Although spending on biomedical research is at an all-time high, fewer new drugs are coming to market. Industry leaders and officials at the Food and Drug Administration are examining procedures and seeking ways to encourage drug development, as seen in numerous FDA initiatives announced in the past year. The over-arching goal is to speed access for all Americans to safe and affordable new medicines, according to a January 2004 FDA white paper on Protecting and Advancing Consumer Health and Safety. 

A sign of the problem is FDAs fairly thin pipeline of new drugs under develop-ment and in line for market approval. Last year FDA approved only 21 new molec-ular entities (NMEs), up from a lowly 17 in 2002, but still far below early 1990 rates when the agency cleared about 30 NMEs each year.

 Similarly, the number of commercial INDs (investigational new drug applications) filed with the agency has hovered around 425 for the last four years, well below the high of 498 INDs submitted in 1998. Prospects are low for a big surge in new approvals this year, as the cadre of medical products in late-stage clinical trials remains steady, similar to the number of applications for NMEs filed in recent months.

With the FDA application approval process already up to full speed, FDA commissioner Mark McClellan aims to accelerate product development by clarifying clinical research requirements and reducing unnecessary burdens on researchers. An FDA goal is to limit excessive paperwork that goes beyond regulatory requirements, according to David Lepay, senior advisor on clinical science in FDAs Office of Science and Health Coordination. Sponsors and investigators often raise questions about the value of certain procedures, and FDA seeks to respond to these concerns, Lepay explained at the December 2003 annual conference on IRBs (institutional review boards) sponsored by PRIM&R (Public Responsibility in Medicine and Research). 

One objective is to minimize differences in rules for obtaining informed consent and for reporting adverse events among FDA and other agencies in the Department of Health and Human Services (HHS). Lepay is working closely with Bernard Schwetz, acting director of HHS Office for Human Research Protections (OHRP), to establish common policies for reducing conflicts of interest, registering IRBs, and overseeing pediatric and international studies. OHRP and FDA are gaining assistance in evaluating these issues from the Secretarys Advisory Committee on Human Research Protections (SACHRP), which has mapped an agenda for its first full year in business (see sidebar). Clinical research policies and programs slated for re-examination and clarification this year cover a number of areas key to clinical trial management:


In November 2003, FDA announced plans for electronic submission of INDs for cancer therapies in collaboration with the National Cancer Institute. The policy aims to test e-filing procedures to set the stage for electronic submission of all INDs in the future. As part of its campaign to shift from paper to e-submissions, FDA also plans to require sponsors to electronically file clinical data that supports NDAs, biological license applications, supplements, and generic drug applications. These e-submissions would use standard data structure, terminology, and code sets to make it easier for FDA staff to process, review, and archive information from clinical studies. Instead of paging through patient medical files whenever new questions arise, FDA reviewers will be able run data searches large volumes of patient information.


A top priority for FDA, OHRP, and the National Institutes of Health (NIH) is to harmonize policies for defining which adverse events in clinical studies should be reported to whom and when. These issues were discussed at the December 2003 SACHRP meeting, with a focus on how the task of reviewing reams of adverse event reports is overburdening IRBs. Efforts to more clearly identify those critical adverse events that warrant further IRB review aim to both halt the adverse-event reporting flood and also improve compliance among investigators and sponsors.

In a related area, FDA is working to finalize a November 2001 draft guidance on the establishment and operation of Data Monitoring Committees (DMCs). The initiative reflects increased use of DMCs in industry-sponsored trials, in addition to NIH-funded studies that involve severely ill patients. The main purpose of DMCs is to determine if a trial should be stopped earlyeither because efficacy data is so strong that treatment should be provided to more patients sooner, or because adverse events indicate clear safety problems. The guidance aims to clarify how these committees should monitor study data during trials in order to provide an objective, confidential assessment of interim results. Using DMCs increases the complexity and cost of trials, however, and sponsors are wary that FDA may require DMC oversight too broadly.


FDA seeks to clarify its policy for accepting data from foreign clinical studies not conducted under an IND. The proposal would clarify that such studies must be conducted in according with good clinical practices. This includes review and approval by an independent ethics committee, in line with standards adopted by the International Conference on Harmonization (ICH). 


 A new FDA proposal would require sponsors to promptly report any information indicating that any person may have falsified data related to designing, recording, supervising, reviewing or reporting research results. 


	A prime goal for FDA and OHRP is to address concerns about the roles and responsibilities of overburdened review boards. OHRP seeks to define more clearly what research institutions should do to ensure that IRB officials and other personnel who oversee clinical studies receive appropriate training and education about human subject protection requirements. At the PRIM&R conference, Schwetz commented on the need to clearly define the role of IRBs in order to improve the biomedical research enterprise. He noted a wide diversity in how IRBs do business, and that this has an impact on protocol reviews. 

A prime initiative of FDA and OHRP is to require all IRBs to register with HHS in order to facilitate government communication with these panels. FDAs proposal calls for IRBs to provide information on institutional affiliation, key personnel, and type and volume of FDA-regulated products under review. Registration also will help FDA identify those IRBs that warrant on-site inspection. 

Along theses lines, FDA is evaluating the effectiveness of its program for inspecting about 300 IRBs each year to ensure compliance with agency regulations. Most site visits examine processes more than specific studies, but a few are for cause inspections, resulting from past problems or complaints. Inspections target new IRBs and highly active boards involved with numerous FDA-regulated studies.


Increased pressure from patient advocates is prompting FDA to clarify policies affecting how patients with serious and life-threatening conditions may obtain early access to therapies still being tested. In January, the agency issued a draft guidance that calls for sponsors to provide information about early access policies through the agencys Clinical Trials Data Bank. A related new rule would describe how patients may obtain investigational drugs for treatment use, particularly in emergency situations and through treatment protocols.

FDA also is developing a proposed rule to clarify when and how sponsors may charge patients for experimental drugs. The policy will describe the types of investigational uses for which a sponsor may charge, which costs may be recovered, and criteria for permitting such charging practices.

1: www.fda.gov/bbs/topics/NEWS/2004/NEW01005.html.


