FDA officials responsible for the agency's good clinical practices (GCP) program emphasize that few, if any, GCP-related areas generate as much industry uncertainty as the Form FDA 1572—Statement of Investigator. Through this seemingly mundane form, a clinical investigator must provide a study sponsor with information on the education, training, and experience that qualifies him/her to conduct a particular study as well as his/her commitment to conduct the proposed study in accordance with the protocol and federal regulations. 

Over the years, several factors have contributed to industry uncertainty regarding the 1572 and its use, among them the fact that, today, the 1572 has both mandatory and practical, nonmandatory uses. Complicating matters has been lingering uncertainty regarding the 1572's use at non-U.S. study sites, and questions about what U.S. sponsors can and should require of foreign-based investigators who may be reluctant to sign the 1572, which is often viewed as a formal contract. 

In developing the May 2004 second edition of our new text, 

Good Clinical Practice: A Question & Answer Reference Guide 

we invested considerable time and effort to explore and resolve many of the long-standing and troublesome questions regarding the 1572. The series of questions below, which is excerpted directly from the text, addresses several of these questions. 

Because it is used for a few different purposes, there is uncertainty in some cases about the Form FDA 1572—Statement of Investigator, in particular when its use and submission is mandatory. What is the 1572's regulatory purpose, and in what ways is the form used in practice? 

 The 1572 itself declares that, "No investigator may participate in an investigation until he/she provides the sponsor with a completed, signed Statement of Investigator, Form FDA 1572." And FDA regulations at 21 CFR 312.53(c)(1) add that, "Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following: (1) A signed investigator statement (Form FDA—1572)...." Therefore, the Form 1572 is a document that 

an investigator must submit to the study sponsor.

Through the 1572 Form and the attachments typically sent with it, an investigator provides a sponsor with, among other things, information on his or her education, training, and experience (CV or other statement of qualifications) that qualifies him or her to undertake the clinical investigation, information on the relevant facility, IRB, and subinvestigators, protocol information, and the investigator's commitment to conduct the study in accordance with the protocol and FDA regulations. 

So where is there uncertainty about the 1572's use? In many cases, companies submit the completed and signed 1572s to the FDA in the original IND and subsequently when new investigators are added to a study. IND applicants and holders do this as a convenient way of fulfilling an FDA requirement at 21 CFR 312.23(a) (6)(b), which calls for a clinical trial protocol submitted in an IND to provide "the name and address and a statement of the qualifications (CV or other statement of qualifications) of each investigator." 

Because this has become such a common practice, some incorrectly assume that this is an FDA requirement. In fact, the IND form (Form FDA 1571) explicitly gives sponsors the option of fulfilling 312.23(a)(6)(iii)(b) by submitting either "Investigator data [21 CFR 312.23(a) (6)(iii)(b)] or completed Form(s) FDA 1572." 

In informal correspondence on this issue, the FDA stated that, "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 information required under 21 CFR 312.23(a)(6) (iii)(b)." 

Since it is such common practice for companies to provide the 1572 and accompanying CV and other information to the FDA in the original IND and subsequently when a new investigator is added to the study, has that become an agency expectation or even a 

None of several Center for Drug Evaluation and Research review divisions contacted recently claimed that the submission of the 1572 was a divisional expectation. And most did not express even a preference in terms of the format (i.e., a 1572 or alternative format) in which IND applicants should provide investigator qualification-related information. 

It is important to note, however, that there are differences between some CDER review divisions, and that applicants should ask about a division's policy in this area. Under a 1992 policy, for example, the Division of Oncology Drug Products asks that sponsors of commercial INDs (i.e., those submitted by industry) not submit either the 1572 or the investigator's CV for new investigators because such submissions are "inefficient and cumbersome." Rather, in its "no CV letter," the division asks all IND holders to submit summary information, including "the minimum qualifications of investigators selected for the protocol...and a statement that each investigator meets or exceeds those qualifications" (see sidebar, "Division of Oncology Drug Products' 'No CV Letter'").  

Division of Oncology Drug Products' "No CV Letter" 

In the letter, the Division of Oncology Drug Products emphasizes to applicants that, "You are, of course, also required to maintain the information provided to you by the investigator on the form FDA 1572, which is to be retained by you. In addition, you must maintain in your files a current C.V. of each investigator which must be updated as investigators are added. Only upon request of the Agency, will you be required to submit the current C.V. for a specific investigator." 

Occasionally, European clinical investigators and sites are reluctant to sign the FDA Form 1572—Statement of Investigator. Is this ever acceptable for studies conducted under INDs and, if so, what is done in lieu of the 1572? 

For a variety of reasons (e.g., the need for an IRB, which some countries do not have), some foreign investigators may refuse to sign the FDA Form 1572—Statement of Investigator, in part because they do not want to enter into a contract directly with the FDA (U.S. government). All study investigators who will participate in studies under an IND must sign the 1572, however. In such scenarios, then, trial sponsors must find other investigators who are willing to sign the form.  

But does this mean that, if a sponsor has an IND under which it is studying a specific drug, then investigators at all non-U.S. sites conducting studies involving that drug must complete sign a 1572? 

Not necessarily. Only those sites involved in studies specifically included under the IND are required to sign a 1572.  

In a February 2004 informal response to this question, the FDA stated the following: 

"There is no FDA requirement that study sites outside of the United States operate under a U.S. IND. FDA regulations (21 CFR Parts 312.120 and 314.106) [establish the criteria under which the agency will accept] non-U.S., non-IND studies/data for purposes of FDA review in support of applications (IND or NDA). The decision to operate under an IND at non-U.S. sites is therefore discretionary on the part of the study sponsor. 

"HOWEVER, should a sponsor make the decision that non-U.S. studies/sites [will be conducted] under a U.S. IND, then all FDA IND regulatory requirements must be met. This includes submission of the 1572 with its investigator certification that U.S. IND requirements are understood and will be met. 

