Subject diaries are used  to collect primary and secondary endpoints in about 25% of all clinical trials.1 In recent years, the traditional paper diary booklets have been replaced in some instances by small electronic devices for recording diary information.2 Our series of articles is aimed at helping clinical researchers understand the development, implementation, and regulatory compliance of these electronic patient diary systems. Our particular focus is on the reasonable apprehensions expressed by clinical teams considering whether to use electronic diaries. They worry about these issues.	

Lack of clarity about complying with the regulations governing electronic systems (discussed in Part 2)

Lack of knowledge about how an electronic system is specified, built, and deployed

The effect of including an electronic diary in the clinical trial development process and timelines

The number of work process changes that could be required of participants in the clinical trial process: sponsor staff, monitors, investigators, and subjects. 

To address these concerns, this series presents the clinical, technical, and regulatory issues involved in the development and implementation of electronic patient diary (EPD) systems that meet regulatory requirements. Part 1 compared paper and electronic methods in the context of existing FDA and ICH regulations and guidance for capturing diary data.3 We concluded that newer, electronic methods are in fact more compliant with FDA and ICH data standards than traditional paper diaries. In Part 2, we began discussing the clinical and technical considerations for developing an EPD system. We focused on the clinical protocol and its definition of the medical moments-the health experiences-to be recorded by the subject, and we concluded that it is key to the success of an EPD system.4	

In Part 3 we discuss the development and validation of an EPD system based upon a clinical protocol. As shown in Figure 1, a computerized EPD system extends beyond the hardware and software used by the subject. It also includes the systems components and work processes for all users of the system; the core of the EPD system is the diary device containing protocol-specific software. The device also requires some type of communication software and hardware-for example, a peripheral wired modem that connects to a regular phone line-to transmit the subject data to a central data repository or server.	

Figure 1. Computerized system for electronic diaries.				

Once it is on the server, the subject's data can be processed and viewed in a secure environment by those responsible for trial management and conduct. The investigative site can use this information to evaluate the subject's compliance with protocol procedures. The sponsor's clinical team can review the data from the server to monitor the investigative sites' activities and to assess the subjects' performance. The components of a successful EPD system include the activities carried out by the subjects and the trial managers as well as the hardware and software. 	

The key players in developing an EPD system are the clinical team responsible for the trial and a technical team that brings the EPD technology and the expertise to customize the technology for a particular trial. To design and develop an EPD system that meets the needs of the protocol takes close collaboration between those two teams. Many aspects of the collaboration should be familiar to the clinical team, given that every trial requires a well-coordinated effort between the sponsor, CRO (where appropriate), investigative sites, and subjects.		

Unique features of the collaboration of the clinical and technical teams are the development of the EPD technology and the support structures-training materials, for example. This development, however, should be greatly facilitated by the technical team's expertise. The result should be that the experience of developing an electronic diary system and then executing the trial in which it is used should feel much like that of any trial for a clinical team. 	

A successful collaboration of the clinical and technical teams depends upon clearly defined responsibilities, tasks, and deliverables. Figures 2 and 3 diagram the tasks required to develop, implement, and eventually retire an EPD system in the context of a clinical trial. Figure 2 illustrates the system development life cycle (SDLC), activities primarily driven and executed by technical team. Figure 3 depicts an EPD clinical trial life cycle (CTLC), which summarizes the activities and support structures needed, mapped onto the typical steps involved in planning, launching, executing, and closing out a trial. CTLC activies are driven by the clinical team and executed through collaboration of the clinical and technical teams.	

In Part 2 of this series we discussed Steps 1 and 2 of these life cycles, the development of a clinical protocol and the user requirements specification (URS) for an EPD system. Assuming a clear set of specification documents for the system, we focus here on Steps 3 through 6 of the SDLC and CTLC, or the preparation of EPD system for trial launch. The two streams of activities that occur during preparation are the building and testing of the EPD software (SDLC), and the development of all of the support infrastructures for the software (CTLC). 	

Details of the tasks, responsibilities, and deliverables at each step are described below. As in any GCP study, an essential component of all of these activities is careful and clear documentation of the process. Figure 4 diagrams the computerized system validation (CSV) documentation that results from this documentation. The outcome of Step 6 in the system development life cycle and the clinical trial life cycle (diary acceptance) is a validated electronic diary system that performs as intended.	

Infrastructure (Paty, clinical-regulatory) Once a protocol is approved, the clinical team begins to establish the infrastructure for the study. This includes selecting a CRO, if one is to be used, and sites for the study. The sites do not need to be technically proficient if the EPD system is designed with end users in mind. In our experience the most important site qualifier is willingness to learn something new. Of course, if the site has previous experience with an electronic diary system, this can significantly aid the implementation of the trial. For many EPD systems, the infrastructure requirements for sites are minimal: a regular phone line and Internet access. 		

Figure 2.  The System Development Life Cycle (SDLC).				

Equipment selection and purchase is another component of preparing for an electronic diary system. With the technical team's advice, the clinical team makes the final decision about the hardware best suited for the subject population being recruited for the trial. Subject hardware includes the data collection device and possibly communications hardware (an attachable wireless or wired modem, for example). 	

Investigative sites may need specific hardware to support the system, but for systems that rely on the Internet, sites may simply require Internet access and standard browser software. The same applies to the sponsor and/or CRO staff. For global trials, the subject hardware selected needs to support multiple languages. Communications device needs may differ from country to country given variability in wired and wireless capabilities in Europe, Asia, and South America. Once the hardware decisions are final, early procurement ensures that equipment is not a bottleneck in developing and launching the trial.	

Diary design (Stokes, technical-regulatory). Steps 1 and 2 in the EPD system development life cycle translated the clinical protocol into a user requirements specification (URS). The technical team's first action in diary design is to translate the user's view of a diary (their URS) into the functional requirements specification (FRS), a technical document that describes the EPD system in a way that a programmer knows what has to be built (Figure 2, Step 3). To maintain the integrity of the original protocol throughout the validation of the electronic diary, the technical team creates a traceability matrix that links the requirements in the protocol to those in the URS and then to the FRS. The traceability matrix has a central role in ensuring that anyone can begin with the protocol and trace through all of the documents to ensure the system was built as specified. 	

Traceability matrix. It is important to create a traceability matrix showing how the URS addresses the Protocol sections and how each and every URS statement is addressed by one or more FRS statements. Here are some examples of protocol statements with corresponding URS and FRS statements.	

Protocol statement (from clinical team). "Weekly Assessment: The following question will be assessed approximately every seven days during treatment period as part of the subject's daily assessment . . ."	

URS statement 24 (from clinical team). Flow chart made to show Q&A dialogue for daily assessment and also the insert prompt for a weekly summary assessment.	

FRS statement 53 (URS 24) (from technical team). Screen prompt question is "Answer the following item according to how you have felt during the past week." This prompt and subsequent dialogue is to show in the EPD on study days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77. 	