After taking more than a year to get organized, the Secretarys Advisory Committee for Human Research Protections has identified several specific topics where it hopes to have an impact. At its inaugural meeting in July (2003), the committee established three subcommittees on key issues:

 Significant expansion in clinical studies involving children is prompting SACHRP to continue previous examinations of procedures for overseeing pediatric research proposals that involve more than minimal risk or that fail to directly benefit the participant. The panel has called on OHRP to provide guidelines for IRBs evaluating such research protocols in order to identify those studies that warrant further HHS review. Approaches for reviewing high-risk studies involving children are under review at FDA in an effort to seek harmony between FDA and HHS regulatory procedures.

 The panel is reviewing a 1978 policy to reflect increased demand from prisoners to participate in clinical studies. The subcommittee may call for major changes in HHS policies to more clearly define which incarcerated individuals and which studies fall under the rules plus prisoners rights to follow-up care. A confusing issue for IRBs and sponsors is how to deal with participants who become incarcerated after entering a clinical study.

 This subcommittee is examining the potential impact of these programs, what incentives spur research institutions to seek accreditation, and the need to certify accreditation organizations themselves. The panel generally supports accreditation and is weighing the benefits of  accreditation standards and accreditation of IRBs.  

SACHRP also plans to discuss the effect of new privacy rules on clinical research operations, namely participant recruitment practices and access to databases and tissue repositories. Additional topics on the agenda include the impact of litigation on clinical research and the role of central IRBs in overseeing large studies. SACHRP plans to establish a new subcommittee on adverse event reporting when the accreditation panel completes its work.

Articles

View from Washington

Policymakers want to harmonize for safety reporting, IRB operations, patient access, and other areas to spur product development.

FDA, HHS Seek to Clarify Research Policies

ACT Editorial Advisory Board members are experts in their field who volunteer to review and comment on manuscripts being considered for publication. EAB members also provide valuable feedback on special programs and projects as well as keep our editorial staff current on the state of the industry.  ACT would like to welcome two new members to our Editorial Advisory Board, Scott Grisanti and Uwe Gudat, as well as introduce them to our readers.	

 serves as Senior Vice President, Business Development and Chief Marketing Officer for eResearchTechnology (eRT), which provides technology and services to optimize the digital collection, management, analysis, and distribution of cardiac safety and clinical data throughout the new drug development process.  In this capacity, Scott is responsible for managing eRT's global sales, marketing, and alliance activities. He has worked extensively with sponsors in the pharmaceutical, biotechnology, and medical device segments, along with CROs and government organizations, to help enhance and accelerate key clinical development processes and ensure effective compliance with emerging regulatory imperatives. Scott has published articles in numerous trade journals and has served as a speaker at industry events. He joined eRT from ClearCross, Inc., where he served as Area Vice President of Sales. Prior to ClearCross, he was Director of Sales for Metasys, Inc., Director of Workflow and COLD Business Development for Computron Software, and Director of UNIX Product Marketing for Information Builders, Inc. Scott graduated Rutgers University, where he was elected to Phi Beta Kappa and named a Rutgers Scholar.		

Scott Grisanti, eResearchTechnology (eRT).	

, MD, received his medical degree from the Philipps University in Marburg, Germany. He then moved on to the University of Dusseldorf, Germany, where he trained in internal medicine and diabetology, in the Department of Metabolism and Nutrition, a WHO collaborating center for diabetes. During this time he conducted research on the effects of exercise on metabolic control in patients with diabetes and practical aspects of health care delivery for diabetic patients. In 1995 Uwe joined the pharmaceutical industry at Eli Lilly & Company in Bad Homburg, Germany, where he was instrumental in Phase III and IV development of Insulin lispro and its fixed mixtures. In 1999 he moved to Switzerland, to take up a position as medical director of the CRO Hesperion in Basel. In 2001, he founded Aretaeus, a consultancy firm providing expertise and services for clinical development in the field of diabetes and related metabolic disorders. One year ago, Uwe joined Novartis Pharmaceuticals, where he is currently a clinical project leader. He has published research papers, reviews, and book chapters in the field of diabetes, and has been a regular contributor to the ACT European Summit conferences.		

Meet the EAB

ACT Editorial Advisory Board members are experts in their field who volunteer to review and comment on manuscripts being considered for publication. EAB members also provide valuable feedback on special programs and projects as well as keep our editorial staff current on the state of the industry. ACT would like to welcome two new members to our Editorial Advisory Board, Scott Grisanti and Uwe Gudat, as well as introduce them to our readers.

Meet the EAB 2004

Subject safety in clinical trials has received much recent media attention, most publicly because of the death of a young man during a gene therapy study at the University of Pennsylvania.

 Some large and important clinical trials have been halted before their planned conclusions for safety and other concerns (for example, the Women's Health Initiative).

Data monitoring committees (DMCs, sometimes called data and safety monitoring boards or DSMBs) have played an important role in providing oversight to critical clinical trials. A DMC is an independent group of experts who monitor unblinded safety and efficacy data while a trial is ongoing. They can recommend making changes to the conduct of the trial, including recommending to terminate the trial early for safety concerns, for overwhelming treatment efficacy, or for demonstrated futility in being able to show a benefit of treatment. In November 2001, the U.S. Food and Drug Administration (FDA) published draft guidance on DMCs

 explaining their need and how they should be integrated with clinical investigations. An extremely useful text by Ellenberg, Fleming, and DeMets covers many of the topics in this article.

Not all clinical trials need a DMC. The draft guidance published by the FDA

 provides some insight in deciding if a DMC is needed for a trial:				

DMCs have generally been established for large, randomized multisite studies that evaluate interventions intended to prolong life or reduce risk of a major adverse health outcome such as a cardiovascular event or recurrence of cancer. Because monitoring of accumulating results is almost always essential in such trials, DMCs should be established for controlled trials with mortality or major morbidity as a primary or secondary endpoint. They may also be helpful in settings where trial participants may be at elevated risk of such outcomes even if the study intervention addresses lesser outcomes such as relief of symptoms.

DMCs can also prove useful in clinical trials where mortality or major morbidity is not the primary endpoint. Figure 1 provides a diagram to help determine when a DMC is appropriate.

Figure 1. When a DMC is needed. (Adapted from Ellenberg et al., [4], p. 160.) 			