"On the other hand, a sponsor may decide and indicate that a study's non-U.S. sites [will not be conducted] under a U.S. IND. In this case, elements of IND regulations (beyond provisions for FDA's acceptance of non-U.S., non-IND studies/data under 312.120/314.106) are not FDA-enforceable requirements per se. That is, there is no FDA regulatory requirement for completion of a 1572 when a sponsor has designated the non-U.S. study or sites as 'non-IND' (although a sponsor may still request completion of the 1572 as part of an internal SOP—and FDA, of course, expects SOPs to be followed). 

"The distinction, then, is whether the sponsor has chosen/committed to operate its non-U.S. sites under U.S. regulations (in which case, the 1572 and all IND requirements must be met at non-U.S. sites) or as non-IND (in which case the FDA regulatory requirement for a 1572 does not apply)." 

Under a June 2004 proposed regulation, the agency proposed to revamp its sometimes-vague regulatory standards for non-U.S. clinical trials by specifically referencing its good clinical practice regulations as the FDA expectation for such studies. Although U.S. GCP standards have long been the expectation for non-U.S. clinical trials conducted under INDs, the agency has traditionally accepted foreign studies that were not conducted under an IND if they conformed to either the Declaration of Helsinki or national requirements, whichever afforded the greater protections to study subjects. While the proposed rule would make U.S. GCP the standard for all clinical studies to be used in supporting U.S. regulatory applications, it would not affect the 1572-related requirements discussed above.  

Good Clinical Practice: A Question & Answer Reference Guide, 

available from Barnett Educational Services (

 MBA, RN, is vice president of GCPA, Inc., Fairfax Station, Virginia. 

 is director of publications with Barnett Educational Services.

One might think that the topic of FDA form 1572 would not be fodder for lively discussion with colleagues in our industry, but over the years as GCP auditors, the late Dr. Douglas Mackintosh and I have found ourselves involved in some heated discussions about the required elements of the form, who should be listed on it, and whether or not the form is really required at all. The pervasive misinformation about the form, along with long-held conventions regarding its content and reporting requirements, was the stimulus behind the creation of this article.  

Vernette J. Malloy Vice President GCPA, Inc. Fairfax Station, VA 

Investigational site staff, as well as sponsors, often struggle with questions that they cannot get clear answers to, such as: do we have to update the form every time new hospital residents join the study in whatever minimal capacity; do we have to submit the 1572 or is there another venue by which we can submit the required information to the FDA; can two investigators be listed as co-investigators on the 1572 or does the FDA require that only one investigator be named Principal Investigator and other investigators participating in the study be named as Sub-Investigators. As more studies conducted under U.S. INDs were conducted overseas, we found that some of those participating investigators were reluctant to sign the 1572...what to do in that scenario? 

Inspired by these types of questions, we decided to share what we have heard and learned from colleagues and regulatory personnel internationally and develop a manuscript that would concisely answer some of our colleagues' questions , which hopefully would help demystify the form and its related ambiguities. 

Since the article,  "A Closer Look at the 1572," written by Mackintosh and colleagues was published in this journal in 2004, there has been new leadership at the FDA committed to protecting the public. Margaret Hamburg, MD, Commissioner of Food and Drugs, in her address to participants at the Food and Drug Law Institute in 2009 stated:

Felix Khin-Maung-Gyi Chief Executive Officer Chesapeake Research Review, Inc. Columbia, MD 

"Again and again, from all sides of various questions, I heard support for a strong FDA... an agency that protects the safety of the food supply... an agency that facilitates access to safe and effective medical products... an agency for the American public to count on. A strong FDA has credibility with the public. A strong FDA is transparent in explaining its decisions. A strong FDA pursues creative solutions to long-standing problems and is always looking for novel ways to prevent illness and promote health. And a strong FDA enforces the law." 

Recently, the FDA has visibly and noticeably enhanced its enforcement activities and stepped-up efforts to take swift and aggressive action against violators,

  evident by the increased number of warning letters, NIDPOEs, and 483s. As such, the clinical research community is keenly aware of the need to be even more diligent and compliant with all aspects of the regulations in light of the increased likelihood of an ad hoc FDA inspection. 

There continues to be confusion regarding the regulatory role of the Form FDA 1572. The concern is that missteps in completing appropriate regulatory forms will result in additional citations. Mackintosh and colleagues' approach to appropriately completing the 1572 is as valid today as it was when initially introduced in 2004. Their article, in conjunction with the recent FDA Guidance issued in May 2010,

  will guide clinical research practitioners on best practices to remain in compliance with the requirements of the Form FDA 1572. 

1. M. A. Hamburg, "Effective Enforcement and Benefits to Public Health" Remarks at Food and Drug Law Institute, August 6, 2009, 

http://www.fda.gov/NewsEvents/Speeches/ucm175983.htm

2. B. M. Kuehn, "FDA Steps Up Efforts to Find, Remove Violators of Clinical Trial Regulations," JAMA, 302( 16) 1739-1741 (2009). 

3. Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs Frequently Asked Questions–Statement of Investigator (Form FDA 1572), May 2010 

Articles

Feature Article

A new reference guide clarifies uncertainty surrounding this sometimes misunderstood document.

A Closer Look at 1572: Interpreting the FDA's Statement of Investigator Form

Overall, sponsor companies and CROs have a fairly consistent view of the criteria used to select CROs, although there are some notable differences. The pharmaceutical industry makes widespread use of CROs and, most likely, this trend will increase in the coming years. But little empirical research exists on why and how pharmaceutical companies select CROs.  

The University of the Sciences in Philadelphia (USP) and TTC, a drug development data company, are conducting a multiyear research program on the factors associated with improved speed and cost effectiveness in clinical studies. Since outsourcing to CROs represents an integral part in developing drugs, USP and TTC will also analyze how CROs are selected and used in clinical trials. Part of this CRO analysis involved a Web-based survey of sponsor pharmaceutical companies and CROs to understand the following:  

Specific outsourcing processes and techniques, such as project budgeting, CRO selection, managing studies, bid grids, and managing cost overruns

Perceptions of how CROs and sponsor companies interact in the areas of business development, CRO selection, and project management

Training needs for professionals to improve CRO selection and CRO project oversight.

