The Electronic Solution to the FDA Submission

							Electronic submissions to the FDA are gradually being implemented by the biotechnology community. Even small companies are able to use off-the-shelf, available software to convert operations to an electronic format. A modest computer set up and a box of CD-ROMs can replace the mountains of paper once required to prove the safety and efficacy of a new product. Starting at the front end with the Investigational New Drug application (NDA), through the clinical trial process with electronic data capture, to the biologics license application (BLA), biotechnology companies can ultimately convert all systems to an electronic format.   

 Table 1.  Components of the Rituxan (rituximab) and the Zevalin (ibritumomab tiuxetan) Electronic BLAs Submitted to FDA						

IDEC Pharmaceuticals Corporation, a growing San Diego, CA, biotechnology company with two approved oncology products, is one company pursuing the electronic route. The company filed its first BLA in 1997 for the monoclonal antibody Rituxan, the first monoclonal antibody for the treatment of non-Hodgkin's lymphoma.

 At that time, the United States Food and Drug Administration (FDA) had published a draft guidance manual for Computer-Assisted Product License Applications (CAPLAs); however, final standards and requirements were still under development.

 The BLA was a new entity and no guidelines had been published specifically for its electronic submission in 1997. Therefore, IDEC worked with the Center for Biologics Evaluation and Research (CBER) to design a user-friendly e-BLA, while simultaneously laying the groundwork for future standards. Because all parties were new to the process in 1997, and 21 CFR 11 had not been implemented, IDEC was required to provide the FDA with a paper version as a backup to the electronic version of the Rituxan application. Preclinical data and case report forms were provided in hard copy only. Table 1 displays the components and cost of creating the first BLA for Rituxan and second one for Zevalin.

While FDA/CBER had received electronic applications prior to IDEC's BLA, submission standards that would ensure consistency had not been implemented. Applications were submitted using several different types of media. Orienting reviewers was challenging as formats varied between submissions, thus preventing reviewers from applying knowledge learned from prior applications to subsequent ones. Because of the inconsistencies, archiving applications was difficult.  			

IDEC's 1997 Rituxan submission was part of a new era. This electronic BLA was affordable and the process could easily be replicated by other companies. Several factors made replication possible.  					

In-house employees were used to create the final product, avoiding the need for costly outside consultants.  

The electronic BLA (e-BLA) featured a new design and was the first CBER submission to fully integrate all application sections and supply them on CD-ROM. Subsequently, safety updates were also submitted in this format.

The Table of Contents, for the first time, acted as a roadmap to hyperlinked data, much like linked text found commonly on Internet Web sites. A series of bookmarks functioned as an index that enabled reviewers to jump to sections of choice and navigate between documents. Because these sections were linked but independent, individual reviewers could focus on their areas of expertise but easily access other sections at will. 

A footnote capability enabled reviewers to add electronic memos directly on the document. 

A "cut and paste" function allowed CBER reviewers to copy text and tables from the application, edit them, and subsequently place them directly into their reviews. 

It was the first CBER BLA to be submitted with text entirely in PDF format on a CD-ROM. This type of presentation later became CBER's standard for all electronic and paper submissions.

Based on the success of the first e-BLA submission, IDEC geared up for a second electronic filing three years later. This second product, 90Y Zevalin for the treatment of non-Hodgkin's lymphoma, ultimately became the first radioimmunotherapy approved by the FDA.

 By then, the FDA had established specific guidances for the process based on its overall submission experience. A paper back-up was no longer required. Therefore, the entire application was submitted electronically. More extensive hyperlinking was included to create a user-friendly, comprehensive package. The entire BLA fit on 7 CD-ROMs, with 23 additional CD-ROMs required for subject CT scans and gamma camera images. 			

The benefits of converting to electronic submissions have been enormous. Simply stated by Michael Fauntleroy, Director of Electronic Submissions at CBER, "Electronic submissions provide a huge advantage to reviewers. They are able to get to the hard-hitting discussion points quickly. They are able to access databases quickly. Data are presented in context rather than in a disjointed fashion. Reviewers have the option of moving throughout the documents rapidly." All of these points ultimately benefit the pharmaceutical company as review time is decreased. 			

Importantly, reviewers have rapid access to the submission once the CDs arrive at the FDA. When an e-BLA is sent to CBER, it is first delivered to the document control center (DCC). Within two days of receipt, the electronic submission is loaded onto the server known as the Electronic Document Room (EDR) and a notice is sent to reviewers indicating that the submission is available for review. Then reviewers can download any pertinent sections of the submission onto their computers or onto a network space for review. If reviewers are traveling or want to review the application from home, they can copy the required documents onto their laptop or a CD-ROM, or they can access the submission remotely through a high-speed, secure connection. With electronic submissions, no paper routing and no paper delays occur. The documents are available to the reviewers 24 hours a day, seven days a week.  

The accessibility of electronic submissions contrasts sharply with the traditional process at the FDA, where paper documents are physically stored in the DCC. When hard copies are stored in the DCC, reviewers must submit their document retrieval requests after the initial regulatory review and wait for the paper copy of the submission to arrive at their offices. Typically, this takes a couple of days, depending on the reviewer's location. If reviewers don't want to be subject to DCC turnaround time, they obtain the volumes that they are responsible for reviewing and keep them in their office. This leads to additional storage problems. 

Electronic submissions simplify the review process for those at the FDA. They also facilitate communication between the agency and the biotechnology or pharmaceutical company. "What I found most useful," commented Antonio Grillo-Lopez, MD, chief medical officer and senior vice president of Medical and Regulatory Affairs, during the approval process, "was sitting in front of the screen and knowing that we at IDEC were looking at the same data as the reviewer in Bethesda when we discussed issues over the phone." 

The team that designed the e-BLA estimated that some former submissions had cost sponsors as much as $500,000 to $1.5 million for an FDA filing. In the past, companies even provided each of their FDA reviewers with a software-loaded computer and the detailed training required to use a customized system.

 All the equipment and resulting documentation required long-term storage space at government expense. In comparison, IDEC prepared the Rituxan electronic submission in less than three months using the equivalent of four full-time individuals. IDEC prepared the more comprehensive Zevalin submission in just under one year, also with four full-time employees. These employees, hired initially to create the e-BLA, remain an asset to the company by furthering the goal of converting all phases of IDEC drug development to an electronic format. Of note, those who orchestrated the project were recruited for their regulatory background, not for their technological expertise. According to Daniel Kim, manager of the electronic submissions program, the project required familiarity with a few software tools—it didn't demand a technological wizard. 

The e-BLA represents the first piece of the puzzle. Several more pieces must be added to complete the picture. The company is taking steps toward  			

that goal through its participation in two pilot programs sponsored by CBER. One allows for electronic submission of INDs, the other, known as Electronic Secure Messaging (ESM), provides for secure e-mailing of documents and electronic signatures. Both of these programs have recently moved beyond the pilot stage and become standard practice. Both programs offer unique benefits. Submission of electronic INDs could impact the pharmaceutical industry positively, as the ratio of submitted INDs to finalized BLAs or New Drug Applications (NDAs) is high. Thus, a growing percentage of FDA review time could ultimately be spent with electronic documents. With ESM, IDEC is able to email IND amendments to the FDA as formal submissions. Documents that once required several days to reach reviewers can now be on their desktops in 15 minutes (see Table 2).  

Table 2.  Comparison of Information Transfer Time

Aside from FDA interactions, IDEC is looking for additional ways to eliminate hand-written documents, such as case report forms (CRFs), that are scanned for submissions. Along these lines, electronic data capture (EDC) will be tested in an upcoming trial. With EDC, data are entered directly at the clinical site, thus eliminating the paper CRF. The potential rewards to the company are considerable. EDC could facilitate data collection during the trial and simplify preparation of both the clinical study report and BLA after the study is concluded. 