The DMC is in the unusual position of being able to review unblinded study data while the trial is ongoing. Using prespecified monitoring guidelines, the DMC might, based on the data it sees, recommend stopping a study early. In general, there are three scenarios under which a DMC might recommend stopping a trial:	

The data sufficiently demonstrates efficacy at such a high level of significance that it is very unlikely that if the trial were to continue the results would change

There is a safety concern important enough to warrant changing or stopping the study

There is sufficient data to indicate that even if the trial were to continue to its conclusion, it is extremely unlikely that the new treatment would show a statistically significant benefit (so-called futility curtailment or stopping for lack of efficacy).

Stopping a trial for futility can save subjects from unnecessary risk and can represent a substantial savings of the sponsor's money and time that would otherwise have been spent completing a trial highly unlikely to produce a positive result.	

A DMC will always monitor for subject safety; however, the monitoring boundaries for overwhelming benefit or demonstrated futility must be specified to the DMC in advance, and are at the ultimate discretion of the sponsor with input from the DMC as well as the FDA or other regulatory agencies. Choosing appropriate monitoring boundaries is an important strategic decision for the sponsor. Furthermore, regulatory agencies should be informed about the use and responsibilities of the DMC and of the monitoring boundaries to be used.	

As the DMC monitors for safety, it takes into account all available information. This might include, for example, the results from toxicology studies, or results from other clinical trials using the same class of drug. The DMC will need to carefully assess the risk-benefit balance. Because there are no set rules or guidelines for making decisions and recommendations regarding safety, this is an area where the expertise and judgment of the DMC members is critical. 	

The timing of DMC meetings is typically based on the number of patients with endpoint data; calendar time may also be a factor. DMC meetings might be convened based on some threshold, for example occurrence of more than one Serious Adverse Event, or more than two for a cancer trial since some level of side effects is tolerable. Again, the specifics of the disease and the treatment need to be weighed in setting up such guidelines.	

The role of the DMC is advisory to the sponsor and study leadership. The sponsor (and possibly the study leadership) has ultimate responsibility for making decisions regarding the trial. As a trial is organized, it is important to consider to whom the DMC will report their recommendations. In many cases, a steering committee led by the sponsor is responsible for the conduct of the trial. Because the DMC may recommend major changes in the study, someone on the steering committee needs to have the authority to accept and implement the DMC recommendations.  	

Interim monitoring boundaries provide guidance to the DMC by defining the threshold beyond which the DMC might recommend stopping or altering a trial. They must be designed and agreed upon prior to the first "look" at the data. It is a nontrivial statistical task to design these boundaries, given that the DMC will review the data multiple times over the course of the study.                       				

With repeated looks at the data, the observed p-values at each look cannot be compared using traditional measures of statistical significance (say, p < 0.05 or 0.01). The more often one looks at the data, the more likely one is to see a significant p-value totally by chance. Therefore, a higher level of statistical significance (smaller p-value) is needed earlier in the trial. An example of a possible boundary is shown in Figure 2. The "Normalized Z-Score" is a measure of the benefit or lack of benefit of the new treatment compared to the old (either placebo or standard) treatment. A larger Z-score indicates greater benefit, and a smaller (or negative) Z-score indicates lack of benefit or even harm. Thus, a Z-score of zero indicates neither benefit nor harm from the new therapy. If the observed Z-score crosses the top boundary of the "funnel" shown in Figure 2, then the DMC could recommend termination for overwhelming benefit. If the observed Z-score crosses the bottom boundary of the "funnel," then the DMC could recommend termination for demonstrated futility or lack of benefit.		

This example presumes that the maximum enrollment would be 1,200 participants and that the DMC will meet after every 200 participants to review data.  	

These boundaries can be modified to fit the desires of the sponsor, DMC, and regulatory agencies. The shape of the boundary determines how conservative the DMC will be in making its recommendations. For example, a sponsor may be pursuing multiple indications for a single agent. One indication will, potentially, have a larger market than another. The sponsor may design the boundaries for the less marketable indication so that it is more likely that the study would be stopped for lack of benefit (to cut losses sooner). Alternatively, the sponsor may want to collect as much data as possible.  In this case, the sponsor would only want to stop the trial in the case of demonstrated harm to subjects, but would otherwise continue even in the presence of results that are highly positive or that have little chance of a final positive result.	

The particular sample boundary shown in Figure 2 is an Emerson-Fleming symmetric boundary.

 An interesting feature of this particular boundary is that at the halfway point of 600 participants, a Z-score of zero or lower (no observed difference or a negative trend) would trigger a DMC recommendation to halt for demonstrated futility. If the trial went all the way to the end (n = 1200), the critical Z-score for statistical significance would be 2.02. This Z-score corresponds to a one-sided p-value of 0.022, very close to a traditional one-sided p-value of 0.025. This slightly higher hurdle at the end of the trial is indicative of the relatively small statistical price paid for the advantage of potentially stopping the trial with fewer participants.		

Figure 3. Sample boundary with observed interim results.	

The statistics allow considerable flexibility in scheduling when the DMC will look at the results. For example, if the first scheduled analysis was after 200 subjects had been enrolled, but there was a safety concern that prompted the next analysis at 300 instead of 400 subjects, the boundaries could be adjusted to take this into account.	

Figure 3 depicts a hypothetical trial with hypothetical results. At the first look (n = 200) there is basically no difference in the two treatments. Results look promising at the next two looks (n = 400 and 600), and at the fourth look (n = 800) the results have crossed the threshold for overwhelming benefit. Assuming there were no other issues that the DMC was concerned about (e.g., side effects that warranted additional monitoring), the DMC would issue a recommendation to terminate the trial early for benefit.	

A DMC is composed of independent experts who each bring separate knowledge to the group. The number of members can range from three to ten, with three to five being typical. A more complex study may require a greater number of DMC members. At least one DMC member will be a statistician and one will be the DMC chair. Clinicians knowledgeable about the disease indication should be represented, as well as clinicians knowledgeable in the fields of any major suspected safety effects (e.g., nephrology and cardiology). A few long, visible trials may include an ethicist or even a representative from a patient advocacy group.			

Table 1. Sample DMC charter table of contents*				

Locating potential members can be difficult. This is especially true in regards to identifying a DMC statistician. There are a relatively small number of statisticians experienced in looking at clinical trial data with the particular skill required to interpret early results of the trial.  	

DMC members are generally independent consultants to the sponsor. Their compensation should be fair, but not so excessive as to make an outside observer think that the DMC members may be unduly swayed to consider the sponsor interests over those of the subjects.	

