalty of $100 per occurrence ($25K max) • Federal Criminal penalties for persons who knowingly obtain or disclose health information in violation of Privacy Rule.

What is Protected Health Information?

• Either oral or recorded information in any form or medium – Is created or received by a health care provider, health plan, etc.

– Provision of health care to an individual

What is De-Identification?

• • De-Identification information is no longer covered by the HIPAA requirements.

All identifying information has been removed including – Names – Geographic subdivisions smaller than a state (i.e., no city, no zip code), except for the initial three digits of the zip code if, according to the current publicly available data from the Bureau of the Census, the geographic unit contains more than 20,000 people – Any date (except year; i.e., no month or day of month) – For subjects older than 89 years of age, specific age may not be mentioned – Telephone number – Fax number – E-mail address

What is De-Identification?

– Social security number – Medical record number – Health plan beneficiary number – Any other account numbers – Certificate or license numbers  Vehicle identification number   Medical device identification or serial number Personal website URL    Internet protocol (IP) address Fingerprint, voiceprint, or other biometric identifiers  Full-face photographic images Any other unique identifying number, characteristic, or code

Impact of Reviewing Records for Research Participation

• Allows covered entities to permit researchers to review PHI held in medial records or elsewhere for “review Preparatory to research” for the purpose of assessing the pool of potentially eligible subjects.

• Contact of these subjects is related to whether the individual is a member of the covered entities workforce

Other Issues

• Adverse events may be reported to research sponsors, public health agencies and health oversight agencies without obtaining authorization • IRBs, DSMBs, or other investigators should be identified in the original authorization form.

Authorization Core Elements

• A description of the PHI to be used or disclosed, • The names or other specific identification of the person or persons (or class of persons) authorized to make the requested use or disclosure • The names or other specific identification of the person or persons (or class of persons) to whom the covered entity may make the requested use or disclosure • A description of each purpose of the requested use or disclosure • Authorization expiration date or expiration event that relates to the individual or to the purpose of the use or disclosure ("end of the research study" or "none" are permissible for research, including for the creation and maintenance of a research database or repository) • Signature of the individual and date.

What does this mean practically speaking?

• In the clinic use first names only • Sign-in sheets should have cover over previous names • Limit access to the clinic to essential personnel only • Name tags should only have first name • Screen saver on clinic computers, if first and last names are displayed

In Summary

• Historical misuse and abuse • Key Investigator responsibility • Informed consent is critical component • IRB oversight • Patient Privacy

Questions!!!!!!

care research community

Drug Development Process

Donna W. Dorozinsky, RN, MSN, CCRC teach

Course Objectives

• • •

Discuss the differences in Phase I, II and III of the drug development process.

Identify the key requirements of a New Drug Application.

Discuss the different types of studies done at the CPU

© 192

Introduction:

• Only 5 in 5,000 compounds that go into pre-clinical make it to human testing.

• It takes 10-12 years from conception of a new drug to its approval • Time is money © 193

• $1B/year in sales • $2.7m/day • 2 week delay = $38m © 194

Drug Development Costs

•

Triangle Pharmaceuticals Cumulative Drug Development Expenses

© 195

Drug Development Costs

• 2003 as reported by University •

$897M

• 2006 as reported by CEO at Lilly •

$1.2B

• 2010 forecast by CEO at Lilly •

$2B

© 196

Contributions to Rising Costs • Soaring R&D costs • Lowered drug approvals • Increased development times • The loss of patent protection on several blockbuster • Safety issues • Pricing pressures. © 197

Drug development difficulties:

• Drugs usually do not cure diseases.

