Both large and small pharmaceutical companies have learned that the value of their development candidates increases once clinical research has demonstrated their proof of concept. Sponsor companies face the challenge of moving new blockbuster drugs to market as rapidly as possible. During development, they try to recognize, and minimize their spending on, products that can never make it through the registration process because of toxicity or lack of efficacy. Focused drug development using the best scientific approach accepted by regulatory authorities has become (or at least should become) a major objective for clinical research departments. That approach can include the use of appropriate biomarkers during preclinical and clinical drug development. 

As a general principle, a suitable clinical biomarker must be selected for which a reasonable relationship has been demonstrated to the clinically relevant endpoint. A few biomarkers are so closely linked to the clinical outcome that regulatory authorities have considered them valid primary variables in pivotal clinical trials and a substitute for a hard clinical endpoint during the marketing authorization process. It generally takes considerably less time and fewer subjects-and therefore less money-to demonstrate a significant effect of a drug on such a surrogate than on a "hard" endpoint. Based on these clinical biomarkers, preclinical models should be chosen that have some relevance to the effect of the drug in patients with the target disease. 

In April 1999, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) cosponsored a conference on "Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications."1 The concepts of biomarkers and surrogates have been summarized by the NIH Definitions Working Group as follows:  

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

A clinical endpoint is a characteristic or variable that reflects how a patient feels, functions, or survives.

A surrogate endpoint is a biomarker that is intended to substitute for a clinical endpoint. 2

Although more complex definitions have been suggested since then, the NIH definitions present a concise summary of the basic concepts. Preclinical project team members should choose appropriate (and, if possible, "humanized") biomarkers that are relevant to normal and/or pathological biology or physiologically associated with the target disease and the action of the new drug in humans.

In early clinical studies, suitable biomarkers should be applied to help to demonstrate proof of concept and identify appropriate dose regimens for efficacy studies. Doing so-and learning, for example, which subpopulations are most likely to benefit from the new treatment-can help in planning later efficacy studies. Although the approach may seem straightforward, the use of biomarkers and surrogates carries with it a number of practical problems and pitfalls. Cardiovascular research will be used as an example here, because the concepts have often been applied in this clinical field. 

It should be noted that any clinical observation in a given subject might serve different purposes, and each purpose can have implications for the way these characteristics are used, documented, validated, and interpreted. In clinical practice, for example, blood pressure (BP) is measured to assess the individual risk for a given patient and to decide upon that patient's further diagnostic and therapeutic management. The same characteristic may be determined in epidemiological research, for example. Finally, blood pressure may be used as an outcome measure for a company's decision making in a research project. It may help to answer such questions as "Does the antihypertensive drug work?" or "Does the new drug create any side effects related to blood pressure?" The same measure may become a valid surrogate and an essential element in the regulatory review process to be used for the decision about marketing approval for the new drug. Researchers in cardiovascular drug development have access to clearly defined and rigorously validated biomarkers, surrogate endpoints, and clinical endpoints. 

Biomarkers include biochemical and functional characteristics or signals; ideally they should be noninvasive. Examples for biochemical biomarkers for cardiovascular conditions are high-density lipoprotein (HDL) cholesterol, lipoproteins, creatine kinase MB band (CK-MB), troponins (markers for myocardial cellular damage), high-sensitivity C-reactive protein (hs-CRP, a marker for inflammatory processes), fibrinogen, or plasminogen activator inhibitor-1 (PAI-1, an indicator of the activity of the blood coagulation system-and thus a risk for intravascular thrombus formation).3, 4 Functional or physiological characteristics include endothelial function, arterial or venous blood flow, arterial stiffness, and left ventricular systolic or diastolic volume or function. Finally, examples for signaling characteristics are ST depression recorded in the ECG (exercise or pharmacological stress testing, for example), and findings obtained by an imaging method such as quantitative coronary perfusion, coronary calcification (electron beam tomography), intravascular ultrasound, magnetic resonance imaging (MRI), or nuclear imaging (99mTc-SPECT) that include exercise or pharmacological stress testing. 

The most important criteria for valid biomarkers to be used in drug development are their clinical relevance; their sensitivity, specificity, and reliability (do they measure what they are supposed to); and their practicality and simplicity.5 

The list of cardiovascular biomarkers that have been accepted as surrogate endpoints is much shorter, of course, and includes such characteristics as blood pressure, cholesterol, and low-density lipoprotein (LDL). 

The most important criteria for valid surrogates are summarized in the International Conference on Harmonisation (ICH) Guideline E9, Statistical Principles for Clinical Trials.6 These mainly define the relationship between the surrogate endpoint (high blood pressure, for example) and the "hard" clinical endpoint (such as stroke) actually relevant when treating the condition. To show this relationship, the following must be demonstrated:  

statistical relationship in epidemiological studies 

evidence from clinical studies that treatment effects on the surrogate correspond to the clinical outcome.

For the same disease, the relationship between surrogate and clinical endpoints may depend on the mode of action. This means that for the same condition, regulatory authorities may accept that the surrogate is valid for one class of drugs, but not for other classes. 

"Hard" clinical endpoints for cardiovascular disease include such events as death, myocardial infarction, and stroke. These require no further validation, but are clinically relevant per se. However, use of these measures is often impossible in early proof-of-concept studies, because those studies require a large number of subjects and a long time period-often years from the beginning treatment until the event. 

Drug development was traditionally described as a sequential occurrence of formal, well-defined phases-usually described as preclinical development followed by clinical Phases 1 through 4. Today, drug development is seen as an integral data-driven process in which the phases overlap and-more importantly-use all information gained to create an optimal design for the next steps.7 Furthermore, unexpected findings at a later stage of development may necessitate planning new preclinical studies or Phase 1 and Phase 2 trials.  

In preclinical development, biomarkers are an essential element of the processes used to optimize the science of drug development. These include a number of modern technologies, such as functional genomics, proteomics, imaging, modeling and simulations, computational methods/informatics, modern analytical technologies, and specific humanized preclinical models. 