A DMC charter is a required3 document that defines the standard operating procedures of the DMC and the roles and responsibilities of all the involved parties. Some studies separate the DMC charter from the standard operating procedures for the DMC; others combine these two documents. A sample table of contents is given in Table 1.	

Some publications have recommended using an "independent statistical center."

 This group receives data from the sponsor and the contract research organizations (CROs), as well as the randomization codes from the agency responsible for handling the central randomization or creating the master randomization list.	

The independent statistical center is key to the DMC's functionality for a number of reasons. First, it ensures that the statistical report the DMC reviews can be created with the sponsor and the CROs remaining blinded to any treatment effect. By remaining blinded, the sponsor can alter the protocol or type of data being collected without suspicion that these changes were influenced by unblinded results. For example, if the sponsor were unblinded to the trial results, it would be unethical for them to make adjustments to the sample size if the expected difference between treatment arms was not as great as expected. Second, an independent statistical center can facilitate the logistics of the DMC that could unblind the sponsor, such as creating minutes of DMC deliberations or creating tables for the DMC.  	

The programming for the DMC report can be done by the sponsor using "dummy" randomization codes and then turned over to the independent statistical center to be merged with the actual codes. Alternatively, the programming can be contracted to the independent statistical center.	

The first meeting of the DMC will likely be organizational. While no data will be presented, the DMC will review and approve its charter. The sponsor can use this as an opportunity to explain the protocol to the DMC in some depth and also to give background on results from other related trials, for example detailing expected side effects of the treatment. The sponsor will also want to clearly communicate to the DMC its goals for the trial and any business objectives it wishes to be taken into consideration. This opportunity for a face-to-face meeting is especially valuable if some or all of the subsequent meetings are by teleconference.				

Interim data and reports will be presented at subsequent meetings of the DMC. In preparation for these meetings, there are a number of steps and data sources that should be considered.	

A timeline should be established well in advance of the DMC meeting. The timeline establishes the data cutoff for inclusion in the report, for sending data to the independent statistical center, and for sending DMC reports out for review.	

The following are examples of the many sources of data that might be necessary for creating the DMC report:	

Traditional case report form data from the clinical database

Serious Adverse Event (SAE) data from the safety database

Randomization codes and up-to-date enrollment information

Special assays or lab data that could unblind the sponsor

Last-minute endpoint or mortality data prepared via an endpoint sweep.

Endpoint sweeps are a process for collecting up-to-the-minute primary endpoint and/or mortality information more current than CRF data. The DMC may want these data in order to make the best possible recommendation. For this reason, sponsors should plan for an endpoint sweep to be conducted within two weeks prior to the planned DMC meeting. Endpoint sweeps can be conducted using a log that the site completes either from information on hand or by telephoning the study participants.	

In planning for "freezing" the data for a DMC, it is important to keep in mind that the DMC is generally concerned more about the completeness of primary and secondary endpoint and safety data than whether the data has outstanding queries. The DMC may be willing to review unmonitored data, unadjudicated endpoints, and other data from nontraditional sources in its quest for maximal, timely data. The sponsor or the sponsor's CROs should prepare for a special round of monitoring visits in preparation for a DMC meeting or should plan on the endpoint sweeps described above. Information on data completeness should be presented to the DMC.	

Typically, two versions of the DMC report are produced: an open report that shows results aggregated across treatment arms (blinded data) and a closed report that shows results stratified by treatment arm (unblinded data). Only the open report goes to the sponsor, while both reports get sent to the DMC. These reports are distributed so that there is sufficient time, usually at least a week, for the DMC and sponsor to review their respective reports prior to the meeting.	

A typical DMC meeting will begin with an open session where a sponsor representative will discuss the blinded data, trial management issues, or any other topics not involving unblinded data. The open session is an opportunity for the DMC to learn whether the sponsor's objectives for conducting the trial have changed. Has a competitor introduced a new drug? Have there been any interactions with the FDA? The open session is attended by the DMC, the sponsor, and possibly the sponsor's CROs.	

Feature Article

Subject safety in clinical trials has received much recent media attention, most publicly because of the death of a young man during a gene therapy study at the University of Pennsylvania.1 Some large and important clinical trials have been halted before their planned conclusions for safety and other concerns (for example, the Women's Health Initiative).2

Data Monitoring Committees in Practice

Medidata Solutions' newest addition to its Rave suite of programs allows for ad-hoc real-time query reporting

Medidata Solutions (New York, NY) offers an advantage for the clinical trial world similar to a recent moviemaking technology innovation. In Hollywood, post-production work can now start in the middle of filming instead of only afterwards. In a CRO, that means the ability to fully utilize data when it comes in during a trial, not after.				

Its new Vision Developer system is an ad-hoc query, reporting, and analysis solution. Anyone who can get on the Web can access the database: no hardware required. It allows metric and clinical data to be combined, and allows sponsors to customize their data queries using countless approaches. Data warehouse searches utilizing the entire database are no more difficult than finding out how many people are enrolled at a particular site. Each search can be represented in graph or table form, too, for easier analysis. Since it can run queries with whatever data has been inputted, it can reveal fixable red flags during the trial instead of after. This, Medidata notes, can significantly increase study efficiency.	

The data mining potential is designed for big jobs, but smaller jobs will be able to appreciate the data-manipulation. Vision Developer is an optional part of the company's Rave suite of programs.	

Gentiae Clinical Research, a new Bay Area CRO, also has a side business making software for cardiac labs

Gentiae Clinical Research, Inc. (San Francisco, CA) is creating satellite businesses to serve its main occupation as a CRO. Its new LifeSignals System is at the center of its cardiac core labs side-project. 				

LifeSignals is able to take data from 100 ECGs and, less than a half-hour later (near-real time), offer up usable information to the client. The system has automated a lot of manual processes that previously took days or weeks to accomplish. By offering its information on the Web, it allows PIs and sponsors access to their information within minutes from any online computer. And special triggers will notify all involved if an adverse event is recorded.	

Gentiae is a for-profit spinoff of the nonprofit Ischemia Research and Education Foundation, and its unusual name, picked by President Michael Kokesh, means "people of the world" in Latin. Next up for the company is a diagnostic imaging system, to store cath lab, nuclear lab, MRI and CT images for viewing over a secure Web portal. It should be available in a month or two, part of Gentiae's umbrella plan for CRO services.	