• Diseases don’t follow a predictable path • Sometimes measurements of a disease are subjective © 198

Drug Development Steps

• Pre-clinical (animal) testing • Filing Investigational New Drug Application (IND) with the FDA • Phase 1 studies • Phase 2 studies • Phase 3 studies • New Drug Application (NDA) • Drug approval by FDA © 199

Drug Development Steps

• Pre-clinical (animal) testing • Filing Investigational New Drug Application (IND) with the FDA • Phase I studies • Phase II studies • Phase III studies • New Drug Application (NDA) • Drug approval by FDA © 200

© www.fda.gov/cder/handbook/develop.htm 201

Pre-Clinical Testing

• Pre-clinical studies are studies that test a drug on animals and other non-human test systems • Start with initial chemical development of a compound © 202

Pre-Clinical Testing

• Studies are done with cell tissues, isolated tissues, and animals to determine: – Pharmacologic effects – Toxic effects – LD-50 (lethal dose) – ADME © 203

Pre-Clinical Testing

• ADME – Absorption : how it goes from being a pill or liquid to a biologically available form. (a form the body can actually use) – Distribution : getting the drug to the tissue – Metabolism : (biotransformation) getting the drug from the biologically available form to a more water soluble form – Excretion : moving metabolites from tissue to circulation to organs of excretion • Kidneys • Liver • bowel © 204

Pre-Clinical Testing

• Must think about marketing considerations before going to Phase I – What is the intended population and what is the incidence in that population?

– Do competitors have similar compounds in their pipeline?

– What are current therapy options for this disease and are they effective and safe?

– Are there any unique or disqualifying toxicology results for this specific compound?

– What will be the likely route of administration?

– What will be the dosing frequency?

© 205

The IND When…

• Filed prior to human dosing • If no response from the FDA, the clinical trial may start 30 days after it is received.

• Annual IND update.

© 206

The IND Why….

• FDA to ensure the safety and rights of subjects • In Phase 2 and 3, help assure that the quality of scientific evaluation is adequate to evaluate safety and efficacy.

• Allow for shipping of drugs across state lines.

© 207

Investigational New Drug Application (IND) • An IND is – Submitted to the FDA demonstrating there is reasonable justification for studying the drug in humans – Includes results of pre-clinical testing – Shows plan for human testing – Must be obtained before the first dose in humans © 208

Investigational New Drug Application (IND) • Includes – Table of contents – Introductory statement – General investigational plan – Investigators Brochure – Protocols including study protocols, investigator data, facilities data, IRB data – Chemistry, manufacturing and controls (CMC) – Pharmacology and Toxicology information – Previous human experience, if any – Additional information including drug dependence and abuse potential – Any other relevant data © 209

Investigational New Drug Application (IND) • Becomes effective 30 days after it is received by the FDA • Updated annually and amended to reflect protocol changes, additional protocols, and information about serious adverse events • FDA decides if it is safe to move on to testing in humans © 210

Clinical Trials

• Human studies designed to distinguish a drug’s effect from other influences.

• Necessary to determine if a drug is safe and effective, establish dose efficacy, and identify side effects • Best way science has come up with to determine what a new drug really does • It is important to test drugs in the population of people that they are meant to help • Need to design clinical studies that ask and answer the right questions © 211

Clinical Trials

Phase 1 Phase 2

20-100 Up to several hundred Several months Several months to 2 years

Phase 3 # of Patients Length

Several hundred to several thousand 1-4 years ©

Purpose % of Drugs Successf ully Tested

Mainly safety 70% Some short term safety but mainly efficacy Safety, efficacy, dosage 33% 25-30% 212

Study Design Terminology

• Blinding – Unblinded or open-label – Single Blind – Double-blind © 213

Study Design Terminology

• Subject Assignment – Randomization – assigned by chance – Stratification – assigning someone to a treatment group based on their sex, weight, age, disease state • Cross-over design – Each patient receives both treatments • Parallel Design – Patients are randomized to one of two treatment groups and usually receive the same treatment through-out the entire study © 214

Phase I

• Primarily intended to determine the tolerability of the drug • Conducted in healthy volunteers • Establishes a dosing range • Establishes the route of administration • Determines the most frequent adverse events © 215

Phase I

• Determination of pharmacokinetics and pharmacodynamics – Pharmacokinetics (PK) • What the body does to the drug • ADME • Usually measured in blood or urine – Pharmacodynamics (P-dyne) • What the drug does to the body • E.g. heart rate, ECG, blood pressure © 216

ADME

© 217

© 218

© 219

Phase I

• Usually start with single dose study • Dose escalation to maximum tolerated dose • Multiple ascending repeat dose studies • Kinetic profile is established • Drug interactions • QTC intervals © 220

Phase I

• Future is in establishing early signaling of drug efficacy.