A well-documented example for the selection of appropriate and validated preclinical biomarkers is cardiac safety models to assess the potential of a drug causing prolongation of QTc, an ECG biomarker for life-threatening ventricular arrhythmia. Several regulatory guidance documents have recently been published on appropriate biomarkers for the proarrhythmic potential of drugs, and a harmonized guideline for the United States and Europe is expected for this year.8â11 Relevant preclinical models include in vitro tests such as ionic channel assays and hERG (human ether-a-gogo) channel binding, guinea pig myocytes, rabbit or dog Purkinje fibers, anesthetized guinea pig or dog, and conscious dog studies. These models are considered reliable and practical. They fulfill the requirements for suitable biomarkers and are related to the corresponding clinical biomarker, QTc prolongation. 

Preclinical or clinical studies frequently are performed without assessing the concentration dependency of the observed effects. This information would be very valuable, however, to predict appropriate dosage regimens in initial studies that use pharmacokinetic/pharmacodynamic (PK/PD) modeling techniques. Thus, in vitro concentrations or in vivo exposure, by sparse sampling methods (example: toxicokinetics), should regularly be determined in preclinical models. 

A recent "Position Paper on the Non-Clinical Safety Studies to Support Clinical Trials with a Single Low Dose of a Compound" drafted by the Committee for Proprietary Medicinal Products (CPMP) proposed minimum requirements for early pilot studies on the pharmacokinetics of a new chemical entity in human subjects using subpharmacological doses.12 This procedure allows for selecting appropriate animal species for preclinical studies-especially safety studies-and also for better use of preclinical information to predict dose dependency of efficacy or toxicity data in humans. 

Biomarkers play an especially critical role during Phase 2a of drug development (that is, during early proof-of-concept studies in a well-defined target population). This phase has been defined as "human trials providing sound evidence supporting the postulated effects of a new therapeutic drug product." The effects may be a relevant pharmacological action or a change in disease biomarkers, established surrogate endpoints, or clinical outcomes. Particularly, it should be noted that the relevant drug effects might be beneficial (that is, related to efficacy) and/or toxic (related to potential side effects).  

To properly interpret the outcome of clinical studies in which the primary outcome variable is a biomarker that substitutes for the relevant clinical outcome, researchers must consider the complex relationship between the medical condition, the biomarker, and the clinical outcome. Simplified relationships between disease, biomarker (surrogate endpoint), and clinical outcome (clinical endpoint) are shown in Figures 1 and 2. 

Hypertension is a straightforward example; it is associated with the biomarker elevated blood pressure-one of the few generally accepted surrogate endpoints in cardiovascular drug development-is associated with a clinically relevant outcome such as stroke, myocardial infarction, or renal failure. But the apparently straightforward association between disease, biomarker, and outcome oversimplifies the underlying (patho-) physiology. Thus, a disease generally is associated with several clinical manifestations, which may or may not serve as biomarkers, and which may be associated with the relevant clinical outcome. An example of a complex clinical condition is the metabolic syndrome, which is defined as insulin resistance (with or without manifest type 2 diabetes) and at least two of the following criteria-hypertension, dyslipidemia, obesity, and microalbuminuria. Clinically, this disease is associated with an increased cardiovascular risk. 

The possibility that the clinical outcome is time dependent must also be taken into account when interpreting the outcome of studies using biomarkers (Figure 3). An example is the pharmacological group of phosphodiesterase (PDE) 3 inhibitors (amrinone and milrinone, for example) for which a significant increase in cardiac contractility could be demonstrated in subjects with congestive heart failure. Following chronic administration of these drugs, mortality increased in this subject population. 

It can be concluded that biomarkers and clinical endpoints are not completely dependent on one another, but that there is a more or less well-defined relationship between the two. The use of a clinical biomarker as the primary outcome of a pharmacological intervention must therefore be interpreted very cautiously, taking into account the underlying (patho-)physiology, the possibility of false positive or false negative results, and time dependency of the clinical outcome. 

In cardiovascular medicine, blood pressure is a biomarker with a clearly demonstrated relationship to clinically relevant endpoints. BP has been accepted as surrogate endpoint for cardiovascular morbidity and mortality, by both the medical community (as reflected in current World Health Organization guidelines) and regulatory authorities. Major prospective, randomized clinical studies (including meta-analyses) and epidemiological evidence (the Framingham Heart Study conducted over more than 40 years13) have clearly demonstrated that high blood pressure is associated with increased morbidity and mortality, and that lowering blood pressure is beneficial. Some of the main findings: 

Treated hypertensive subjects have a 10-year mortality rate about 25% (for men) to 33% (for women) lower than that of untreated hypertensive subjects.

Reducing diastolic blood pressure by 5 mm Hg results in a decreased incidence of stroke (down 42%) and coronary artery disease (down 14%).

The maximum benefit seems to be achieved with a target blood pressure of 130â140/80â85 mm Hg.14

Antihypertensive treatment is indicated in both men and women and both young and elderly people.

To use a biomarker as a surrogate endpoint in a regulatory submission, researchers must validate the clinical study method for reproducibility, sensitivity, specificity, interrater reliability, variability, and bias. When using blood pressure as biomarker, for example, a considerable diurnal fluctuation exists. Because the maximum BP values occur in the late morning and early evening, ambulatory blood pressure monitoring (ABPM) is more appropriate than occasional office blood pressure recording. 

If a company wants to use additional claims in its marketing application, it needs to use auxiliary biomarkers in the clinical program, such as: 

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Both large and small pharmaceutical companies have learned that the value of their development candidates increases once clinical research has demonstrated their proof of concept. Sponsor companies face the challenge of moving new blockbuster drugs to market as rapidly as possible.

Biomarkers and Surrogate Endpoints in Clinical Drug Development

It its core, good clinical practice (GCP) is a set of broad regulatory requirements, standards, and recommendations that apply to thousands of highly specific tasks, processes, and roles in the conduct of clinical research. Given the disparity between the specificity of clinical trial processes and tasks and the general GCP requirements and standards under which they occur, it is not surprising that interpreting and implementing GCP standards continues to present challenges to the pharmaceutical, bio-technology, and medical device industries.