Not all BLAs or NDAs are created equal. In particular, applications for cancer drugs are based on fewer subjects and shorter follow-up periods than those for treatments outside the oncology field. The BLA for Rituxan was relatively simple; the second for Zevalin was more complex. Overall, both applications were small compared with those for other diseases. The challenge of creating electronic applications is certainly greater for pharmaceutical companies testing more conventional treatments. However, the rewards are worth the effort. 

As noted, CBER has initiated these pilot programs to further their goals of completing the electronic puzzle. Industry participation in pilot programs is one way to advance the mission. CBER is actively setting standards so all of industry can function on the same page. "When the electronic submission program was first initiated," Fauntleroy said, "we took whatever industry wanted to bring us. This was a totally untenable situation." Providing standards helps both the pharmaceutical industry and the FDA—it makes the FDA's job of reviewing submissions easier and provides a starting point  for companies that are new to the game. 

In conclusion, developing electronic submissions need not be a daunting, overwhelming task. The expense is manageable, even in a small company. And the benefits are great for both FDA and industry. But ultimately, the greatest beneficiaries will be the patients as electronic submissions improve the efficiency and thoroughness of the drug review process, allowing needed products to reach the public rapidly. 

1.   Antonio J. Grillo-López, "Monoclonal Antibody Therapy for B-cell Lymphoma," International Journal of Hematology, 76 (5) 385-93 (2002). 			

2. Food and Drug Administration, Draft Guidance Manual for CAPLAs (FDA, Rockville, MD, 1996). 

3. Antonio J. Grillo-López, "Rituximab: An Insider's Historical Perspective," Seminars in Oncology, 27 (6 Supplement 12) 9-16 (2000). 

4. U.S. Department of Health and Human Services, Guidance for Industry: Providing Regulatory Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format—Biologic Marketing Applications. (DHHS, Rockville, MD, Novemeber 1999). 

5. Mary A. Buesing and Edward McSweegan, "Submitting Biologic Applications to the Center for Biologics Evaluation and Research Electronically," Drug Information Journal,  33 1-15 (1999). 

6. Alice Wei and David Shen, "Supporting the Smaller Enterprise: IDEC Experience," Drug Information Association Workshop 1998. 

7. Antonio Grillo-López, "Zevalin: The First Radioimmunotherapy Approved for the Treatment of Lymphoma," Anticancer Therapy, 2 (5) 485-93 (2002). 

 is vice president of Regulatory Affairs and Quality, Favrille, Inc., 10865 Altman Row, Ste. 150, San Diego, CA 92121, (858) 450-5945, fax (858) 450-5948, 

 PhD, is senior director, Biostatistics, Favrille, Inc. 

 is manager, Regulatory Affairs, IDEC Pharmaceuticals Corporation, 3030 Callan Rd., San Diego, CA 92121, (858) 431-8977, fax (858) 431-8889, email: 

 MD, is  chairman, Neoplastic and Autoimmune Diseases Research Institute, P.O. Box 3797, Rancho Santa Fé, CA 92067. 

*To whom correspondence should be addressed. 

Articles

Notes from the Field

The expense of developing electronic submissions is manageable, even in a small company, and the benefits are great for both FDA and industry.

For the past year, Food and Drug Administration officials have been highlighting the importance of relating regulations and enforcement actions to product risk. FDA Commissioner Mark McClellan has stressed the need to spur medical product innovation by minimizing regulatory hurdles for new therapies that offer important benefits. He noted in a speech at the National Press Club in August that there are almost 3000 investigational drugs under development, including many “far more sophisticated products than ever before.” Even with additional resources, FDA cannot apply equally stringent oversight to the thousands of medical products it approves and inspects. 

In a five-part strategic action plan unveiled 20 August 2003 (

), McClellan reiterated the need to use “efficient, science-based risk management” to reduce public health threats. The overarching goal is to devote more resources and stricter rules to higher-risk products and processes, and to reduce oversight for situations presenting lower health risks. A key element of the plan is to apply risk management to achieve more timely and efficient review and approval of new products. This involves improving FDA’s internal review processes and issuing more guidance for industry to clarify development pathways for new therapies, particularly for emerging technologies such as genomics and combination products. 

In September, McClellan followed up by announcing several new policies related to FDA’s campaign to update good manufacturing practice (GMP) requirements for human and animal drugs and biologics. In addition to new guidances for managing postapproval changes and for ensuring the quality of sterile drugs produced by aseptic processing, FDA unveiled a final guidance that aims to clarify policies for implementing 21 CFR 11 electronic records and electronic signatures (GMP progress report, guidances and other documents available at 

More importantly, FDA also said it would start over in this area by launching a formal rulemaking process to revise 21 CFR 11 regulations, an initiative that will take several years to accomplish. The main task is to revise the preamble to the rule to clarify its scope and intent, explains Janet Woodcock, Director of the Center for Drug Evaluation and Research. 

FDA has been struggling for years to set standards and rules for how regulated companies should ensure the integrity of electronic records and signatures that replace paper documents required by FDA for a broad range of purposes. The regulation applies to all electronic records maintained or transmitted to meet FDA requirements, including those related to clinical research, laboratory testing, and application submissions.

The agency adopted final regulations implementing 21 CFR 11 in March 1997 as a way to encourage firms to submit data electronically to the agency. Unfortunately, the new rule generated loud complaints from industry about confusion and high implementation costs. Issues came to a head recently as FDA inspectors began to cite firms for noncompliance during GMP inspections, and companies indicated they would go back to paper-based record systems to avoid such problems. 

In response, FDA launched a broad review of the regulation and computer validation issues as part of its risk-based regulatory initiative. Last February the agency withdrew five earlier guidances on specific 21 CFR 11 components and issued a draft policy announcing its intent to adopt a more relaxed enforcement posture for this complex policy (see ACT View from Washington, April 2003). FDA said it would use “enforcement discretion” in applying 21 CRF 11 and that “merely incidental” use of computers would not trigger regulation requirements. 

The September document offers similar advice for firms to follow while the rewrite goes on. The final guidance reiterates that FDA does not intend to strictly enforce compliance with requirements for validating computerized systems, for maintaining computer-generated, time-stamped audit trails, and for ensuring future access to records and to copies of records. FDA also will use discretion in calling for legacy systems (those operational before 20 August 1997) to meet 21 CFR 11 requirements. Companies must continue to maintain and submit electronic information that meets requirements in predicate rules, such as those requiring controls on access to electronic record systems and written policies and system checks to ensure the integrity of electronic records and data. Additional guidance may be issued on specific issues during the lengthy rule-writing process. 

FDA officials are working to clarify 21 CFR 11 and offer new policy guidance as part of its broader effort to encourage industry to adopt new technologies and modern information systems. The aim is to encourage firms to comply more readily with FDA regulations and reduce the need for oversight and enforcement action. 

FDA’s risk-based approach to regulation is moving forward in the compliance area where staffers are developing risk-based models for selecting sites for inspection based on specific risk factors linked to manufacturing process, type of product, and the compliance history of a particular site. McClellan emphasizes that FDA is serious about prosecuting individuals and organizations that break the law, particularly those involved in “more sophisticated and large-scale criminal activity” that threatens public health. At the same time, he acknowledges that FDA lacks resources to inspect every manufacturing plant and clinical site. 

Thus the agency is looking to set priorities based on risk factors for a range of regulatory policies. A first step announced in September involves reducing the number of mandatory inspection categories for preapproval inspections to focus on more high-risk products and processes. It now will be up to district field office managers to decide if a preapproval inspection is needed for every product on the list of top-200 most prescribed prescription drugs or for all narrow-therapeutic-range therapies. The change aims to give district offices more flexibility and also provide additional resources for more high-risk preapproval and postapproval manufacturing inspections.

FDA also announced plans to form a special cadre of highly trained field staff to inspect pharmaceutical facilities and to include more drug review specialists in plant inspections. Another initiative involves establishing a program to discuss and resolve scientific and technical disputes related to GMP issues. These changes currently do not apply to bioresearch monitoring programs that oversee clinical investigators and institutional review boards, but the agency plans to extend some risk-based approaches to those areas. 