• Proof of Concept often conducted in Phase I then move to phase II while completing drug interactions, food interactions, etc.

© 221

Phase II

• Primary objective – To examine safety and therapeutic effectiveness in patients – Proof of concept--To find out whether the drug works in people who have the targeted disease or condition. © 222

Phase II

• Goals – Determine dose and regimen – Evaluate potential study endpoints – Evaluate therapeutic regimens including concomitant medications – Evaluate target population including disease severity Determine all of above for further study in phase 2 or 3 © 223

Phase II

• May be divided into two phases – Phase 2A: proof of concept pilot studies – Phase 2B: • Demonstrate efficacy • Assess short term safety • Dose finding/dose ranging • Uses a few dozen to 300 subjects • Duration: short to medium length lasting up to a few months © 224

Phase II • Information defined in Phase 2 – Safety in patients – Efficacy – Pharmacodynamics – Pharmacokinetics – Bioavailability – Drug/disease interactions – Drug/drug interactions – Efficacy at different doses – Pediatric information © 225

Phase III

• Primary objective – To confirm therapeutic effectiveness and safety in a less restricted patient group • Consists of well-controlled trials to support marketing approval by confirming preliminary data collected in phase 2 on safety and efficacy in intended patient population © 226

Phase III

• Uses several hundred to 3000 subjects • Duration: – parallels anticipated treatment – May be several years for chronic conditions • Takes place at multiple centers including hospitals and doctors offices • Study design has broader patient eligibility and may have 2-3 treatment groups • Tests final formulation of drug © 227

Phase III

• Information typically defined: – Efficacy and safety in population subgroups including different disease stages – Dosing interval – Dose response relationship – Efficacy with another drug (drug combination therapy) – Drug/drug interactions – Drug/disease interactions – Risk/benefit information © 228

Pravachol Approval

• • • • • • Pravachol Primary Prevention Study, also known as the West of Scotland study, was pivotal phase III study used to file NDA The Pravachol Primary Prevention Study, evaluated the use of Pravachol in 6,595 subjects over a five-year period, demonstrated that Pravachol reduced the risk of first heart attack by 31%.

Death from cardiovascular disease was reduced by 32%, and there was no increase in death from non-cardiovascular causes. The study showed that Pravachol reduced the need for coronary procedures such as balloon angioplasty and bypass surgery by 37%. Another major finding from the Pravachol Primary Prevention Study was that Pravachol benefit, in terms of reduction in first heart attacks, begins at about six months after the initiation of therapy.

http://www.centerwatch.com/patient/drugs/dru142.html

© 229

The NDA What….

• Formal step a drug sponsor takes to receive FDA approval to market a new drug in the USA • Application to market a new drug under Section 505 of FDA.

• Establishes an efficient and thorough drug review process © 230

When?

• Once all pre-clinical and clinical reports are available to support the file.

© 231

New Drug Application (NDA)

• Includes: – Index – Overall summary of drug and study results – Technical sections • Chemistry, manufacturing, and controls (CMC) • Non-clinical pharmacology and toxicology • Human PK and availability • Clinical microbiology if applicable • Clinical data • Statistics © 232

New Drug Application (NDA)

• Includes – Case Report Tabulations – Case Report Forms – Patient information and certification – Establishment description – Environmental assessment or exemption – Includes samples of the drug • Typically consists of over 100,000 pages and may contain data on more than 3000 patients © 233

New Drug Application (NDA)

• Once the NDA is filed, the FDA has 60 days to decide whether to file it for review • FDA’s Center for Drug Evaluation and Research (CDER) will then review the drug for approval © 234

New Drug Application (NDA)

• Review team consists of: – Chemists – Pharmacologists – Physicians – Pharmacokineticists – Statisticians – Microbiologists © 235

New Drug Application (NDA)

• Team evaluates the drug to see if it is “safe” and effective for proposed use – “Safe” means the benefits of the drug outweigh the risks – They analyze the results and look for any weaknesses of study design or analyses – They determine if they agree with the sponsors or need additional information © 236

New Drug Application (NDA)

• Prescription Drug User Fee Act passed in 1992 to provide funding in an effort to reduce FDA approval time and bring drugs to market faster.