As is true of any area in which interpretation plays such a central role, the GCP discipline is today, as much as it has ever been, characterized by many long-standing and emerging questions regarding how broad GCP standards should be applied in the real world of clinical trials. Today, emerging questions in such areas as Part 11 and electronic clinical trials, as well as the new Privacy Rule and its implications for clinical research, are taking their places alongside long-standing GCP gray areas, including the way FDA GCP standards intersect with ICH GCP principles and the federal governments Common Rule.

Recognizing this, we set out to systematically collect, catalog, and answer the most important, emerging, and difficult questions regarding the interpretation and implementation of GCP standards today. In doing so, it is our hope that the resultant work, 

Good Clinical Practice: A Question & Answer Reference Guide

, will represent the next step in GCP training and instructionone that begins where all others leave off. To Plato, the most important intellectual activity was a question and answer processthe dialogue. We have, in a way, entered into a print dialogue that permits us to highlight, address, and explore a vast array of GCP-related questions that have persisted for many years without definitive answers.

In creating this work, we selected a few hundred questions culled from a much larger list. In addressing these questions, we had one clear and overriding goal: To provide definitive answers where they exist, and to provide informed, thoughtful, and well-researched answers where they do not. In developing these answers, we called upon our own experiences in clinical research, reviewed hundreds of regulatory documents, and consulted directly with dozens of FDA officials and a network of colleagues, opinion leaders, attorneys, and clinical researchers.

The answers in this reference guide reflect the multiple layers of standards that may be applied under GCP. In many areas, for example, emerging best-practice standards or international standards (ICH, for example) may surpass those required or recommended by FDA GCP.


Many areas lack an absolute consensus in approach, and there is no perfect knowledge in the complicated, evolving discipline of GCP, which intersects with several other complex and evolving disciplines, including ethics, medicine and nursing, health systems, regulatory, administrative and case law, management science, information technology, biostatistics, risk analysis, public health, and health policy. Reasonable practitioners with varied backgrounds can, and sometimes do, disagree about how best to interpret and implement GCP standards and guidelines.

We anticipate that not all readers will agree with some of the answers provided in this reference guide. Put simply, we could not have endeavored to provide meaningful answers without assuming such a risk. It is our fondest hope, however, that this work can spark new discussions or further existing dialogue that will, in the end, lead to more clarity and consensus in areas in which they are so badly needed.

It is important to note that the reference guide addresses GCP as it applies to clinical research on human beings. It does not discuss GCP as it might apply to the practice of medicine or nursing, to health care administration, to veterinary or nonclinical studies, or to non-U.S. laws or customs.

 In the FDAs view, what is an acceptable monitoring frequency for clinical studies?

 Industry and even FDA officials often speak of an informal industry standard under which each clinical trial site should be visited, on average, every four to six weeks. At an April 2003 FDA workshop, for example, CDER Office of Medical Policy Director Robert Temple, M.D., mentioned that the usual industry standard of every four weeks [for] every site [to be inspected] may not be appropriate for large, simple safety trials, which some agency officials have been advocating in some cases.

The FDAs GCP regulations state only that the sponsor shall monitor the progress of all clinical investigations under its IND. Although it is far from definitive, the FDAs Guideline for the Monitoring of Clinical Investigations (1988) adds, under a section entitled Periodic Visits, that the monitor should visit the investigator at the site of the investigation frequently enough to assure that:


 The facilities used by the investigator continue to be acceptable for purposes of the study.

 The study protocol or investigational plan is being followed.

 Changes to the protocol have been approved by the IRB and/or reported to the sponsor and the IRB.

 Accurate, complete, and current records are being maintained.

 Accurate, complete and timely reports are being made to the sponsor and IRB.

 The investigator is carrying out the agreed-upon activities and has not delegated them to other previously unspecified staff.

Although the ICHs GCP guideline says a bit more under Section 5.18.3-Extent and Nature of Monitoring, it does not provide specific advice on monitoring frequency, leaving that determination to the sponsor: The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring before, during, and after the trial; however, in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP.

Perhaps the greatest determinant of appropriate monitoring frequency is rate of enrollment. Sites that enroll a large number of patients in a short period of time need to be monitored far more frequently than sites that are low, slow enrollers. Depending on the complexity and frequency of protocol-required study visits, an average enrolling site might have a monitoring visit once per month or once every other month.

The frequency of monitoring visits is less important than the quality of monitoring visits, however. A rushed, perfunctory routine visit that includes only a cursory review of source documents is worthless.

 But in CPG 7348.811 (Inspections of Investigators), FDA instructs agency field inspectors to briefly describe the method (on-site visit, telephone, contract research organization, etc.) and frequency of monitoring. So obviously, the FDA makes certain assessments in this regard. How does the FDA assess the adequacy of monitoring frequency (that is, what criteria are used), and what are the typical red flags that the FDA looks for in this area?

 CDER Bioresearch Monitoring (BIMO) Program officials concede that it is extremely difficult for the agency to prospectively determine, for each and every trial, how often monitors should visit sites. For this reason, companies are left to determine what monitoring frequency is appropriate for their specific trials. Admittedly, this does not much help a sponsor wondering what standards it will be held to in terms of monitoring frequency. In informal correspondence on this question, however, CDER BIMO staff noted that, in assessing the adequacy of monitoring frequency, they will ask several questions, including:


	Was there sufficient early contact between the monitor and investigator to ensure that the study started out well?

	Was monitoring frequency sufficient relative to the rate of enrollment (for example, did monitoring visits increase in response to extremely rapid enrollment)?

	How many times did the monitor visit a site relative to the studys length?

	If the monitor discovered serious site-related problems, did he or she increase the frequency of visits and/or appropriately follow up?

	How complicated were the study and the records that the monitor had to review?

As a practical matter, however, the agency only truly scrutinizes monitoring frequency when agency inspections uncover specific problems at a clinical site. Therefore, it is the compliance problems that become the red flag for possible inappropriate monitoring frequency. In assessing the reasons for such problems, the agency will scrutinize monitoring frequency as a potential cause or contributing factor.

In short, monitoring frequency will not receive significant scrutiny in the absence of compliance problems. Not surprisingly, CDER DSI staffers report that a sponsor has never been cited for inadequate monitoring frequency when no other problems were found with a study. Because most agency inspections are conducted retrospectively (i.e., following a studys completion), monitoring frequency is, by definition, deemed adequate when a study/site is found to be fully compliant.