Previous studies have reported that industry professionals involved in outsourced clinical studies expect the overall level of outsourcing to continue to grow. In addition, quality and timelines of a CRO's work dominate as the basic selection criteria.

  This article accepts that previous work quality is a central criterion for selection and focuses on other issues that might be involved in the CRO selection. Set within the anticipated continued growth of CRO usage, the article examines these additional key criteria that individuals working in drug development use to select CROs, highlighting the differences between the selection criteria that sponsor companies emphasize and how CROs think sponsor companies decide. 

Using factor analysis, we also determined that the individual elements used to select CROs can be summarized within a set of five broader dimensions: Processes for Issue Identification and Resolution; the Specifics of Project Execution; Team Chemistry; CRO Experience; and CRO Capabilities. 

Pharmaceutical company participants indicate that approximately two thirds (64%) of all post Phase I studies involve the use of CROs for one or more parts of the study. However, when measured by pharmaceutical company size, there are very large differences in current outsourcing practices. For example, within the largest 20 pharmaceutical companies, half (52%) of all post Phase I studies use CROs, a number that jumps to 88% for smaller companies. These smaller pharmaceutical companies often do not have the permanent in-house staff to conduct all aspects of a clinical trial, especially where the trial involves many sites and multiple countries. The smaller companies may, for any number of reasons, also lack the employee headcount or expertise to carry out clinical trials. 

While many industry professionals expect the use of outsourcing to increase [see Table 1], only one quarter of people from pharmaceutical companies think that their company is better than competing companies in selecting CROs, with no significant differences based on the size of the companies involved. That is, large companies are no more likely to think they are especially good at CRO selection than are small companies. Similarly, there are no appreciable differences based on a participant's geographic location, whether it be North America, Europe or other locations worldwide. There is a slight but statistically insignificant difference in the age of individuals who think their company is better than others in selecting CROs—they are a year older, but have the same number of years of industry experience.  

There is a general agreement between the reasons pharmaceutical companies cite for selecting an outsourcing organization and how CROs think pharmaceutical companies select them. There are also some striking differences in the individual decision criteria. Survey participants evaluated 17 individual considerations often used in selecting a CRO and rated each item on a scale ranging from very important to not important at all [the 17 criteria arose from our literature review and preliminary interviews with industry professionals]. Five of these 17 items were deemed to be especially crucial in the selection of CROs—that is, specified by at least half of all the study participants. 

The most important overall quality in selection is a sense of positive sponsor–CRO project team relationship. Both sponsor company and CRO respondents think that the sponsor wants to know above all else that they could work with the CRO. More than any other single selection criterion, sponsor companies stressed the importance of a good relationship between the two company teams. These teams must work closely with each other for an extended period of time, often on projects involving multiple countries and large sums of money. The sponsor company needs to know that both its team and the CRO's team share the same values, work ethics, and general approaches. CROs also clearly understand the need sponsors have for teams that work well together.  

The CRO's project management team contributes significantly to the overall positive sponsor–CRO project team relationship. Yet sponsors were far more likely than CROs to stress the importance of the project management team as a CRO selection criterion. While more than two thirds (68%) of the pharmaceutical company participants stressed this criterion in their selection process, only half (51%) of the CRO respondents thought sponsor companies valued this as very important. 

Sponsor companies and CROs placed great weight on a CRO's relevant experience, both in the same indication as the study and in the CRO's overall experience in the appropriate therapeutic area. Sponsor companies and CROs differed somewhat on the importance of a project member's background. While only 45% of the pharmaceutical company participants considered this very important, 62% of the CRO respondents considered it very important to sponsor company decision makers. Sponsor companies seem more interested in the overall cohesiveness of the CRO team members than their vitae. A vitae may be a constructive starting point, but positive sponsor–CRO project team relationship is vital to the project's success. As one pharmaceutical company project manager put it: "CVs can only take you so far. You want to know that the CRO's team fits with the way you want things done and the way you want to work." 

Another essential criterion (i.e., raised by more than a third of the study's R&D professionals), was the project execution plan. On no other single criterion, though, was there a greater difference between sponsor company and CRO responses. Fifty-nine percent of pharmaceutical company professionals considered the execution plan as fundamental in hiring a CRO; only 28% of respondents from CROs placed the same importance on the execution plan. 

In their responses to this criterion, the pharmaceutical company decision makers appear to be emphasizing a level of project specificity that many of the CROs may not appreciate. Far more than the CRO project team's background, pharmaceutical companies want to see a convincing project execution plan, including such concrete items as resources, countries, and site selection. According to one pharmaceutical company outsourcing professional: "Every CRO claims to be customer oriented, responsive, and so forth. Exactly how a CRO proposes to carry out a project...now that can be convincing—or not." 

Sponsor companies are also more likely to value the internal processes CROs use to make appropriate senior CRO managers aware of project problems. Forty-seven percent of the pharmaceutical company participants considered this capability to be essential in selecting a CRO. In contrast, only a third (34%) of the CRO respondents thought it was essential for sponsor companies. 

A smaller number of respondents, from both sponsor companies and CROs, considered the CRO's role as a preferred provider and the CRO's geographic scope to be very important. CRO staff turnover was somewhat more critical to the sponsor companies than many CROs thought was the case. 

Of the remaining criteria, one in particular merits its own discussion: the role of the lowest price bidder. Sponsor companies and CROs differ in how they view the role of the lowest price. According to an experienced business development manager from a major CRO, "Pharmaceutical companies rarely say price is important. But we know that it really is." But in this study, fewer than one in 10 (7%) of the sponsor company respondents considered the lowest price as decisive in selecting a CRO. In contrast, more than a third of the CROs (38%) felt price was a fundamental selection measure for sponsor companies. 

