1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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.

8. 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

9. 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

10. 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

11. 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.

12. 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?

13. 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)

14. 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.

15. 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.

16. 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

17. 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

18. 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

19. 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

20. 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

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