 Can a monitor review photocopies of medical records, also called shadowcharts, instead of the originals? Which one does the FDA inspector reviewduring site inspections?

As a general rule, site monitors should always review original medical records for example, actual physicians office notes, clinic notes, and hospital medical records. Monitors often ask site staff to photocopy original records for their review. Unfortunately, this request is often made for the convenience of the monitoreither the monitor does not want to spend the time reviewing the medical records or is not able to navigate through the documentation to find pertinent data.

A fundamental problem in relying on photocopies is that the monitor cannot be certain that the documentation is complete. That is, data may have been advertently or inadvertently deleted from pages (in the margins or on the back page of the original record, for example). In addition, there may be data in other parts of the record, however small, that may not have been photocopied.

When a specific original record cannot be made available, a certified copy of the original records may be used. A record is considered certified when a qualified individualoften in the medical records departmentattests that the copies are accurate and complete. In its April 1999 draft industry guidance entitled, Computerized Systems Used in Clinical Trials, the FDA defines certified copy as a copy of original information that has been verified, as indicated by dated signature, as an exact copy having all of the same attributes and information as the original. [Authors note: while this guidance addresses certified copies in the context of electronic records, FDA officials maintain that this definition is equally relevant to paper-based records.]

In recent informal correspondence on this issue, the FDA stated that, obviously, the source documents are the gold standard for study monitoring . . . In general, source documents should be the basis for monitoring. If a sponsors monitor elects to use shadow charts they are free to do so as the regulations do not specify how monitoring is to be performed. However, in our opinion they would be foolish to rely on shadow charts without establishing that the shadow charts were the equivalent of the source documentsthat is, that they are a certified copy, meaning a copy of original information that has been verified, as indicated by dated signature, as an exact copy having all of the same attributes and features and information as the original. Thats just an opinion. We instruct FDA investigators to audit against source documents.

In practice, the FDA may accept, for the purpose of an inspection, a photocopywhen the original of a specific document is unavailable or has been destroyed. The FDA inspector and the reviewer at the agencys headquarters will decide if a photocopy is acceptable in a particular case. The agency, however, is more likely to accept a photocopy of an isolated record than photocopies of an entire research record.

If FDA field staff decide to rely on a certain number of photocopies during a site inspection, agency officials would expect the inspector to examine the adequacy of the document certification process, including the standard operating procedures for that process.

The guide is not intended to provide specific regulatory or legal advice. Readers should consult their companys standard operating procedures (SOP), clinical and regulatory departments, and legal counsel for guidance when applying GCP standards in clinical research.

A newly published reference guide answers a wide variety of GCP questions.

Clinical Monitoring: Answers to Questions about Good Clinical Practice

Monitors have long visited investigator sites at the outset of a trialand periodically throughout the course of the trialto ensure that the trial is conducted and documented properly.

 Among the variety of activities they engage in to that end is the key task of verifying that source data/documents and other trial records are accurate, complete, kept up-to-date, and maintained.

Monitors pore over source documents to confirm that the raw data can be retrieved in its original form and has been recorded in a logical and consistent manner. They want to see that data can be linked to an identifiable study subject and that data can be attributed to the person at the study site who collected and/or recorded it. Monitors make sure that information in the source documents is accurately conveyed to the sponsor in the case report form. Until recently, most source data verification was performed by comparing paper source documents to paper case report forms (CRFs). But the paper era is rapidly ending.

Today, when monitors visit research sites at hospitals, clinics, research organizations, and private practices they are as likely to encounter electronic record-keeping and electronic data capture systems as they are to find paper. Principal investigators, study coordinators, and research subjects are all clicking, beaming, scanning, and emailing. Many hospitals now scan a study subjects medical record into an imaging system and shred the original paper. Physicians, nurses, and other research personnel enter subject assessment data directly into bedside computers or handheld devices. Automated instrument recordings of physiologic measurements (temperature, blood pressure, volume measurements, flow rates, and others) become clinical trial source data. 

Laboratory values are held in computerized systems at both research sites and central laboratories with which sponsors have contracts. Study subjects enter diary information into handheld computers, and the data is uploaded into a central system at scheduled study visits. Site personnel and research subjects enter data directly into Web-based data collection systems. Investigational pharmacists use computers to record treatment assignments, and in preparation and labeling of the study drug. Research personnel use a myriad of software products to record subject encounters and visit schedules. Clinical research coordinators make study tools and trackers from commercially available software products. The list is endless, and ever-increasing.

Often, a research subjects source data is derived from multiple electronic systems. In a recent review of a subjects medical record for an inpatient trial, I counted six different computerized systems that contributed source data for the trial, but institution personnel described their clinical milieu as not computerized yet.

In August of 1997, 21 CFR 11 (FDAs Electronic Record, Electronic Signatures regulation) became effective. It describes the technical and procedural requirements that must be met when electronic records and/or signatures are used in lieu of paper records and signatures. The regulation works in conjunction with other FDA regulations that require record-keeping. Those laws and regulations (predicate rules) establish requirements for record content, signatures, and retention.

 In short, 21 CFR 11 requires that computer systems and any electronic records that are created, modified, maintained, archived, retrieved, or transmitted under any records requirement set forth by FDA regulations:


	have the ability to generate accurate and complete copies in human-readable and electronic form, suitable for review by the agency.

	limit access to authorized individuals, trained in the use of the system.

	provide written policies to ensure user accountability for actions initiated under the users electronic signature.

	be protected and retrievable throughout the record-retention period.

	use computer-generated, time-stamped audit trails.

	control access to system operation and maintenance documentation.

	encrypt records, or otherwise protect record authenticity, integrity, and confidentiality if system access is open.

	meet specific requirements for electronic signature components and controls.

Following an initial grace period, FDA began enforcing the regulation; the evidence is in recent 483s and Warning Letters that contain 21 CFR 11 citations. Although the vast majority of these citations occurred at pharmaceutical sponsors and manufacturing facilities, investigator site systems and the records they generate are subject to regulatory scrutiny under the regulation, and are likely to be inspected with increasing frequency in the future. 