• CDER’s goal is to review and act on at least 90% of NDAs for

standard drugs

no later than 10 months after the NDA is received and no later than 6 months for

priority drugs

– Standard drug: Drugs that offer only a minor improvement or no improvement over drugs currently on the market – Priority drug: a drug believed to represent potential major advances in healthcare © 237

New Drug Application (NDA)

• FDA has worked to shorten time devoted to clinical trials by – Having meetings with drug companies to streamline studies and eliminate duplicate studies – Expediting approval of innovative agents • As part of the review process, on-site inspections are made of some of the clinical sites © 238

New Drug Approval Time by Year Median of Total Approval Times (in months) 20 15 10 5 35 30

32.9

25

29.9

27.2

29.3

24.3

22.1

22.6

23.0

17.5

15.9

14.3

13.4

12.0

11.6

15.6

n = 20

1986

n = 21

1987

n = 20

1988

n = 23

1989

n = 23

1990

n = 30

1991

n = 26

1992

n = 25

1993

n = 22

1994

n = 28

1995

n = 53

1996

n = 39

1997

n = 30

1998

n = 35

1999

n = 27

2000

239

© 240

New Drug Application (NDA)

• Advisory committee – Panel of outside experts – Review the safety and efficacy results – CDER is does not have to take the committees recommendations but they usually do © 241

New Drug Application (NDA)

• Three possible results – Approved – Approvable: drug can probably be approved after resolution of certain issues – Not approvable © 242

©

I N D &

243

15 10 5 20 25

New Drug Approval Time by Year

Median of Total Approval Times (in months) 35 30

32.9

29.9

29.3

27.2

24.3

22.1

22.6

23.0

17.5

15.9

14.3

13.4

12.0

11.6

15.6

n = 20

1986

n = 21

1987

n = 20

1988

n = 23

1989

n = 23

1990

n = 30

1991

n = 26

1992

n = 25

1993

n = 22

1994 Cale ndar Ye ar

n = 28

1995

n = 53

1996

n = 39

1997

n = 30

1998

n = 35

1999

n = 27

2000

© 244

Label

• When the FDA approves a drug, it approves the label for the drug • The label is what appears on the package insert for the drug. This information also appears in the PDR.

© 245

Label

• Label includes: – Description of the drug • Chemical class and structure • Pharmaceutical action • Product presentation – Clinical Pharmacology • Mechanism of action • Pharmacodynamics • Pharmacokinetics and metabolism © 246

Label

• Label includes – Indications and usage – Contraindications – Warnings, WARNINGS – Precautions • Drug interactions • Carcinogenesis • Mutagenesis • Fertility Effect • Nursing Mothers • Pregnancy • Children • Elderly © 247

Label

• Label includes – Adverse Reactions • By organ or body system • Stratification by % incidence – Drug abuse and dependency potential – Overdosage – Dosage and Administration – How supplies © 248

Label

• May include a Black Box warning – This is a separate warning that is highlighted for the drug – May be mandated by the FDA as terms of approval – Not desirable © 249

Phase IV

• These are studies that occur after a drug has been approved • May explore long term effects • May explore how participants respond to different dosages • May compare with competitors products to support marketing claims • May look at the incidence of adverse reactions © 250

• ??????

Questions

© 251

care research community teach

Legal Issues in Research

Priya Sankar, Esq.

Assistant General Counsel Associate Director, Contracts and Budgets

25 3

Red Flag

25 4

ROAD MAP

I II III IV General Contracts A.

Why have a Research Agreement?

B.

C.

D.

Confidentiality Agreements Clinical Trial Agreements Government Grants/Cooperative Grants Fraud & Abuse Regulations A.

Conflict of Interest Regulations B.

C.

Federal Anti-Kickback Statute Federal False Claims Act Other Legal Issues

25 5

Type of Clinical Research

1.

Internal 2.

3.