There were major differences in the importance the survey participants placed on the 17 individual items. People rarely make decisions using one consideration at a time. Rather, they relate one consideration to another and decide what's best. Companies follow the same process in selecting CROs. In fact, as mentioned earlier, sponsor companies use five general dimensions in evaluating and selecting a CRO:   

Processes for Issue Identification and Resolution

The study used factor analysis to distill these five dimensions from the 17 individual survey items. 

Factor analysis only provides a mathematical solution to how the various items relate to each other and how they relate to any underlying dimensions. Factor analysis does not label the individual factors. Items heavily associated with a factor are said to "load on" that factor. Items that load more heavily than others have a bigger explanatory role in understanding the communality of the items associated with that factor. Only a review of the items associated with a given factor can provide a rationale for what the individual items may have in common.  

The individual factors appear in the order of the variance they explain, which is often a function of the number of individual items "loading on" that factor. That order does not necessarily mean that a given factor's explanatory importance is more or less than the factors before or after it. [Table 2, available on the 

 Web site, summarizes which of the individual selection criteria load on each factor; a more complete matrix can also be found on the Web site.] 

In this survey, five items load heavily on the first factor, Processes for Issue Identification and Resolution. The individual items all concern the same general issue area: processes used to identify and resolve project and financial issues. Three items are associated with the second factor, the Specifics of Project Execution. Critically, price is inversely related to the other criterion in this factor. The more participants stress the other two items of the factor—quality of the project team and the project execution plan—the less likely they are to emphasize price. Conversely, those who stress price put less weight on the quality of the other items in the factor. The third factor covers the Project Team's Chemistry, including the individuals, their backgrounds, staff turnover rates, and the sponsor company's sense that they can work with the CRO's personnel. Two items, both related to relevant CRO experience, load on the fourth factor: CRO Experience. The fifth factor addresses items associated with a CRO's Capabilities, including the CRO's relationship to the sponsor company.

The factor analysis provides a score for each individual for each factor. The higher the score for an individual participant on a factor, the more prominent that dimension is to the individual. The relative importance of these five decision-making dimensions differs within key groups involved in selecting and using CROs. For example, sponsor companies and CROs view the importance of one dimension, the Specifics of Project Execution, quite differently.

As we have seen, sponsor companies value the quality of the execution plan far more in selecting an outsourcing partner than many people in CROs realize. CRO personnel tend to think that price plays a larger role in the selection process than sponsor companies do. There is also one important difference that relates to an organization's size. Participants from the 20 largest organizations, whether they are sponsor companies or CROs, differ from individuals in smaller organizations on one decision-making dimension: CRO Capabilities.

Larger pharmaceutical companies and CROs give more weight to a CRO's size, geographic reach, and relationship with the sponsor companies. Large organizations, both sponsor companies and CROs, may be more comfortable working with one another as large organizations, especially for bigger studies requiring extensive geographical coverage.

The greatest differences across the dimensions are associated with a respondent's geographic location. The components of the CRO selection criteria are important to both Europeans and Americans. However, Europeans and Americans do differ on three of the dimensions. 

For example, Europeans are far less interested than others in the details and mechanics of identifying and resolving issues and, ultimately, in a CRO's willingness to accept accountability. Americans are more likely to consider Execution Specifics and CRO Capabilities important. They want to see the details of the project plan and project management team devoted to the study. They are more interested in a preferred provider relationship with a larger CRO having geographic reach. 

While Americans stress the mechanics of the CRO/sponsor company relationship, Europeans tend to emphasize more intangibles. These differences by a respondent's geographic location remain significant even when we use ANOVA (analysis of variance) to control for the possible influence of other variables, such as company size and whether a person works for a CRO or sponsor company. 

Most of the pharmaceutical companies surveyed believe that they are on the same skill level as their competitors in selecting CROs, although a few believe that they are more adept at the process. Interestingly, there is no difference in the selection criteria between those companies who believe they are better at CRO selection and those who do not. No matter how well a survey participant's company believes they handle CRO selection, there is no difference when it comes to the five dimensions of selecting a CRO. 

In later research we will examine in more detail the impact of geography in how people approach CRO selection. In addition, we will also present the profiles of companies who do consider themselves better at selecting and managing CROs. 

, PhD, is a professor of health policy at the University of the Sciences in Philadelphia and the president of TTC, llc, 4548 Market St., Suite M-20, Philadelphia, PA, 19139, email: 

, MBA, is an associate director at TTC, llc.

*To whom all correspondence should be addressed.

1. T. Hintz, "Premiere of Exclusive Survey Results: Sourcing Models that Create Value in CRO Partnerships," 16th Annual Partnerships with CROs and Other Outsourcing Providers Conference, IIR, April 14–16, 2007. 

A recent survey uncovers key criteria that influence a sponsor's decision when selecting a CRO.

Key Factors in CRO Selection

Medical imaging is employed in all phases of new drug development. Imaging can guide the diagnosis, treatment, and management of disease and serve as biomarkers for prognosis, progression, and outcomes. Whereas traditional imaging methods are largely directed at obtaining anatomical information, functional (i.e., molecular or mechanistic) imaging quantifies real-time physiologic and metabolic processes at the cellular or molecular level. These novel imaging techniques have become attractive biomarkers in clinical trials. Through early determination of drug efficacy, functional imaging techniques promote efficient decision-making in clinical trials, saving time and money.  

Mehdi Adineh Scientific Director of the Imaging Core Laboratory ACR Image Metrix Phliadelphia, PA			

In today's pharmaceutical development world, a great deal of emphasis is placed on developing better drugs as quickly as possible and in the most economical way possible. Adaptive trials now allow sponsors to make dynamic assessments and changes to their studies to minimize costs and development time. However, this dynamic environment creates new challenges for supply chain support vendors and their ability to react to changing procurement, manufacturing, and logistics requirements. Supply chain/procurement vendors today must be agile and nimble with scalable services, flexible manufacturing schedules, and robust procedures that can quickly react to the needs of this evolving marketplace.  

