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Feature Article

Getting answers to the right questions can help you decide how to choose and implement an electronic system that is a good match for your company's SAE reporting needs and its available resources.

Serious Adverse Event Reporting

A systematic survey of 96 pharmaceutical companies and clinical research organizations revealed which systems sponsors are using for clinical data management and adverse events tracking and reporting.

Clinical Research Software

The EUs Committee for Proprietary Medicinal Products describes the process clinical investigations should follow.


The European Union is treading delicately into new territory with draft guidance on developing diabetes products. The EUs senior scientific body for medicines, the Committee for Proprietary Medicinal Products, has just released the text for consultationuntil January 2002. It acknowledges that it is operating in a complex area with this guideline, and, unusually, it even includes a section on endpoints that it openly admits is almost speculative in nature.

The Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Diabetes Mellitus (CPMP July 2001; www.emea.eu.int/ pdfs/human/ewp/108000en.pdf) describes the type of clinical development program that should support the registration of new medicines for the treatment of diabetes mellitus. 

Prevention of diabetes and fixed combinations of oral antidiabetic agents are not covered by this guideline because, the CPMP says, there is only limited experience in this field. The note is intended to assist applicants during the development phase, offering guidance rather than binding rules. Even so, any deviation from the advice should be explained and discussed in the expert report, the CPMP insists.

The overall view is that global treatment of diabetes mellitus should aim not only at lowering blood glucose to near normal levels but also at correcting metabolic abnormalities and cardiovascular risk factors. Although several international trials have shown that any decrease in the level of blood glucose monitored by the glycated fraction of hemoglobin (HbA

) reduces the risk of microangiopathy, multiple cardiovascular risk factor intervention is the key issue in type 2 diabetes, it says.


For developing oral antidiabetic agents for type 2 diabetes mellitus, study design recommendations include a washout period of up to three months for subjects already treated with oral antidiabetic agents who are starting therapeutic exploratory studies with a treatment period up to around three months, in order to decrease the influence of previous treatment on the parameters of blood glucose control, which could last for a large part of short-term studies. For therapeutic confirmatory studies with active control of at least six months duration, a washout period is not considered necessary for previously treated subjects, because the final HbA

 level will not be influenced by the former therapy.

Placebo-controlled trials are necessary to get relevant information on the hypoglycemic effect of the investigational drug, the guideline says. But, for ethical reasons, controlled trials of three to six months should be reserved for subjects at an early stage of the disease who are not already on treatment with other oral antidiabetic drugs. And protocols will need to stipulate that subjects will be withdrawn from the study if their glucose control consistently deteriorates.

The guideline endorses the current clinical practice of titrating a new oral antidiabetic agent until an optimal effect is seen, or until maximal tolerated or allowed dose is reached. But it stresses that the hypotheses on doses made at the early stages of development should be carefully tested, and the dossier should contain well-designed, dose-finding studies to justify the dosage used in confirmatory clinical trials and claimed in the Summary of Product Characteristics. Titration steps should in most cases last for at least four weeks unless a different duration is justified.

Study design should also aim to determine if there are demographic, genetic, metabolic (such as C-peptide or other measure of beta-cell function), or other factors that may predict response to a particular class of oral antidiabetic agents.

The guideline also says it is important to determine whether the pharmacokinetic behavior of the drug in elderly people is different from that in younger adults, particularly as related to hypoglycemia. A reasonable number of subjects over 65 years and possibly over 75 years should be included in therapeutic confirmatory studies, and specific efficacy and safety trials in this population may be needed. Type 2 diabetes might tend to become prevalent in obese adolescents, so trials in older adolescents are also recommended.

In respect of associated cardiovascular risk factors, any claim for improvement in lipids will require evidence of efficacy over and above the reversion to normal of hypertriglyceridemia that usually occurs with good glycemic control. Similarly, improvements in hyperglycemia related to weight loss in obese diabetics is certainly desirable and could potentially be a labeled indication, but will not be accepted as the sole basis for approval unless the glucose lowering effect of the antiobesity agent has a clear pharmacologic rationale, and is sustained and clinically relevant over and above that explained by effects on weight.

Positive effects on long-term macrovascular and microvascular complications can be evaluated properly only in large scale and long-term controlled clinical trials, which will be required only when specific claims are made or when there are suspicions of a detrimental effect of the tested drug. 


In the assessment of efficacy, the primary purpose of therapeutic confirmatory studies is usually to demonstrate an improvement in blood glucose control, the guideline states. Because glycohemoglobin (HbA

) is the most widely accepted measure of overall, long-term blood glucose control in type 1 and type 2 diabetes, and reduction of HbA

 is directly related to a reduced risk of development of vascular complications, it is an appropriate primary endpoint. The primary analysis of HbA

 should evaluate the difference in change from baseline HbA

 between the test compound and the active comparator/placebo. But as the goal of treatment is to reduce the risk of complications, not just to lower HbA

, a new agent could not be approved based on a reduction in HbA

 if there is evidence that the agent directly increased the risk of diabetic complications.