Thus, todays monitors continue to perform source data verification as before, but in a whole new technological arena that currently seems to raise more questions than answers. As the answers emerge, monitors stand in a unique position; they are objective representatives of sponsors, and they are closest to the electronic source data throughout the duration of the trial. The monitor is likely to be the first to detect potential 21 CFR 11 compliance issues. 

Compliance assessment during site selection


Initial 21 CFR 11 compliance assessments of a sites systems should begin during the site selection process. Most research sites continue to be selected for participation in a given trial based on a two- to four-hour visit to the site by a representative of the sponsor, CRO, or SMO. (Sometimes the person that conducts the site evaluation and selection also functions as the site monitor or CRA. For purposes of this article, we assume that they are two separate persons.) It is important that initial questions about system security, SOPs, validation, training, and other factors be asked and answered at this meeting. 

Some sponsors send a computer compliance survey or questionnaire to an investigator before the site evaluation visit so that the answers can be reviewed and clarified by their internal computer quality group. The sponsors then consider compliance issues before determining investigator participation. Sponsors may schedule an on-site computer compliance assessment by a qualified person, especially if particular concerns exist. And sponsors may insist on the use of a paper system if the compliance issues cannot be corrected in a reasonable time. These cautious evaluations seem wise and are helping to raise awareness of the 21 CFR 11 regulations on the part of investigators and site staff.4 Still, one wonders about the feasibility of conducting on-site system evaluations for research as general practice. For a large, multicenter trial, the cost of these visits alone would seem prohibitive. 

So many, if not most, sites continue to be selected after the traditional two- to four-hour visit. During those visits, many agenda itemsprotocol and budget discussion, assessment of required patient population, tour of the facility, and visit to the pharmacycompete for the time a busy researcher has allotted  to the visit. At the time of site evaluation, it is quite likely that the study protocol may not be finalized by the sponsor, and more likely that the CRF will not yet be in its final form. Without a final protocol or CRF at this point, it can be difficult to identify (and evaluate) the system(s) that will ultimately provide the source data. Although it seems possible to detect flagrant 21 CFR 11 issues during a site selection visit, this meeting may not allow enough time and detail to find more subtle, potentially serious system and user issues.

Site initiation and electronic source documents


The monitors first contact with the site is often at the site initiation visit, several months (and maybe longer) after the site selection visit. In the interim, many changes are possible with the investigators systems and staff. During the site initiation visit, further dialogue should take place surrounding electronic source documents. Good questions to ask include, What part(s) of the CRF have an electronic source? How will I access the system? How do you access the system? How were you trained to use this system (run the tests, take the measurements)? How are changes to the data made in the system? Have you ever lost data in the system, or had a system crash?

Monitors, be prepared for the answers! Among others, I have heard:


	You cant get on the computer. Well just print out everything for you.

	Here, you can just use my password to get on.

	Were not computerized yet (when multiple systems and e-source documents are evident).

	I dont use this system, so I dont know. I just copy the values off the printouts into the CRF.

Even at prestigious academic and research centers, it is not unusual to find, at best, only a nodding acquaintance with the 21 CFR 11 regulations. Monitors can spend a good deal of time explaining concepts as basic as electronic documents and passwords.

 If a document is created (modified, maintained, archived, retrieved, or transmitted) in electronic form, the electronic document is the source, and should be what the monitor views. Paper printouts lack important behind-the-scenes data (metadata). Explaining that FDA expects to be on the same technological plane as the investigator site (hence, the monitor should see what FDA will see) can help to ease initial resistance to having a monitor access the system.

 The monitor should access the system(s) under a temporary (auditor) password, or at least looking over the shoulder of a registered investigator site user logged on to the system under his/her own ID and password. Study coordinators must often contact a sites system administrator to obtain a temporary password. It is wise for the monitor to discuss this with the coordinator or investigator before they actually need to view records, because getting a password can take time and effort on the part of the research staff.

Once the monitor has access to electronic source data, he or she typically receives a crash course in system navigation, usually from the study coordinator. From that point forward, the monitor remains in close contact with site systems, electronic data, and site users throughout the duration of the trial. 

Monitors spend many hours at investigative sites. They often work physically close to where data is being collected, and sometimes may even observe electronic data collection in progress. Monitors can become aware of site operational issues, including frustrated, overworked, and even angry coordinators, investigators, and ancillary staff. They may sense an impending resignation or political situation that could cloud judgment, or adversely motivate someone with access to electronic data. For the monitor, a sense of the site milieu and the ability to access and review the electronic data are a strong pair in detecting potential serious issuesno advanced computer skills required!


Malintent aside, at many investigator sites a large obstacle to 21 CFR 11 compliance seems to center upon a lack of awareness and understanding of the regulations. Broaching the subject of these laws at investigator sites generally results in blank stares. The existence and ramifications of the regulations dont seem to be abundantly clear, even to educated and highly skilled personnel. I have, for example, witnessed one coordinator innocently take over for another coordinator during a lengthy electronic data collection session (without logging off, then back on) so that the first could go to lunch. Most medical personnel clearly understand the need for attribution in handwritten chartingthey wouldnt sign someone elses progress notebut when a computer is involved, somehow all of that can be forgotten. 

Not understanding can sometimes lead to resistance to questions or finding out the answers. When discussing electronic record-keeping issues, more than once Ive heard, We shouldnt have to deal with thisthats what IT is for. Data is often collected using systems for which the investigator has no control of upkeep, training, back-up, or other services. Computerized systems, especially in institutions, often serve more than research purposes alone. Understandably, physicians who rely on their institutions systems to conduct their research have difficulty being held accountable for systems not under their direct control. 

A monitors lack of awareness of the Electronic Records, Electronic Signatures regulations and associated FDA guidance is also a significant concern. Taking the time to access and navigate a sites computer system(s) certainly takes more time and initiative, and can be more cumbersome than looking at paper. Monitors who lack confidence in their own computer skillsor are pressed for timemay find that a pile of printouts provides a much greater comfort level. 

Monitors generally have an excellent understanding of original paper source documents, but often have a poor grasp of what defines an electronic source. Additionally, many monitors fail to identify all the different electronic systems in use at a site, all of which can potentially contribute data to a given research subjects case report form.

 a monitor approach multiple systems, given that source data verification is but a portion of what needs to be checked in assessing proper trial conduct, and given that there are only so many hours within which to conduct a site visit?