Industry Sponsored Government-Funded (e.g. NIH)

Public Health Service (PHS )

Department of Health & Human Services (HHS) National Institute of Health (NIH) Center for Medicare & Medicaid Services (CMS)

25 6

Agency for Healthcare Research & Quality (AHRQ) Health Resources & Services Administration (HRSA) Food and Drug Administration (FDA) Center for Disease Control (CDC) Agency for Toxic Substances and Disease Registry (ATSDR) Substance Abuse and Mental Health Services (SAMHSA)

25 7 HHS PHS OHRP

What do they do?

  Department of Health & Human Services Protecting the health of all Americans and providing essential human services   Primary division of HHS Component of HHS that makes up the key agencies (e.g. NIH, FDA, etc.)   Office of Human Research Protections Oversees national system of protecting human subjects in research (i.e. Institutional Review Boards) through regulations, oversight, guidance

25 8 NIH FDA OIG

What do they do?

  NIH is the government’s research organization. It supports 38,000 research projects nationwide in diseases including cancer, Alzheimer's, diabetes, arthritis, heart ailments and AIDS. Includes 27 separate health institutes and centers.   FDA assures the safety of foods and cosmetics, and the safety and efficacy of pharmaceuticals, biological products, and medical devices   Office of Inspector General Protect the integrity of Department of Health and Human Services (HHS) programs, as well as the health and welfare of the beneficiaries of those programs

25 9

Key Players in Clinical Research

Study Subject PHS (HHS OHRP) St. Peter’s University Hospital Researcher NIH FDA IRB Industry Sponsor

26 0

ROAD MAP

I General II Contracts A.

B.

C.

D.

Why have a Research Agreement?

Confidentiality Agreements Clinical Trial Agreements Government Grants/Cooperative Grants III IV Fraud & Abuse Regulations A.

Conflict of Interest Regulations B.

C.

Federal Anti-Kickback Statute Federal False Claims Act Protection of Human Subject (HIPAA)

26 1    

Why Have A Contract?

Anti-Kickback Safe Harbor Ensure Compliance Protect Existing Rights • Intellectual Property • Confidential Information Allocate Rights and Obligation • Publication Rights • Intellectual Property (Inventions) • Liabilities (Indemnification & Insurance) • Cost

26 2   

Confidentiality Agreements

The Contract before the Research Contract What is it?

Usually required by Industry Synonyms: • CDAs • NDA • Nondisclosure Agreements • Secrecy Agreements

26 3

Key Terms Confidentiality Agreements

1.

2.

  Defines what is “Confidential Information” Study Drug/Device Study  Never undefined Defines what is not “Confidential Information:    Public Information Already Know Already Given by Third Party   Required to Disclose by Law Independently Developed

26 4

Key Terms Confidentiality Agreements

3.

4.

5.

Defines how it will be disclosed Defines who it may be disclosed to Defines how long it shall be held confidential

26 5

Confidentiality Agreements

     Protect Yourself! Protect your Colleagues! Know your institution’s policy Be careful what you sign Be careful what you open Make sure you are aware of your obligations.

When in doubt, seek legal counsel You may be personally liable!

26 6

Clinical Trial Agreements

5 Key Provisions

     Intellectual Property Confidential Information Publication Indemnification Patient Injury Compensation (if clinical)

26 7

Government Funded

(e.g. PHS Funded Research) Grants    Funds transferred to awardee Work independently Report results at end Cooperative Agreements   Substantial involvement Gov’t involved in planning and implementation Subcontracts to Grants/Cooperative Agreements

26 8

ROAD MAP

I General II Contracts A.

B.

C.

D.

Why have a Research Agreement?

Confidentiality Agreements Clinical Trial Agreements Government Grants/Cooperative Grants III IV Fraud & Abuse Regulations A.

Conflict of Interest Regulations B.

C.

Federal Anti-Kickback Statute Federal False Claims Act Protection of Human Subject (HIPAA)

26 9

What is Conflict of Interest?

Conflict of interest exists if it actually or potentially may have influence over the outcome of the research

27 0

Laws & Regulations

Each agency has developed differing definitions of conflict of interest and how and to whom conflict disclosures should be made.

27 1

Laws & Regulations

Neither the PHS or FDA regulations: 1.

Identify specific conflicts of interest or financial interests that are prohibited.

2.

Define the role of the IRB in dealing with conflict of interest.