The system design description (SDD). In order to tell the programmer how to build the diary, the technical team converts the FRS statements into a system design description (SDD). Usually a design description statement covers more than one FRS statement. Thus, an item-for-item traceability to the SDD is not useful, but an overall system design review should be performed to ensure that all the FRS statements have been covered somewhere in the system design. Taking the FRS example described above, the appropriate SDD statement (from technical team) would be		

Figure 3. Electronic patient diary clinical trial life cycle (CTLC).	

Code the system with a study-day tracking variable (variable SD4) so that the EPD tracks the current Study Day number. Code the Daily Assessment to always check variable SD4 whenever it is called in the code and to check if the Study Day (SD4) is day 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, or 77. If Study Day matches, then code system to display extra dialogue item as per UR24. If no match is made, then code so that no extra display is issued to the EPD user.	

The process of moving from protocol through to functional requirements and software design is usually an interative one. It can be readily accomplished with consistent and effective communication between the clinical and technical teams. After several EPD trials, when the clinical team learns the capabilities of the technology, it can refine the protocol statements to more easily translate into functional requirements. The technical team can then develop standard diary modules and the whole EPD development process becomes faster and more efficient.	

Software review, training, and plans (Paty, clinical-regulatory) With the sites selected and the technical system specifications written, the clinical team-with considerable support from the technical team-can focus on planning and implementing various components of the EPD system. They can				

Review and approve EPD software prototypes 

Develop a plan for deploying units during the study.

Software review. A very important component at this stage of development of the EPD system is a clinical team review of alpha (early stage) software. This review allows the clinical team to determine whether the technical team is developing software that accurately reflects the protocol. Most important, it is an opportunity for the clinical team to determine whether the software is "coming alive" in the way they had expected. If it is not, this is the time to pause and reconsider the design of the system and its specifications. When the clinical and technical teams collaborated during the specification process, the typical outcome of the alpha review is making only a few minor changes to the system.	

Training materials. In an EPD study, concise and clear training is essential for all users of the system. 21 CFR 11.105 states that persons using an electronic data capture system need to be appropriately trained on the system. Training materials need to be developed for the different user groups-subjects, the investigative site staff, sponsor/CRO clinical research associates (CRAs), and other study management staff. The technical team often provides a core set of training materials that are customized for the specific trial. The customizing requires knowledge of the protocol and the system, suggesting a clinical-technical team collaborative effort. 	

Help desk. Another component important to the planning of an EPD trial is a plan for a technical help desk that will support the study. The clinical team's input is important here, because the technical help desk will be dealing with the subjects, the investigative site personnel, and the CRAs. As such, help desk personnel will need to understand how to address technical issues that may be specific to the EPD protocol. The technical team provides the technical details, and the clinical team provides protocol-specific content. That content is then reflected in scripts for the trial that guide help desk personnel who respond to questions from the trial participants. In multinational trials, the scripts can be developed so that they can be readily translated to all relevant languages. Implementing the scripts and general management of the help desk is typically the responsibility of the technical team.		

Figure 4. Electronic patient diary computerized system validation (CSV) package model.	

Equipment deployment. The clinical and technical teams will plan the provisioning (loading software onto the EPD units) and shipping of equipment to investigative sites. Their plan needs to take into account the exact provisioning process, who will perform the activity, how and when units will be shipped to sites, and the timing for returning units from the investigative sites. Given that some trials are conducted with thousands of subjects in several countries, a well conceived plan for provisioning and shipping is an important component of trial preparation. The clinical team will provide input based upon knowledge of the sites' locations, and the technical team will delineate the process and manage the provisioning and shipping process. 	

Data management. The data management and statistical groups may begin their planning at this point. Based on the database design described in the specifications, the sponsor-CRO data management team can work with the technical team to ensure that the method and format for delivering the data is clear. This will ensure that data can be delivered regularly to the sponsor or CRO for inclusion in the clinical database. 	

CTLC Step 4 summary. Once the planning, development, review, and approval activities have established the support stucture for an EPD study,	

the materials are prepared to train the system users.

the plan is in place to support the users if/when they have questions or problems.

the plan is in place for getting the EPD devices to sites for subjects.

the plan is in place for delivering data to the sponsor.

The clinical team is ready to initiate sites for the trial, hold the investigator meeting, and launch the study. 	

Articles

Feature Article

The study protocol and a set of specifications are the road map for developing the software and the support structures for an EPD study.

Developing and Validating Electronic Diaries

A sampler from recently published EU documents that set out to guide the way member nations regulate clinical research in Europe. 	

ust like London buses, you wait for one for ages, and then a whole bunch come along at once. That's what's happened with the European Union's guidelines on how the new clinical trials rules should be applied at national level.	

After months of anguished expectation from the clinical trials community across Europe-and just days before the EU member states had to bring in their national rules to give force to the 2001 EU directive1-a plethora of guidance documents suddenly appeared at the end of April.	

Companies developing drugs and academia had been loudly critical of the delay and the risk of confusion that a legislative vacuum would create. The final stage in the process is for the new framework to become obligatory-as from May 2004.	

The recently released new texts give detailed guidance on	

The request for authorization of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments, and declaration of the end of the trial.

The application format and documentation to be submitted in an application for an ethics committee opinion on the clinical trial on medicinal products for human use.

The collection, verification, and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use.

The European database of suspected unexpected serious adverse reactions. 

The detailed guidance will be included in the overall notice to applicants that the European Commission publishes to advise companies on what to include in their applications for marketing authorization for new medicines.	

The 2001 directive foresaw that the guidelines would be published in time to influence national transposition, by May 2003-so that the rules can come into force at the national level by May 2004. The urgency was underlined by the European Forum for Good Clinical Practice, whose members are drawn from European public and private health research, regulatory authorities, ethics committees, hospitals, patients, and researchers. They argued loudly that the original EU intention to create a research environment in Europe in the interest of improved public health "will be seriously curtailed if the Commission's responsibilities for producing guidance documents do not achieve an adequate European framework." Now that the framework is out in the public domain, the European clinical trials community can give its views on how far the new rules will make Europe-wide clinical trials more feasible and more efficient.	

There's no way of doing justice to this mass of new rules in just one column, but as a taster of what the new guidelines look like, here's a snapshot of how the one on requesting authorization of (and amendments to) a clinical trial shapes up. 		

It's a 40-page document, about half of which is explanation, the other half taken up with a model application form. (Yes, the application forms are themselves 17 pages long!) The directive required the Commission to work with the member states to prepare detailed guidance on the application itself, and on the documentation to be submitted in support-on the quality and manufacture of the investigational medicinal product, any toxicological and pharmacological tests, the protocol, and clinical information on the investigational medicinal product including the investigator's brochure.	

The sponsor must be EU-based or have an EU-based legal representative, and the application must contain the core information required by that member state.	

The application must be in the right language for the member state concerned, should also indicate where else applications have been made, and with what outcome (including copies of any ethics committee opinions).	

A cover letter must draw attention to any special issues related to the application, such as special trial populations, unusual investigational medicinal products (IMPs), or unusual trial design.	

It must contain the number of the trial allocated under the Eudract system, the European clinical trials database, which will identify the protocol for a trial whether conducted at a single site or at multiple sites. 	