Changes in fasting plasma glucose is an acceptable secondary measure of outcome, and in some situations a reduction of postprandial glucose levels can be used as an endpoint. Future use of devices allowing continuous blood glucose management is also encouraged.

A reduction in insulinemia in subjects treated with oral hypoglycemic agents, or a reduction in insulin dose itself in insulin-treated type 2 diabetic subjects, is not considered a measure of efficacy unless accompanied by improvement in HbA

. But the elimination of the need for insulin entirely, or a reduction in insulin dose accompanied by a clinically significant improvement in the evolution of body weight, could be considered a measure of efficacy in insulin-treated subjects, provided that studies had appropriate controls.

Serum lipids (LDL and HDL cholesterol, triglycerides) levels should be documented regarding short and long-term effects, as available evidence supports benefit of reduction of LDL and increase in HDL. 

Body weight should be documented regarding short- and long-term effect. If a novel agent causes weight increase in association with a decrease in HbA

 it should be established that beneficial effect on HbA

 is maintained long term in spite of the weight increase, and the nature of the weight increase should be addressed.

The proposed mechanism of action should be described in relation to preclinical data obtained in animal models, because the mode of action of candidate antidiabetic drugs for type 2 diabetes may indicate in which type of subject the drug may be most recommended, and may suggest different approaches for combination therapy.

Although there are no specific requirements for pharmacodynamic testing of oral antidiabetic agents in humans, the mechanism of action of the drug should be evaluated in relation to drugs already available. When possible, the direct pharmacodynamic effect should be evaluated independently of the effect on blood glucose level.

It may not be assumed that the pharmacokinetic properties observed in healthy subjects will be the same in diabetics. Factors such as delayed gastric emptying due to autonomic neuropathy can be expected to complicate drug absorption and disposition in a significant number of type 2 diabetic patients.

In the clinical studies themselves, the subjects enrolled must be representative of the target population in terms of demography, co-morbidity, and severity of the disease; and groups should be sufficiently balanced with respect to age, gender, body weight, and severity and duration of disease.

Dose-ranging studies should thoroughly assess the lower end of the effective dose range, as well as the optimal dose. At least three dosages should be studied with a total therapy phase of at least eight weeks and usually up to three months.

Parallel group, randomized, double-blind, placebo and comparator-controlled studies are necessary for therapeutic confirmatory studies. Results of confirmatory dose-finding studies can also be supportive for the proof of efficacy. Therapeutic confirmatory trials should normally aim at demonstrating superiority over placebo (where appropriate) and noninferiority to an active comparator. Criteria for equivalence/noninferiority must be predefined and well discussed. In respect to the noninferiority design of the pivotal studies, the guideline notes that it has recently been confirmed that even an apparently small reduction in HbA

 is considered clinically relevant in terms of risk reduction of diabetic complications. It is therefore necessary to balance the degree of potential inferiority against some other clinical advantage such as safety, tolerability, or compliance. The applicant should demonstrate that this advantage can be equated to the loss of efficacy in some sense.

The overall duration of therapeutic, confirmatory, comparator-controlled, monotherapy studies should be no less than six months, including a maintenance period of at least 16 weeks. For oral antidiabetic agents with an original mechanism of action, a 12-month controlled overall duration may be required. For confirmatory studies, a run-in period (usually two weeks) is generally sufficient, during which the investigator must carry out baseline evaluation of subjects, including full clinical and laboratory assessment.

If the product is intended for use as an add-on therapy for subjects insufficiently controlled despite therapy with an established treatment, a study comparing the established agent as monotherapy against the combination of the new agent and the established agent is mandatory. Usually, a 16-week duration of the maintenance period is sufficient to demonstrate efficacy.

It is necessary to demonstrate a statistically significant and clinically relevant additional HbA

 reduction (or improvement in blood glucose control) and, optimally, improvement in responder rates with the combination in subjects who did not respond sufficiently to therapeutic doses of monotherapy. For combination with insulin, efficacy on glycemic control should be documented against placebo. For monotherapy, add-on therapy, and combination with insulin, continuation or extension of the studies to at least 12 months is desirable to assess the maintenance of efficacy and safety in the long term.


Blood, liver, and skin disorders should be carefully monitored and documented. Special efforts should be made to assess potential adverse events characteristic of the class of products being investigated, depending on the mechanism of action and pharmacodynamic properties. Add-on studies alone do not allow a definitive assessment of the safety of a new compound. However, it is necessary to show that any additional safety concerns do not outweigh the additional benefit of the combination.

The applicant should establish a definition for less severe episodes of hypoglycemia, including a set of symptoms and self-monitored blood glucose. A high level of specificity is needed to make claims, so the definition needs to be more rigorous than in clinical practice. A detailed analysis of hypoglycemic episodes noted in clinical trials should be provided (broken down by age and by diurnal distribution), and the severity of symptomatic episodes graded according to the need for external assistance.