27 2

PHS FUNDED RESEARCH

27 3

PHS Regulations (42 CFR § (45 CFR § 50 ) 94)

Applies to: PHS grants or cooperative agreements

27 4

How does PHS regulate conflict?

Regulations Require:  Institution to act as “Enforcer” and “Reporter”  Investigator to disclose “significant financial interests”

27 5

Institution as “Enforcer”

1.

Must establish and enforce a written process that identifies, and manages , reduces, or eliminates any significant financial interests of an Investigator. 2.

Inform Investigator of process and reporting responsibilities. 42 CFR § 50.604

45 CFR § 94.4

Institution as “Reporter”

1.

2.

Must certify to PHS agency that written enforced COI process is in effect.

Must report any COI (including Significant Financial Interest) to PHS agency and assure that the COI has been managed, reduced, or eliminated on an annual basis or as new reportable Significant Financial Interests are identified 3.

Must report to PHS agency any failure of an Investigator to comply with Institution’s COI process 27 6 4.

Must make COI information available to HHS 42 CFR § 50.604, 50.606

45 CFR § 94.4, 94.6

27 7   

Who must disclose a Significant Financial Interest?

Principal Investigator Any other person who is responsible for the design, conduct, or reporting of the PHS grant (e.g. Co-investigators). Their spouse and dependent children 42 CFR § 50.603

45 CFR § 94.3

27 8

What is a Significant Financial Interest?

Anything of monetary value 42 CFR § 50.603

45 CFR § 94.3

Examples Significant Financial Interest?

27 9    Salary other payments of services (consulting fees, honoraria) Equity interests (stocks, stock options, any ownership interests) Intellectual Property Rights (patents, copyrights, and royalties)

42 CFR § 50.603

45 CFR § 94.3

28 0    

Examples Not Significant Financial Interest?

Salaries, royalties or other remuneration from the Institution Income from seminars, lectures, teaching engagements sponsored by public or non- profit entities Equity Interest that does not exceed $10,000 in value and does not represent more than 5% ownership interest in any single entity Salaries, royalties, or other payments that do not exceed $10,000 over a 12 month period 42 CFR § 50.603

45 CFR § 94.3

     

How does an Institution manage, reduce or eliminate COI?

Public Disclosure of SFI Monitoring of PHS research by independent reviewers Modification of the research plan Disqualification from participation in all or part of the PHS research Divestiture of significant financial interests Severance of relationships that create actual or potential conflicts 42 CFR § 50.605

45 CFR § 94.5

28 1

28 2

FDA Regulations (Clinical Trials)

28 3  

Who is a Clinical Investigator?

Investigators or Sub-Investigators who are directly involved in the treatment or evaluation of research subjects Their spouse and dependent children 21 CFR § 54.2



What financial relationships and interests must be disclosed?

Compensation to the investigator for conducting the Study is based on the outcome of the Study   Any significant payments of other sorts from Sponsor of monetary value of more than $25,000 (i.e. grant to fund other research, equipment, consulting fees, honoraria) Any proprietary interest in the Drug/Device  Any significant equity interest in the Sponsor.

- Publicly-held entity: Exceeds $50,000 - Privately-held entity: Cannot be readily determined  Any steps taken to minimize the potential for bias resulting from any of the above arrangements, interests, or payments 21 CFR § 54.4

28 4

28 5

FDA Review

After the Study is completed, Sponsor will submit its IND/IDE application to the FDA which will contain Form 3454 (Certification) or Form 3455 (Disclosure) for each Clinical Investigator.

If FDA determines that the disclosed financial interests raise a serious question about the integrity of the data, it may take any action necessary to ensure reliability of the data.

21 CFR § 54.5 42 CFR § 50.606

45 CFR § 94.6

28 6    

FDA Actions

Audit of the data Requesting further analysis of data Requesting further independent studies to confirm results Reject results 21 CFR § 54.5

28 7

ROAD MAP

I General II Contracts A.

B.

C.

D.

Why have a Research Agreement?

Confidentiality Agreements Clinical Trial Agreements Government Grants/Cooperative Grants III IV Fraud & Abuse Regulations A.

Conflict of Interest Regulations B.