The application should identify the organizations and key individuals responsible for the conduct of the trial. The protocol must be included in the application, and its content and format should comply with the guidance in the EU guideline on Good Clinical Practice (CPMP/ICH/135/95). It should also include all currently authorized amendments, a definition of the end of the trial, and any plan for treating the participants after the trial if that differs from current practice. Among other things, it should include the justification for including subjects who are incapable of giving informed consent.	

The investigator's brochure (IB) should be prepared from all available information and evidence that supports the rationale for the proposed clinical trial and the safe use of the investigational medicinal product (IMP) in the trial. And the content, format, and procedures for updating it should comply with the EU Good Clinical Practice guideline.	

The dossier on the IMP should give information on quality-including reference products and placebos to be used in the clinical trial and data from nonclinical studies and its clinical use-or justify in the application why information is not provided. The application may cross-refer to the IB for the preclinical and clinical parts of the IMP dossier but, if so, the summaries of preclinical information and clinical information should include data, preferably in tables, providing sufficient detail to allow assessors to reach a decision about the potential toxicity of the IMP and the safety of its use in the proposed trial. 	

A simplified IMP dossier may be submitted if information related to the IMP has been assessed previously as part of a marketing authorization in any EU member state or as a clinical trial application to the competent authority concerned. For products already marketed in the EU and used in the same form, for the same indications, and with a similar dosing regimen, the sponsor may submit the current version of the Summary of Product Characteristics as the IMP dossier.	

A full IMP dossier has to be supplied when the sponsor has not previously submitted any information about the chemical or biological product concerned to the competent authority and cannot cross-refer to information submitted by another sponsor-such as when no marketing authorization exists in any EU member state. The dossier should include summaries of information related to the quality, manufacture, and control of the IMP, nonclinical data, and clinical data. The dossier required will depend on many factors, including the nature of the medicinal product, the stage of its development, the population to be treated, the nature and severity of the disease, and the nature and duration of exposure to the investigational medicinal product.	

Summaries of chemical, pharmaceutical, and biological data are required for any IMP. The Directive requires that sponsors supply IMPs for a clinical trial whose manufacture complies with EU rules on good manufacturing practice.	

Summaries of nonclinical pharmacology and toxicology data-or justification of why they are omitted-are required for any IMP to be used in the clinical trial, along with a reference list of studies conducted and appropriate literature references. A mere factual summary of the studies conducted is not enough. The sponsor should provide a critical analysis of the available data, including justification for deviations and omissions from the detailed guidance, and an assessment of the safety of the product in the context of the proposed clinical trial.	

All studies should be conducted according to currently acceptable state-of-the-art protocols. In addition, where appropriate, they should meet the requirements of good laboratory practice guidelines. The sponsor should justify any deviations from these guidelines and provide a statement of the GLP status of all studies. The test material used in the toxicity studies should be representative of that proposed for clinical trial use in terms of qualitative and quantitative impurity profiles. The preparation of the test material should be subject to appropriate controls to ensure this and thus support the validity of the study.	

Previous clinical trial and human experience data should also be provided when available. Compliance with the principles of good clinical practice (GCP) should be confirmed by the sponsor in a statement of the GCP status of all studies. If this is not the case, an explanation or justification should be provided. 	

An overall risk and benefit assessment should also be provided. Sponsors are expected to offer an integrated summary that critically analyses the nonclinical and clinical data in relation to the potential risks and benefits of the proposed trial. As a guide to what may occur in humans, the sponsor should integrate all the available data, analyze the pharmacological and toxic actions of the IMP, and use the results to suggest possible mechanisms and the exposure required to produce them. Where appropriate, safety margins should be discussed, in terms of relative systemic exposure to the investigational medicinal product. The text should discuss the reason for terminating any study prematurely. The provisions of the EU clinical trials directive should be taken into account when evaluating studies on minors and incapacitated adults. There should also be discussion of the clinical relevance of any findings in the nonclinical and clinical studies, along with any recommendations for further monitoring of effects and safety in the clinical trials.	

The guideline also covers amendments to the conduct of a clinical trial after its commencement. Amendments that are substantial must be notified to the competent authority and the ethics committee concerned. They may arise from changes to the protocol or from new information relating to the scientific documents in support of the trial. Amendments to the trial are regarded as "substantial" where they are likely to have a significant impact on the safety or physical or mental integrity of the subjects, the scientific value of the trial, the conduct or management of the trial, or the quality or safety of any IMP used in the trial.		

Where a substantial amendment affects more than one protocol for a particular investigational medicinal product, the sponsor may make a single notification to the competent authority concerned, provided that the covering letter and notification includes a list of all affected protocols with their Eudract numbers. A cover letter should draw attention to any special issues related to the amendment and indicate where the relevant information or text is in the original application. In the case of substantial amendments that affect information submitted to both the competent authority and the ethics committee, the sponsor should make the notifications in parallel. For substantial amendments to information that only the competent authority assesses, the sponsor should not only submit the amendment to the authority but also notify the ethics committee that they have made the application. Similarly, the sponsor should inform the competent authority of any substantial amendment to information for which only the ethics committee is responsible. 	

The sponsor may implement a substantial amendment if the ethics committee opinion is favorable and the competent authority has raised no grounds for nonacceptance. For amendments submitted to either the ethics committee alone or the competent authority alone, the sponsor may implement the amendment if the ethics committee opinion is favorable or the competent authority has raised no grounds for nonacceptance.	

It might be expected that after completing all this standardized information-and after so many years of discussion of harmonization of clinical trials in Europe-an authorization like this would be good for the whole of the European Union. Not so. The guideline clearly states that authorization of a clinical trial by the competent authority of a member state "will only be valid for a clinical trial conducted in that member state." 		

1.	European Parliament, Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (EU Official Journal, L121, 5 January 2001. p. 34).		

2.	The new guidelines can be consulted on 

http://pharmacos.eudra.org/F2/pharmacos/docs.htm#news

View from Brussels

Just like London buses, you wait for one for ages, and then a whole bunch come along at once. That's what's happened with the European Union's guidelines on how the new clinical trials rules should be applied at national level.

Les Nouveaux Clinical Trials Guidelines Sont Arrives

The clinical and technical teams use the protocol and a set of specifications as a road map for developing the software and the support structures for an EPD study.

Technology Update: Electronic Diaries, Part 3--Developing and Validating Electronic Diaries

Ensuring a HIPAA-Compliant Informed Consent Process

Kimberly Irvine and Eileen Hilton (CenterWatch, Boston, MA, 2003), 158 pages, paperback, ISBN: 1930624395, $39.99.


This book is a handy size, 158 pages. Of this total, 113 pages are devoted to printing the HIPAA Privacy Rule in its entirety. With 14 pages used for a glossary and table of contents, only 31 pages remain on which to outline the informed consent process and the HIPAA Privacy Rule patient Authorization Agreement. It would have been helpful to go into further detail on some of the points of informed consent and the application of the Privacy Rule. For example, page 5 contains the statement IRB approval may not be required for the separate authorization form although organizational policy may vary. If the regulatory basis for this statement were provided, it would have given the reader a sound basis on which to make a decision. Except for patient authorization, none of the pathways included in the Privacy Rule for use of protected health information in research were outlined. Parts 160 and 164 of HIPAA Privacy Rule regulations are provided without comment or guidance of any kind. 

