Carl Anderson

The Form FDA 1572, Statement of the Investigator, is a basic contract between a clinical investigator and the FDA. It is required in all clinical trials conducted under an Investigational New Drug application. It has also been the source of numerous discussions about exactly who belongs in Section 6 as a subinvestigator. Now, FDA is making it clear.

FDA has made some big changes in the final version of the Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs—Frequently Asked Questions—Statement of the Investigator (Form FDA 1572), released in May. The FAQ states that study coordinators should "usually be listed in Section #6 of the 1572." This is a significant change from the July 2008 draft FAQ. Many sites do not list study coordinators on the FDA 1572, which means that most coordinators will need to file financial disclosure information. It will be a significant change in the way FDA inspects sites.
 
Specifically, the FAQ document states: "Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the study data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572."

This is a big change from the draft FAQ that says: "If a research coordinator is performing critical study functions and collecting and evaluating study data, the coordinator should be listed on Block #6." This is also a very significant difference, and not just because they changed Block #6 to Section #6.

Articles

Key Updates to the 1572

Electronic medical records (EMRs) have been considered a panacea for cutting down on medical errors, streamlining recordkeeping, and delivering quality care to patients by health care providers, medical technology companies, and even the president of the United States.

  They are also seen as a boon to clinical research by assisting in matching cancer patients with the right clinical trial,

  aiding in cost effective subject recruitment, and rapidly identifying adverse events.

  However, not everyone agrees that EMRs are ready for prime time. 

In a recent practice improvement study, researchers looked at 50 primary care centers to evaluate the effect of EMRs on outcomes for treating diabetes. The study found that primary care centers using EMRs were less effective in treating diabetes than centers using standard recordkeeping systems. The researchers noted that there were significant differences among commercially available EMR systems, including the amount of training and technical support available.  

Photography: Getty Images    Illustration: Paul A. Belci 

, concluded that "a high level of support for EMR implementation will be required" to meet the federal goal of EMRs for all Americans by 2014 while preserving and enhancing the quality of medical care. This analysis has promoted a lively discussion on the journal's Web site, with comments containing alternate viewpoints.

Sponsors of clinical research are responsible for monitoring the progress of the investigation.

  In addition, medical device sponsors are responsible for having written procedures for how they will monitor the study.

  When monitors and quality assurance auditors visit clinical sites, they are confronted with a number of concerns about EMRs. These concerns fall into three broad categories:  

Privacy: How does the Health Insurance Portability and Privacy Act (HIPAA)

  impact a monitor's ability to review EMRs?

21 CFR Part 11: How does FDA enforcement of Part 11

  impact a sponsor using EMRs as source documents?

Data integrity: Do EMRs provide the same level of data integrity that a paper record does?

A look at federal laws, regulations, and guidance documents as well as two case studies, provides answers to some of these questions and establishes a framework for GCP-compliant monitoring and recordkeeping. 

With the advent of HIPAA in 1996 and the Privacy Rule regulations of 2002,

  many institutions began limiting access to EMRs. Clinical investigators, however, are required by FDA to maintain "adequate and accurate case histories."

  The principal GCP guideline, the ICH Guideline for Good Clinical Practice (E6), states that a sponsor specify that the investigator and institution shall "provide direct access to source data/documents for trial-related monitoring."

The Privacy Rule requires that an individual participating in research provide signed permission or "authorization" before records may be accessed for researchers. This issue can be effectively dealt with in the informed consent form (ICF) that a research participant signs prior to any research related activities. The FDA-required elements of informed consent include a confidentiality clause that notes the possibility that FDA may inspect the records.

  ICFs routinely include that sponsor representatives may review the records. However, this one clause isn't sufficient to meet the requirements of the privacy rule. The ICF must also explain that a participant may withdraw from the study, the duration of the study, and the participant's signature and date. Each of these elements is necessary to meet HIPAA requirements. However, it is important to note that some institutions require a "stand alone" authorization that is separate from the ICF. In addition, some states may also require stand alone authorization. The sponsor needs to be aware of local regulations and policies. 

The National Institutes for Health have also published a guidance document on Clinical Research and the HIPAA Privacy Rule.

  These guidances indicate that it is not necessary to have a stand alone HIPAA disclosure. Compliance with the Privacy Rule can be accomplished with an appropriate ICF. 

The Privacy Rule reinforces the importance of the informed consent process in clinical trials. It is important that the research participant be given a copy of the ICF in the language used during the consenting process. The Privacy Rule emphasizes that the consent authorization "must be written in plain language."

  If the investigator and sponsor prepare an adequate ICF and conduct an effective informed consent process, there is nothing in the Privacy Rule that prevents the monitoring of any medical record, including EMRs, even if the EMR is part of a larger record that includes nonresearch related health information. That is no different than the paper-based medical chart that monitors have been reviewing for decades. The question of privacy is resolved with appropriate disclosure in the ICF. 