The concept of risk management, explains Woodcock, explicitly acknowledges that “some things are more important than others”—in the laboratory, in the plant, and in the clinical area (see “What Is ‘Risk?’” sidebar). This approach will be particularly important as industry moves away from the 1990’s manufacturing model geared toward big, blockbuster production and towards development of more drugs tailored to individuals, Woodcock commented earlier this year. Small subject populations will require more flexibility in testing and production methods, and “we’re all going to have to change.”             

View from Washington

FDA plans to rewrite rules governing electronic records while offering new policies to encourage risk-based regulatory approaches to application review and inspections.

Regulation and Risk Management

"In all affairs it's a healthy thing now and then to hang a question mark on the things you have long taken for granted."-Bertrand Russell

The economic consequences of inefficient work processes in clinical trials are significant. The average daily cost of drug development runs about $30,000 per day and rises by 10% to 12% per year. Development cycle times range from three to 12 years.

 In typical operational practice, the line management of a competitive firm strives to achieve the highest volume of successful new drug application (NDA) submissions (effectiveness) in the shortest practical time (efficiency). This combination reflects the business throughput of an organization. Unfortunately, the usual methods of management and reporting seem to reach their methodological limits early and invariably slow throughput because of various obstacles:	

The focus of management conversation around the cost of drug development has been moving gradually from efficiency to effectiveness. These factors can be distinguished by the relationship of process to outcome: 	

Efficiency seeks the shortest operational path to the result

Effectiveness balances strategy toward the best outcome.

If effective business throughput is the key to the ongoing health of a pharmaceutical organization, then the strategic priority is determining the actions to support this. Numerous contract-based tactics are available such as arrangements with contract research organizations (CROs) or site management organizations (SMOs). A strategic move that has a significant impact on a firm's long-term competitiveness and prosperity is that of pushing processes further outside the boundaries of the organization. This has long been a mainstay concept of traditional quality methods. The orchestration and integration of the processes between internal and external organizations is both a collaborative effort and a hurdle that many quality programs overcome with carefully designed procedures and standards for interaction. Many drug development operations follow this thinking by prescribing rigorous standard operating procedures (SOPs) as the standard of interaction. However, uniformity of procedure is really less important than predictability of positive outcome. 	

One promising theoretical model is the Virtual Research Organization (VRO). Although many companies are looking into this approach, at this point in time, most companies have chosen to keep data concerning implementation confidential. Despite the fact that early evolutionary instances of this approach are visible in the relationships between pharmaceutical companies and CROs, progress toward strong collaboration is slow. Therefore, much of this discussion is theoretical. This paper examines this theoretical model in survey form and proposes some additional clarifying elements and approaches.		

The structural essence of the VRO model is drawn from traditional quality theory.  In this model, the importance of reducing and managing variance is linked to the relationship between companies and their suppliers. Most effective quality management scenarios begin by attempting to control variability in the environment. Exposing and managing processes is a first step toward reducing variance. Understanding the influence of uncontrolled factors on variability is a consequence of examining processes.  Intersecting departments, divisions, or suppliers can reduce predictability if they do not rigorously participate in the local quality culture.				

Many companies with evolved quality management programs view suppliers as an integrated business element. In other words, the relationship is not merely a matter of efficient ordering and order fulfillment based on simple contractual parameters. Rather, a limited number of key suppliers become partners involved in the realities of manufacturing and product delivery. In some cases, a supplier will actually maintain an office or on-site staff within a client organization. The permutations of this model can range from straightforward supply of technical products-computing technology to surgical adhesives-to services such as management or clinical consulting.	

Just as manufactured items often depend on parts from various suppliers, work process functions depend on information from numerous sources. The VRO, therefore, takes the quality management approach and develops it using process and information as the basis of interdependence. For example, within a clinical trial, data is constantly changing along the work process map. It is critical to effective trial management to be able to communicate and fill informational gaps. One of the first steps in developing an optimal process map within the VRO is developing a clear understanding of the path between the necessary sources of data. Organizational intersections are more easily established with a clear high-level map of the process with data feeds identified. Modern competitive pressures often cause organizations to succumb to the practice of sniping at defects rather than effectively eliminating their root causes. In the constitution of a VRO, what is especially important is the real-time visibility of relevant and appropriate data across the virtual organization-not just as a disclosure in intermittent reports.	

 According to the Gartner Group, "process logic consistency, flexibility and accountability will be prime reasons for deploying workflow-enabled e-health applications."

 Workflow process management in a shared virtual environment requires a new operational approach for controlling and understanding the clinical process. Once the evident structure of the VRO has been described, the organizations involved must establish it as an operation to achieve a more effective clinical trial process. However, this goes beyond addressing technical complexity. Organizations must move toward higher levels of performance by reducing latency or delay within clinical study process. A more collaborative organizational app-roach with more consistent practices is a key element in reducing delay. The VRO is an organizational and technology model within which the work process map is designed less with consideration for organizational boundaries and more with the goal of achieving effective work process.				

For example, a pharmaceutical company may contract data entry with a CRO, quality review to yet another CRO, and handle discrepancy processing internally. Although numerous organizations touch the work process, technology can provide a means to assign participants to work queues along the same map. By implementing a VRO using work process automation, allied but distinct organizations can be tied together allowing real-time access to information related to the clinical trial. Consequently, various groups can assume new roles in the clinical trial process to better address the unique requirements of each group as well as streamline the process itself (Figure 1). Several straightforward business benefits are possible:	

Clearer common purpose to organizational relationships.

Specifically, a VRO approach can provide a history and traceability of data from clinical sites to sponsors and expedite the internal review and release process.	

 Each drug development project may have unique procedures and present many management hurdles that typically lie across organizational boundaries. Technology becomes the means of integrating the process map into the operation. By beginning with the trial as an end-to-end process, implementing work-process automation offers a competitive approach to managing activities throughout the clinical trial by breaking down some of the common hurdles in the clinical study process:

Duplication of data and data entry efforts.

Failure to disseminate information in a timely manner to the right people-getting good information too soon or too late or to the wrong place.

Miscommunication between site managers, physicians, and others involved in trial management and administration.

Failure to identify drugs that are not viable before expending significant resources that could have been used on another project.

Lack of globalization and harmonization between countries causes a duplication of effort that wastes resources.

Using technology, the traditional work- process structure and the organizational management can reflect the purposes of the VRO. A work-process automation server not only facilitates the business rule flow, it also coordinates the delivery of information along many common or possible delivery channels-scanned paper, faxed documentation, email delivery, wireless communication delivery, formatted file transmission, or XML-based CDISC structures. A typical example of work-process delivery is the automatic generation and transmission of an email message to an appropriate work group when an adverse event becomes evident. Another common use of a delivery mechanism is the automatic transmission of a message to a supervisor or project stakeholder if work remains in a process queue too long.	

Integrating work-process automation, Internet technology, and emerging standards provides a powerful technical means to create a clinical dashboard that helps orchestrate the dissemination and movement of information to where it needs to be in the VRO. It presents data in an easy to use format regardless of the underlying technologies supplying the data. A quick display of daily work activities and work queues enables the data to be presented at the time it requires attention. This helps streamline the business process. The potential result means weeks of time savings to the clinical study. For example, a small four-hour delay moving work from one department to another, or from one person to another, needs to take place only 10 times during the study to result in a week's delay. Other slowdowns originate in well-intentioned but non-contributing efforts. Research has indicated that the longest running queries appear to deal with matters that have little impact on study conclusions.

 It becomes easy to see how these process inefficiencies can prolong a study.	

The notion of a clinical dashboard in the VRO is more than just a front-end Web application that provides an extended view of a particular tool. It sits above the underlying technologies and processes, pulling together the data, providing a view of the total business process. By orienting key actions, decisions can be anticipated and made more quickly. Better information at the right time improves the effectiveness of interacting organizations and reduces guesswork or after-the-fact action. For example, not every area of clinical query is relevant to the study outcome, and extra time spent on certain kinds of queries can actually cause delay with no benefit. (Think of an example of concomitant medications where the data can be useful in the case of an adverse event, but don't usually have much effect on the overall outcome of the study.) Organizations are able to operate independently of their discrete functions and locations as if they were organized around the processes and with less inclination to reorganize or merge. By offering a large number of incremental improvements, the VRO model is able to improve the overall effectiveness of the resources associated with the trial. Actual results are typically measurable through data available within the work-process engine.	