In several places in the book, blanket or all-inclusive statements are made. It would have been helpful to list the conditions and exceptions to those statements. For example, page 5 contains the statement Specifically, subjects must authorize the use or disclosure of their protected health information (PHI). The HIPAA Privacy Rule provides for five other pathways to use PHI for research purposes. The book does not describe the pathways or state the conditions under which a patient Authorization Agreement would be required.

Another example is the statement at the top of page 6, Subjects enrolled prior to 14 April 2003, will not have to be reconsented. This statement may lead the reader into a false sense of being in compliance, as it is true only until the consent document is revised to include new information. 

The endnote references to the FDA and HHS regulations are not helpful, because they refer to the general informed consent regulations but do not guide the reader to the specific regulation that contains the element. Reference 1 incorrectly cites the regulatory reference to the elements of informed consent rather than the regulation requiring written documentation of consent. 

The U.S. Department of Health and Human Services Regulations at 45 CFR 46 are incorrectly referred to as the Office for Human Research Protections regulations. Also, the book incorrectly implies all of the subparts of the 45 CFR 46 regulations are contained in the Common Rule.

The requirements of the ICH Good Clinical Practice E-6 guideline are contrasted with the FDA and HHS regulations. It would have been helpful to reference the specific sections of the ICH Guideline for Good Clinical Practice.

The sample assent form on page 26 does not meet generally accepted standards for assent. It does not contain a simplified explanation of the study and the procedures to be followed, but only statements that the study procedures, discomforts, risks, and inconveniences have been explained to you.

The second entry under General Requirements on page 27 fails to mention that the copy of the HIPAA Authorization Agreement given to the study subject must have been signed and dated by the subject. This is an important point, as the FDA and HHS regulations do not specifically require the copy of the informed consent form given to the study subject to include the signature of the study subject. 

The second entry under Guidance incorrectly states that all ongoing research projects will require an authorization form or consent modifications at the time of continuing review. Already enrolled subjects may continue to participate indefinitely without providing HIPAA authorization, as long as the consent document is not changed to provide new information to the subject. All new subjects enrolling into ongoing research projects on or after the compliance date (14 April 2003) must sign HIPAA-compliant authorization agreements. 

The information provided for genetic substudies is very good and complete. 

This book could be a useful initial reference for a first venture into HIPAA, but readers should confirm the accuracy and completeness of the information. It is not a definitive reference to practical application of either informed consent or the HIPAA Privacy Rule.            

Media Review

The mission of an investigative site is to conduct ethically sound clinical studies while protecting and caring for the subjects. Ethical and scientific criteria for clinical research standards have been laid down by the Declaration of Helsinki, in FDA regulations and guidelines, and in the ICH Guideline for Good Clinical Practice. Some innovative organizational practices at investigative sites can enhance and facilitate adherence to regulations and guidelines. This article rests on the premise that investigative sites have an ethical and scientific mindset, trained and motivated personnel, progressive management, and an adequate infrastructure.

Investigative sites are part of a wider environment, which consists of a large number of partners involved in the clinical trials process. The partners can include sponsors, contract research organizations (CROs), central laboratories, couriers, providers of interactive voice response systems (IVRS), and others. In these times of regulatory and economic constraints, each brings to the partnershipalong with its responsibilities for conducting a clinical trialits own demands and expectations. All involved parties need to be finely coordinated from within investigative sites to ensure that trials run smoothly.


Sponsors generally conduct themselves in the manner of other commercial enterprises that work with subcontractors. That means they grade investigative sites on such factors as data quality, speed and reliability of subject recruitment, number of protocol violations, on-site facilities (personnel and infrastructure), respect for data deadlines, number of data clarifications, audit reports, and more. Sponsors that need to choose investigative sites for early pivotal or registration studies therefore tend to collaborate with efficient sites that are capable of the highest quality. 

FDA regulations and the ICH Guideline for Good Clinical Practice must be respected. New European Union Directives will become law by 2004, and also must be considered when addressing matters of informed consent, ethics committees, and EMEA (European Medicinal Evaluation Agency) inspections of investigative sites. Investigators who conduct investigator-initiated studies must assume the responsibilities of sponsors in their dealings with other investigative sites. 

Investigative site trial teams must be made fully aware of differences between European and FDA regulationsand trained to adhere to appropriate regulations and guidelines in their clinical investigative practices.  

Sites are conducting more and more complex studies designed to address regulatory needs, safety and efficacy, health economics, quality of lifeall in one protocol. These are high stakes studies for sponsors, and that puts investigative sites under pressure to provide high quality data that must stand up to the most stringent audits and inspections.

In addition, physician-investigators are aware of the debate on the therapeutic orientation to clinical trialsand they must guard against obscuring ethically significant differences between clinical research and medical care.

 Clinical trial subjects today are more informed about their rights, have greater access to information and new drugs, and therefore have higher expectations than ever before. In parallel with the many regulations to protect them, however, have come more complex demands upon the subjects.

Not only the studies but also the concepts being studiedgenetic testing of biological samples, for exampleare complex. Long, comprehensive patient information documents require effort to understand before making informed consent to participate in a study. In addition, subjects are required to complete more and more questionnaires and diaries at and between study visits so that investigators can collect data on medication adherence and quality-of-life evaluations. For investigative site personnel, this means allocating a great deal of time to coaching and encouraging subjects during their participation.


In the setting described, pressure on clinical investigative sites comes from the outside environment and, of course, the desire to perform high-quality studies should also come from within the sites. Investigative sites therefore must be highly organizedyet allow a little space for creativity.

Here are a number of practices that can be said to have been finely distilled from those trials we call experience. The source document templates described below, for example, were refined and redefined upon the advice of an excellent auditor who generously offered her ideasduring an audit visit, of course.

Over time, we developed our practices in a bid to optimize staff time management and to keep faith in the concept that quality of life for an investigative site team is indeed compatible with an evolving clinical trials environment.

 It is surprising that in todays clinical research practicewhich is of such ethical, medical, and scientific importanceinvestigative sites are not obligated to document the way in which study procedures are carried out. Other safety-conscious and highly regulated fields that collect safety and efficacy data (aeronautics and engineering, for example) require rigorous documentation.

SOPs are simple, clear descriptions of the methods of practice for an investigative site. In the not too distant past, in clinical research, those documents were the exclusive domain of pharmaceutical companies, CROs, and site management organizations (SMOs). Now, however, sites also need to develop written SOPs to document and standardize their practices for site personnel. It is, for example, preferable to avoid a situation in which staff members weigh subjects differentlyone with subjects in their undergarments, another with the subject fully dressed (possibly in winter attire with pockets full of change and keys). Over successive visits, a subject haphazardly weighed could show significant weight gain (or loss). This could potentially create a serious situation for a subject or a study of heart failure or metabolic disorders.