There have been few issues as confusing as the FDA regulation of electronic records and electronic signatures under 21 CFR Part 11. This confusion was compounded when some FDA inspectors probed the Part 11 compliance of hospital EMR systems. This continued even after FDA scaled back enforcement of Part 11 in the August 2003 Part 11 Scope and Application guidance document.

One of the results of industry's Part 11 concerns is that sponsors began taking a closer look at the EMR systems in use at clinical sites. Sponsors wished to ensure that their data was being collected and recorded in a system that FDA would find acceptable. It is important to note that FDA has not asserted jurisdiction of medical institution EMR systems for compliance with Part 11. Instead, they issued the guidance document, 

Computerized Systems Used in Clinical Investigations

  This document is essentially protocol specific and does not mention EMR systems at institutions. 

The concept of protocol specific compliance is very important. FDA regulates drugs, medical devices, and biologic products and not the practice of medicine. A case history can be used to illuminate this point. 

A clinical study coordinator was approached by a sponsor with a lengthy questionnaire regarding the institution's compliance with Part 11.

  The sponsor wanted a detailed response from the institution's IT department. The IT members were not familiar with Part 11 and adhered to different technical standards. The questionnaire was not necessary because the FDA does not have jurisdiction over an institution's recordkeeping, only the investigator's records for a specific protocol. If the electronic recordkeeping system is specific to the protocol, it should follow the May 2007 guidance. If the institution's recordkeeping system is used for the practice of medicine, then it is not in FDA's jurisdiction. Essentially, sponsors should make sure that their own systems are compliant for their specific protocol, not the institution's. However, this does not mean that Part 11 should be ignored. In fact, the May 2007 guidance is instrumental in helping to ensure that records generated by an EMR system are GCP compliant. There is a continuing need for quality standards for recordkeeping of clinical research. 

An example is when it is the intention to print EMRs and use them in a subject case history for a clinical trial. Then, it should be done in a manner consistent with FDA guidance. The guidance document allows for a certified copy to be made of an electronic record. Using certified copies is one way of maintaining data integrity of EMRs. The guidance requires a dated signature to attest that the EMR has "all of the same attributes and information as the original." 

Developing quality standards is best done at the beginning of the study. Sponsors must familiarize themselves with the recordkeeping system of each clinical site and work with investigators and study staff to establish consistent documentation of protocol required data. When using EMRs it is necessary to establish the source document and how the integrity of that document will be maintained. 

A look at another case study can show us why.

  A clinical site printed out an EMR and used it as a worksheet or study "source document" in a clinic chart. Several copies of the printout existed with undated and unsigned handwritten annotations. There were three or more versions of the same intake summary or operative report, each with different data.  This is in direct conflict with the recordkeeping maxim of Attributable, Legible, Contemporaneous, Original, and Accurate (ALCOA). This resulted in an audit finding that was discussed with the investigator and study staff. It easily could have resulted in an inspectional finding listed on a FDA Form 483 Inspectional Observations during an FDA inspection. 

Sometimes it is necessary for a monitor or auditor to travel to a specific workstation at a location other than the investigator's offices to review an institution's EMRs. That should be determined at the beginning of the study and built into a monitoring or auditing plan. Case report forms (CRFs) need to be compared against source documents. If the source document is a printed EMR, then the monitor needs to periodically verify the accuracy of the printed version. First, it should be a Certified Copy with a dated signature. If the source document is the EMR, then the monitor needs to have access to the EMR to do the comparison with CRFs. This is particularly important for review of adverse events (AEs). If the EMR is not reviewed, then review of AEs is not occurring. 

The inherent problem with EMRs is the fact that they can be changed over time. The need to document certain data at a certain point in time can be addressed with the "certified copy." For example, if you want to document adverse events at study visit three, then you need to have some means of documenting data entry on the date of visit three. 

Here again we encounter the concept of a protocol specific electronic record. If the clinical investigator wants to use an EMR to document a protocol required activity, then a certified copy is a useful tool. However, if the source document remains in a medical center's EMR system, while the sponsor and FDA have the right to review it, there is no way to guarantee that the record has been changed since the protocol required activity occurred. It is a difficult situation that sponsors and investigators are grappling with. 

Electronic medical records and computerized systems are now a part of daily life, but EMRs still have a way to go before they can actualize everything that's expected of them. In the mean time, sponsors can take steps to ensure the protection of each participant's privacy and the integrity of data captured on EMRs. 