The standard for converting data, Integic's CRF WorkManager makes clinical trials more efficient 

Integic Corp. (Chantilly, VA) specializes in speeding up workflow of industries by putting all relevant information in one easy-to-access place. For clinical trials, the company has developed CRF WorkManager. 				

CRF WorkManager is able to take a CRO's data in all its various forms and make it accessible in one format: an Oracle Clinical database. Printed docu-ments can be scanned into the online database, and a new feature allows for offline scanning as well. Faxes are entered through a similar process. Elec-tronic information from other programs can be cleaned up for importation. New data can be entered directly into the mix. That data can then be used for mining or warehousing purposes. 	

Integic claims this can dramatically cut time off the clinical trial cycle.	

News

Medidata Solutions's Vision Developer, Gentiae Clinical Research, Inc.'s LifeSignals, and Integic Corp.'s CRF WorkManager

eShowcase

According to the Bible, we should have been resting every seven days all these years. If only we could have such a schedule. 

Many of us in clinical research find ourselves working part of every day. Our regular workdays are filled with meetings and teleconferences, our nights and weekends are filled with real work: reading, writing, planning, thinking. And all too little of the latter, because we are too busy following through on action items from all those meetings.

Meaningful process improvement in clinical research is hindered by a cultural cataclysm: a Julian calendar in a digital age. We are still scheduling our time by the rhythms of the planets, while communicating in digital time. This cultural dissonance results in two fatal flaws: the unnecessary weekly meeting and the under-use of enterprise information, which could take its place.


The reason why our workdays are filled with meetings is the tyranny of arbitrary frequency. When we get our department or team together, what is the first thing we talk about? We decide to meet once a week! Why? What is the connection between seven solar days and the needs of the work at hand? Maybe we should be meeting every three days. Maybe we only need to meet every 11 days. We never consider these possibilities; instead we book yet another weekly meeting into our PDAs. The result is that we are either meeting too often or not often enoughrarely just right.

Unnecessary meetings are perpetuated for several flawed reasons. One is the tyranny of the team, something I have written about previously. Indeed, it is often hard to tell which is worsethe teams or the meetings they generate. We also suffer through meetings of habit. Think about the spectrum of your weekly meetings, and ask yourself: when did this meeting first begin? There may have been a good reason for it originally, but is there still? Or are you meeting out of habit, because its the way we always do it. When I was once running a large organization with a number of senior managers who reported directly to me, we of course started meeting once a week. After a while, the meetings were getting thin in content; mostly we talked about the latest gossip or personal news. I realized the management team was running well enough that we didnt need to meet, and I changed it to a meeting on demand schedule: any of the managers could call a management meeting when each others counsel was needed. As long as I did my job correctlystaying in touch closely with each of them individuallythis new system worked very effectively. An hour of our workweek had been liberated.

We also suffer from meetings of inclusion, not dissimilar from the ubiquitous team meeting. These are the meetings we have when we dont want to leave anybody out, or hurt someones feelings. We want to keep up with corporate political correctness, or were trying to be inclusive of others. Inclusion is only worthwhile if it is sincere, and if so, it can be insightful and mind-bending. If we are including people for the wrong reasons, you can be sure they will feel it very quickly, resent the waste of their time, and thereby undercut our original cynical purpose.

The worst and most common sin, of course, is having meetings where people look at each other and have nothing to say or learn. Many observers have advised cogent fixes to this problem. In the words of one successful manager, if people need an agenda for a meeting, they dont belong there. One of the famous and most effective ways to make meetings efficient is to hold them in rooms without chairs. Its amazing how fast those meetings go.


But beyond making meetings more efficient, we have to question their frequency. Our work rhythm is no more dictated by the rotation of the earth and moon than any other natural phenomenon. So why are we meeting every week?

What is a week? A biblical invention, perhaps. It is at best an arbitrary subdivision of the lunar cycle, adjusted to the frequency with which the sun rises and sets, the two cycles of which do not line up mathematically. And anyone familiar with the tortured history of the creation of the Julian calendar will remember that our months are even more arbitrary (indeed, the calendar looks very much like the product of a committee meeting!).Similarly, when we ask for reports, we ask for them monthly. Why monthly? Is that frequently enough? Is it too often? Who knows? We let the moon decide how frequently we will summarize and communicate information. Whats important is that meetings and reports (i.e., information) are tightly interrelated. If we had more timely information (reports), do we need the meetings?

Well, sure, you are saying, but weeks and months are what everyone is used to and its easier this way. Weekly meetings, for instance, are the safest way to fight that fiercest of corporate battles: booking the conference room! But to accept these arbitrary schedules as inevitable is a cop-out. 

From daily work to weekends and back again


Before the rise of the corporation in the twentieth century as the dominant form of employment in industrialized societies, we all worked every day. We had to, to keep animals fed, wood chopped, water carried. But we had many fewer meetings! And each day had a rhythm that naturally included some fresh air, exercise, family, and quiet. In the last century we became boxed into the structure of the work week, creating the phenomenon of the weekend. No longer did we have a fluid continuum of daily tasks with little discrimination; instead the lines were clearly drawn between work and leisure, and an artificiality was introduced.

With the advent of ubiquitous, intrusive, and all too easily accessible communication technologies, our weekends have now all but disappeared. The globalization of clinical research, and its resultant round-the-clock phone calls and air travel demands, have further eaten into whats left of free time. Thus is the price of the Digital Age. But if our world is digital, why are we still meeting once a week? 

If technology has ruined our free time, it is because we are keeping both behavioral archetypes in place: the Julian and the digital (the weekly meeting and the cell phone). The bottom line is that I suspect most meetings do not have to happen weekly, and most reports are needed more often than monthly.


In clinical research, all of our operational processes are about generating information, some of it of a defensive nature like regulatory record-keeping, and some of it mission-critical to enterprise decision-making: keep developing the drug or kill it? Most organizations have long recognized that information technologylisten to the semantics of that phrase!can help manage this information. Unfortunately, as anyone who has tried to acquire or design a good CTMS knows, these software applications have focused much more on getting the data in than on getting useful information out. Once we get better at this, we can envision information when we need it, not prepared on a schedule determined by a cold gray orbiting celestial body.