At our center, we find that documenting everyday activities leads our teams to reflect on the way things are done. Large investigative teams (more than 10 persons) may wish to nominate an SOP Group to draw up the SOPs, organize discussions, and supervise revisions, reviews, and archiving. A list of topics for site SOPs, though not exhaustive, includes study medication handling, biological sample processing, serious adverse events management, subject recruitment methods, the informed consent process, preparing for monitoring visits and audits, subject visits to the site, and filing systems and other administrative procedures. The SOPs checklist box provides a list of minimal standards to strive for with SOPs.

Documentation of procedures and detailed job descriptions can be of tremendous help when used as teaching aids (in-house training) for new site personnel and for ongoing training of more seasoned members of the team.

It seems inevitable that in the near future regulatory authorities and sponsors will require rigorous documentation of all procedures being performed in clinical trials at investigative sites.

 Many sites conduct a number of  trials simultaneously. Consequently, physician-investigators and research nurses see subjects who are involved in different studies during the same clinic session.

Subject follow-up visits are most often managed in a busy hospital or clinic environment. The inherent challenge, therefore, is finding a successful compromise between time limitations and the quest for quality. Subjects are in a hurry to get back to their work or college. Mothers are rushing to pick up children from school or nursery. Site personnel are equally hurried to complete the procedures necessary for the studies while maintaining the quality of care for their subjects, and producing reliable data for sponsorsand reasonable job satisfaction for themselves. The Follow-up Visits checklist provides a guide that can make the process easier for subjects and investigators.

 Case report formsthe classic paper versionscan weigh up to several kilos. Every site professional knows how cumbersome and inconvenient they can be in a clinic. In parallel to this, documentation of source data at study visits is of the highest importance for the study and the subjects medical file. Our center developed a system of support source data collection documents (see below) to ensure that all procedures are performed and that complete data is collected at each follow-up visit.

For studies in which study medication is dispensed and returned at follow-up visits, it is useful to incorporate into the documents a template for precalculating the medication expected to be returned by subjects at each follow-up visit. This can easily be adjusted if the subject comes before or after the planned appointment date. In this way, poor adherence or nonadherence to the study regimen is apparent from the pill count and can be addressed immediately with the subject.

Subject management could include providing them with prospective visit schedules at the start of the study. The schedule could include information about all of the expected clinic follow-up visits for the whole study follow-up period. This can help subjects plan other activitiesvacations and holidays, for example. This also helps investigative site personnel to order additional study drug and materials as needed.

Important study documents (such as drug accountability and consent forms) can easily be misplaced in the busy environment of hospitals and clinics. Print these documents on paper of distinctive colors so that they are easily recognized by everyone, and therefore treated with extra care and less easily lost.

To conform to the ICH guideline for GCP, we found it useful to develop support systems in source data documentation for the convenience of clinical research personnel. During any one follow-up visit as many as 20 items of data may have to be noted. Documenting clinical trial follow-up data by hand is laborious, time consuming, and sometimes incompletebecause busy people may forget to perform some procedures. Easy-to-use standard document templates, which can be tailored to each study and each follow-up visit, help prevent these data collection oversights (see Preparing Source Documents checklist). At the beginning of each study, the research nurses and research assistants responsible for the management of the study assemble all the data required for the study from the protocol and case report forms (CRFs) and draw up study-specific data collection forms. We use the same text as the CRF to avoid any risk of ambiguity in language (the mother tongues of our clinical research team are French and Dutch).

Phase 2, 3, and 4 studies generally require three types of forms: screening, baseline, and follow-up. Data for screening and baseline visits are study-specific. The form for follow-up visits includes spaces for the same data required for all study visits, but has not applicable options for information that is not required at a specific follow-up visit.

Very important datasuch as The design and side effects of the study have been explained to the subject, and A copy of information for subjects and the consent documents have been given to the subjectis preprinted on the document with a space for the investigator to sign and date at the screening visit. Those who perform each procedure and write the results (the physicians or research nurses) identify themselves with their initials or signature, and they date the documents, making the process completely traceable. The completed documents are placed in each subjects medical file at each visit because they serve as both the medical record of the patients visit and the source data for the study. Templates cover source documentation on clinical data, drug accountability, concomitant medication and other documents you may wish to include.

The advantage of the above support system is that the clinical research team simply needs to complete the appropriate parts of the data collection forms. That allows them to concentrate on the care and concerns of their subjects, who benefit from a subject-oriented rather than a data-oriented approach to their follow-up visits. There is complete and rapid documentation of all data required for the study, and monitors and auditors have a reliable and easy system of clear source documentation.

 Radio-controlled digital clocks are a good investment in accuracy, especially when study procedures are carried out by personnel who move from one consulting room to another. The time on a conventional round-faced clock can be interpreted differently depending on the angle from which it is viewed. With digital clocks all set at the same time, an auditor is unlikely to find documentation indicating that the same research nurse was in two places, performing two different procedures, at the same time. When an auditor made that discovery at our site, subsequent investigation revealed that the problem was the minute hand setting on the clocks in two neighboring consulting rooms. 


Investigators generally have no opportunity to reflect on a studys design or discuss it with the sponsor before they receive a protocol. When the investigator and his team find themselves uncomfortable with a protocols ethical, scientific, or feasibility issues, the investigator should write to the sponsorand be satisfied with the sponsors responsebefore agreeing to participate in the study. Before accepting a study, a site must also consider finance, staffing, compatibility with practice guidelines and SOPs, the amount of time and space required, and other practical matters. Once the investigative site team  accepts a study, and it is approved by the ethics committee or IRB, the most critical and challenging time of the studyeven when things go wellbegins: the study start-up.

Unless thorough testing and verification is carried outbefore study start-upon every procedure, apparatus, and system that a sponsor provides to a site, problems are likely to occur. That is a cruel, but certain, fact of life for the research professional. Even with conscientious preventive measures, trouble may still follow. Sponsors, through their monitors, should ensure that everything provided to the site is functional. Those at the site level should have trust (without naivet), but verify everything prestudy.

Try out the interactive voice response system (IVRS). Test new equipment, especially any with novelty features, such as telephone transmission of electrocardiograph signals to a central reading facility with a 12-hour time difference.

Do not be anaesthetized into complacency by video demos of new equipment or systems. The wise know that real-life technical problems are never shown in those demos, so try it out in the comfort of a prestudy setting without a live subject in a study situation.

If your center is the very first to recruit subjects in a large multinational, multicenter trial with central laboratories, IVRSs, and multiple external service partners chosen by the sponsor, enroll slowly at first. Despite following all the testing and verification advice above, the first center to screen subjects (thus activating the study) is the pioneer that discovers the unforeseen, time-consuming early start-up problems. Planning for this probability can avoid stress and heartbreakand, after all, the solutions will benefit all the other centers participating in the study.

Be aware of hidden timelines. In keeping with the concept of rapid flow data, investigative sites must fax data to some sponsors within a very short time after the subjects follow-up visit and prior to on-site data monitoring. This is often announced at the initiation visit just before study startup. It requires specific management at the site and may justify an amendment to the financial agreement.