Two areas of emerging technology that will dramatically improve the leverage of the VRO are standards-XML (eXtensible Markup Language) and CDISC (Clinical Data Interchange Standards Consortium). They offer new technical currencies for moving data more quickly and authoritatively. Proposed CDISC data standards offer a consistent modeling approach for describing the data associated with clinical trials. The current CDISC Operational Data Model (ODM) takes into account numerous subtleties of vendor-independent clinical data exchange including key structures and consistency with submission requirements. The relationship of CDISC to XML will become more fully defined over time.	

In the context of pharmaceutical industry data management, XML currently provides a reliable set of "wrapper" services to simplify the movement of data among applications or organizations. Of particular value in a VRO discussion is the ability to associate digital signature functions with the movement of information via XML. In this case, a VRO-specific XML schema would be deployed to contain data and other required process-related structures. This will ensure that data is moved through the process with integrity and authority (Figure 2). This means that as data is processed and as it travels from one organizational domain to another and back, its defined requirements for consistency and quality can be more practically maintained. Biometric technology is offering a superior integration opportunity for organizations to stamp their data authoritatively. Any biometric identifier that is used, however, must be acceptable according to several criteria-universal, consistent, unique, permanent, inimitable, collectible, tamper-resistant, and comparable.

 Additionally, the more authoritative nature of digitally signed data offers a stronger backbone to 21 CFR 11 requirements. 			

Pharmaceutical companies partner with CROs and other pharmaceutical support organizations (PSOs) to battle the increasing cost of the drug development cycle, and to help meet the growing needs of the drug development pipeline. According to the Tufts Center for the Study of Drug Development, pharmaceutical organizations will increasingly outsource to niche service providers despite increased regulatory and legislative attention to the clinical trials process and as full-service CROs continue to consolidate.

 Senior management must still convert the competitive pressures of the market and the logical demands of the clinical trial process into a coherent strategy tailored to a more effective operation.				

In developing a VRO strategy, the evaluation and strategic decision-making process will generally follow an identifiable path:

Require the involvement of senior management.

Involve the allocation of major resources over an extended period.

Have a significant impact on the firm's long-term prosperity.

Have multi-functional or multi-business consequences.

Require consideration of the firm's external environment.

Feature Article

The economic consequences of inefficient work processes in clinical trials are significant. The average daily cost of drug development runs about $30,000 per day and rises by 10% to 12% per year. Development cycle times range from three to 12 years.1 In typical operational practice, the line management of a competitive firm strives to achieve the highest volume of successful new drug application (NDA) submissions (effectiveness) in the shortest practical time (efficiency). This combination reflects the business throughput of an organization.

Merging Collaboration and Technology: The Virtual Research Organization

Rebecca Daniels Kush, with Paul Bleicher, Wayne R. Kubick, Stephen T. Kush, Ronald Marks, Stephen A. Raymond, and Barbara Tardiff (Thomson CenterWatch, Boston, MA, 2003), 200 pages, soft cover, ISBN: 1-930624-28X, $79.00. 

This manual, according to its publisher, is the first-of-its-kind resource for biopharmaceutical companies, CROs, and investigative sites searching for guidance in implementing technology to accelerate and improve their clinical trials. The authors claim there is a great need for assistance in this area, particularly when one compares the progress of the financial community to the healthcare industry. Healthcare is clearly lagging behind, and most physicians do not even have electronic access to patient records. While it is unreasonable to expect the entire industry to move en mass to a paperless delivery system, clinical trials, say the authors, are a prime candidate for improvement.      

Sponsors and CROs indicate that they are using eClinical technologies for 24% of phase 1–4 trials (up from 12% in 2000), and they anticipate using eClinical technologies for nearly half of their clinical projects by 2004 according to a 2002 CenterWatch/CDISC research project cited in the book involving approximately 750 organizations. However, more widespread implementation can lead to roadblocks. Proponents of eClinical trials face a myriad of hurdles, including disparate data systems, the lack of a link between healthcare data and clinical trial data, real and perceived regulatory risks, and, according to the authors, “the overall slowness of adoption that is characteristic of the pharmaceutical industry.”	

The important topics that this book covers are: The Optimal Electronic Clinical Trial; Process Redesign and Supporting Technologies; Achieving eClinical Trials; Metrics for Electronic Clinical Trials; Performing Electronic Clinical Trials in accord with Regulations; Data Quality and Data Integrity; The Impact of eClinical Trial Technology on Safety and Surveillance and IRBs; Industry Data Standards; and Ensuring the Success of Electronic Clinical Trial Implementations. 

Organizationally, the book benefits throughout from graphically distinguished “Notes” stressing important points and highlighting relevant research. Other favorable features of the book include flowcharts detailing current, paper-based clinical trial processes and eClinical trials. The book’s Appendix also adds value, particularly the Glossary, which, although offering very basic terms, also includes electronic terminology such as “Health Level Seven (HL7),” an application protocol for electronic data exchange in healthcare environments. The Traceability Matrix, which covers compliance to 21 CFR 11 rules involving electronic records, is another useful aspect of the Appendix. 

In another section of the book—Guidance for Industry:  Computerized Systems Used in Clinical Trials—issues pertaining to computerized systems used to create, modify, maintain, archive, retrieve, or transmit clinical data to the FDA are also addressed.

The book is a useful resource for those new to the eClinical trials industry as well as those already involved in planning and implementing eClinical trials.

The book’s accomplished authors include Rebecca Daniels Kush, PhD, a founder and current president of the Clinical Data Interchange Standards Consortium (CDISC).            

Media Review

eClinical Trials: Planning & Implementation is a useful resource for those new to the industry as well as practitioners already involved in planning and implementing eClinical trials.

eClinical Trials: Planning & Implementation

Earlier this year, Applied Clinical Trials published "Clinical Monitoring: Answers to Questions about Good Clinical Practice," another excerpt from the book, Good Clinical Practice: A Question & Answer Reference Guide. Readers are referred to the July 2003 issue (pages 27-29) to read the full text of the reference guide introduction.	

When is an individual considered "qualified" to conduct a clinical trial? For example, can non-physicians, such as Ph.D.s, Pharm.D.s, D.O.s, or D.D.S.s, be considered qualified to serve as principal investigators? 				

 FDA GCP regulations at 21 CFR 312.53(a) require that investigators be "qualified by training and experience as appropriate experts to investigate the drug." The ICH GCP guideline adds that an investigator "should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial and should meet all the qualifications specified by the applicable regulatory requirements." Although the FDA's GCP regulations make no reference to a medical degree or other specific education or training necessary to qualify as an investigator, the ICH GCP guideline is somewhat more definitive. In Section 2.7 of "The Principles of ICH GCP," the guideline states that "the medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist."	

In recent informal correspondence on this question, the FDA stated that, "while technically a non-physician can be a principal investigator, this requires that the nonphysician be qualified to personally conduct or personally supervise all aspects of the study. In practice, we have found it very rare that a non-physician can comply with this requirement. In general, where we have seen non-physicians listed on the 1572 as a principal investigator we usually would find an M.D., as a subinvestigator, to perform those study functions requiring the appropriate level of medical expertise. For example, a Ph.D. pharmacologist may be listed as a principal investigator on a pharmacokinetic study with an M.D. as a subinvestigator. Another example might be a clinical psychologist principal investigator with an M.D. subinvestigator." As a general rule, a non-M.D. can be listed on the Form FDA 1572 as the principal investigator, provided that there is an M.D. involved in the study to assume medical responsibility for enrolled subjects.	