Perhaps technologies can be put into service to restore free time, and a near-agrarian rhythm to our lives, by enabling just-in-time meetings and real-time reports. Instead of double-booking unnecessary weekly meetings (whose agenda is often filled with speculation about information unavailable because we dont have our monthly report yet!), we can start meeting only as often as needed. And the meetings we will have will be so much more informed, and therefore shorter, because operational data will be at our fingertips.

From the day we arrive on the planet
And blinking step into the sun
Theres more to see than can ever be seen
More to do than can ever be done.


Lets not waste that time in unnecessary meetings, scheduled by the arbitrary rhythm of our planet. There is so much to be done.

Process Improvement

Arbitrarily scheduled meetings eat away at valuable time otherwise spent actually getting things done.

The 11-Day Week

When FDA commenced discussions on the use of electronic records in lieu of paper records in 1991, it embarked upon a six-year consultation exercise culminating in the issuance of the final rule "21 CFR 11,"

 which came into force on 20 August 1997. The final rule itself is succinct (approximately 2000 words), but has given rise to massive amounts of commentary and interpretative text. The latest guidance aims to address issues with these secondary texts rather than the rule itself.		

Throughout its discussion of the consultation process,

 FDA made clear that the rule addressed "criteria under which FDA will consider electronic records to be equivalent to paper records and electronic signatures equivalent to traditional handwritten signatures," where "electronic records may be used in lieu of paper records."				

Over the period between August 1997 and February 2003, a body of guidance documents, expressions of opinions, and findings from regulatory inspections led to a perception in industry that the scope of 21 CFR 11 was far wider than stated above. The root causes of this widening seem to be:	

confusion between "records," maintained to meet the requirements of the predicate rules (other rules enforced by FDA, e.g., CFR GCP) and other documents, which might be subject to inspection by an FDA inspector (e.g., operating procedures). 

the computing industry's imprecise terminology--the term "record" can mean just about anything stored on a computer.

a desire by the entire pharmaceutical industry to have explicit and definitive direction about the requirements for regulatory compliance, making anything specific seem welcome.

The consequences of the expansion in scope has been twofold: it has served to make some units less likely to use/update computer-based technologies (contrary to FDA's declared intent), and it has diverted quality & compliance efforts onto unnecessary programs that add to neither patient safety nor regulatory compliance. 	

New FDA guidance finalized in August 2003,

 under FDA's initiative to review pharmaceutical cGMP, effectively returned the rule to its original intent as previously described. This replaced five previous draft guidance documents and an associated compliance policy guide, which have been withdrawn.

 The draft guidance identifies the scope to be applied in considering if a record is subject to 21 CFR 11: 				

"Records that are required to be maintained...in electronic format in place of paper format" 

"Records...maintained in electronic format in addition to paper format, and are relied on to perform regulated activities"

"...Records submitted to FDA, under the predicate rules...in electronic format..."

"Electronic signatures that are intended to be the equivalent of handwritten signatures...."

The following exclusions are also listed:	

"Records...that are not required to be retained by predicate rules...are not Part 11 records"

"A record that is not itself submitted, but is used in generating a submission, is not a Part 11 record unless it is otherwise required to be maintained by a predicate rule and it is maintained in electronic format."

This statement of the scope is now referred to as the "narrow interpretation." One indirect effect of the narrow interpretation is to make any citation with respect to Part 11 more significant, in that it will directly impact on the core regulatory arena.	

The only previously issued 21 CFR 11-related guidance document not withdrawn is: "Guidance for Industry-Computerized Systems Used in Clinical Trials."

 While possibly an oversight, it is more likely that FDA has reviewed the guidance and considers it appropriate. This guidance, which informs day-to-day regulatory decisions, addresses the circumstances in which computer system records are considered to be "source data/source documents" and the nature and extent of computer system validation that needs to be conducted. It is the authors' opinion that the document is unlikely to be withdrawn. The clinical trials community is therefore in the position of having the most complete guidance of any sector with regards to 21 CFR 11.				

 FDA has stated that: "For those records that we are now clarifying are subject to Part 11, we intend to exercise enforcement discretion with regard to Part 11 requirements for validation, audit trails, record retention, and record copying...and in applying Part 11 to systems that were operational before the effective date of Part 11."				

21 CFR 11 states the requirement to achieve "Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records."

 FDA has stated that during the period when 21 CFR 11 is under review, they will apply their discretion with regards to computer system validation. However FDA emphasizes that: "Persons must still comply with all applicable predicate rule requirements for validation."

While it is tempting to focus on the discretion aspect, it is important to remember that the concept of validation was not introduced by 21 CFR 11. The vast majority of cases where there is a genuine need to validate a computer system is based on other regulations. In practice, where the need for validation was identified based solely on 21 CFR 11, it is likely that the assessment was mistaken/faulty. Where the requirement is based on other rules, the requirement stands. It is the authors' opinion that this does not constitute a material relaxation in FDA's originally intended enforcement policy but serves to draw industry's attention to the real drivers for validation.	

The requirement for audit trails is an area where 21 CFR 11 can be viewed as being very prescriptive. It is possible that FDA will change the detail of audit requirements in 21 CFR 11 after review. The underlying requirements for audit trails are described in FDA's discussion of the consultation process

"representations of database information have been generated in a manner that does not distort data or hide noncompliant or otherwise bad information, and that database elements themselves have not been altered so as to distort truth or falsify a record."

"the audit trail provide a record of essentially who did what, wrote what, and when."

"record changes must not obscure previously recorded information."

While the rule may be amended in this area to become less prescriptive, it is unlikely that FDA would relax the underlying requirements as outlined above.	

Once a record keeper has identified that a given system does indeed create or maintain records which fit within the scope of 21 CFR 11, we believe that the abilities of the system should be assessed against the three basic requirements as identified above. If the system does indeed allow for all three to be met with a high degree of confidence, then it would be reasonable not to change or update the system simply to provide an audit trail that is compliant with 21 CFR 11. If the system does not meet the above requirements, then it is highly likely that it does not meet other regulatory requirements. Remediation should be considered as a matter of priority.	

The new guidance reiterates the need for FDA to be provided with "reasonable and useful access to records during an inspection." The requirement for providing electronic records is essentially the equivalent of "certified copies" for paper records: "...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."

In the context of an electronic record, "attributes" here should be interpreted as including (where practical) the ability to sort, search, selectively print, etc. In the short term, the authors recommend that organizations should maintain copies of all electronic records in unchanged form on durable media (e.g., WORM Copy), or copied to "PDF" format and secured if this is not practical.	