Prior to their enrollment as subjects in clinical trials, patients biological follow-ups are part of their records in the hospital and clinic computer systems. Investigative sites can request that sponsors periodically forward biological results from central laboratories on diskette or by email in addition to those results forwarded by fax and on hard copy. This procedure can prevent any blanks in subjects hospital or clinic biological files during their participation in a clinical trial. Be aware of the timelines and of any particularities (for example, insurance requirements or transport expense refunds to subjects) required by the institutional review board (IRB) so that any problems can be resolved with the sponsors before the submission of the protocol and study documents. 


Monitors are often the only representatives of sponsors in contact with an investigative site during a study. They have important responsibilities regarding study data and are the pivotal persons for contact between the site, the sponsor, and other partners (such as central laboratories) in the study process. Investigative sites can improve the quality of life for these precious collaborators.

It is helpful at study start to have the names and contact information for the organizational and medical supervisors. It is also useful to have SOPs in place for site personnels management of monitor visits. Monitors often find it helpful at study start to have a letter from the site that includes clear guidelines on the sites practices (the SOPs). This could include names of site personnel and their functions (who will do what for the study, with first- and second-line responsibilities), the availability of center staff, schedule of ethics committee meetings, requirements of the investigative site from central laboratories. This can help to ensure smooth collaboration during the study.

When sponsors and CROs are actively involved in the study, make sure to document clear definitions of the role of each during the study preferably with only one contact person. That can avoid the awkward situation in which site personnel have to deal with two organizationsboth applying pressure on the investigative site at the same time. When problems arise with a central laboratory, an IVRS, a courier, or others, we prefer that a study monitor contact them, if a first contact by the center personnel is unsuccessful. This keeps sponsors aware of poor service to investigative sites by their partners. It also has frequently been our experience that a sponsor can elicit a much more rapid resolution to problems than an investigative site team can. He who pays the fiddler, calls the tune.


The processes involved in conducting GCP-compliant studies are, paradoxically, both complex and simple. Planning and preparationwhen practiced with some imaginative innovationcan result in best practices at investigative sites. The desire to perform these high-quality studies with innovative organizational systems must, however, come from within the investigative sites themselves.

Sites that respond to pressure from sponsors, subjects, and regulators by developing the capacity to perform scientifically relevant, high-quality, ethical studies will be in a position to offer high-quality care to their subjects, high-quality data to sponsors, and high-quality scientific papers to the scientific community. This is the complete win-win-win scenario.

1. Franklin G. Miller and Donald L. Rosenstein,  The Therapeutic Orientation to Clinical Trials, 

Planning and preparation, along with imaginative innovations, can put an investigative site on the road to best research practices.

Innovations at an Investigative Site

The 50th anniversary of the discovery of the double helix in April 2003 also marked the completion of the Human Genome Project. Leaders of this landmark undertaking unveiled the finished version of the human genome sequence and mapped plans for tackling the next challenge: translating genomic research into medical treatments. The project identified more than 1400 disease genes and studied how human genetic make-up may affect ethical, legal, and social issues. Francis Collins, MD, PhD, director of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH), declared that it was time to move from large-scale DNA sequencing to more specific research projects. 

Collins and colleagues describe the immense task of translating initial genome research into medical treatments in a recent Nature article, A Vision for the Future of Genomics Research.1 This blueprint for future genomics research examines the resources and technological developments critical to developing powerful new therapeutic approaches to disease.

Further success in defining genetic networks and protein pathways and how they contribute to cellular and organism phenotypes is expected to contribute fundamentally to the design and testing of new therapies. One approach may be to explore gene variants that contribute to good health and resistance to disease. This could involve identifying a healthy cohort of individuals with unusually good health that could be compared with cohorts of individuals with diseases to examine genetic variants linked to disease.

To promote prevention and early detection of disease, scientists are exploring ways to develop genome-based approaches to predicting disease susceptibility and drug response, which may lead to development of individualized preventive medicine. Related research is focusing on further technological advances that would reduce the cost of genotyping. New molecular taxonomy may improve early detection of disease and could lead to more effective and less costly treatment. Such sentinel methods might include analysis of gene expression in circulating leukocytes, proteomic analysis of body fluids, and advanced molecular analysis of tissue biopsies.


Such activities raise new issues regarding the proper conduct of research involving genetic analysis of study participants and the resulting information. The ability to identify genetic traits of population groups and of individuals raises concerns about the need for community consultation and for obtaining consent from non-examined family members. An obvious issue is the potential for using genetic information to discriminate in employment and insurance coverage. 

In addition, gene expression studies that predict toxicity of candidate compounds and identify biomarkers for toxicity and drug response may help define study populations and avoid overloading trials with inappropriate subjects. Although such approaches may reduce potential injury and make studies safer, they also may be criticized as attempts to merely improve study results.

Pharma companies now regularly examine how genomic data may provide clues about how and why individuals respond differently to a pharmaceutical. Pharmacogenomic (PG) research increasingly is being used to:


	develop new sets of biomarkers for toxic responses in animals and humans, which may eventually reduce the scale of animal studies.

	predict who will respond to a drug based on genetic differences in pathogenesis.

	predict who will have serious side effects based on toxicogenomic analysis.

	rationalize drug dosing using genetic/phenotypic tests for metabolizer status.


Such analyses have the potential to revise drug development processes and produce more effective, less toxic drugs more quickly and more efficiently, commented Janet Woodcock, MD, director of FDAs Center for Drug Evaluation and Research (CDER) at the April meeting of FDAs Science Board. However, FDA is concerned that companies are not presenting pharmacogenomic (PG) analysis to the agency for fear that it may prompt requests for even more data and only delay new product approval. Woodcock wants to clarify FDA regulatory policies to encourage PG analysis and also to gain access to information that could advance scientific discovery. 

Woodcock seeks to overcome industrys dont tell attitude by issuing new guidances on how PG data relates to the regulatory process. She envisions policy statements on co-development of drugs and diagnostic tests and on general pharmacogenomic study standards and techniques. A key guidance will address when PG data will have a regulatory impact by identifying which PG studies should be submitted to FDA, and when study data will not be required in investigational or new drug applications. FDA says it is likely to request formal evaluation of PG information used in:


	studies supporting enrollment in clinical trials by genotype in order to enrich responders or avoid bad outcomes.

	dose selection data based on metabolizer genotype.

	animal genomic data that explains why a toxic finding is unique to that species.

	data that may influence the course of the clinical development process.

Alternatively, FDA wants to define a research information package that manufacturers would share with FDA, but would not have any impact on application review. Such data would be discussed separately by a new Interdisciplinary Pharmacogenomic Review Group (IPGRG) composed of representatives from all FDA Centers. Data collected for research use that would not affect regulatory and approval decisions might include:


	evaluation of new transporter gene diversity vs. response in clinical subjects.

	genomic SNP data collected in clinical trial subjects.

	gene expression microarray screen in trial subjects or in animal toxicology study. The first step will be to develop concept papers on the topics, followed by draft guidances and final guidances, which FDA hopes to issue by the end of 2004. 