C.

Federal Anti-Kickback Statute Federal False Claims Act Protection of Human Subject (HIPAA)

28 8

Federal Anti-Kickback Statute

 Arrangement between vendor and healthcare professional  Induces or influences the purchase, order, or referral of drugs, devices, products, services, or other items  Reimbursable under a federal healthcare program

   

Federal Anti-Kickback Statute

Criminal Offense Penalties up to $25K or imprisonment up to 5 years, or both Exclusion from Federal healthcare programs (i.e. Medicare, Medicaid) HHS may seek civil penalty $50K for each act that violates the AKS 28 9

29 0

Personal Services Safe Harbor

(Application to Research Agreements)  Contract in writing and signed by parties  Specify all services  Term of contract over 1 year  Compensation • • • Set in advance FMV Not determined by volume, referrals, etc.

29 1

Relevance in Research?

Research arrangement is suspect when:  Initiated/directed by Sponsor’s marketing dept  Study results not shared with Sponsor’s science dept  Duplicate research/ serves no legitimate purpose  Product promotional activity masked as postmarket research  Payments for services above FMV

29 2

ROAD MAP

I General II Contracts A.

B.

C.

D.

Why have a Research Agreement?

Confidentiality Agreements Clinical Trial Agreements Government Grants/Cooperative Grants III IV Fraud & Abuse Regulations A.

Conflict of Interest Regulations B.

C.

Federal Anti-Kickback Statute Federal False Claims Act Protection of Human Subject (HIPAA)

29 3

Federal False Claims Act

Organization knowingly submits a false claim for payment/approval to an agency of the federal government.

“Knowingly” includes  actual knowledge  deliberate ignorance  reckless disregard of the truth

29 4

Relates to Research?

Certification Theory Gov’t requires certifications:  Apply for a grant   Submit an application to the FDA Submit a claim for reimbursement for research-related care Whenever a false certification is made, FCA is violated.

Examples in Research

• False certification in grant applications • False statements in use of grant funds • Failure to make financial disclosures (FDA Form 3454) • Failure to make complete financial disclosures (FDA Form 3455) • Allocations of costs in funded research • Medicare/Medicaid billing • Double-billing 29 5

Federal False Claims Act

     Civil action May include criminal penalties Damages plus $11K penalty for each false claim If brought by whistleblower, s/he may receive as much as 30% reward if government does not intervene Potential exclusion from federal healthcare programs 29 6

29 7

AKS and FCA Cases

Warner-Lambert (FCA)

•

$430 million

• $83.6million for FCA Violation • $106.4 million for State Settlement • $240 million Federal Criminal Fine • Whistleblower’s share = $24.64 million • Corporate Integrity Agreement

29 8

AKS and FCA Cases

TAP Pharmaceuticals (AKS & FCA)

•

$875 million

• $559.5 million for FCA Violations • $25.5 million for State Settlement • $290 million federal criminal fine (DOJ’s Crime Victims Fund ) • Whistleblower share 1 = $78 million (TAP VP of Sales) • Whistleblower share 2 = $17.1million (Tufts Health Plan & Physician) • Corporate Integrity Agreement

29 9

AKS and FCA Cases

Arizona Heart Institute (FCA)

•

$6.7 Million

• $5.8Million Arizona Heart Institute • $900K Medical Practice Groups • Corporate Integrity Agreement (5 years) • Violated FCA by submitting Medicare claims for experimental procedures

30 0

ROAD MAP

I General II Contracts A.

B.

C.

D.

Why have a Research Agreement?

Confidentiality Agreements Clinical Trial Agreements Government Grants/Cooperative Grants III IV Fraud & Abuse Regulations A.

Conflict of Interest Regulations B.

C.

Federal Anti-Kickback Statute Federal False Claims Act Other Issues

30 1

Double-Billing

Seeking multiple reimbursement for same services Seeking Medicare/Medicaid reimbursement for services reimbursed by sponsors/grant funds

30 2

HIPAA

Informed Consent – Authorization Limited Data Set Agreements

30 3

Insider Trading

Providing results to a third party for the purpose of assessing corporate stock violates insider trading laws Violates Confidentiality Agreements