Because cardiovascular disease is the main cause of morbidity and mortality in type 2 diabetes, any new product in this area must have well-documented data regarding effects on blood pressure, hyperlipidemia, and clinical indicators of cardiac function. The total clinical experience must generally include long-term safety data on a large and representative group of subjects. The applicant should justify the  duration of trials.


For insulin preparations with novel pharmacokinetic and pharmacodynamic properties, such as insulin analogues, long-term efficacy and safety data are essential. Clinical studies in type 1 diabetic children are mandatory, a reasonable number of geriatric patients should be included in the therapeutic confirmatory studies, and attention should be paid to hypoglycemia with long-acting insulin preparations in elderly subjects.

Due to the wide intra- and intersubject variability in the response to insulin in type 1 diabetes, pharmacodynamic data are of primary importance to demonstrate therapeutic equivalence or differences between insulin preparations, including their use in mixtures. For the pharmacokinetic evaluation of a new insulin or insulin analogue, the comparator drug should be an insulin or an analogue with a similar pharmacological profile. Comprehensive data should be provided on the insulin bioavailability based on peak insulin concentration and area under the insulin-time curves.


The draft guideline also contains a section on efficacy endpoints relating to the complications of diabetes, which the CPMP itself says should be considered with caution because experience of clinical development in this domain is limited, particularly with regard to neuropathy. Its starting point is that an antidiabetic agent or an agent acting independently of a hypoglycemic effect may seek to slow the progression of diabetic complications. Overall, a clearly documented and clinically significant change in the natural history of a diabetic complication would be considered as a primary measure of efficacy, says the guideline. It adds that unfortunately valid intermediate markers of most of the long term complications of diabetes which could be used in clinical trials are currently lacking. So before undertaking such studies, sponsors are invited to seek scientific advice from the CPMP.

Hard endpoints in terms of morbidity/mortality trials are still required for macrovascular disease. For retinopathy, endpoints based on the progression of diabetic retinopathy documented on well-validated grading scales are considered clinically meaningful. For nephropathy, hard endpoints are time for doubling plasma creatinine and the evolution to chronic renal failure defined as need for maintenance dialysis or transplantation or sustained increase in plasma creatinine to greater than 250 mol/L. As an intermediate endpoint, microalbuminuria is considered highly predictive of subsequent progression to manifest diabetic nephropathy and eventual chronic renal failure, especially in type l diabetes. Delay in onset of microalbuminuria, definite and sustained reduction of microalbuminuria, or delay of progression to microalbuminuria are relevant measures, but should be supported by long-term data (of at least 24 months) indicating a favorable evolution of glomerular filtration rate.

Send comments to the EMEA (fax +44 20 74 18 86 13) by January 2002.            

View from Brussels

The EU?s Committee for Proprietary Medicinal Products describes the process clinical investigations should follow.

EU Drafts Research Guidance for Diabetes Treatment

Making electronic CRFs friendly to both investigators and reviewers is a challenge.


In bygone days, when I was doing my PhD research, my advisor often reminded me that no experiment was complete until the results had been published or otherwise reported. There is no more important place for the reporting of results than in clinical development. No matter how good the data, a clinical trial must be written up and submitted to the FDA or other regulatory authorities to be considered in support of the approval of new drugs, biologics, or medical devices. 

A fundamental difference between the review processes for scientific publications and regulatory submissions significantly affects the management of primary data. In all scientific and clinical research, the researcher is expected to collect and retain the primary data from which all research results and conclusions are made. When a paper describing a scientific investigation is submitted to a journal, the reviewers of the paper typically examine derived data, summary tables, and analyses to determine whether the conclusions are justified from this data. Unless there is an investigation for impropriety, the primary data are typically never examined, and are assumed to be accurately reported.

In contrast, regulatory reviewers of clinical trial data dont make the same assumption. The stakes are too high. Tens of thousands of lives are in the balance, and a number of factors create the potential for fraud or unintentionally inaccurate reporting of clinical trial data. Like journal reviewers, regulatory reviewers also determine whether conclusions are justified by the data. Beyond this, however, regulatory reviewers need to be sure that the summary data are properly developed from the listed data, that the listed data accurately reflect the case report form (CRF) data, and finally, that the CRF data accurately represent the investigators observations. Often this is accomplished by field investigations and audits. However, regulatory reviewers usually want to see the actual data from cases that are critical to decision-makingdeaths, dropouts, unexpected serious adverse events, and others (depending on the indication and class of drug). CRFs from these subjects and others must accompany most New Drug Applications (NDAs) and Biologics License Applications (BLAs). In the past, all this happened only on paper. But a new paradigm is quickly emergingthat of the electronic submission of data from electronic clinical trials.