 1. G. Bush, 2006 State of the Union Address, The White House Web site, http://

 2. J.W. Goldwein et al., Abstract No. 6626, 

, 2007 ASCO Annual Meeting Proceedings, Part 1 Vol. 25, No. 18S (June 20 Supplement) 2007: 6626. 

 3. M. Mowry and D. Constantinou, "Electronic Health Records: A Magic Pill?" 

 4. J.C. Crosson et al, "Electronic Medical Records and Diabetes Quality of Care: Results From a Sample of Family Medicine Practices," 

, Title 21, Part 312 Section 56(a) (U.S. Government Printing Office, Washington, DC). 

, Title 21, Part 812 Section 25(e) (U.S. Government Printing Office, Washington, DC). 

 7. U.S. Department of Health & Human Services, Health Insurance Portability and Privacy Act of 1996 (U.S. Government Printing Office, Washington, DC). 

, Title 21, Part 11 (U.S. Government Printing Office, Washington, DC). 

, Title 45, Parts 164-168 (U.S. Government Printing Office, Washington, DC). 

, Title 21, Part 312.62(b) (U.S. Government Printing Office, Washington, DC). 

11. Food and Drug Administration, "ICH E6 Good Clinical Practice: Consolidated Guidance, Section 4.9.7, 

, Title 21, Part 50 Section 25(a)(5) (U.S. Government Printing Office, Washington, DC). 

, Title 45, Part 164 Section 508(c)(2) (U.S. Government Printing Office, Washington, DC). 

Guidance for Industry: Part 11 Electronic Records; Electronic Signatures—Scope and Application

Guidance for Industry: Computerized Systems Used in Clinical Investigations

Shedding light on common EMR concerns about privacy, government regulations, and data integrity.

The Ins and Outs of Electronic Medical Records

A common document at many clinical sites is the memo or note to file (NTF). When used properly, an NTF can be a positive practice. A useful NTF has the following parts: A problem is identified, a procedural change is identified for preventing recurrence, and this procedure is then instituted. In the event of an FDA or other regulatory inspection, the inspector may still leave a citation for the initial problem, but the change in procedure mitigates the citation and provides the site with a strong response to the finding.  

	Some in the clinical trials community, however, seem to think an NTF is a panacea for all things that have gone wrong. Make a mistake? Then write an NTF and stick it in the regulatory binder or subject case history. The practice has become so ubiquitous that new CRAs and study coordinators sometimes think that they are a regulatory requirement. But this is a misconception. There is nothing in FDA's regulations or guidance documents that requires sponsors and clinical sites to use NTFs. Nothing.

	And many think that an NTF indicates a corrective action-with a quick one written without regard to correcting the problem. Sometimes, NTFs are even generated well after the deviation has occurred and all is considered right with the world-this isn't the case. In fact, FDA recently reprimanded a sponsor for after-the-fact memos.

	In a Warning Letter dated October 23, 2007 (

www.fda.gov/foi/warning_letters/s6551c.htm

), FDA wrote: "Our investigation found (the sponsor) failed to take any action except to generate numerous memos to file after all the subjects completed the study." The Warning Letter then noted at least 89 memos were generated after a monitoring visit. Instead of writing NTFs, the sponsor's time is better spent qualifying the site and training study staff.

	Documenting a mistake means absolutely nothing during an FDA inspection. What requires documentation is the corrective action taken and whether the action worked. If an effective quality system is in place prior to subject enrollment, then the sponsor, monitors, investigator, and study staff will each understand how the study will be monitored and how discrepancies will be communicated and corrected. Sponsors cannot depend on postmonitoring visit letters to secure compliance in serious situations.

	During my own auditing experience, I have noticed that NTFs are frequently a contentious issue between monitors and study staff. I have seen trivial NTFs placed in regulatory binders at the request of inexperienced monitors. In addition, some study coordinators have developed a habit of writing NTFs instead of developing good recordkeeping practices. All an NTF accomplishes is documenting poor performance. And ineffective work seldom impresses FDA. 

	Clinical trials are hard work and require professional cooperation to quickly address queries and genuine findings that need correcting. Once an NTF is written and becomes a study record, it cannot be retracted. The result is a lose–lose situation for everyone. These NTFs are a road map for any inspector and air all of the site's faults.

	A better solution is to develop a quality system from the clinical study's beginning that includes training on monitoring and data correction that everyone understands. Sites should document the actual corrective action and keep NTFs few and far between.

Senior Consultant Biologics Consulting Group, Inc. email: 

Carl Anderson, senior consultant for Biologics Consulting Group, addresses the frequent overuse of Notes to File and concludes that documenting a mistake means absolutely nothing during an FDA inspection.

Carl Anderson

Articles

Key Updates to the 1572

The Ins and Outs of Electronic Medical Records

Note to File (NTF) is Not an FDA Panacea