Frequently in the past, the FDA has been asked specifically about whether nonphysicians can serve as investigators. One of the more definitive declarations of FDA's policy on this subject came in an October 4, 1989, memo (see exhibit below) from Office of Drug Evaluation I (ODE I) Director Robert Temple, M.D., and then- ODE II Director James Bilstad, M.D., which stated: "Qualified individuals who are not M.D.'s can participate in clinical trials either as principal investigators or sub-investigators provided that an M.D. or D.O. (or D.D.S. depending upon the study) is either a sub-investigator or is listed in the IND as an individual who will be responsible for drug administration and evaluation of patient safety."	

In a 1983 response to a letter addressing the participation of clinical pharmacists as principal investigators, then-FDA Associate Commissioner for Health Affairs Stuart Nightingale wrote: "In [your] letter you posed the question whether Doctors of Pharmacy (Pharm.D.) may serve as investigators in clinical pharmacological studies of investigational drugs. You noted that you have received varying interpretations of our regulations on this point from different manufacturers who sponsor pharmacological studies. It has long been FDA policy to accept Doctors of Pharmacy as primary investigators of studies of investigational drugs within their areas of expertise. Because such studies may require the diagnosis of disease and the recognition and treatment of adverse reactions or other medical incidents occurring during the course of the study, we have required that a person licensed to diagnose and treat disease be officially associated with the study to be performed. This is ordinarily done by naming such an individual in the Form [FDA-1572] as being responsible to the principal investigator of record. Alternatively, both the Doctor of Pharmacy and the licensed individual may sign the form [FDA-1572] as co-investigators, having equal responsibility in the performance of the study in question."	

According to an American College of Clinical Pharmacy (ACCP) commentary appearing in Pharmacotherapy (2000;20(5):599-608), Nightingale then responded to an ACCP request for clarification on whether the above comments applied only to pharmacokinetic studies:	

"Doctors of Pharmacy may serve as clinical investigators for both clinical pharmacology studies and clinical trials of a drug provided they do so in conjunction with a person licensed to diagnose and treat disease." In its commentary, ACCP notes that FDA again emphasized "that a physician be a subinvestigator to assess the patient and make medical decisions."	

An April 1990 response from then-CDER Director Carl Peck, M.D., to a similar American Association of Colleges of Pharmacy clarification request stated: "You asked whether FDA would consider pharmacists, especially Pharm. D.'s with adequate training and experience eligible to be principal investigators in 1) pharmacokinetic studies and 2) clinical efficacy studies. This question has been addressed on a number of occasions, beginning in 1980 with Dr. Marion Finkel, then director of the Office of Scientific Investigations (now called the Offices of Drug Evaluation I and II), and most recently in a [1989] memorandum . . . from the Directors of the Offices of Drug Evaluation. In 1980 and at present, the conclusion is the same: pharmacists can serve as principal investigators in any clinical trial. Section 506(1) of the Food, Drug, and Cosmetic Act requires that FDA assure that the investigational drug will be provided only to 'experts qualified by training and experience to investigate' a new drug. Whether or not FDA will permit a particular pharmacist to be an investigator in a clinical study will be determined on a case by case basis, and may depend on the type of study (pharmacokinetic study, clinical efficacy study) proposed in the IND." 	

What is a subinvestigator, and how does a subinvestigator relate to a principal investigator? Since subinvestigators conduct important trial-related tasks (e.g., make clinical decisions), must a subinvestigator meet the same "training and experience" qualifications as an investigator? Can nurse coordinators, ARNPs, PAs, Pharm.D.s or Ph.D.s be subinvestigators? And who must be listed as subinvestigators on the FDA Form 1572-Statement of Investigator? Can subinvestigators be investigators that recruit patients at other offices or sites, or must a subinvestigator work at the same office/facility as the investigator?				

Under FDA regulations (21 CFR Section 312.3(b)), an "investigator" is "an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. 'Subinvestigator' includes any other individual member of that team." Block #6 in the Form FDA 1572-Statement of Investigator asks for the "names of the subinvestigators (e.g., research fellows, residents, RNs) who will be assisting the investigator in the conduct of the investigation."	

In essence, a subinvestigator is any other member (i.e., other than the investigator in charge of the study) of the study team who makes clinical decisions during the study. The ICH GCP guideline defines subinvestigator as, "any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., residents, research fellows, RNs)." The implication, then, is that the subinvestigator will have a clinical degree and training.	

Since the investigator signs the Form FDA 1572 while the subinvestigator does not, it is the investigator who assumes all of the commitments specified in the form, including ensuring "that all associates, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above requirements." Confusion frequently arises about who should be listed as subinvestigators on the 1572. Normally, these are the people who make study-related medical decisions regarding the diagnosis and treatment of the disease under investigation. Those who are responsible for completing study paperwork need not be listed on the 1572.	

Today, however, FDA officials continue to acknowledge that "subinvestigator" is among several trial-related terms that could use further clarification, despite agency attempts to clarify this area in the past. In the preamble to its 1987 IND regulations, for example, the FDA specifically responded to a request that the agency define the term "subinvestigator," and that it clarify whether the term includes non-physicians, nurses, technicians, and other assistants to the clinical investigator. "Studies frequently are conducted by a team of individuals who share responsibility for designing and conducting the investigation," the agency stated. "The principal investigator is the responsible leader of that team. Subinvestigators include all other professionals who assist the principal investigator in the design and conduct of the investigation. Subinvestigators would not include those technicians and other [assistants] who assume no responsibility for the conduct of the study."	

In recent informal correspondence regarding this question, the FDA stated that, "in general, if individuals involved in the conduct of the study are performing functions within the scope of their professional license they would be deemed to be qualified. A subinvestigator may, but does not necessarily have to have the same credentials as the principal investigator . . . However, the investigator is responsible for fulfilling all of the commitments listed in Block #9 [Commitments of Form FDA 1572] at all of the remote sites. If the investigator cannot realistically accomplish these responsibilities, it would be preferred if the subinvestigator at a remote site sign a separate 1572 as investigator for that site."	

As a practical matter, NPs, PAs, and other care providers who make clinical decisions regarding study subjects should be listed as subinvestigators. The same advice applies to clinicians who write orders for, or "prescribe," the study drug for each subject. Some sponsors request that pharmacists who prepare a study drug based on patient characteristics such as weight or body mass index also be included as subinvestigators.	

 When must the 1572 be revised for changes in study personnel?				

A revised 1572 is required in the following scenarios:	

A change in the principal investigator for the study.

The addition of a local lab or health care facility to which study patients make visits.

In recent informal correspondence on this issue, the FDA stated that ". . . regarding when a 1572 must be revised, that really is more of a matter for the sponsor to decide for themselves. People seem to obsess over the 1572. We wonder how many people realize that the 1572 is not even required to be submitted to the FDA. In theory, we could never even see it. In practice, however, the 1572 is typically submitted to the IND by the sponsor as an efficient means to provide the information required under 21 CFR 312.23(a)(6)(iii)(b) which requires the sponsor to provide, among other things, the following [in an IND submission]: (b) The name and address and a statement of the qualifications (curriculum vitae or other statement of qualifications) of each investigator, and the name of each subinvestigator (e.g., research fellow, resident) working under the supervision of the investigator; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board.	

"Likewise, the sponsor is required to file an amendment to their IND under 312.30 when certain changes are made. One of the changes requiring an amendment is the addition of a new investigator (312.30(c)), in which case the sponsor must submit the same information as described above. Again, a sponsor may elect to provide the 1572 for a new investigator as a means to report this information."	

It is worth noting that, within industry, there are different approaches to reporting certain types of study personnel changes. Some companies, for example, report changes such as an inactivated subinvestigator immediately, while other firms wait and batch this change and perhaps others in a submission used to report a more significant change, such as the addition of a new subinvestigator (see Q&A 3.1).	

Earlier this year, Applied Clinical Trials published "Clinical Monitoring: Answers to Questions about Good Clinical Practice," another excerpt from the book, Good Clinical Practice: A Question & Answer Reference Guide. Readers are referred to the July 2003 issue (pages 27-29) to read the full text of the reference guide introduction.