FDAs Electronic Record, Electronic Signatures regulation presents significant challenges to traditional data monitoring. Armed with knowledge of the regulations, and supported by other agents of the sponsor, monitors can still be instrumental and effective in detecting potential compliance issues. Consider the following: 


	In reviewing electronic data, a monitor determines her level of access to be greater than read-only. 

	A monitor observes data being collected by means of a laptop computer that uses a program designed by the investigator. The laptop is left open and unattended in the presence of substance-addicted subjects.

	A monitor reviews computer printouts, on which all of the dates have reverted to the year 1904.

	The monitor ascertains that a computer upgrade performed on a hospital system renders previously restricted pharmacy screens (detailing blinded treatment assignments) unrestricted for many hospital personnel to view. 

No advanced computer knowledge is required to understand the potential impact on data integrity revealed by these real-life examples. Additionally, even if site systems are deemed compliant at trial outset, human actions can contribute to compliance issues at any point in the trial. 

Encountering situations such as these, monitors are likely to sound the first compliance alarm. Thereafter, resolution will certainly require the efforts of the team. The team may include sponsor IT experts for help with technical issues and sponsor QA experts to assist in properly identifying and escalating 21 CFR 11 issues, and for help in formulating corrective action. IT and QA personnel can help develop and implement comprehensive, systematic checklists and tools to ascertain system compliance during site selection and throughout trial duration, making sure that the right questions are askedand that site evaluators and monitors know what to do with the answers.

Keenly aware of their regulated business, sponsors also seem likely to spearhead the 21 CFR 11 education efforts needed to enlighten their own research personnel and those at investigative sites. A good place to start could be training sessions, at start-up and other investigator meetings, focused on the Electronic Records, Electronic Signatures regulation.

In the midst of exponential increases in the use of electronic systems to collect and process data for clinical trials, 21 CFR 11 adds a whole new dimension to monitors responsibilities for ensuring that the trial is conducted and documented properly.1 Armed with knowledge of the regulations, proper tools, and back-up from knowledgeable sponsor experts, monitors can be key in furthering awareness of the regulatory requirements at investigator sitesthus helping to ensure compliance throughout the course of the trial.


1. Guideline for Good Clinical Practice, International Conference on Harmonisation, Federal Register 60 (90) 2569125709 (9 May 1997).

2. Food and Drug Administration, Compliance Program Guidance Manual, Bioresearch Monitoring, Chapter 48 (FDA, Rockville, MD, 23 February 2001).

3. Code of Federal Regulations, Title 21, Part 11, Section 11.111.300 (U.S. Government Printing Office, Washington, DC).

4. Marta Haley Fields, The Implications of 21 CFR Part 11 for Clinical Research, 


1. Food and Drug Administration, Guidance for Industry, Computerized Systems Used in Clinical Trials, April, 1999.

This article is based on the authors presentation at the 37th Annual Meeting of the Drug Information Association (held in July 2001 in Denver, Colorado).

CRAs now have to monitor sites? compliance with FDA?s Electronic Record, Electronic Signatures regulation.

21 CFR 11 Compliance at Investigator Sites

Among the many current regulatory projects in Europe on medicines development, one that has lain fallow for a year or so is now emerging again into the limelightthe promotion of clinical trials on pediatric medicines. But progress is slow enough to bring to mind the child who the melancholy Jacques describes with satchel and shining morning face, creeping like snail unwillingly to school.

 There has still been no full discussion in the European Union about how to turn the idea into a reality. Instead, the latest move is that the EU has announced plans to carry out an extended impact assessment of a draft European Commission proposal on medicinal products for pediatric use.

Extended impact assessments are all the rage in Brussels nowadays. The idea is to check out in advance whether proposals are sound, rather than wait until the law is on the statute book and then find out it doesnt work as intended. The aim of this one is to evaluate the economic, social and environmental impact of the different elements of the Commission proposal as well as the impact on sustainable development.

No mean feat. And because the Commission doesnt feel up to the task itself, it is farming the work out. It has just published a call for tenders to do the job. 

The Commissions draft proposal for medicines for pediatric use still has no legal status, as it remains an internal consultative document. It sets out a system aimed at stimulating development of products adapted to the needs of the pediatric population through a mixture of requirements and incentivesand the EU underlines the importance of striking the right balance between the two. 

Now the EU wants to analyze how effectively that system might work. So it wants someone to study key elements of its outline proposal. Under particular scrutiny will be:


	the requirement to include the results of an agreed pediatric evaluation plan as part of an application for a marketing authorization.

	the incentive of an extension by six months of the duration of the period of supplementary patent protection (by comparison with the alternative of an extension by six months of the period of data protection).

	the creation of a priority list of products for which there is a need for adaptation for pediatric use.

	the creation of a European network with specific expertise in the performance of trials on pediatric populations.

	the requirement to collect long-term safety information in the pediatric population.

	the publication of information on trials conducted in the pediatric population.

	the establishment of a pediatric study fund and alternative means of financing the fund.

	the establishment of a new category of marketing authorizationthe pediatric marketing authorizationassociated with a five-year period of data protection.
In addition, the EU wants a comparison with what would happen in a no policy change scenario.

The contract is due to be signed in September this year, and to run for six months.The EU knows why it wants to move ahead. It has already recognizedas have some individual countries, and notably the United Statesthat the absence of pediatric information in marketing authorizations poses risks for children:


	Inadequate dosing information can create adverse reactions that could be avoided.

	The lack of pediatric safety information risks age-specific adverse reactions.

	The absence of pediatric testing can lead to ineffective treatment through underdosing, or prevent access to therapeutic advances, because physicians choose to prescribe existing, less effective medications in the face of insufficient pediatric information about a new medicine. 

If pediatric formulations are not developed, younger patients that cannot take the adult formulation may be denied important new therapies, or they may have to take extemporaneous formulations that may be poorly or inconsistently bioavailable. 

