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SURVEY : 2010 Salary & Satisfaction Survey  CRO/SPONSOR : Mergers and Acquisitions Prevalent in Pharma  LABS : Discordance Between BICR Readers  Also in this issue : $500 Million a Year Earmarked for Disease Research, EMA Addresses Possible Conflicts of Interest, Investigative Sites in Financial Trouble, Suicide Risk Monitoring

Applied Clinical Trials Digital Edition - November 2010

The increased suicidality risk attributed to new drugs is a cause of heightened safety concerns among patients, sponsors, and regulators. Even medicines previously thought to have minimal effects on the central nervous system can pose a potential suicidality risk.   

To address this problem and safeguard health, the FDA issued the draft guidance for prospective suicidality monitoring. 

Historically, as new safety requirements have been introduced, the responsibility to produce reliable assessments in clinical trials falls to the investigator sites. It is essential that pharmaceutical companies identify a reproducible suicidality monitoring method to relieve the burden on investigator sites and facilitate compliance.  

Using computer-automated interviewing methods to support site efforts is not new. It has actually been in practice for over 35 years, triggered by concerns about the procedural reliability of assessments performed by human raters. Studies demonstrate that patients tend to disclose more suicidal thoughts and behaviors in computer interviews. A new electronic solution will prospectively monitor suicidality in clinical trials in a scientifically-sound, cost-effective, and reliable way. The eC-SSRS is a self-rated version of the Columbia Suicide Severity Rating Scale (C-SSRS), which is the FDA-approved assessment for prospective monitoring of suicidality. 

The eC-SSRS is a fully-structured C-SSRS interview comprised of standardized questions, appropriate branching to follow-up questions, and error-handling routines using interactive voice-response (IVR) technology. Like the C-SSRS, it assesses lifetime suicidality during an initial baseline evaluation and then monitors ideations and behaviors at subsequent study visits.  

The industry can benefit from using this new approach in a number of ways. First, the C-SSRS algorithm ensures that all questions are asked in a consistent manner, reducing clinical variability. Second, suicidality risks are identified with prompt feedback to study sites for timely follow-up. Third, the investigator site burden is reduced and sponsors can save as much as 45 percent.  

The eC-SSRS is designed to meet the objectives of the FDA guidance for prospective suicidality monitoring by providing procedural reliability in content and delivery, scalability for delivery to thousands of patients with accurate recording, and storage and documentation of patient responses. 

Kelly Posner, PhD, primary author of the C-SSRS, has stressed the need for improved and more standardized suicidality monitoring. Closely collaborating in the design and implementation of the eC-SSRS, she believes it is a faithful and accurate representation of the "perfect" C-SSRS interview and has been carefully designed to produce consistent outcomes.  

Recently, in a survey of more than 250 clinicians and study managers, 99 percent of respondents agreed that the eC-SSRS can serve as an effective approach to meeting the pending FDA regulatory requirements. An impressive 97 percent of respondents stated that using this coordinated self-rated solution versus a clinician-only administered approach could reduce their costs.  

The eC-SSRS is a powerful new tool for suicidality monitoring and patient safety. Risk is assessed reliably and reproducibly in line with upcoming regulatory requirements. It is essential that pharmaceutical companies embrace this effective monitoring method to relieve site burden.

A Closing Thought

eC-SSRS can serve as an effective approach to meeting the pending FDA regulations.

Compliance: Suicidality Monitoring

CenterWatch reported in June that sales for vaccines were projected to double to $39 billion by 2013. A segment of the vaccine market, the influenza vaccine, gets a lot of attention with the onset of winter in the Northern Hemisphere. To prepare, the FDA at the end of July issued its approved vaccines and their manufacturers for the 2010-2011 influenza season in the United States. They are as follows: Afluria, CSL; Agriflu and Fluvirin, Novartis Vaccines and Diagnostics; Fluarix, GlaxoSmithKline Biologicals; FluLaval, ID Biomedical; FluMist, MedImmune Vaccines; and Fluzone and Fluzone High-Dose, Sanofi Pasteur. 