It is unlikely that any eventual change in 21 CFR 11 will alter record retention periods (set by predicate rules), or introduce different retention periods to be applied to electronic versus paper records. It is, however, quite possible that firms will now be allowed to build online, system-independent, electronic record repositories. During the period while FDA establishes its long-term policy for record retention, it is advisable that organizations retain any systems they choose to retire, or at least such portions of them as allow the firm to fully recover, access, and copy the records held. 	

In the long term, we believe that it is likely that FDA will agree to such records systems being either mothballed indefinitely, or the records transferred to an offline system-independent archive. We would suggest that transfer of records to nonelectronic forms, allowed in the new guidance, should be avoided if possible, as this may render it difficult to transfer them into any future long-term electronic archive.	

 FDA has stated (with certain provisos) that: "The Agency intends to exercise enforcement discretion with respect to all part 11 requirements for systems that otherwise were operational prior to August 20, 1997, the effective date of Part 11."				

This seems to be a significant change in FDA's policy. At a practical level, it is difficult to see that a large number of systems that correctly fall within the scope of 21 CFR 11 would be affected. Most such systems are likely to have undergone significant change if not replacement in the interim, particularly given "Y2K," and are therefore unlikely to be exempted.	

FDA, by applying a risk-based approach, has essentially indicated that if a system has remained fully compliant with all other rules for more than the last six years without material change, then the risks involved in making it 21 CFR 11 compliant are likely to exceed the benefits that may accrue.	

FDA has stated more clearly than previously how it expects to interpret the applicability of Part 11 to hybrid systems. 				

When FDA commenced discussions on the use of electronic records in lieu of paper records in 1991, it embarked upon a six-year consultation exercise culminating in the issuance of the final rule "21 CFR 11,"1 which came into force on 20 August 1997. The final rule itself is succinct (approximately 2000 words), but has given rise to massive amounts of commentary and interpretative text. The latest guidance aims to address issues with these secondary texts rather than the rule itself.

Navigating the New 21 CFR 11 Guidelines

As every attentive reader of this column knows only too well, the final word on the European Unions three-year-long review of pharmaceutical regulation is awaited almost dailyand this will change many of the ground rules and operating conditions for the London-based agency, giving it responsibility for assessment of an even wider range of medicines.

At the same time, the 10-year countdown to the EUs biggest-ever enlargement has just weeks to go: on 1 May 2004, the current 15 EU member states will be joined by 10 additional members, with eight of them from the former Soviet bloc. The EMEA is going to have to cope with a flood of new business, new people, and, undoubtedly, new problems.

By coincidence, this historic date also marks another deadline, long-awaited by the clinical trials community in Europe. This is the date when the EUs member states are due to start enforcing the provisions of its clinical trials directive adopted three years ago

in their national legislation. These new rules are going to route much more work through the EMEA, since it will be responsible for scientific assessment of new medicines, and all EU states will be readying or submitting marketing authorization applications to the agency.

Not surprisingly, therefore, the agency is trying to make sure it is ready for so much change.

To prepare for the final decision on the EUs review of pharmaceutical legislation, the agency is aiming to reinforce its scientific evaluation processes with greater professionalism. A spokesman for the EMEA said the immediate changes are not pre-empting EU legislation, but merely implementing policy decisions already taken to streamline the agencys work.

The EMEA action plan focuses particularly on quality management, in light of a 2003 audit of the scientific committee responsible for human medicines, the Committee on Proprietary Medicinal Products (CPMP). The integrated quality management system available at the EMEA will be strengthened to achieve what the agency sees as an adequate level of scientific and regulatory consistency in the outcome of the scientific evaluation processes. 

One of the key elements to boost the quality and the scientific and regulatory consistency of the work undertaken by the EMEA and the CPMP will be increased consultation with pharmaceutical companies during the early development of new medicines. Increased interaction with companies, including thorough oral explanations and discussion of development plans, can lead to greater efficiency in providing EMEA scientific advice and assistance in developing drug-testing protocols, the agency says.

More high-level specialized expertise will be brought into the scientific evaluation processes, so that the agency is able to do justice to authorization applications for products on the frontiers of new science. At the same time, the monitoring of medicines already on the market will become more proactive through the agencys pharmacovigilance services, again with the involvement of specialized expertise.The preparations are also well under way to ease the impact of EU enlargement in May. 

The EMEA has been working systematically on this since July of last year, providing information and guidance to applicants and marketing authorization holders during the run-up to accession of the new member states. There have been numerous meetings with the regulatory staff of the acceding states and with the pharmaceutical industry, focusing on the phasing-in of the EMEAs centralized authorization procedure, pharmacovigilance, documentation requirements, product information, and linguistic review. There is a huge task to be accomplished just in ensuring that labels, leaflets, and other documentation are adequately translated into the 19 official languages that the EU will work with starting in May.

As to the impending deadline for the full implementation of the clinical trial directive, events are currently in the hands of the member states, who are supposed to be putting into place all the necessary regulations and guidelines to operate according to the new rules. By the end of Januaryjust a dozen weeks away from the deadlineonly Denmark, Sweden, and Italy had actually transposed the directive into their national law, so the chances are not looking too good for an EU-wide outbreak of clarity, harmony, and understanding on 1 May. The European Commission, the EUs civil service legally responsible for ensuring that member states obey EU rules, laconically informed 

 in January: The Commission is carefully following the implementation process of Directive 2001/20/EC in the member states.

The EMEA has, however, already earmarked some of the time allocation of its efficacy working party in 20042005 to assessing the implementation of the directive (see also below).


Meanwhile, the EMEAs specialized working party on efficacy, which handles most of the clinical trials-related business of the agency, has drawn up a formidable work program for 20042005. It aims to meet four times a year, for two days each, and it is going to have plenty to talk about if its plans are to be realized.

Most of the work will take the form of creating and consulting on a huge series of guidance notes on clinical investigation of different product groups. By mid-2004 it is planning to release concept papers relating to neuropathic pain management and social anxiety disorder for consultation, and to finalize notes for guidance relating to products for generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder.

In the cardiovascular field, it is planning by mid-2004 to finalize further guidance relating to acute cardiac failure and lipid disorders, and, by the same time, to put out updated draft guidance or concept papers on stable angina pectoris, hyptertension, secondary prevention of cardiovascular events, and fixed combinations of antihypertensives and lipid-lowering agents.