The FDA has worked with electronic submissions for more than a decade. In the early 1990s, the Computer-Assisted New Drug Application (CANDA) was seen as a way for FDA reviewers to have rapid access to report and data together, in a format that allowed efficient and high-quality analysis of data. Unfortunately, the CANDA era led to a proliferation of unique and proprietary formats for CANDAs, most of which required a stand-alone desktop computer on the desk of each regulatory reviewer. A whole variety of strategies for CANDAs emerged, from simple to complex. Each CANDA required a reviewer to learn a new system for accessing the data, a daunting task in many cases that few reviewers had time for. There were no standards for the structure of a CANDA and no common software platform or file format for the data. The results were mixedmany reviewers and sponsors were delighted with the efficient review that CANDAs provided, but others were unwilling to train on and use multiple different systems, sometimes simultaneously. The FDA soon called a halt to the unstructured CANDA era. But this was certainly not the end of the submission of electronic data.


In 1997, the FDA revealed the beginnings of a new method of electronic submission. The increasing volume of NDAs and the need for expedited review caused by the 1992 Prescription Drug User Fee Act (PDUFA) initiatives demanded that the FDA develop an approach for the efficient review of electronic data. The FDA was looking for a way to deal with the accumulating volumes of paper in its file rooms and the logistical problem of distributing sections of regulatory submissions to appropriate reviewers. By means of a series of guidance documents, the agency intended to carefully define the structure and technology that was acceptable for electronic submissions. In this way, starting with data listings and CRFs, the FDA could ensure a consistent set of electronic submission documents and reviewers could be comfortable that any electronically submitted data would be viewable in a familiar format.

Shortly after the first guidance documents were issued, electronic submission of NDA documents became an emerging standard for many pharmaceutical sponsors, eliminating the need for manual printing, duplication, pagination, and other processes. CRFs required for submission could easily be scanned into PDF form and submitted in the structure and style that the guidance suggests. However, the recent emergence of widespread electronic data capture, and specifically Internet clinical trials, adds a new twist to the task of electronic submissions.


At first glance, the paper CRF and the electronic CRF have much in common. Both typically consist of questions and answers through which subject data is collected and entered into a database. From here, their form and function rapidly diverge. The paper CRF usually has an audit trail that is visible directly on the CRFs. Changes to individual fields are indicated with a single-line cross out, with the changed data appended, along with the signature or initials of the person making the change, a date, and perhaps a reason for change. Comments are often written in the margin of these CRFs. Data clarification forms are appended to the CRF and contain the questions and responses that generated the change. This time-honored format creates a complete case record with audit trail that is familiar to regulatory reviewers and investigators.

An electronic CRF may appear somewhat similar to the paper CRF, but actually represents a view or report of a relational database. For example, the Internet electronic CRF assembles data from multiple tables into a single Web page, yet that page doesnt exist anywhere in electronic form except on the screen. In addition, audit trails and comments are not found in the margins of an electronic CRFthey are viewable through links from the CRF and also are simply user-friendly representations of data tables. Finally, the databases containing the electronic CRFs also contain metadatadata about the data. Metadata may include who entered the data, exactly when, and so on. These metadata can be used to understand and ensure the quality of the actual CRF data, and must be made available to demonstrate the attributability, legibility, contemporaneousness, originality, and accuracy of the data.


When electronic CRFs are submitted as part of an NDA, the unique attributes of the CRFs must be married to the CRF submission guidelines and philosophy of the FDA. Reviewers have conflicting needs when reviewing electronic CRFs. On the one hand, they would prefer that the submitted CRFs closely resemble the actual electronic CRF that the investigator saw when it was completed. It is easy to understand why this would be the case. Subtle differences in the design of a CRF can greatly influence the answers obtained. Optimally, the CRF should be displayed with the questions, controls (text boxes, radio buttons, pull-down lists, and so on), and answer choices that the investigator viewed. The questions must be assembled and displayed as the investigator viewed them. In addition, the audit trails, comments, electronic signatures, and possibly even data clarifications must be viewable along with the CRF itself.

On the other hand, the FDA does not want the CRFs to be overly complicated for the reviewer to navigate. With the experience of the CANDA era in mind, the FDA is trying to ensure that reviewers are not besieged with dozens of different electronic CRFs, each from a different electronic data capture system, that would require learning new navigation, icons, and functionality with each submission. Optimally, the electronic CRF should be as easy to navigate as paper for the regulatory reviewer. Important CRF items such as audit trails and comments must be viewable through obvious means, not through sophisticated functionality.

Another important consideration is that of printing the electronic CRFs. While some FDA reviewers may be comfortable reviewing electronically, many are more interested in printing the CRFs and audit trails and reviewing them off-line. This requirement creates special challenges for the design of an electronic submission of electronic CRFs. Many of the features of electronic CRFs work very well on the computer screen, but may be difficult or impossible to print while still maintaining their context. Anyone who has tried to print out a standard Web page understands that what you see is not necessarily what you get in your printout. In addition, the design decisions for electronic CRFs and paper CRFs may differ, so that a printout of a single subjects CRFs may be hundreds of pages. Somewhere along the line, the designer of an electronic CRF submission must decide whether to optimize the system for printing or for viewing on line. 

