FDA regulations on eClinical trials

The following general guidelines are proposed by FDA in reference in Computerized systems in clinical trials, the complete document is available at http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm

A. Each study protocol should identify at which steps a computerized system will be used to create, modify, maintain, archive, retrieve, or transmit data.
Comment : This means that the study protocol has to receive input from the data manager. Most of the companies include these steps as SOPs so that they can be referenced in the study protocol.

B. For each study, documentation should identify what software and, if known, what hardware is to be used in computerized systems that create, modify, maintain, archive, retrieve, or transmit data. This documentation should be retained as part of study records.
Comment : This level of detail is not mandatory, and is often missed out in most study protocols.

C. Source documents should be retained to enable a reconstruction and evaluation of the trial.
Comment : This requirement is fulfilled via a Audit trial so that FDA/ independent audits can be performed.

D. When original observations are entered directly into a computerized system, the electronic record is the source document.
Comment : The specific condition where this rule will not apply is for lab data, the source data is obtained electronically from the lab. The data is then batch loaded into the CDM system, still the source data is the lab data.

E. The design of a computerized system should ensure that all applicable regulatory requirements for recordkeeping and record retention in clinical trials are met with the same degree of confidence as is provided with paper systems.
Comment : 21 CFR Part 11 and ER/ES are two common regulatory requirements. The "degree of confidence" is set via a validation process for each CDM system.

F. Clinical investigators should retain either the original or a certified copy of all source documents sent to a sponsor or contract research organization, including query resolution correspondence.
Comment : Though this sounds simple, it is complicated for investigators to maintain a source data archive.

G. Any change to a record required to be maintained should not obscure the original information. The record should clearly indicate that a change was made and clearly provide a means to locate and read the prior information.
Comment : All updates on source data will include a reason for change, data and time of change, person initiating the change, data value before change and data value after change. Sometimes the change in data may require sign-off by a study manager.

H. Changes to data that are stored on electronic media will always require an audit trail, in accordance with 21 CFR 11.10(e). Documentation should include who made the changes, when, and why they were made.
Comment : Refer to above

I. The FDA may inspect all records that are intended to support submissions to the Agency, regardless of how they were created or maintained.
Comment : Refer to above

J. Data should be retrievable in such a fashion that all information regarding each individual subject in a study is attributable to that subject.
Comment : Refer to above

K. Computerized systems should be designed: (1) So that all requirements assigned to these systems in a study protocol are satisfied (e.g., data are recorded in metric units, requirements that the study be blinded); and, (2) to preclude errors in data creation, modification, maintenance, archiving, retrieval, or transmission.
Comment : Refer to above

L. Security measures should be in place to prevent unauthorized access to the data and to the computerized system.

Electronic Health Records (EHR) in clinical trials

Electronic Health Records (EHR) are standard instruments used to capture patient encounter data in clinical practice. They offer some key benefits in relation to clinical trials by supporting : 1. Increased patient recruitment, 2. Increased physician participation.

Study Set-up
Query EHR database to establish number of potential study candidates.
Incorporate study manual or special instructions into EHR “clinical content”for study encounters
Study execution
Incorporate study-specific data capture (just as you would do with a CRF in a clinical trial) as part of routine clinical care / clinical documentation workflow.
Auto-populate study data elements (for example demographics) into CRFs from other parts of the EHR database.
Embed study-specific data requirements (modules not already included in the EHR) as special tabs/documentation templates using structured data entry.
Implement rules/alerts to ensure compliance with study data collection requirements (EHR systems have inbuilt validation checks)
Create range checks and structured documentation checks to ensure valid data entry

Study Enrollment
Implement study screening parameters into patient registration and scheduling.
Query EHR database to contact/recruit potential candidates and notify the patient’s provider(s) of potential study eligibility.

Submission & Reporting
Provide data extraction formats that support data exchange standards (for example CDISC)
Document and report adverse events (Note : EHRs often use ICD-9/10 coding, while CRFs would need MedDRA codes)

Safety Reporting to FDA

We have received lot of requests to write about Safety related reporting, coding and regulation. This blog will feature these aspects for the next 10 days, if you wish us to write on a specific topic please email us at contact@clinnovo.com. Thanks for your interest.
Pre-Approval - To IND
Unexpected fatal or life-threatening experience associated with the use of the drug
7 calendar day reports (telephone or fax)
From All Studies Worldwide (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
Findings from long term tox tests in laboratory animals suggesting a significant risk to humans (mutagenicity, teratogenicity, carcinogenicity)
15 calendar day reports (telephone or fax)
Spontaneous Reports from Marketing Outside the U.S. (Serious and Unexpected)
15 calendar day reports (telephone or fax)
Reports in the scientific literature including unpublished manuscripts (Serious and Unexpected)
15 calendar day reports (telephone or fax)
Reports from foreign regulatory authorities (Serious and Unexpected)
15 calendar day reports (telephone or fax)
From Studies Worldwide (Serious)
Annual IND reports
Post-Approval - To IND
From IND Studies (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
From IND Studies (Serious)
15 calendar day reports (telephone or fax)
Post-Approval - To NDA
From All Studies Worldwide (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
Spontaneous Reports Worldwide (Serious and Unexpected)
Spontaneous and Periodic
Consequences of not following the schedule
Pre-Approval - Termination of IND
21 CFR 312.44 in Phase 1, 2 or 3 : (b)(1)(vii) “The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with part 312 section 32 or fails to make any other report required under this part.
Post-Approval- Withdrawal of NDA
21 CFR 314.80 (K) : "If an applicant fails to establish and maintain records and make reports required under this section FDA may withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.”