Investigators and Sites: Answers to Questions about Good Clinical Practice

As I write this column, two European Union actions to improve drug treatment in the developing world are taking place. One is the assertive EU interventions at the World Trade Organization to ease the supply of generic medicines to poorer countries. The finalization of negotiations on this complex subject was greeted by European Trade Commissioner Pascal Lamy as having taken “too many months to complete,” but finally showing that “the WTO can respond flexibly and pragmatically to the concerns of developing countries and contribute to the fight to combat killer diseases.” 

The other action, more directly related to clinical trials, involves Lamy’s colleague, European Research Commissioner Philippe Busquin. He is in southern Africa to raise the profile of the European and Developing Countries Clinical Trials Partnership (EDCTP) and to encourage African countries to mobilize around the initiative.  

The EDCTP program, launched last year, was described in some detail in this column in November 2002—but in short, it is an initiative to combat HIV and AIDS, malaria, and tuberculosis backed by ‚200 million of European Union money. The European Commission is supporting a long-term partnership between Europe and developing countries for the development of new medicines and vaccines against these three diseases by facilitating and accelerating clinical trials. And the EU member states will contribute at least another ‚420 million. 

Now, Commissioner Busquin has decided to put his mouth where his money is. Recognizing that providing funding is not enough, he has gone to Africa to visit key research sites and meet ministers in Tanzania, Mozambique, and South Africa, in particular at a WHO meeting in Johannesburg where he is addressing the Ministers of Health of African States.  

According to Busquin:Research into treatments for diseases doesn’t just mean working in laboratories, it also means working with the victims in their own communities. By visiting some of the hardest hit parts of Africa, I hope to highlight what the clinical trials program means in real terms. 

European countries working in partnership with developing countries and the pharmaceutical industry to reduce suffering and poverty is a fine concept, the Commissioner says. But “African and European countries must unite in their efforts to share expertise and build genuine political consensus, together driving forward long-term policies and programs to tackle HIV and AIDS and other poverty-related diseases.” 

Conscious that 95% of deaths from these three diseases are in the developing world, and that 90% of these deaths are in Africa, the clinical trials program is initially targeting that continent as its top priority.  

EDCTP foresees increased collaboration among European countries, among developing countries, between the northern and southern hemispheres, and with the pharmaceutical industry. It is focusing on developing new interventions that are appropriate for the African population by doing clinical research in Africa, where African scientists play a crucial role. But it also urges that development aid should be directed into the fight against poverty, through substantial investment in research and training, and by sharing expertise, infrastructures, and results. 

Busquin’s trip takes him initially to Dar-Es-Salaam in Tanzania, where he meets Anna Abdallah, Minister for Health. Then, in Mbeya, in the southwest of the country, he visits a state-of-the-art clinical research facility focusing on HIV and AIDS. This is the medical research program set up in 1988 with the German Agency for Technical Cooperation and Munich University. The center is involved in the EU-funded HIV Superinfection Studies (HISIS) trial, based on a cohort of 600 women who are examined regularly over a three-year period, with interview and medical examination, counseling, and medication if needed. 

And while in Mbeya, the Commissioner is visiting Kihumbe, a nongovernmental organization that provides education and advice for out-patients, assists people in home-based care for AIDS patients, supports affected families, and works to mobilize and educate the community on voluntary counseling and testing to reduce HIV spread. He is also seeing the HISIS project’s follow-up mobile clinic and dispensary in a small, rural village, Igurisi. 

From Tanzania, Busquin goes to Maputo in Mozambique, where he meets the prime minister as well as EU ambassadors, and takes a car ride to ManhiÃ§a to see the facilities at the local Health Research Center—including a demographics and data management center and a bacteriology laboratory. Projects underway there include a malaria vaccine trial involving 2000 children, a pregnancy intermittent treatment for malaria, and an HIV and AIDS mother-to-child program. The final stage is a visit to Johannesburg in South Africa to visit a public/private research partnership for TB research. 

Cynics may say that Commissioner Busquin might just as well live in Africa for all the use he is in Europe, particularly now that the EU’s research program that he is responsible for is at last up and running. But even if the research portfolio in the European Commission (and its incumbent) does not enjoy quite the same prestige as the politically more influential Commission portfolios such as economic and monetary union or competition policy, Busquin’s initiative is not to be dismissed so lightly. This is a hands-on visit (with an international press entourage accompanying him) that will throw some light onto what the EU is doing in this desperately needy corner of the world. And it should confer some added significance on the EU’s practical involvement in clinical trials and development aid at the local level, rather than in the physically more comfortable world of politics and regulatory affairs. 

Meanwhile, the European political and regulatory reflections on clinical trials continue back home. One of the most recent outcomes is a report on how the EU orphan drugs rule (

) has functioned since it came into force on 28 April 2000.  

After three years, the European Commission has decided to clarify some questions on the implementation of the designation and market exclusivity provisions of the rules, providing guidance to the EMEA (European Agency for the Evaluation of Medicinal Products), the member states, the pharmaceutical industry, and other interested parties.  

For instance, in the case of a medicinal product intended for the diagnosis or prevention of a condition, one of the key criteria for designation as an orphan—the population affected by the condition—may be interpreted in several ways, the Commission observes.If a product for the diagnosis or prevention of a condition is effective, this may result in a decrease in the population actually suffering from the disease or condition to less than five in 10 thousand persons in the European Union [the threshold fixed in the EU rules—Ed].  

So, because the objective is to provide incentives for product development, the prevalence calculation in such cases should be based on the population to which such a product is expected to be administered on an annual basis, the Commission has decided. 

Similarly, to clarify the criterion that “there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the EU,” the Commission is refining its scope. Commonly used methods of diagnosis, prevention, and treatment that are not subject to marketing authorization (for example, surgery and medical devices) may be considered satisfactory methods if there is scientific evidence as to their value. But the assessment as to whether a particular method may be considered satisfactory shall take into account the experience with the method in question, documented results, and other factors including whether or not the method is invasive and/or requires hospitalization. 

But it is in relation to “significant benefit” that the new Commission guidance is likely to be of most direct interest to the clinical trial community. The EU rule states that where a satisfactory method of diagnosis, prevention, or treatment of the condition exists, the sponsor has to establish “that the medicinal product will be of significant benefit to those affected by that condition”—with “significant benefit” defined as “a clinically relevant advantage or a major contribution to patient care.”   

In other words, the applicant for orphan drug designation is required to establish significant benefit compared with an existing authorized medicinal product or method at the time of designation. But “as there may be little or no clinical experience with the orphan medicinal product in question, the justification for significant benefit is likely to be made on assumptions of benefit by the applicant.” It is the job of the authorities (and particularly the EMEA’s Committee on Orphan Medicinal Products) to assess whether or not these assumptions are supported by available data and evidence supplied by the applicant, the Commission points out. 

The Commission’s new guidance focuses some of the possible claims more clearly. Considerations such as ease of self-administration may be considered a benefit if the patient is ambulant, it says, but they may not be considered a benefit if the patient is likely to be hospitalized during treatment. And if the argument for significant benefit is based on an increase in supply/availability of the method, the sponsor must provide details of the supply/availability problem and explain why this results in the unmet needs of patients. If the supply of existing methods is sufficient to meet patients’ needs in the orphan indication, an increase in supply will not be viewed as a significant benefit. 

A product that is authorized and available in all member states may constitute a significant benefit compared with a similar product that is authorized in only a limited number of member states. But supply problems arising from manufacturing process limitations should be differentiated from those that arise due to cost limitations or healthcare policy. And where supply/availability problems with existing methods are of a transient nature, due for instance to manufacturing problems, it will not be possible generally for sponsors to argue significant benefit based on supply problems unless it can be shown to be a recurring problem or a long-term interruption in supply. Assumptions of significant benefit may also be based, says the Commission, on expected benefits to a particular population subset, including benefits in patients resistant to the existing method and on expectations of a clinically relevant improved safety profile. But the reasons for these expectations must be justified, either by clinical experience or exceptionally by reference to the pharmacological properties of the product. o            

View from Brussels

European Research Commissioner Philippe Busquin tours Africa to bring attention to the plight of developing nations unable to afford modern medicines.