Have no doubt, electronic data capture and electronic submissions are here to stay. These systems promise to speed the review of clinical data, and to increase the quality and veracity of clinical trial data. As with most technology, the successful deployment of these advances requires careful consideration of the desired outcome and the needs of the people involved in the process. In the long run, the benefits will accrue to both the regulators and the regulated.            

Technology Viewpoint

The Evolution of Electronic Submissions

While Health and Human Services builds a comprehensive program to ensure the safety of human subjects, Congress weighs proposals to stiffen the rules.


When the Office for Human Research Protections shut down clinical studies at Johns Hopkins University in July, one objective was to send a strong message that OHRP will not tolerate lax oversight of human research by even the most eminent medical institution. Since it was established in June 2000, the Office for Human Research Protections in the Department of Health and Human Services has gained visibility for waving a big stick at noncompliant research organizations, while expanding the governments capacity for setting policy, monitoring studies, and educating all segments of the research community. OHRP director Greg Koski is leading the charge, working with other government agencies to build an aggressive oversight program. 

OHRP is working closely with the Food and Drug Administration, which has established an agency-wide office to coordinate oversight of clinical trials and ensure that studies provide unbiased and sound data to support market applications. FDAs good clinical practice staff (which may be renamed Office for Human Research Trials) in the Commissioners Office of Science Coordination and Communication now oversees FDA bioresearch monitoring programs, in coordination with the Office of Regulatory Affairs and individual product centers. David Lepay, senior advisor for clinical science, heads the GCP staff; he represents FDA in meetings with other federal agencies and at external policy forums. Stan Woollen has moved from the Division of Scientific Investigations (DSI) in the Center for Drug Evaluation and Research (CDER) to assist Lepay, prompting CDER to name Martin Cohen, medical officer in CDERs Division of Oncology, to head up DSI on an acting basis. Health issues analyst Bonnie Lee rounds out Lepays GCP staff. The group plans to revise FDA Information Sheets for investigators and Institutional Review Boards (IRBs) along with other policy initiatives.


Administration efforts to step up oversight of clinical research may be encouraged by action on Capitol Hill. In August, the House International Relations Committee approved a measure that aims to protect individuals participating in clinical trials overseas. If finalized, this amendment to the Export Administration Act could require pharmaceutical companies to obtain approval from a U.S. IRB and from federal regulators to sponsor clinical studies in developing nations.

Members of Congress also are weighing new legislation to expand federal oversight of human research studies and to impose penalties on noncompliant researchers. Representative Diana DeGette (Democrat, Colorado) leads efforts in the House to enact legislation to codify certain human research protections for both private and publicly funded studies. Senator Ted Kennedy (Democrat, Massachusetts), chairman of the Senate Health, Education, Labor and Pensions Committee, may go further and offer legislation to establish a central federal clinical research agency, as recommended by the National Bioethics Advisory Commission. Kennedy also supports giving FDA and NIH the authority to levy fines on researchers who violate the rules, as an alternative to shutting down research activities altogether. Academic research institutions and industry sponsors are leery of added mandates and penalties. But the research community may encourage Congress to signal its support for stronger research oversight by increasing funds for OHRP and FDA to expand educational efforts and boost inspections of clinical study sites and IRBs.


Other than funding initiatives, Congress may hold off making major changes in human research policy until the Institute of Medicine (IOM) completes a broad assessment of the nations system for overseeing human research. The same IOM panel (headed by Daniel Federman of the Harvard Medical School) that issued recommendations for accreditation standards for research organizations in April (View from Washington, June 2001) has launched this broader project, due to be completed in the fall of 2002. OHRP requested this IOM review. The panel held meetings in May and August, and another is planned for November. One objective is to identify ways to measure system effectiveness in order to establish models for improvement.

During the August session, the panel examined the role of private-sector organizations in protecting human research participants. David Lepay described FDA policies and procedures for regulating commercial clinical trials. Bert Spilker (senior vice president, Pharmaceutical Research and Manufacturers of America, or PhRMA) described the role of industry sponsors, and Helen Wyn Davies (senior vice president, Quintiles) explained how large contract research organizations (CROs) operate. Davies noted that too often examinations of the biomedical research system focus on federal agencies, research institutions, and investigatorsleaving out sponsors and CROs. Increased outsourcing of clinical trials, she explained, has transformed CROs from subject recruitment and support providers to full partners in drug development that are well positioned to ensure the safe treatment of study subjects and maintain quality research programs. 

Another group examining the research enterprise is the Human Subjects Research Subcommittee of the White House Office of Science Technology Policy. This government-wide panel chaired by Koski evaluates specific issuessuch as international research policiesas well as big-picture initiatives. For example, its SUEE task force on simplification, uniformity, efficiency, and effectiveness will meet in November to discuss ways to make government oversight more efficient. The subcommittee also plans to form a think tank to explore ways that a new, high-tech system could be designed to capture information in real time and prevent harm to research subjects.