According to a VisionGain "Influenza Vaccines Market Outlook 2010-2020" report, 2010 and onward will feature increased sales of influenza vaccines. Novel vaccines are expected to boost the pharmaceutical industry for many reasons. For example, unlike other drugs and biologics in development, influenza vaccines are important in both developed and developing nations. For the developing countries, all infectious diseases remain high on the healthcare agenda. 

According to figures based on PhRMAs Medicines in Development report, there are currently 37 vaccines in development for various strains of influenza. Last year, the concern over the H1N1 virus spurred development for a vaccine. In addition, preparing for a global pandemic of influenza has led governments to stockpile antivirals as a core strategy, according to Market Research Media. Specifically, the report stated that since the outbreaks of bird flu in 2005 and the swine flu in 2009, the stockpiling of antirvirals has increased, and "migrated across all branches of the healthcare systems and sub systems." The size of antirviral pandemic stockpiling spending has grown faster than the market overall.  

For clinical trials professionals involved in the design of an influenza vaccine or a drug affected by seasonality, there are a number of factors to consider. These were highlighted in a January 2010 article in 

Recruitment planning: drugs that require enrollment as soon as a disease is diagnosed, such as influenza, require rapid recruitment and enrollment. Site selection would involve sites that could handle larger number of patients in a shorter time frame.

Regional profiles in global trial planning: peak incidence and peak timing of the indication for these different regions, as well as variations in hemisphere. 

Study start-up: should be carried out in phases, to give priority to the peak area regions/countries and rolled out accordingly.

Feasibility studies: these should include a review of the incidence of disease in previous season for the sites/regions.

BiondVax Pharmaceuticals, an Israeli biopharmaceutical company has begun to immunize subjects in a Phase IIa clinical trial of its Universal Flu Vaccine candidate Multimeric-001. The Phase IIa study is a randomized, double-blind, placebo-controlled, multi-center, safety and immunogenicity study in 200 healthy volunteers being conducted at two clinical research centers in Israel. The company expects results by mid-2011. The study has a 

Daiichi Sankyo received approval to manufacture and market Inavir® for the treatment of influenza in adults and children in Japan. Inavir is Daiichi Sankyo's brand of laninamivir octanoate, also previously known as CS-8958. This is the first drug of a new class of long acting neuraminidase inhibitors (LANIs) to address the limitation of current products, which require daily or more frequent dosing. Inavir is an antiviral, not a vaccine, and was developed under a co-ownership agreement with Biota Holdings, which will receive royalties on all sales in Japan. It has a 

Phase News

Tis the Season, For the Flu

The pharmaceutical industry has been ripe with merger and acquisition activity for the last several years and it is expected to continue for another 12 to 18 months. This profound increase in activity can be attributed to a variety of direct and indirect factors, such as impending healthcare reform in the US, increased regulatory pressure, non-robust development pipelines, and increased generic competition. The drivers of M&A activity warrant an honest and introspective look at the industry and what the organizations that comprise it are experiencing today.  

In this era of economic uncertainty and increased pressure on margins, organizations that possess the bandwidth are seeking growth and a competitive advantage through M&A transactions. Results from Aon Hewitt's new survey, 

Human Capital and the Success or Failure of M&A,

 reflect this trend. For example, 59 percent of finance and human resource executive participants stated that adding complimentary products, brands, or service lines ranked among their companies' primary objectives for M&A over the past two years.  

Survey results also reflect a trend towards gaining access to new markets. Fifty-two percent of participants in this survey indicated that gaining access to new markets ranked among their primary M&A objectives. Within the evolving pharmaceutical industry, some companies are gaining a competitive advantage by balancing their portfolios with service line extensions into the generic and consumer product offerings. This growth trend is particularly relevant for pharmaceutical companies and CROs that have been prospecting pharmaemerging regions, such as India and more recently Latin America, for several years from a manufacturing/clinical perspective and now also from a market perspective.  

Regardless of the impetus and strategic drivers, what truly facilitates a successful M&A transaction? This really depends on a successful and appropriately proportioned blend of the correct understanding, resources, and expectations in the context of the specific time and industry, taking into account all internal and external factors. Often times the term "M&A" evokes a notion of something insurmountable, but with the correct forethought and process it can be managed utilizing the same structure, process, and communication mechanisms that are attributed to other successful projects. 