Says the EU
The problem persists because the ethical obligation to ensure that the paediatric population has access to suitably adapted, tested and labelled medicines is outweighed by the lack of commercial interest for pharmaceutical companies to develop medicines for use in children. Studies in children are described as being difficult to conduct, ethically challenging and expensive. The development of specific formulations adapted for use in children presents an additional expense. Furthermore, there is little incentive to apply for the authorisation of products for use in the paediatric population when it is common practice, albeit through necessity, for health care professionals to prescribe off-label.
It is easier to find answers to the question of how to introduce effective obligations and incentives for new products or products that are still covered by patent or data protection than for off-patent products. Extensions of existing periods of patent or data protection can be used to provide incentives, and requirements to provide the results of a pediatric study program can be imposed when an application for marketing authorization is submitted. 

But for older products, there is no period of protection to be extended. And the product will often be marketed mainly (sometimes only) by generics manufacturerswhich tend not to have large resources for research and development, or expertise in conducting clinical trials that go beyond the studies required to demonstrate that their product is equivalent to the innovator product. The original innovator may no longer be interested in developing the product.

Nevertheless, because many of the products used most frequently off-label or on an unlicensed basis for children are off-patent, it is important to deal with these products too. So one idea is to create a study fund to support studies on off-patent medicines, available to both commercial and non-commercial sponsors, and aimed at pediatric studies that could support the inclusion of pediatric information in the terms of a marketing authorization. 

Sensitivities are high, however, over the size of such a fund, its source of financing, its management, and the way it would allocate money to sponsors. Because sorting out these problems may well take a long time, the current EU thinking is to move ahead first with a proposal on new medicines, and leave the question of older medicines until later.

An informal draft of a legislative proposal was discussed with member state experts in the EUs Pharmaceutical Committee during May, and European ministers looked briefly at the plans at their June 2 meeting. Belgium was particularly outspoken in urging rapid action at EU level to fill the voidwhat it called the precarious situation in relation to the production of medicines for children. Belgium insisted that particular attention should be given to the ethical aspects of clinical trials involving children. 

An EU ad hoc expert group has been set up to study the matter further. It will hold its first meeting in July. A formal EU proposal is likely to emerge once the impact assessment has been completed, at the end of this year, or early in 2004.


Meanwhile, the bigger picture of EU drug legislation shifted slightly at the same early June meeting of EU ministers. The EU plan to update the way the European Agency for the Evaluation of Medicinal Products operates (which has also been held up by conflicting views among EU member states) moved one step closer to becoming reality. Ministers provisionally agreed to a typical European compromise which satisfies no-one completely, but is not downright obnoxious to anyone.

The compromise covered the two most contentious points in the proposed new rulesthe scope of the EUs centralized procedure for granting marketing authorizations, and data protection. 

 the initial plan to make it obligatory for all new products was watered down. It will now be obligatory only for products for human use containing a new active substance for which the therapeutic indication is the treatment of AIDS, cancer, neurodegenerative disorders, or diabetes. Everything else can still use the national procedures, and win EU-wide market access through the alternative decentralised or mutual recognition procedure. 

the time during which a company would be able to protect its rights to clinical data on a product against another company using them to seek authorization for a competing productsome harmonization of divergent national practice was agreed, but less than had been planned. The deal will let generic companies apply for marketing authorization eight years after the original medicinal product was granted a marketing authorizationbut the generic could be placed on the market only after an additional period of two years, that is, 10 years in total. And for products where the centralized procedure is compulsory, the 10-year period can be extended to 11 years in the case of a new indication.

But the European pharmaceutical industry didnt like the compromise. The European Federation of Pharmaceutical Industries and Associations immediately said that EU ministers missed an important opportunity by not fully supporting the proposal to provide 10 years of regulatory data protection for all new products, across the board. It interpreted the agreement to provide a weaker level of protection for some products registered as missing the opportunity to boost the competitiveness and innovative capacity of the European pharmaceutical industry, and the research that patients need and expect.

The deal agreed to by ministers (they will have to formalize their views in October) offers some small improvement on what is already available in most of the EUs fifteen member states, by providing for an eleventh year of protection for a new indication on an existing product. It will, however, improve the situation in the handful of current member states which currently offer only six years exclusivity, and in the ten new member statesmainly from the former Soviet blocthat will join the EU in May 2004. 

View from Brussels

The issue of prioritizing clinical trials of pediatric medicines continues to simmer, as plans for planning the possible future legislation develop.

EU Pediatric Rules ?Creeping Like Snail?

John Vogel, clinical researcher turned consultant, is passionate about outsourcing. He believes that pharmaceutical companies can gain competitive advantages through drug development outsourcing. In fact, that's what his company (John R. Vogel Associates, Inc., Wailea, HI) is all about. He provides in-house training and support to pharmaceutical and biotechnology companies in the United States and abroad, as well as contract research organizations and other outsourcing providers. 	

"I spend about 70% of my time working with pharma companies-helping them understand how to outsource, helping them choose outsourcing partners for specific projects and recognize and solve problems with their outsourced projects," he explains. The other 30% of the time he's meeting with the other side of the equation-the outsourcing providers.	

Top:  Vogel was presented with an award for his decade of service to the Partnerships with CROs conference. Bottom:  Vogel has condensed his workshop into a two-hour seminar for pharmaceutical company managers.	

Although outsourcing is now a mainstay for Vogel, he has had another passion during his career. While at Schering-Plough in the 1980s he accepted the position of senior director, International Medical Research, with the mandate from his superior to determine whether global clinical trials were helping the company to develop new products. He proved that they were. 	

Vogel became an advocate of worldwide drug development, a position that was somewhat unpopular during the 1980s. Oftentimes at DIA meetings he would find himself debating the pros and cons of global clinical trials. 	

"There was no end to the people who would volunteer to argue against my position," he says. "At that time the majority opinion was that trials conducted abroad were inferior in quality and less likely to be accepted by the FDA." Both of these views turned out to be incorrect. Now, thanks in part to Vogel's certainty and promotion, global trials are ubiquitous. 	

Vogel was right about global clinical trials being the way of the future for drug development and he thinks he's right about outsourcing. So far he's on track. His training workshops are so popular that he often ends up conducting 10 or 12 sessions for a company when only one was originally scheduled.	

One of his current interests is developing clients in Japan and other Asian countries.	