And moving onto the stage is the White House Council on Bioethics, which President Bush announced in August as part of his program to permit limited government funding for stem cell research. The new panel will monitor studies of embryonic stem cells while also addressing broader biomedical issues. It may replace the National Bioethics Advisory Commission, which was scheduled to go out of business in October 2001. Bush raised some eyebrows by naming University of Chicago bioethicist Leon Kass to chair the council. Kass opposes cloning human embryos to derive stem cells, but supports adult stem cell research and is considered fair-minded and well-versed in the issues. 


Meanwhile, Congresss General Accounting Office is assessing how well government agencies have improved research oversight since the death of Jesse Gelsinger, the first recorded gene therapy fatality, in fall 1999. These issues were discussed at the July meeting of the National Human Research Protections Advisory Committee, which advises Health and Human Services (HHS) and OHRP on specific policies. Participants at the meeting outlined a number of initiatives by OHRP, FDA, and the research community to address public concerns.

 OHRP and FDA have launched an online program to register all IRBs in order to facilitate oversight and enhance communication with IRB officials. All organizations that receive government research funding will have to register an IRB. FDA is developing a rule that would require registration of all IRBs regulated by the agency and hopes to issue it by year-end. In addition, an NIH Regulatory Burden Working Group is studying IRB operations to better assess resource needs.

 To improve the review and monitoring of multicenter trials, academic institutions and PhRMA are promoting increased reliance on accredited central IRBs. These bodies will demonstrate expertise in overseeing complex research studies and compliance with good IRB practices, which are being developed by a joint government/private-sector panel. FDA and OHRP would encourage this system by instructing all IRBs that an expedited review will suffice for a component of a multicenter trial that has been approved by an accredited IRB. 

 To help IRBs oversee ongoing studies, OHRP and FDA are encouraging research institutions and sponsors to make greater use of data and safety monitoring boards (DSMBs) to monitor research and evaluate adverse event reports. NIH has issued guidance supporting DSMB review of adverse events for certain multisite and high-risk studies, and FDA is developing additional guidance on DSMB use. 

Separately, the Center for Biologics Evaluation and Research (CBER), which is responsible for regulating gene therapy research studies, is weighing new policies to improve clinical trials monitoring. CBER has formed a working group to evaluate the need for earlier agency review of sponsor monitoring plans to make sponsor oversight requirements clearer and more specific.

 HHS has issued a draft interim guidance on financial relationships involving investigators and institutions, largely to help IRBs and researchers evaluate proposals and programs. Academic institutions have complained that the agency is going too far in micromanaging research arrangements, and HHS is reviewing these comments.

Promote accreditation. HHS is pilot testing accreditation programs by nongovernmental organizations, as recommended by the IOM April report mentioned above. This initiative should be spurred by the August release of final accreditation standards by the Department of Veterans Affairs and the National Committee for Quality Assurance for VA-sponsored research. 

 HHS now requires investigators applying for NIH grants to meet educational requirements on human subject protections. A national educational summit in August recommended forming a national council to promote educational efforts.

 A main goal for OHRP is to reshape informed consent from a system that documents subject consent to one that promotes understanding of the research process as a prelude to voluntary participation. NIH is conducting studies on how well individuals can understand risks and benefits in research, and FDA is reviewing these issues.

Enhance adverse event reporting. HHS and FDA are working to reduce differences between their AE reporting requirements to make it easier for investigators to understand and comply with the rules. 


To carry out these multiple assignments, Koski has organized OHRPs staff into units that reflect the agencys roles and responsibilities.Education. This division, headed by Jeffrey Cohen, provides training programs for professional societies, IRBs, and other government agencies on research policies and ethics. It co-sponsors workshops for investigators with organizations such as PRIM&R, and plans a series of town meetings to explain research practices and policies to the public.

 An important OHRP initiative under George Gasparis is streamlining the process for NIH grantee institutions to provide the required assurance that they will comply with research regulations. The online assurance system has approved about 800 federal-wide assurances, with 3000 expected in the long run. This division also is testing a quality self-assessment tool for human research protection programs that could lead to a site visit by the agency. OHRP aims to conduct 60 quality improvement interactions with research organizations each month, reaching all 125 accredited medical schools in the coming year. 

 Kristina Borror leads OHRPs Division of Compliance, which investigates research institutions, primarily after receiving a complaint or learning of a potential problem. In addition, the agency is beginning to conduct not-for-cause site visits, which eventually will mesh with a voluntary accreditation program. A goal for Koski is to shift the perception of compliance from an administrative burden to an opportunity to learn about policies and how to fulfill responsibilities appropriately. 

 With human research increasingly global in scope, OHRP has established a small international affairs office headed by Melody Lin. OHRP is playing a lead role in developing federal policies related to the conduct of clinical trials overseas, including non-biomedical research. 

 OHRPs policy office under Irene Stith-Coleman helps to assess and develop proposals related to a broad range of research issues, such as studies involving prisoners and children.