The first half of 2004 is also the expected release date for draft guidance on steroid contraceptives, ankylosing spondylitis, juvenile arthritis, and psoriatic arthritis. At the same time, a new concept paper is scheduled on hepatitis B, as well as a final version of guidance on bacterial infections.

Consultation is going to be opened up during 2004 on some of the biostatistical and methodological issues arising out of the agencys scientific discussion of marketing authorization applications. Top of the list is the choice of the inferiority margin, but draft advice is also forthcoming on flexible design and analysis of confirmatory clinical trials and on data management boards.

Pharmacokinetics, too, will be under the spotlight during this year. Draft guidance is scheduled on clinical investigation of the pharmacokinetics of peptides and proteins, and on the pharmacokinetics of medicines in children and in patients with hepatic impairment. Plus, a finalized version of guidance on pharmacokinetics in patients with impaired renal function is also due to appear shortly.

Finalization is also envisioned before the end of 2004 for guidance on clinical documentation for metered dose inhalers, on products for the treatment of psoriasis, on products for allergic rhino-conjunctivitis, on clinical requirements for modified release products submitted as a line extension, and on comparability of products containing biotechnology-derived proteins as their active substance.

New draft guidance is scheduled on products for sepsis, anti-emetics for use in oncology, clinical trials in small populations, post-marketing data on products for use in pregnancy, and risk assessment of human reproductive products. And an efficacy working party paper on quality of life is due for publication before the end of 2004.

The working party is also due to contribute to International Conference on Harmonisation activities during 2004, including making its input to reflections on assessing QT prolongation potential, and pharmacovigilance planning. 

Without a fixed date, and therefore more likely in 2005 than 2004, are plans for draft guidance on local products containing known ingredients, fixed combination products, and clinical trials with haematopoietic growth factors for the prophylaxis of infection following myelosuppressive or myeloablative therapy. 

It comes as no surprise that the list of guidance notes and activities for 2005 is less complete and explicit: if the working party manages to do everything already scheduled for 2004 it will deserve a breakand so will the clinical trial community!

Throughout the entire two-year period, the working party is also expected to play its part in EU regulatory activities, such as following up the implementation of the common technical document that is being introduced for marketing authorization applications, and offering views on possible changes to EU rules on the summary of product characteristics (as well as following up on the clinical trial directive, as mentioned above). And it is tasked with liaisoning with the FDA and other national and international agencies, and meeting with learned societies and organizations of health professionals, patients, and drug companies.

In addition, the working party expects to be requested to give scientific advice on 10 products per year, as well as six times a year on protocol assistance, product assessment, and postauthor-ization issues.


The provision of scientific advice by the EMEA is a rapidly growing activity. New figures just released show how busy the CPMP is becoming in its fieldas part of its bid to become more proactive and professional in its dealings with applicants and potential applicantsof marketing authorizations for innovative products.

In January 2004 alone, the CPMP issued nine separate advice letters and accepted requests to give advice in another five cases. The type of advice covers straightforward scientific advice and guidance on developing protocols, and companies can come back for follow-up after receiving initial input. The topics on which advice can be sought are classified by the agency as pharma-ceutical, preclinical, clinical, and significant benefitbut in every case in January, it was the clinical area that companies were seeking assistance on. 

The products the CPMP was asked to advise on were biologicals for prophylaxis of HPV infection, Fabry disease, and treatment of multinodular goiter, as well as chemical-based treatments for Parkinsons disease, uraemic pruritis, type 2 diabetes, functional dyspepsia, chemotherapy-induced nausea and vomiting, and prostate cancer.


Looking to an even more distant future, the European Union has just announced plans aimed at helping Europe develop in the growing field of tissue-engineered products, a market predicted to be worth 4 billion worldwide by 2007, and subsequently 400 billion and beyond. It may not mean more work for the EMEA, because the current haphazard classification of such products keeps them separate from medicines. But their development is sure to mean a big boost to the clinical trials sector, even if its a different regulatory authority that will be in charge.

A new study carried out for the EU anticipates developments outstripping the current range of tissue-engineered products such as artificial skin, cartilage, and bone, and predicts the emergence of complex products in cardiovascular and central nervous system indications. It raises the prospect of tissue-engineered heart valves, vessel grafts, and heart muscle tissue, or treatments for Alzheimers and Parkinsons, and for damaged nerve fibers and spinal cord injury. The breakthrough will come when tissue-engineered products appear that can save life or that are much more effective or cheaper than existing conventional treatments, says the reports author, Anne-Katrin Bock, of the EUs Institute for Prospective Technological Studies. Further ahead, the report suggests the construction in vitro of human organs to overcome the scarcity of donor organs, and to improve treatment of diseased urinary bladders, kidneys, hearts, livers, and pancreases.

The EU is promising to bring in a new and clearer regulatory framework to stimulate the sector. European Research Commissioner Philippe Busquin says divergent European regulations are an obstacle to the growth of tissue-engineering markets in Europe. He aims to help tissue engineering companies overcome the challenges they face because of uncertainties in market development, and nonreimbursement of their products by health insurance systems. He recognizes that the small biotech companies involved do not have the resources for large, long-term clinical trials to provide information on the cost-effectiveness of the treatment compared to conventional alternatives. And, says the study, the lack of cost-effectiveness data is the main reason insurance companies refuse to reimburse treatment with tissue-engineered products.

1. Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

SIDEBAR: Whos Who in the Enlarged Europe 


The 10 new member states that will join the European Union on 1 May 2004 are: Poland, the Czech Republic, Hungary, Slovakia, Estonia, Latvia, Lithuania, Slovenia, Cyprus, and Malta. These will make a 25-member EU, as they are added to the existing 15: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Ireland, Luxembourg, Netherlands, Portugal, Spain, Sweden, and the United Kingdom. The work of the EMEA also covers Iceland, Norway, and Liechtenstein. Those three countries are linked to the EU on pharmaceutical matters through their membership of the European Economic Area, a grouping designed to bring the members of the EU and the European Free Trade Association together. It will have 28 members after the EU enlargement. Switzerland, although a member of EFTA, did not subscribe to the EEA and remains therefore autonomous in pharmaceutical legislation.

View from Brussels

With increasing authority, the EMEA is indeed living in interesting times.