John Buchholz Amimed Associate Director, Clinical Trials Winchester, KY			

Pharmaceutical companies are facing pressures not only to bring new medicines to market, but to demonstrate long-term safety and real-world value (i.e., clinical performance, cost-effectiveness, and improved quality of life). There is increasing recognition that the conditions under which products are examined for approval are not the conditions under which they may actually be used. Navigating the post-approval landscape requires a roadmap that looks different from the Phase III paradigm. When CROs are viewed as true partners, we can provide the leadership and vision to help our clients achieve success through effective planning, design, and execution of Phase IV research initiatives.  

Jeffrey Trotter Executive Vice President, Phase IV Development PharmaNet Princeton, NJ			

Recently, the industry has seen enormous increases in the number of technology solutions available to help conduct clinical trials. With this has come increased expectations of the way technologies will improve processes, study management, and conduct. Companies now face the problem that management and clinical data are contained within multiple internal and external systems.  

Bill Byrom Senior Director, Product Strategy Perceptive Informatics Waltham, MA			

Today, the industry can realize the benefit of improved data integration and a fully-integrated eClinical platform using product convergence models, offering the ability to see the "big picture" of a compound's characteristics as it moves through clinical development. Furthermore, we can expect to see an increase in simplified end-user workflow, making functionality that resides in one product available through another. 

Historically, IVRS solution providers modeled solutions around "vendor standards," requiring clients to adapt their business processes to conform to pre-formed models. While this approach may save a supplier time and effort, it is an unrealistic expectation of a client whose project is uniquely complex. Today, most clinical studies are unable to successfully mold their needs into such a generic "box." Success in the IVRS-Clinical Trials space requires a keen understanding of client's study-specific needs. IVRS solution customization is inevitable in today's complex world of clinical trials. Now, with study-specific tailored solutions, achieving accelerated implementations of highly-complex studies with improved quality and reduced cost is the new reality.  

Robert MacDougall Vice President Cenduit LLC Durham, NC			

For the interactive version of the timeline, visit 

http://appliedclinicaltrialsonline.findpharma.com/retro

 Also, for more industry resources, go to 

 The events chosen for the timeline were made by industry experts, the EAB, and the editors.

A list of the most influential events affecting the clinical trials industry over the last 30 years.

Timeline

The quality of clinical trials is highly dependent upon the ability of clinical investigator sites to perform their responsibilities effectively. As clinical protocols become increasingly more complex and clinical development becomes more global in scope, the ability to fully meet the needs of investigator sites is also becoming a more critical factor in ensuring the successful outcome of clinical trials. 

Understanding and responding to the daily challenges that sites face, as well as their views on the tools they use to communicate about and manage the study, can also foster a better working relationship between the site, study sponsor, CRO, and central laboratory. 

In 2008, ICON Central Laboratories, a global central laboratory provider, surveyed over 9000 investigator sites around the world to obtain more detailed information about the environment in which sites work, the stresses they encounter, and the types of services that might improve the way they manage daily research activities. The survey responses provide interesting trends and insights regarding how study coordinators, in particular, view and/or are affected by: 					

The type of clinical setting in which they work

The balance between rendering patient care and conducting research functions

The most time consuming aspects of the research responsibilities

The means by which they communicate with the study team and central lab

The type of support services provided by their central laboratory

These results offer study sponsors, CROs, and central laboratories guidance in how they can refine their services to better support investigator sites as they fulfill their critical roles in the conduct of clinical trials. 

ICON Central Laboratories' first annual investigator site survey was conducted in May 2008. The survey was disseminated via email to over 9000 sites worldwide using a commercially available Web-based survey software. It included 33 questions, most involved the use of a rating scale as well as "skip logic," which drilled down to additional questions only when previous responses warranted it. The survey also included several open-ended questions to permit elaboration and additional comments. 

Input regarding the survey design was obtained from B2B International, an internationally recognized market research firm with experience in the pharmaceutical industry. The survey was conducted in English only. To improve response rate, responders were entered into a drawing to receive one of 15 iPod nanos. 

The overall response to the survey was 24%, a rate considered quite good given the mode of survey delivery, the nature of follow-up, and the single language (English) in which the survey was provided. The response rate from North American sites, which represented 69% of those surveyed, was 26%. The response rate for sites in the rest of world (ROW) was 19%. The regional distribution of respondents is indicated in Figure 1. 

  Figure 1: Regional Distribution of Sites			

Due to the low response rate in certain countries/regions, it was not possible to perform a comprehensive geographic analysis of the survey responses. However, some differences could be discerned between some regions and countries that could prove useful in both targeting and refining services. 

Respondents were overwhelmingly study coordinators, with 85% describing themselves as serving in that role. For that reason the responses of study coordinators are the focus of this article. Figure 2 displays the distribution of respondents by research role. 

For the survey, as a whole sites were fairly evenly distributed by inpatient, outpatient, and strictly research facilities. However, when analyzed by country/continent, there were some significant differences, notably the percentage of respondents in non-U.S. sites that indicated their setting was a hospital. This trend likely reflects the manner in which health care is delivered from country to country and, in the case of the United States, also reflects the degree to which clinical research has permeated all facets of the health care delivery system. 

One objective of the site survey was to ascertain the work intensity and stress associated with managing research. As one such measure, survey participants were asked the number of clinical investigators for whom they worked. The responses trended bi-modally with a relatively even distribution between site personnel working for only one investigator or for between three and five investigators.  

The number of study subjects seen weekly was also used as a measure of job stress and intensity. The majority of responses fell into two categories: those seeing between four to 10 subjects per week, and those seeing between 11 to 30 subjects per week. However, in the United States, Canada, Africa, India, and Asia, some 20% of respondents indicated that they saw over 30 study subjects per week. 

As another possible indicator of job stress and intensity, participants were asked whether their positions entailed performing non-research related tasks and, if so, what percentage of time was spent on such activities. Almost all coordinators had at least some non-research related functions, although there were some significant geographic differences with respect to the amount of time spent outside of research. Figure 3 reflects some of these regional differences and may offer insight for CRAs as they plan site visits and other interactions involving coordinators.  

