Data Integrity – The Basis for “Generalizability” to Substantiate Change Balancing Efficacy with Clinical Power Frederick A. Curro, DMD, PhD PEARL Network Dental PBRN Executive Management Team New York University / Bluestone Center for Clinical Research

Organization of the PEARL Network Practice Based Research Networks: The PEARL Experience Organization of the PEARL Network Collaboration among NIDCR (funding), NYU College of Dentistry (administrative center), and the EMMES corporation (data coordination center) NYUCD Administration Center Cores (Executive Management Team) Protocol development and training - V.Thompson, DDS, PhD Recruitment, retention and operations – F. Curro, DMD, PhD Information dissemination – R.Craig, DMD, PhD Dr. Jonathan A. Ship, New York Univ 2

Data Integrity Health care was once thought of as outer space – “no limits” The Nation is rethinking the cost of “no limits” and capping health care is now discussed The FDA has issued a record number of black box warnings Pharmaceuticals and procedures are now compared to others instead of a placebo to achieve best practice

Data Integrity The need for an infrastructure Should a PBRN be concerned with data integrity? Does a clinical infrastructure go against the principles of a PBRN? PBRN studies vs. Randomized Clinical Trial

Data Integrity Confidence in making a decision related to the clinical study Confidence in applying that decision to a broad population Confidence in using that decision to implement change Confidence in the return of investment

Data Integrity Quality Assurance Standard Operating Procedures Audit Trail GCP The pharmaceutical industry has QA layered within the R&D structure – clinical, regulatory, corporate, outside consultant, FDA

GCP – Effectiveness vs Comparative Phase III trial are designed to assess the effectiveness of the new intervention, either drug or device, against a placebo Comparative clinical trial is one that measures the efficacy of a given treatment by comparing the test results of two groups, one given the test treatment while the other is given the standard or no treatment. May or may not be randomized and/or blinded.

Data Integrity Investigators and office personnel Office procedure Standard of Care study Effectiveness study Randomized Controlled Clinical Trial Protocol Drift to Office procedure – clinical protocol reinforcement

Data Integrity Requirements for a PBRN – to support the practitioner in adhering to the protocol Limit turnover rate of PIs Support the practice research coordinator(s) to adhere to the protocol Create an electronic data capture system that is user friendly and has controls Practice responsibility to follow up with patient

GCP – Good Clinical Practice Creating a pathway for compliance and standardization in the conduct of a clinical trial – the Audit Trail Protocol adherence Reporting of adverse events and information

Informed Consent 21 CFR parts 50 and 56 – Protection of Human Subjects; Informed Consent The FDA is charged by statute with ensuring the protection of the rights, safety, and welfare of human subjects who participate in clinical investigations as well as clinical investigations that support applications for research or marketing permits for products regulated by the FDA, including food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products.

Conflict-of-Interest FDA (August 2008) – limits experts to participate in an advisory committee meeting if that individual has a financial interest of more than $50,000 directly related to an issue before the panel. FDA may issues a waiver if individual’s expertise is considered “essential” and conflict is below financial threshold No waivers if committee member has direct links to the sponsor through grants, contracts or involved in clinical trial design or conduct, or holds sizable stock in company. New financial interests guidance replaces one issued in 2000 which had confusing criteria. Just what constitutes a conflict for consulting fees?

IRBs - terminology IRB – Institutional Review Board IRB – Independent Review Board IEC – Independent Ethics Committee (Board) CCI – Committee on Clinical Investigations CHR – Committee on Human Research CPHS - Committee for the Protection of Human Subjects EAB – Ethical Advisory Board EC – Ethics Committee HEX – Human Experimentation Committee HSRC – Human Subjects Review Committee NIRB – Noninstitutional review Board REB – Research Ethics Board (Canada) LREC – Local Research Ethics Committees (UK) MREC – Multicentre Research Ethics Committees (UK)

GCP Audit – Systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor’s standard operating procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirements.

GCP An international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance assures the rights, safety, and well-being of trial subjects that they are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

GCP – Prior to Start Up Investigator’s Brochure Signed protocol and amendments, and sample case report forms Informed Consent Advertisement for subject recruitment Financial aspects of the trial – conflict of interest Insurance statement Signed agreement between all parties

GCP – Start Up Dated, documented approval/favorable opinion of IRB/IEC: protocol, CRF, ICF, advertisement, subject compensation Regulatory approval – domestic, international Qualifications of PI – cv, license Normal values for medical tests Medical lab – certification, accreditation, QC Sample of labels

GCP – Start Up Instructions for handling investigational products Shipping records Certificate of analysis of drug Decoding procedures for blinded trials Master randomization list Pretrial monitoring report Trial initiation monitoring report

GCP – During the Study Investigator’s Brochure updates Revisions and updates – IRB, regulatory, PIs Medical laboratory data – normal values Monitoring visit reports Relevant communication Source documents Signed & dated CRFs Documentation of CRF corrections AE and SAE updates Interim reports Subject screening log Subject enrollment log Drug accountability Signature sheet Record of retained body samples

GCP – After Completion Drug accountability and/or destruction Completed subject identification code list Audit certificate Final close-out monitoring report Final report to IRB Clinical study report

Quality – Infrastructure – EDC – CRA – GCP Data Integrity Quality – Infrastructure – EDC – CRA – GCP Thank You – The End