Into Africa: The EU Puts Its Mouth Where Its Money Is

The software industry has matured over the years. Don’t get me wrong—there is still room for significant growth, development, and improvement in almost every area where software is useful. However, compared to a decade ago, most of the software tools for important business and home applications are sophisticated, easy to use, and stable. One can write a novel, publish a newsletter, organize a photo album, or maintain a home budget and checkbook with relative ease nowadays. In fact, there is software for almost any application you can conceive. The software that most people are familiar with was designed to be installed and operate on a single computer (for example, Microsoft Word). 

Another class of software is often referred to as “enterprise software.” Enterprise software is software that is being used for central and/or mission-critical business applications by users who play a variety of different roles and are located in many different locations. For example, the software that tracks customer complaints at a national cable company would be “enterprise software.” The process of choosing and installing enterprise software is far more complex than simply installing an application on a desktop. The enterprise application often must interoperate with a variety of different software systems, from very old legacy systems to new systems. In addition, software workflow considerations may not only affect individuals, but may have cascading effects on hundreds and thousands of workers, creating measurable changes (either positive or negative) on productivity. For these reasons, companies often create exhaustive evaluation processes for the purchase of enterprise software. Sometimes, they choose to develop the software themselves, either internally or with the help of consulting firms. 

In all cases, the development of high-quality software—from desktop to enterprise—requires a mature, well-thought-out and carefully followed Software Development Life Cycle (SDLC) process. The SDLC is the process by which the conceptualization, planning, and building of complex software are coordinated. Enterprise software demands the use of an SDLC because of the complexity of the system and the business risk of poorly implemented software. Furthermore, regulatory requirements in the pharmaceutical industry require an SDLC for the development, maintenance, and retirement of software used in the collection and analysis of regulated data. The SDLC may seem an unfamiliar concept to the uninitiated, but it is not unlike the planning and development process for a home renovation.  

Home renovations are on my mind a lot these days, mostly because I am currently living through major renovations of my kitchen and family rooms. Each night, as I eat my microwaved dinners off paper plates, I get to discuss the progress of our project and think about a day when I won’t have to wash my dishes in the bathroom sink. Despite the relative chaos that this has created for my family and me, I can see clearly that our contractor is following a carefully coordinated and planned process.  

When we first began to work with our contractor and his architect, we started with our requirements. The architect listened and interpreted, often taking our fixed concepts and turning them into general requirements. After much discussion, questions, and answers, the architect had a pretty clear idea of what we were looking for and created a plan. The initial plan was at the highest level, without certain specifics (for example, the location of the light switches, or even the specifics of lighting). We worked with this plan for a while, fine-tuning it until we were satisfied. We knew that some aspects of it might change at a later date, but we accepted that this would be at an increasing cost to us—knowing that the further along in a project, the more costly the change. 

At a certain point, the design was complete enough to begin building. There were many details that were not yet decided—the color of the paint, the type of pulls to be used on the cabinets, among others. However, we knew that these details weren’t required at first, and would be decided with some “prototyping” at a later date (like trying a few swabs of different paint color on the walls). We still tested the plan in our minds, walking into rooms and turning on lights, moving food between the kitchen and dining room, to validate that the design worked. We also envision what the completed project would look like. Although we didn’t write it down, we know what we will look for in the completed project to determine if it was built correctly. Do the dishwashers work? Does the refrigerator make and dispense ice cubes? Can all the cabinet doors open and swing properly? 

The architect used the design that we created to develop detailed specifications for the installation of plumbing, lighting wires, cabinets, and everything else. These were at a level where the builder could develop materials lists and a project plan for coordinating the work of the plumber, electrician, plasterer, and cabinetmaker. Each of these subcontractors checked the designs carefully, and coordinated as needed, to make sure that their work would mesh with that of the others. All of this detail was done without our participation or knowledge. As “end users” of the kitchen, we didn’t need to know much of the detail of its construction. 

As each step of the project was completed, it was tested to make sure that it met our initial requirements and the specifications of the builder. Sometimes a building inspector would actually need to sign off on a particular phase before work was continued. Over the next month or so, the project will be completed. We will have the opportunity to test the final kitchen and decide whether it meets our specifications or not. Any defects that arise after this will hopefully be taken care of by our builder. However, standard maintenance will be our responsibility. At some point in the very, very distant future, we may even decide that the kitchen is old and in need of renovation again. At this stage, the entire life cycle of the kitchen will have run its course and the life cycle of a new kitchen will begin. 

Software development indeed shares many aspects of the kitchen design and build process. In fact, some of the language of software development derives directly from the construction process (for example, the job title software architect). Despite the similarities between construction and software development, one difference is important to note. In construction, the design and testing processes are relatively short compared with the construction itself. In software engineering this is reversed. The design process is typically quite long and involved compared to the final development stage.   

Although simple software can be “hacked” together by a single individual, most enterprise software requires the closely coordinated effort of teams of individuals, each working on different aspects of the project, with a similarly sized team for documentation and quality assurance. Without a carefully coordinated SDLC, it would be very difficult if not impossible to create software that does what it is supposed to do and can be validated. Software used in the conduct of any FDA requirement must, by definition, use a high-quality SDLC, and be fully validated.  

As with the building of a house, the development of software begins with a requirements phase. Those responsible for the development of requirements must listen carefully to real users of the products, understand, and even observe the workflow of the process being automated. Often the end users will not understand how to translate their needs into a systematic requirement, nor will they have fixed ideas about how they want the software to look. The requirement gatherer must sift through much of the information and develop requirements that are specific enough to base the design of a system on, but not too prescriptive. These requirements must be checked and tested with the end users for feasibility, completeness, ambiguity, and consistency. A final document should be the agreed upon requirements for the software—to be used for checking against the end result. This document is similar to the high-level design drawings of the architect. Although these requirements may change during the software building process, changes come at a cost of time and increased expense. Again, the later in the process a change occurs, the greater the cost. 

Once the requirements are complete, the software team will begin a detailed design specification, much as the construction architect went from high-level drawings to detailed wiring, plumbing, and cabinetry plans. In developing a specification, the software architect makes many decisions about what functionality will be contained in each of the different software modules and how these modules interact. The specification document will form the basis of the test plan for unit and final testing of the software. 

Following the agreed upon design, the software will be implemented—the actual software code will be written and the various modules will then be integrated together. Each individual unit or module will be tested, and the overall integrated product will be tested to make sure that it works as specified. Once the project is completed, it must be accepted by the end users, often through another series of practical tests. It will then be installed and deployed in production.  

As with a house, over time the software will require continued maintenance during operation, which may be as simple as changing an installation parameter, or as complex as rewriting some of the code. Finally, the software will eventually reach an end of its usable life, at which point it will likely be replaced by a new product. The life span of software may be brief (like that of a Web browser) or very long (as in the case of some COBOL-based banking systems from the 1960’s that are still in use today). 

The SDLC model described above is commonly referred to as the Waterfall model—each step takes input from the previous step and produces output that is used by the next step. The development of the software flows from step to step like a waterfall. The steps are:  

Although the Waterfall development is quite straightforward, it doesn’t work well in the current world of rapid application development and complex projects. Waterfall development works best when the user starts the process by specifying requirements, but isn’t involved thereafter until final testing. In addition, it is a relatively inflexible model that limits the ability to predict timing of a project and resource requirements. As in the renovation of a home, there needs to be much back and forth, changing of requirements, and modification of design specifications during the design-and-build process. The Waterfall method works best in an environment where change occurs rarely, so that portions or stages of a project can be completed, closed, and not reopened. For this reason, a number of other theoretical models have been developed.