Woodcock anticipates plenty of public discussion of PG issues through the guidance development process, beginning with a public workshop this fall. Manufacturers already are expressing concerns about new FDA rules in this area. Brian Spear, Phd, director of pharmacogenomics at Abbott Laboratories, told the Science Board that most pharma companies are exploring how PG analysis may help design clinical trials and interpret study data, but they fear that such information could be misinterpreted by regulatory officials if submitted as part of market applications. Spear expressed interest in FDAs idea of establishing a group of agency experts to review pharmacogenomic (PG) studies separately from the review process, but emphasized the need for clearer definition of pharmacogenomic data and research exemption. Without a more explicit policy, manufacturers will worry that FDA and other regulatory authorities could expand requirements later for what studies and data analysis they require for product registration. And while standardization of research approaches may appear useful, increased standardization also carries the risk of encouraging both regulators and manufacturers to favor certain procedures, which may inhibit innovation over the long run. 

Another industry concern is that PG data could be used to narrow product marketing opportunities. A genetic study showing, for example, that 30% of patients could fail to respond to a certain treatment may lead to restrictive product labeling even if the drug appears safe and effective for a general population. Or, data indicating that certain patients respond to a treatment might lead to required diagnostic testing of participants in clinical trials and of potential subjects. In the end, industry willingness to underwrite more PG studies may prompt FDA to require genetic analysis as a regular component of drug development programs.

These are difficult issues, and FDA is building its internal capacity and expertise for analyzing and understanding genomic data, explained Frank Sistare, PhD, acting director of CDERs Office of Testing and Research. CDER has established an internal Nonclinical Pharmacogenomics subcommittee and is expanding reviewer training in this area. The panel will help develop standards for submission, review, and integration of pharmacogenomic (PG) data, and also will work with other government agencies and outside scientists to further develop these initiatives. FDA is seeking input from advisory committees and experts on ways to better understand and assess relevant information as genomics discoveries evolve.

The potential of pharmacogenomic research for making more new cost-effective therapies available to those patients who can benefit most from them has made PG development an important issue for FDA commissioner Mark McClellan. At the April Science Board meeting, he acknowledged that drug developers fear that data from molecular genomics doesnt fit the regulatory process and may raise red flags with reviewers. But he urged industry to share results with FDA so that these issues can be discussed openly and collaboratively. 


1. Francis S. Collins, et al., A Vision for the Future of Genomics Research, 

View from Washington

FDA is exploring policies to incorporate genomic information into the regulatory process.

Genome Discoveries Shape Drug Development and Testing

On 20 February 2003 the FDA issued a new draft guidance document on 21 CFR 11 that surprised many in the industry. The draft guidance spells out a new, narrowed scope to the interpretation of 21 CFR 11, the Electronic Records, Electronic Signatures rule, with an emphasis on a risk-based approach to 21 CFR 11 activities. To appreciate the implications of this change, it is worthwhile to explore some of the original basis of 21 CFR 11, which is good clinical practice. 

In 1974, during my sophomore year in college, I found my scientific idealism shaken at its roots when the Patchwork Mouse scandal exploded onto the national science scene (see box). Unfortunately, this was not an isolated incident in medical research. The ensuing decades have provided many instances of scientific misconduct relating to manipulation and fabrication of data. Some of them took place at the laboratory bench, others were close to homein the clinical trial arena. Some occurred during the past few years and involved clinical trials for the development of pharmaceutical products.

The FDA and other regulatory organizations have long recognized the high stakes of pharmaceutical development and the potential for intentional fraud in clinical investigations. Indeed, regulators have significant experience in uncovering and dealing with fraudulent data in clinical trials. Behind their concern is the very real possibility that fraudulent data could lead to unwarranted drug approvals, exposing hundreds of thousands of patients to a drug that may be more toxic or less effective than was believed from the approval data. The FDA also has experience with another data issuepoor quality data resulting from careless data collection and management. 

The principles of good clinical practice (GCP), originally codified in the Federal Register and expanded by FDA Guidance, industry best practices, and company policies, were created to address many issues of patient safety, explicitly including the mitigation of fraudulent data collection. Certainly, GCP addresses many other issues that may or may not be related to fraud, including informed consent, institutional review board oversight of clinical studies, and reporting requirements to name a few. The most relevant issues to discussions of 21 CFR 11, however, are those related to data integrity and fraud.

GCP includes a number of requirements that share characteristics with the concept of chain of custody for criminal evidence. When a crime is being investigated it is necessary for the investigating team to establish a chain of custody for all evidence. A piece of evidence is typically tagged in some nonalterable fashion and handed from person to person along with paperwork and sign-offs that document its transfer. Only with this complete chain of custody can a jury be sure that the evidence was not tampered with or exchanged. Interestingly, the chain of custody is often written about as the paper trail for an event that documents the process, people, and timing of the events involved in the management of an investigation. In fact, the chain of custody is the entire procedure including, but not limited to, the documentation.

The aspects of GCP related to subject data, as it is typically practiced, closely resemble the chain of custody concept. Those aspects are designed to assure the FDA that the data being examined reflects the actual data obtained by the investigator, and that adequate controls are in place to control and/or identify tampering with data by an investigator or sponsor. In parallel with chain of custody descriptions, many often talk about the GCP of subject data as it relates to the documentation and not the actual process and intent.

For data captured in physical formon paperconventional means can be used for investigation of any irregularities. To begin with, the data are often signed and dated by the person making the entry. The ink used, the handwriting, and various other factors involved in documentation can be compared with eyewitness observations to establish the veracity of written data. If necessary, ink can be checked for date of productionand other sophisticated tools can, and often are, brought to bear. However, the process of data collection on paper doesnt itself create automated recording of the time and identity of the person who created the data. Properly constructed computer systems and applications will do this, and much more.

The application of chain of custody GCP principles to the electronic world requires consideration. Data in the electronic world consists of a series of ones and zeros recorded on a variety of electronic, magnetic, or optical media. By definition, my ones and zeros are exactly the same as any of your ones and zeros. Therefore, the data doesnt have the characteristics of ink and handwriting that can link it to an individual. Furthermore, the concept of a signature attributable to a specific individual must be entirely redefined in the electronic world. Anyone who has access to the computer system holding the data can change some of my ones into zeros and vice versa. Finally, the computer itself might accidentally swap some of my ones and zeroscorrupting, damaging, or even deleting my data. It is these very issues that 21 CFR 11 was designed to address. In fact, in a widely quoted article (www.businessweek.com/archives/1998/b3574124.arc.htm) this very issue was brought to the attention of the public:

The Food and Drug Administration reports that some pharmaceutical companies are discovering errors as they copy drug-testing data that back up claims of long-term product safety and effectiveness. In several recent cases involving data transfers from Unix computers to systems running Microsofts Windows NT operating system, blood-pressure numbers were randomly off by up to eight digits from those in original records, FDA and company data specialists report.

This important observation should give pause to us all; it is a strong vote for the need to validate any data handling process. Those of us who have ever written a search in Google, a simple rule in Outlook, a macro in Excel, or an SQL query of a database know that they dont always work as intended. Each of these computer entries has some similarity to writing software. We have an idea of what we want the rule or query to do. We do the best we can, test, and then rewrite and/or debug.