On a qualitative level, respondents were asked what they viewed as the most frustrating aspect of the job on the day of a subject visit. One study coordinator reflected the view of many respondents by stating, "I try to plan ahead as much as possible, but when my subject is late the whole day is thrown off and it becomes a real challenge to meet the courier pick-up time." Study coordinators also indicated that even when time pressures were not present, the stress of trying to meet the needs of the study subject was a contributing factor to daily stress. One U.S.-based study coordinator reflected this trend, noting that the job is stressful even "when everything goes off as planned but we have to tell the subject 'you are not eligible for the study.'" 

ICON Central Laboratories was particularly interested in understanding sites' access to and attitudes toward computer assisted services in managing their day-to-day research activities. Virtually all sites, regardless of geography, had good physical access to the Internet, email, and other research-related software. Interestingly, however, the U.S. coordinators indicated the most difficulty in gaining access to a computer in their work areas, with 22% responding that they did not have good access. A distant second was Western Europe, with 8% indicating that access was a problem. Otherwise, coordinators in other regions did not view computer access as an issue. 

With the growing use of EDC to efficiently collect study data, ICON Central Laboratories opted to survey respondents about their experience in using such software, particularly as it relates to capturing lab results. The vast majority of sites (90%) had used EDC in the management of a study and, of those, 40% had used it to capture lab-related information. Those using EDC for lab data collection generally found the software helpful, with 70% indicating it was quite helpful or very helpful to them. 

The survey questions were structured to gain insight into the preferences of respondents based upon how "computer adept" they were. Survey respondents were categorized as "computer adept" if they: 					

Were clinical research coordinators/study coordinators

Used email to communicate with sponsors/CROs daily to weekly

Had easy access or access most of the time to the Internet, where specimen collection is performed

Respondents were categorized as "not computer adept" [only 3% of coordinators were in this category] if they: 									

Used email to communicate with the sponsor/CRO no more than monthly

Had difficulty getting access to the Internet or didn't have access at all in the area where they performed specimen collection.

Prior to conducting the survey, it had been assumed that study coordinators who were more computer adept would tend to favor certain service features. However, that was not the case. The survey data show that coordinators, regardless of computer adeptness, prefer receiving lab reports via fax. In fact, 80% of coordinators rated fax delivery as a good to excellent mode of delivery vs. mailed hard copies, emailed lab reports, and report retrieval via a secure Web site. That number is slightly higher among noncomputer adept coordinators, but not significantly. 

When report delivery preferences were analyzed by geographic location, a significantly different picture emerged. Coordinators in the United States favor fax delivery, with 55% favoring that mode and only 29% opting for email. In all other regions, emailed reports were preferred to fax. In many countries, when those preferring email delivery and access via secure Web site were added together, they represented 50% or more of the respondents. 

The most apparent difference between the two groups related to their preferences for new on-line services. The introduction of more computer intensive services such as a Web-based requisition form, a Web-based investigator manual, the ability to order collection kits and supplies online, and the ability to process shipments via the courier's Web site instead of using preprinted airway bills were viewed more favorably in the "computer adept" group, although both groups expressed fairly high levels of support for such new services. 

Coordinator attitudes toward using computer technology seemed to reflect either one extreme or another. "The less I have to go searching on the Internet for lab reports or anything else, the better," noted one coordinator. While another stated that "using online lab tools would be huge." These polarized responses typified the respondents free text comments in this section of the survey.  

Since investigator meetings serve as an important means for communicating information about lab and other study-related matters, two questions were included in the survey to better understand this area. 

The first question related to whether coordinators had actually attended an investigator meeting and heard the lab presentation. Surprisingly, the percentage responding "yes" to this question varied significantly, depending upon the geographic location of the coordinator, with 74% of U.S. study coordinators having attended such a presentation and only 55% of non-U.S. coordinators indicating such attendance. More investigation is needed to understand why this disparity exists, since such presentations are routinely provided as a part of the central laboratory's service package, regardless of the meeting's location. 

The second question asked respondents to rank the lab-related topics of most importance to them when attending the investigator meeting. The question was posed to determine if regional differences would justify a different approach to such presentations depending on the countries participating in a study. Few regional differences were identified from the responses, with virtually all respondents ranking the explanation of kits, the overview of specimen collection instructions, and contact information as the most important topics to address in the lab's presentation. 

The survey also asked respondents to rate their interest in a variety of services that could be made available to them in the future. Regardless of location, coordinators seemed to have the same priorities for such services, with particularly high interest in online access to requisitions and study-specific lab manuals and the ability to reorder kits and supplies via the computer. 

Results reveal insight into the roles, activities, pressures, and priorities of study coordinators.

Investigator Site Survey

Pharmaceutical companies recognize the benefits of carefully managing the quality of data from their drug development and clinical trials. To ensure clinical data accuracy and integrity, it is necessary to thoroughly review these data, to assess the validity of outlying data points, and to carefully document query identification and resolution throughout a study's duration.  

Maintaining accuracy and quality throughout a clinical study is a continual, dynamic process.  Although study requirements are carefully set forth initially in detailed documents such as an approved clinical protocol, a data management plan, and an accompanying project plan, expectations and requirements can change during a study. This ongoing process requires revising mechanisms and communicating these revisions clearly to all investigators and support staff.  

PHOTOGRAPHY: PHOTODISC  ART DIRECTION: PAUL A. BELCI			

the total set of characteristics of a product or service that affect its ability to satisfy a customer's stated or implied needs. 

the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management. 

the systematic and independent examination of all trial-related activities and documents. These audits determine whether the evaluated activities were appropriately conducted and that the data were generated, recorded, analyzed, and accurately reported according to protocol, standard operating procedures (SOPs), and good clinical practices (GCPs).

periodic operational checks within each functional department to verify that clinical data are generated, collected, handled, analyzed, and reported according to protocol, SOPs, and GCPs.