One commonly used alternative to the Waterfall method is a rapid prototyping method. Using languages and tools that make it possible to quickly assemble an application, the programmers can develop one or many prototypes to test requirements and specifications. Users interact with the prototypes, suggesting modifications and improvements. When all prototyping is completed the prototypes are set aside and the code is completely rewritten in a more robust environment, often using a version of the Waterfall methodology. A risk of rapid prototyping is that some aspects of the prototype may be too difficult or expensive to build as part of the final system. The user may have to accept less functionality from the final system than the prototyped one. 

Prototypes can be illustrative prototypes, which can be nothing more than a mocked-up Web page or even storyboard. Other prototypes are functional, which can actually deliver part or all of a working system or part of a system. A major risk of functional prototypes is the temptation to incorporate the rapidly developed prototype into the final system, sacrificing quality and integrity of the process and product.

The SDLC methodology known as the Incremental model assigns requirements to a particular section of the software. The sections are each built to completion and tested individually, beginning with the highest priority module. As each module is added on, the product takes on more and more functionality. Both Microsoft and Netscape manage huge projects with a related methodology using a Synchronize and Stabilize method whereby the entire project is built each night from the currently completed modules. Incremental models allow for adaptation to changing requirements through user interaction with the partially completed software.

Another methodology that is related to the Incremental methodology is the Spiral model, whereby the modules that have the highest risk inherent in them are prototyped. As these are completed, risk is reassessed and the next highest risk module is prototyped. As more and more of the software is completed, the process becomes more straightforward and carries much less risk, until the final software is built from the prototypes. 

There are many, many more models of SDLC methodologies, including the V model, Sawtooth, Shark’s tooth, and others. The most radical is Extreme Programming (XP) wherein the software is rapidly built from user “stories” without formal requirements, through an iterative process. Programmers work in teams of two on discreet parts of the software—providing rapid and high-quality development. This form of SDLC requires a highly committed team with ownership and knowledge. It works well for first-time products in start-up companies.

In simple terms, all of the SDLC models are different variations on making sure that software is properly defined at the beginning, properly built, properly tested, and properly implemented. In the end, the use of any SDLC methodology creates a process that ideally is predictable, repeatable, measurable, and efficient. Through the SDLC we get a high-quality process for the development of high-quality products that can achieve regulatory compliance. In software development and in GCP, the requirements of a fixed process can bring order, but can also suppress innovation and quality in favor of structure. As in the building of a new kitchen, it is essential that everyone involved consider what they are doing, and for whom, throughout the project. Despite the many pressures to complete the software on time and on budget, each participant must be ready to question, reexamine, and modify the process and product to deliver the best quality result.            

Technology Viewpoint

Relatively few people are familiar with the software design process, but many have had their homes remodeled; the two processes are more similar than dissimilar.

Software Life Cycles and Kitchen Sinks

Interactive voice response systems are commonly used in clinical trials to manage the flow of trial medication supplies to sites and to manage the allocation of these supplies to individual subjects. Other advantages and uses include access to real-time information for trial managers, collection of diary card data directly from subjects, and as an aid to subject recruitment.

In this article we focus on the relationship between treatment randomization and supply management in IVR trials. As I will explain, in IVR trials substantial medication savings can be made using medication that is not labeled by subject number. This, however, does mean that it is possible for a site to run out of one particular type of medication but still have stocks of other treatments remaining. In this situation it is possible to restrict the randomization to the treatments for which stocks of medication are available. This has commonly become known as "forced randomization." There are also other situations in which forcing can be used in trials managed by IVR.  	

Most statisticians find the concept of forcing anathema when they first encounter it. After hearing the issues discussed in this article, however, many do permit forced randomization to occur.	

To appreciate the arguments surrounding forced randomization, it is necessary to have an understanding of the rationale for randomization and also how medication stocks are managed in a trial using IVR. 	

Treatment allocation in comparative clinical trials is virtually always performed with some element of randomization. The two principles underpinning the design and execution of comparative clinical trials are minimization of bias and maximization of the precision of treatment effect estimates. Randomization, in conjunction with blinding (for blinded trials), is a key contributor to achieving precise and valid estimates of the treatment effect. Randomization prevents any conscious or unconscious selection bias by the investigator in the allocation of subjects to treatment groups. It provides a sound basis for statistical inference at the analysis stage of the trial. In contrast to any systematic allocation system, it tends to ensure balance between treatment groups on known and unknown factors that correlate with trial outcome independently of treatment. 				

With nonrandom allocation, there may be an underlying systematic reason why balance may not be achieved. To take an extreme example, a system that allocates according to the first letter of a subject's surname may produce groups that are unbalanced on demographic factors because of the association of surname with country. For example, surnames beginning with "M" are particularly common in Scotland and Ireland due to names beginning with "Mc" or "Mac." Balance increases the precision of the treatment effect estimate and avoids so-called accidental bias.	

The main method of randomization employed in clinical trials is allocation from a preprepared randomization list composed of random permuted blocks. For instance, in a trial of two treatments and a block size of B, half of the numbers within each block (B/2) are assigned to each of the treatments in a random order. Use of blocks helps to ensure that treatments are allocated in the planned ratios and helps comparability of treatment groups should subject characteristics vary over time. If there are stratifying factors (for example, gender and current smoking status) then the list is divided into sections, one for each stratum formed by the cross-classification of factor levels (in our example, male smoker, female smoker, male nonsmoker, and female nonsmoker). To prevent selection bias by the investigator, allocation should be sequential as stipulated by the ICH E9 Guidance which states that "The next subject to be randomized into a trial should always receive the treatment corresponding to the next free number in the appropriate randomization schedule (in the respective stratum, if randomization is stratified)."

 The investigator can exercise selection bias if he knows or can guess the treatment allocation for the next subject. For instance, in an open-label trial stratified by center, treatment allocations towards the end of a block become ever more predictable. This knowledge may influence the investigator's decision about subject entry into the trial.	

If there are many stratifying factors, then the balancing properties of stratified randomization may break down because there are too many strata that have incomplete blocks at the end of the trial; this is termed "over-stratification." In these situations, an alternative to the use of a randomization list is dynamic allocation in which the allocation of treatment to a subject is influenced by the current balance of allocated treatments and, in a stratified trial, by the stratum to which the subject belongs and the balance within that stratum. The most commonly used dynamic allocation technique is minimization, which can cope with more stratifying factors for a given trial than randomization from a list. In minimization, allocation is made to the treatment that minimizes the imbalance calculated over the stratification factors. The ICH E9 Guidance states that an appropriate element of randomization should be retained. For example, the treatment that is optimal for balance is identified but then only allocated with a certain probability, for example a probablity of 0.80, in a trial of two treatments. A recent comprehensive review of minimization is provided by Scott et al.

 Other dynamic allocation techniques, including some with slightly greater statistical efficiency than minimization, are detailed in a recent overview.

A complete description of this topic is provided by Dowlman.

In IVR or Web-based trials, savings can be made by separating the randomization numbering system from the medication pack numbering system (as shown in Figure 1). At the time of randomization, the subject is assigned to a treatment corresponding to the next available number in the appropriate section of the randomization list. A pack of the treatment to be allocated is chosen from the stock at the site and the IVR system reads out the pack number to dispense. The choice of pack is best done randomly from the whole stock or the subset of stock with the earliest expiration date-the important point being that there should be no attempt to pick sequentially from an ordered list of pack numbers or else gaps in the list may partially unblind the investigator.

 If supplies are packed into units that cover durations shorter than the whole trial length, using IVR can reduce wastage that would traditionally occur when subjects withdraw from the study because units may be allocated to other subjects in the same treatment group. 		

Figure 1. IVR randomization and medication dispensing.	

Interactive voice response systems are commonly used in clinical trials to manage the flow of trial medication supplies to sites and to manage the allocation of these supplies to individual subjects. Other advantages and uses include access to real-time information for trial managers, collection of diary card data directly from subjects, and as an aid to subject recruitment.1

Applied Clinical Trials-10-01-2003