For a junk mail rule in Outlook, for example, we may check and test it in different ways over the next few days to make sure it is not disposing of our important mail. The testing we have done is a very crude form of validation. Any software being used for handling of clinical trial data (and for that matter any important data) must be validated to ensure that it will reproducibly perform as specified, with the entire gamut of possible inputs. Finally, careless or sloppy data management practices can lead to loss of data as surely as these same practices can lead to loss of paper.

21 CFR 11 was designed to address these and other issues in electronic records. Although electronic records can be far more organized and searchable than paper records, there was definite concern at the FDA that the integrity of electronic records was at risk unless care was taken in the design and implementation of the system. In the briefest summary, 21 CFR 11 addressed the criteria under which the agency considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper. Some particular aspects were covered, including:


	Availability of electronic data in electronic, human-readable form

	Accurate retrieval during the records retention period

	Requirements for valid electronic signatures linked to documents

	Controls over passwords and other means of user authentication.

Although the final rule was only three pages long in the Federal Register, a 29-page preamble clarified, and in some cases even amplified, the literal reading of the rule. Shortly after the final rule was published, FDA published a Guidance for Computerized Systems Used in Clinical Trials (

www.fda.gov/ora/compliance_ref/bimo/ffinalcct.pdf

). The guidance document wove together a good deal of FDA thought about interpretation of 21 CFR 11 and software validation principles to clinical systems. Both the rule and the guidance are still alive and well, and in force. 

Since the issuance of the rule and the guidance, there has been much discussion in the industry about how best to comply with themmuch of it focused on the cost and effort required for compliance, especially for legacy systems and record archiving. The effort required for a company to comply has often been compared to the effort required for compliance to Y2K. Initially FDA signaled that they intended to vigorously enforce the rule, but only when issues of violation of the predicate rule (GCP, GMP, or GLP) were involved. The agency published a series of draft guidances intended to clarify and specify aspects of compliance to the rule. Some aspects of the guidance documents were quite explicit in terms of solutions, and were aimed at a rigorous interpretation of 21 CFR 11. 

In addition, there is an inherent difficulty in regulating technology while encouraging innovation. Regulations take some time to be developed and adopted, and they are often left unchanged for years. Technology, on the other hand, progresses rapidly and often veers off from the expected direction. A good example of this is the emphasis on biometrics in the final rule. Although biometric authentication was not mandated, most readers interpreted 21 CFR 11 to show a strong preference for the application of such authentication. That seemed like the logical direction in the spring of 1997 when the rule was published. Biometrics, however, have been slow in gaining broad use, and even slower in the pharmaceutical industry. It may be some time before biometrics are the standard for authentication in clinical trial systems (or maybe not. The one thing clearly predictable about technology is that it is unpredictable).

It was in this context that the newest draft guidance was released on 20 February 2003. The latest guidance essentially repealed all previous 21 CFR 11 draft guidance(s)but not the rule itself or the original Guidance on Use of Computerized Systems in Clinical Trials. Aside from some minor confusion (Can a draft or final guidance countermand a regulation?), the new draft guidance made the agencys intention quite clear: The FDA will reexamine 21 CFR 11. 

During the reexamination period, they intend to enforce it with a narrower scope, and with discretion. They also expressed their intent to not take regulatory action to enforce compliance with the validation, audit trail, record retention, and record copying requirements of 21 CFR 11. Additionally, FDA announced its intention to use enforcement discretion with legacy systems that were in use prior to 21 August 1997the date that 21 CFR 11 went into effect. Although these items are subject to FDA enforcement discretion, the FDA still intends to enforce signature rules, authentication, education and training requirements, system controls and procedures. Finally, and perhaps most importantly, there is no repeal of the predicate rulesclinical trial data for submission must always meet the integrity and quality standards required by GCP.

If validation, audit trials, and the requirements for record retention (and other aspects of 21 CFR 11) are not covered explicitly by the predicate rules, the agency recommends using a justified and documented risk assessment and a determination of the potential of the system to affect product quality and safety and record integrity. This approach means that industryand for that matter, FDA field inspectorscan use a risk assessment process to determine whether validation, explicit record retention methodology, and audit trails apply to a particular system. With luck, everyone will agree.

This new draft guidance presents definite risks for sponsors. As in many things in life, the risks are at either side of the bell curve of response. On one side, the ultraconservative side, the risk is that pharmaceutical companies will freeze all technology purchases, deployment, and other integration until the dust settles. The dust here may take years to settle, and in the end may be no more specific than it is today. To delay the deployment of technology in this fast-paced time could be to give away a competitive advantage. 

On the other hand, the risk on the liberal side would be to declare 21 CFR 11 as repealed and to stop validation and other best practices that make sense well beyond the Electronic Records rule. In fact, these activities are not specific to 21 CFR 11, make eminent sense, and were expected in deployment of technology in the pharmaceutical industry well before 21 CFR 11 was a regulation. This is an important point to keep in mind.

Discretion is the better part of valor in this case. For the most part, 21 CFR 11 makes good, solid sense as a means to mitigate against data damage and loss. The best approach would be to continue with business as usual while integrating a risk-based assessment of current projects and systems, using the draft guidance. Sponsors should plan for reducing, but not eliminating, 21 CFR 11 activities in areas that are clearly carved out in the guidance. It might not be necessary, for example, to plan a 21 CFR 11 compliance upgrade for a legacy system that has been in place since early 1997 without any modification. If it has been modified since then, it is not yet clear whether it would still be considered a legacy system. In any case, you might decide that the upgrade made sense despite the exclusion under this guidance. Of course, it is also possible to use a risk assessment to prioritize these projects. In the end, in any questionable instance, it is always best to err on the side of compliance.

1. Marcia Stepanek, Data Storage: From Digits to Dust, 

Major factors leading to the development of courses in research ethics are several widely publicized cases of research misconduct. In recent years, one of the first such cases was that of the Patchwork Mouse. William Summerlin, a scientist working at the Sloan-Kettering Institute for Cancer Research in New York in 1974, painted white mice with patches of black, misrepresenting the animals as having accepted skin grafts from black mice.

Summerlin had initially reported that tissue kept in organ culture for a period of time could then be transplanted without rejection into another animal. When these findings werent replicated by others at Sloan Kettering, Peter Medawar, another scientist, suggested that Summerlin had performed this experiment on a heterozygous mouse, one with chromosomes from both white and black parents.

FDA surprises the pharmaceutical industry with its new interpretation of the Electronic Records, Electronic Signatures rule.

Applied Clinical Trials-06-01-2003

Developing and Validating Electronic Diaries

Les Nouveaux Clinical Trials Guidelines Sont Arrives

Technology Update: Electronic Diaries, Part 3--Developing and Validating Electronic Diaries

Ensuring a HIPAA-Compliant Informed Consent Process

Innovations at an Investigative Site

Genome Discoveries Shape Drug Development and Testing

Is Change Afoot? 21 CFR 11 in Transition

The UK Freelance Network

Principles and Practice of Clinical Research

The HIPAA Privacy Rule, Research, and IRBs