Koski acknowledges that OHRP cannot regulate some 5000 IRBs and hundreds of research organizations with a staff of fewer than 50 people. He regards the oversight of biomedical research as a distributed system with many key players, including Congress, the White House, and other federal agencies, along with public and private research organizations. The goal is a network of outstanding research organizations that use quality improvement tools to meet voluntary accreditation standards that ensure compliance with educational and oversight requirements.            

View from Washington

Human Research Oversight Expands

Using electronic data capture (EDC) for your clinical trials creates a few more things to consider than when planning a paper-based project timeline. Perhaps youve used this type of data collection system in the past and you have the lowdown on the who, what, when, and wherebut, just in case you dont, here are some tips on making this new method work for you.

Managers of clinical studies know the basics of project planning: finalized protocol and case report forms (CRFs), selected sites, completed and approved regulatory documents, completed project timelines with all the assorted sundries that can ensure the success of our projects. And, if were lucky, well have all the grants approved and contracts signed.But, with the EDC component, what else do you need to consider? EDC isnt quite as easy as stopping by the cybercaf, logging on, and sending an e-mail (although it seems that it should be, particularly when you can instantly send text messages to anyone around the world). Why is sending clinical data as bits and bytes over the Internet so different? Why cant we just plug and play? 

For starters, youll need to assist in the writing and approval of the various EDC components that will be integrated into your project plan. For example, the EDC vendor may have a form called a Systems Requirements Specification (SRS)a document that contains information about the study and the way the electronic case report forms look and interact with one another. These requirements will be tested by the developers, sent to formal testing, and then to you for user acceptance testing. 

My first thought when I get any new project is, How can I make my project life as uneventful and stress-free as possible? I try to figure out all of the things I can control, because you and I both know that even with all the planning, it seems that Murphys Law will prevailanything that can go wrong will go wrong. So incorporating project planning that includes EDC timelines and other components that affect the operations will make for a more successful project.

 One of the beginning steps is for the EDC vendor to supply you with its Installation Qualification/Operations Qualification document, referred to as their IQ/OQ. This important document states the hardware requirements a computer must fulfill to run the software successfully. If the sites cant meet the minimum requirements, they will be unable to use the EDC software. This is no way to start a project. (Trite as this may sound, the success of this enterprise begins at the site. The use of EDC is in a transitional stage.) The newer generation of clinical professionals wont be as tied to paper processes as their predecessors, because of their experience with computers, personal digital assistants (PDAs), and various types of wireless communication. Right now, however, many of the participants in the electronic revolution are not necessarily volunteers, so the people using this technology may not be embracing it so much as tolerating it. To minimize frustration at the site, a site assessment is crucial.

 For the site assessment, we have to look at the small and what may seem to be obvious details. 

	Do the investigators and study coordinators understand how to use a computer? 

	Does it have Internet-dedicated phone lines or do they have to share lines?

Gleaning the answers to these questions can pay off in many ways. For example, youll know which sites may need additional assistance in using the EDC software. Knowing this can help you plan appropriately. You may be able to set up sites in groups to assist with basic computer support. 

If the site has information technology (IT) support, youll want to meet with the support person to discuss the software to be used to collect clinical trial data. Get tech support persons involved up front. They can make your life easyor they can make it difficult. Youll need them to resolve firewall issues, for example, and to let you know when/if they are going to add or delete software and/or upgrade the computer to the latest and greatest standard mandated by the hospital, university, or clinic. When an upset person from a site calls you about not being able to get into the system or to say its not working right, having a technician in the know at the site can go a long way toward alleviating problems. These are small things that you can do up front to prevent headaches later on down the line. Some of you know what Im talking aboutyou have lived on the new frontier of data capture!

 Once you ascertain some of the basics, check to see whether the vendor knows of any incompatibilities with other software programs that may affect the use of their EDC application. It is similar to learning about drug reactions. If you know that a particular drug has a known reaction to another drug, you have choices: You can choose to avoid the drug or to take it because you know the benefit of taking the drug outweighs the risks of the reaction caused by combining the two drugs. 

Similarly, to avoid serious adverse reactions to EDC, you will want to know up front of any potential risks so that you can weigh them against the benefits. Note of caution: You may find that additional compatibility issues arise once EDC is rolled out to your sites. That situation is similar to the moment when we say, Oh [expletive deleted], I didnt think of that about a project for which we were certain that every contingency was anticipated. A similar event can occur when hundreds of thousands of people are taking an approved drug. With so many individual variables involved, a new problem can be uncovered. So it can be with EDC. 

Quite frankly, I think the site is one of the most important areas on which to concentrate.

	What types of experiences have they had using new tools to capture data electronically?

One thing I find useful when planning a site evaluation visit is to take a demo version of the product to show the site. That way you can have a hands-on session early in the process. Another area to consider is whether they are willing and eager to accept change. If not, you may have a problem. If you thought your life was miserable calling the sites and badgering them about recruitment, just wait until you add the machine to the mix. 