The ongoing challenge in managing the quality of clinical data is to continually monitor data collection procedures and data management practices at every level of the study. This includes: 					

ensuring that data generated during the study reflect what is specified in the protocol (case report form [CRF] vs. protocol)

comparing data in the CRF and data collected in source documents for accuracy (CRF vs. source documents)

ensuring that the data analyzed are the data recorded in the CRF (database vs. CRF).

Quality surveillance continues after the trial has ended and plays an important role in ensuring that: 					

data presented in tables, listings, and graphs (TLGs) correctly match data in the database (TLGs vs. database)

data reported in the clinical study report (CSR) are the data analyzed (CSR vs. TLGs)

all aspects of the data management processes are compliant with SOPs and GCPs.

The quality plan describes how the quality control and quality assurance processes will be applied throughout the clinical trial. It definitively defines the various quality-related tasks in the study. A quality plan documents specific quality practices, resources, and activities relevant to a specific project. This includes both operational QC and QA activities. 

It is critical that trial managers develop a QC plan for each key operational stage of the study that defines standards against which QC will be conducted, including: 					

data source to be used for QC at each operational stage

appropriate methods to report and distribute results.

During the study design phase, QC personnel provide an independent review of the approved proposed protocol. The QC plan includes comparison of the study's CRF to the objectives set forth in the protocol to ensure that it is designed to collect all necessary data. A requirement to review CRF completion guidelines is also an element of the QC plan. 

For overall site management, a complete QC plan addresses the following: 					

investigator selection and qualifications

		– experience in conducting clinical trials

			– experience with the specific indication

			– not on the FDA's restricted or debarred lists

			– subject informed (signed informed consent form)

			– subject's eligibility (inclusion/exclusion)

			– adverse events (AEs) and concomitant medication

			– drug accountability and storage									

			– completed data clarification forms									

			– EU Clinical Trial Directives 2001/20/EC and 2005/28/EC

A system of checks and examinations that helps ensure the quality of clinical trials.

Quality Control and Assurance

There are three key clinical development regions in Asia, namely India, China, and South East Asia. Each of these regions offers similar attractions and poses similar questions with respect to the placement of global clinical trials.  

The similarities between the regions are the attractions of rapid patient recruitment driven by large patient populations with diseases of both the developed and developing world and fewer competitor trials as compared to North America and Europe. In addition, there could be a substantial potential for cost savings as well as the opportunity to penetrate some of the fastest growing pharmaceutical markets in the world.  

PHOTOGRAPHY: COMSTOCK ILLUSTRATION: PAUL A. BELCI 

Although regulatory approval timelines are longer in Asia as compared to North America, they are the most prolonged and uncertain in China. In Singapore and Korea, regulatory processes are the most streamlined, quick, and predictable. 

Regulatory approval in China for clinical trial initiation may take up to nine months as the approvals dossier navigates its path through six regulatory approval bodies, as shown in Table 1. The potential for delay at any one of these bodies contributes to the unpredictability of the process. Factoring in this lengthy regulatory approval process is essential while planning clinical trials in China. A thorough understanding of the local regulatory requirements is necessary to ensure that the dossiers are correctly assembled to keep delays to a minimum.  

Table 1. Six regulatory bodies in China must examine a clinical trial prior to granting approval. 

Korea is positioned at the other end of the spectrum, with its regulatory processes streamlined such that the Korea Food and Drug Administration (KFDA) is able to deliver approval for a clinical trial application within 30 working days. Furthermore, the Institutional Review Board (IRB) approval process occurs in parallel.  

In Singapore, the average regulatory approval period is four weeks followed by an additional four to six weeks for site-level IRB/ethics committee (EC) approval. In Hong Kong and Taiwan, parallel processing of regulatory and IRB/EC approval is possible and takes on an average eight and ten weeks, respectively, to obtain both approvals. This is followed by a further two week wait to obtain the license to import clinical trial supplies.  

Over the past two years, the regulatory approvals process in India has become progressively more streamlined, with median approval times reduced  from 16 to 10 weeks. Approval from local ECs at the site level is processed in parallel. If biological clinical trial samples need to be exported, then additional approval from the Directorate General of Foreign Trade is required, a process that takes four to ten weeks. Because the Drugs Controller General of India (DCGI), driven by the increased volume of international clinical trial applications, has become more experienced and better resourced, the uncertainty regarding regulatory approval times has substantially diminished. This phenomenon will be notable in numerous emerging countries as their nascent clinical development environments become more mature with time.  

Evolving intellectual property protection legislation 

The local pharmaceutical industry in Asia has historically been dominated by generic pharmaceutical companies. Not surprisingly, therefore, innovative pharmaceutical sponsors have concerns about the protection of their intellectual property (IP) in these countries. However, IP protection legislation in Asia is evolving as a result of international pressure as well as domestic economic development.   

India represents a good example of an Asian country that is embracing international IP protection legislation, with important consequences to both its local industry as well as its positioning in the global pharmaceutical industry. Historically, the Indian Patents Act (1970) that replaced British colonial laws related to intellectual property rights did not recognize pharmaceutical product patents. Instead, the manufacturing process patents were recognized for a seven-year period. Not surprisingly, this legislation enabled the growth of a domestic generic pharmaceutical industry. Winds of change were heralded when India agreed to uphold the WTO Trade-Related Intellectual Property Rights (TRIPS) agreement finalized during the Uruguay round of multilateral trade negotiations in 1995. As a signatory to the TRIPS Agreement, India is committed to recognize and enforce product patents in all fields of technology including pharmaceuticals. The Indian Government, DCGI, and the Indian pharmaceutical industry appear committed to fostering a life science innovation-based industry with the realization that robust IP protection is a prerequisite. Furthermore, India's growing software and entertainment companies continue to lobby for robust IP protection legislation capable of protecting the IP that they are generating. Legislation for the enforcement of IP protection was passed by the Indian Parliament in January 2005 in spite of protests from patient consumer groups—evidence that India's legal system has responded to both the external and internal drivers of change. 