"The CRO industry is in its infancy there. Asian pharmaceutical companies and CROs can benefit from lessons learned by their western counterparts," he says. Earlier this year he was invited to give a presentation at the annual meeting of the Japanese Contract Research Organizations Association, and it went well. Next month he will do a workshop for a Japanese pharma company.	

Vogel's start in the pharmaceutical industry came about by happenstance. During his senior year as a psychology major at Rutgers University, he noticed a handwritten note in the psychology department announcing a job opening at Squibb, a local pharmaceutical company. When he arrived for the interview, he was surprised to see that the interviewer was a fellow student from Rutgers. She had thought Vogel would be perfect for the job, but couldn't remember his name. She posted the notice hoping he'd see it and be interested. He got the job.		

Whistler, British Columbia, is a favorite skiing destination. Sailing is something that both John and his wife, Roberta, enjoy; and Maui offers plenty of hiking spots.				

Two years later, his boss accepted a faculty position at Rutgers and offered to fund Vogel's graduate work with his research grant. During that time Vogel was so interested in research that he submitted his own grant proposals to the Sigma Xi Foundation. Vogel received funding and hired a graduate student to be his research assistant while he was still doing research for his boss/professor. 	

When Vogel had finished his graduate work in 1968, he returned to Squibb and studied brain–behavior relationships and developed in vivo assays for predicting therapeutic activity in novel compounds. One of the "conflict" tests he developed has been widely adopted as the standard in vivo assay for anti-anxiety activity.	

Vogel and his wife, Roberta, met when he took a job at the company where she worked. She says that she was struck by the enthusiasm he showed for his work and that "his laboratory was always bustling with activity." 				

"John never seemed to have enough laboratory space," she says. "He needed a quiet, dark area for the conflict test that he was developing. His colleagues were amused when one day he cleaned out a nearby utility closet and transformed it into the new conflict test lab. When John announced his resignation from the company, his staff placed a plaque on the closet door. It read, "The John R. Vogel, PhD, Memorial CNS Pharmacology Closet."	

After spending nearly 10 years in the laboratory, Vogel was ready to move on. He accepted a clinical research position with Bristol Laboratories. Although he was not a physician, Vogel felt that his training in biostatistics and experimental design had provided him with valuable skills for clinical research.				

While at Bristol Laboratories, Vogel became acquainted with Alexander Lane, MD, who was vice president of Clinical Research. Two years later Lane joined Schering-Plough to become president of Research and Development. He offered Vogel the position of director of CNS Clinical Research. Later, Lane asked him to assume the position of senior director of International Clinical Research. It was during this time that he became a proponent of global clinical trials. Eventually, Vogel was appointed vice president of Worldwide Clinical Research. 	

After 11 years in clinical research Vogel grew concerned that, without a medical degree, his career opportunities in pharma industry companies were limited. A psychologist friend suggested that he try consulting. He took the advice and has never looked back. 				

Vogel's involvement in professional organizations helped to further his career as a consultant. He served as chairperson of the International Medical Affairs Committee of the Pharmaceutical Manufacturers Association (PMA), now the Pharmaceutical Research and Manufacturers of America (PhRMA). It was through some of his PMA contacts that he got started as a consultant.	

"Several of them agreed to give me a chance as a drug development consultant, and I saw an opportunity to focus my consulting on outsourcing." For a decade, Vogel also served as chairperson of the annual "Partnerships with CROs and Other Outsourcing Providers" conference.	

At the 2001 Partnerships conference, he was presented with an award in recognition of his involvement with the conference for 10 consecutive years. He now leads a workshop at the conference each year.	

He also chairs the Town Meeting, "Strategies for Maximizing the Efficiency and Cost-Effectiveness of Drug Development" at the annual DIA meeting. His involvement in these conferences and his articles published in Applied Clinical Trials and Global Outsourcing Review helped to establish him as an expert on drug development outsourcing.	

"For years after they first read John's articles in ACT, several readers a year called me in a panic when they discovered that one of the magazines with his articles was missing from their collection," says Applied Clinical Trials Editor-in-Chief, Jane Ganter. "Many of the articles that we publish, particularly those about regulations, become outdated after a time, but it appears that many of the principles in Vogel's series of articles on outourcing are timeless."	

In the future Vogel wants to do more work with managerial level people at pharmaceutical companies.				

"Successful outsourcing requires senior management vision and support," he says. "However, senior managers do not read articles on outsourcing, do not attend outsourcing conferences, and for the most part, do not participate in on-site outsourcing workshops."	

The challenge that he sees is "how to reach the decision makers and help them understand their critical role in achieving value through outsourcing." He wants them to provide direction and support for outsourcing. Something that, he says, doesn't currently happen enough in the industry. Because of this, he has condensed his workshop into a two-hour seminar which pharmaceutical companies can videotape and show to their managers around the world.	

Vogel's success as a consultant comes from his understanding of and experience with the pharmaceutical industry. He also attributes it to his "ability to anticipate success rather than to fear failure."	

Many professionals get so wrapped up in their work that they have little time for recreation, but Vogel is as passionate about play as he is about work. Living in Hawaii gives him ample opportunity to enjoy the sand, sun, and surf.				

Working from home means he can escape as needed. Most mornings he takes an early run on the beach with his wife before stepping into the office to contact clients on the mainland. Maui offers plenty of great hiking spots, and sailing is something that they both enjoy.	

They have sailed in the Chesapeake Bay and among the Society Islands (Tahiti). They are also scuba divers, enjoying the fish, whales, sea turtles, and non-aggressive sharks in the Hawaiian waters. They are also avid skiers and the slopes at Whistler, British Columbia, are a favorite destination. 	

Shannon Booth is a temporary assistant editor of Applied Clinical Trials and a former assistant editor of the magazine.	

Meet the EAB

John Vogel, clinical researcher turned consultant, is passionate about outsourcing. He believes that pharmaceutical companies can gain competitive advantages through drug development outsourcing.

Applied Clinical Trials-07-01-2003

Biomarkers and Surrogate Endpoints in Clinical Drug Development

Clinical Monitoring: Answers to Questions about Good Clinical Practice

21 CFR 11 Compliance at Investigator Sites

EU Pediatric Rules ?Creeping Like Snail?

Meet the EAB: John Vogel