 During project planning, in tandem with the EDC vendor, youll be planning the actual creation of the electronic case report forms (eCRFs) to capture the data electronically. What this does for us is get the edit checks and database set up, prior to study rollout and first subject in. The effect of building the eCRFs early in the study is that database setup is part of the process. As the electronic data elements are defined and added to forms, the database setup is expedited because defining the forms also defines the database. Once the electronic study goes live, by definition, the database must be up and ready to start receiving data.

One of the many beauties of EDC is that the database and edits are built up front. The CRFs will be in an electronic format that will have edit checks programmed in, with annotations if so desired. So when data comes in, you know that the first pass of data cleaning has been done with the automated edit checks. The CRA and data manager can write queries, the applications audit trails record all the changes to all of the data fields, and preliminary reports can be run. When I was a project manager, that was the one area that I could let slide. It is important, but when push came to shove (and it often did), edit checks and databases could be built once the sites were up and enrolling. Even though we knew we would find ourselves in a data crunch, it always seemed we were willing to take our beating later. Those data safety monitoring meetings seemed so far in the future! 

 When you plan your project, it is imperative to plan time for EDC. This means that you and the software developers will work closely to complete several stages of the project. You will define the project. They, in turn, will prepare their project plans with deliverables for both sides. They will work with you to define the initial study requirement specification (SRS), the functional requirements, edit checks with the visit-screen structure, and other information regarding issues such as back-up and recovery. The development of an SRS may take a week or two depending on the type and complexity of the study. The software vendor needs to have final copies of CRFs to build the study accurately.

I cant stress enough the need to pay attention to the SRS document. You must spend time with this document, and make sure it is complete and accurate. Otherwise, a visit to Heartbreak Hotel is in your future. 

First, the software company may have policies that prevent them from beginning work on the trial software until they have an approved and signed SRS. Their time to complete this stage of the project begins then, not before. So when they tell you, It will take approximately six weeks, they usually mean six weeks from the date they have a signed document from you. Once they build the study application, then they do unit testing. This is a first pass to make sure that everything is working as designed. They then send it to their formal testing team where it goes through more rigorous testing to ensure that every requirement in the SRS is exercised and functions as designed.

Once it passes formal testing it is sent to you and your team for user acceptance. If you and your team accept the application, wonderful; its time to start rolling it out and entering data. If not, it is sent back to the developers to fix whatever your team deems necessary. The developers make the changes and send it back to testing. Again, the testers do the formal testing, then send it back to your group for user acceptance. The cycle goes on until the application is completed to the users satisfaction. (A note of caution: If, during development, a specific investigator requests an additional case report with lab data, that request constitutes a change to the originally signed SRS, and it will probably be considered out of scope. The predictable result is an increase in your study budget and a rollout delay.)

You will have the opportunity to review and accept the SRS. Its a good idea to have biweekly meetings and status reports to make sure that everyone is on the right path. Remember that EDC vendors have expertise in design but not necessarily in the nuances of a clinical trial. I have never seen an SRS redone a million times over, but I have seen one go several rounds. This can be attributed to several factors, but the bottom line is this: If you dont understand something, ask. If you change your mind or want something changed, it isnt a one-step process. Communicate with the EDC vendor. Plan appropriately to incorporate the time to define, build the study application, test, and approve it. Once the software is accepted, it is time to plan for site rollout. This can be accomplished many ways depending on the software you have purchased. Is it Web-only or is it an online/offline system? The vendor will either push it out to the sites or ship CDs to the sites for installation. 

The location and number of sites will determine how quickly this task is completed. Once this is accomplished the sites can start to enter the data. Edit checks will pop up, the site will answer them, and CRAs will post queries as often as they need to. They can see the data in real time, and you are on easy street. Youre getting the data, the reports are being viewed, and everyone is wondering why it has taken usor is taking usso long to adopt EDC.

 I know you have difficult jobs; Ive been there. We have to decide what must be done to start a project on time, and what must wait. Working with the hardware and software of the technology world, techies sometimes forget that clinical professionals dont work with widgets, they work with people. It sometimes amuses meand is sometimes downright frustratingwhen technologists think that they can line em up and knock em down and wonder why cant we do the same. 

But we work with people and institutions; we need to take in all aspects of human behavior to do our jobs. When I get frustrated, Id love to just turn off my machine, put it in sleep mode, or go dark. But we cant do that with subjects. We have to continuously work through the problemswhether they involve site recruitment or the nuances of this new tool, EDC. 

With the right planning, education, and training we will all be able to have a positive impact upon our studies. EDC is a wonderful tool, but it is up to us to work with the vendor and plan our project timeline appropriatelynot just at the beginning but through every stage of the project life cycle.

is vice president of Global Client Services, CB Technologies, Inc., 350 Eagleview Blvd., Exton, PA, (610) 280-7400, fax (610) 280-0440, e-mail: d_hellsten@cbtech.com. Christopher Dell is marketing support manager for CB Technologies, and Karla Beckner White, who also contributed to this article, is associate manager, public relations.

*To whom correspondence should be addressed.

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