China has also declared a commitment to comply with TRIPS and has amended several IP related laws including the 1993 Patent Law in 2001, Implementing Rules in 2002, and more recently the copyright law. In addition, the enforcement of IP Rights has been strengthened such that there are stiff penalties for patent, trademark or copyright infringement; options to utilize preliminary injunctions; and criminal liability for trademark infringement. The drivers for these legislative changes are the recognition that strong intellectual property protection is necessary to attract foreign investment, protect indigenous IP, and facilitate alliances with international technology leaders.  

Singapore has been ranked as the top Asian country for strong IP protection and legal enforcement by the World Economic Forum (WEF), the Institute for Management Development (IMD), and the Political Economic Risk Consultancy (PERC) three years in a row, from 2002 to 2004. This has contributed to the fact that in addition to clinical development, Western companies have established successful drug discovery alliances with both academic and commercial organizations in Singapore. 

Looking ahead, the expectation for Asia is that both India and China will ultimately evolve their IP protection legislation and enforcement systems to the same standard as South East Asian countries. Meanwhile, however, sponsors remain wary about the protection of their IP in these countries and exercise cautions with respect to the nature of research activities they outsource or offshore.  

China represents one of the fastest growing pharmaceutical markets in the world and is the most lucrative market in Asia. Today, China is the 7th largest pharmaceutical market in the world in revenue terms, valued at approximately 14 billion USD in 2005. In the next five years, this market is expected to grow by another 10 billion USD. The driver for this rapid growth is a population of 1.33 billion that is expected to substantially increase its consumption of Western pharmaceutical products. China has 160 million people over the age of 60, which is expected to increase to 280 million by 2025. The per capita drug expenditure in China is 12 USD, which equals only 2% of that in the United States. Urbanization and increasing affluence is expected to result in an exponential growth from this modest baseline. Furthermore, large-scale conversion from the exclusive use of Traditional Chinese Medicine would augment the sale of pharmaceuticals based on Western medicine. Hence, not surprisingly, most large pharmaceutical companies have a major presence in China and are seeking to continually augment their sales efforts.  

It is worth noting that the widespread concomitant use of Traditional Chinese Medicines with Western pharmaceutical  products represents a challenge with respect to clinical trial design and interpretation of trial data, as the effect, if any, of drug interaction remains to be delineated.  

The commercial value of the Indian market is presently miniscule in value, but is large in volume and growth potential. In volume terms, it is the world's fourth largest market in unit sales, but ranks 13th in value terms with an annual revenue of approximately 5 billion USD. It remains a highly fragmented market, with Indian companies enjoying 70% of the total market share and the leading player having only a 7% market share. The biotechnology market is worth about 1 billion USD and is enjoying high growth driven by exports and domestic vaccine sales. The present per capita pharmaceutical expenditure is only 4.50 USD, providing a modest base for future growth. India's middle income group is comprised of 300 million, which is increasing both in number and affluence, and represents an attractive market. This is especially true with the relaxation of price controls that is expected to result from changes in the domestic generic industry.  

Korea represents another high growth Asian market—the Korean pharmaceutical market is estimated to be worth 5.6 billion USD and has grown on average 8% annually for the past five years, outpacing the growth in the global market. The Korean pharma market has continued to experience restructuring since 1999, when the Korean Government implemented initiatives to improve the cost effectiveness of health care. The implemented initiatives that have had a significant impact on the pharmaceutical market are: Separation of Prescribing and Dispensing (SPD), Actual Transaction Pricing (ATP), and the A-7 policy of pricing innovative drugs at international prices. These initiatives have improved transparency in the reimbursement system and have facilitated the positioning of multinational pharmaceutical companies' innovative drugs in the domestic marketplace. There have also been positive changes in the regulatory climate that have allowed smoother and earlier market access for new, innovative drugs. This, however, is counter balanced by the drive to fix lower drug prices and promote the use of generics by the financially constrained Korean health care and insurance system.  

Clinical trial data from all Asian countries has now been accepted by international regulatory authorities for pivotal studies. An FDA audit of clinical sites within a country is triggered by the presentation of a certain amount of data to the authority from that country and clinical site. Thus, the occurrence of the first FDA audit serves as an indicator of the extent of global clinical trial activity in a country. The FDA has audited the National Cheng Kung University Hospital and Tri-Service General Hospital in Taipei and the Queen Mary Hospital in Hong Kong with no significant finding. The first FDA audit did not take place in India until mid-2005 when two sites in Southern India participating in a global infectious disease trial were audited by FDA inspectors with no findings. China is yet to receive its first U.S. FDA audit. 

Generally, sponsors have been satisfied with the quality of clinical data provided by clinical trial sites in Asia in spite of the relatively nascent clinical development environments. An important reason for this is the availability of numerous hospitals well suited to serve as investigative sites. The vast majority of specialty care in Asia is provided by state-funded general hospitals. The university teaching hospitals have state-of-the-art facilities and technologies with thousands of inpatient beds to provide diagnostic, therapeutic, and support services in all major therapeutic areas. It is at sites like these that the majority of clinical research in Asia is conducted. There are over 17, 10, and 6 such hospitals in Taiwan, Malaysia, and Singapore, respectively.  

Veteran's General Hospital in Taipei, Taiwan, is a multidisciplinary specialist center with 440 attending specialists, over 500 resident doctors, and 300 beds. In 2005, 2.5 million patients attended the outpatient clinics and 1 million received inpatient care. Various specialists at this hospital have served as clinical trial investigators, and in order to facilitate this activity the hospital has its own ethics committee. The National Taiwan University Hospital is Taiwan's premier teaching hospital and leading medical center. Since its establishment in 1897, the institution has trained more than 10,000 physicians. Presently, 840 students are enrolled in medical and other related programs. The 4000 staff serve approximately 2000 inpatients and 7000 outpatients daily.  

Rapid recruitment, potential cost savings, and investigative sites are just a few of the factors attracting sponsors to the region.

Supplements-09-02-2010

A Closer Look at 1572: Interpreting the FDA's Statement of Investigator Form

Key Factors in CRO Selection

Timeline

Investigator Site Survey

Quality Control and Assurance

Conducting Clinical Trials in Asia