The following are several factors that should be considered for effectively managing M&A activities.  

First, it is important to recognize that all transactions are not the same. Failing to realize this can result in extra effort and directional and structural modifications that don't necessarily add value or are not required. Being cognizant of the type of transaction ensures customization of an approach that leverages appropriate resources, disciplines, and tools in the execution of a successful integration lifecycle. Though the exact names can vary, there are four major types of transactions:   

Expansion: The primary focus is on infrastructure, shared services, and platform synergies for realizing the main cost efficiencies.  

Transformation: This approach typically requires full integration in both front- and back-office functions and requires a dedicated, structured effort to realize significant change across the enterprise.  

Bolt-on: Minimal structural changes are required as the target organization is typically quite smaller in size relative to the acquirer. 

Tuck-in: These integrations are typically fast paced and directive in nature with the target organization being integrated and rationalized within the acquirer's organization.  

Once the type of transaction is recognized, an organization should deliberately review the organization's new strategy. This will have implications on all aspects of integration that can range from organizational design to the core competencies required for key roles. In fact, 80 percent of participants in Aon Hewitt's survey stated that M&A plays a "major" or "contributing" role in their business strategy. In addition, 63 percent said that their organizations' top challenge in ensuring the intended value of the transaction is realized with ensuring proper alignment of the new company culture with business strategy. Nearly 80 percent of survey participants agreed that the assessment and selection of leaders greatly contributes to the financial success of a transaction. In other words, M&A is a core part of today's growth strategies amongst fast-moving industries, and human capital related issues are at the top of executives' list of success factors. In addition, in order to maximize the organizational benefit of effective leadership selection and culture alignment, it is important to implement change initiatives at the top and cascade them down through the organization in an aseptic and arbitrary manner.  

Equally important is the identification of key success metrics in order to ensure a deal meets its primary objectives. These need to be defined against the strategic agenda of the "new" organization. In client-oriented industries, three primary metrics that tend to be highly effective are employee engagement/retention, client satisfaction, and the achievement of financial targets. While the financial variable in this trifecta is often considered the most important, the interdependency and impact of the other two variables on the financial success of the transaction should not be overlooked or underestimated. These three metrics are very much co-dependent and should be assessed and monitored with this concept in mind. For example, if employees are engaged and motivated, they will be more apt to ensure a better client experience which results in repeat business and contributes to the financial success metrics that have been identified. On the other hand, disengaged employees can have catastrophic effects on an organization that is microscopically being observed by all stakeholders. Therefore, as most staff in the industry is client facing, it is critical to maintain high levels of engagement during transaction activity so that clients experience continuity of service and, at a minimum, "business as usual."   

Taking the concept of "business as usual" a step further, metrics can be used to encourage an environment focused on "better than business as usual." After all, the M&A transaction should result in additional value for all stakeholders, including clients and employees. In fact, 72 percent of participants in Aon Hewitt's survey said that employee engagement of the combined workforce was one of the variables that most strongly impacts the financial value of a transaction.  

These metrics must be routinely monitored for a defined period during and beyond integration from an executive leadership vantage with special consideration towards any variance and identification of course correction to ensure the intended value of the transaction is realized. These metrics can also be utilized as a communication tool for further engagement by extrapolating the results into tangible actions for the entire organization.  

Many organizations struggle with realizing the full potential of M&A activities, and those in the pharmaceutical industry are no different. The speed at which M&As are taking place within the pharmaceutical industry, however, has increased executives' focus on how specific human capital strategies, programs, and tools can maximize the success of transactions. Fortunately, pharmaceutical companies know the value of having a structured and value add project management approach for product development and process improvements—now it is just a matter of applying this skill set to a different type of project with the same intent of value creation and strong financial results.  

 Senior Vice President, Corporate Transactions/Transformation, Aon Hewitt, 199 Water Street, New York, NY, e-mail: 

Feature Article

Organizations are seeking growth and competitive advantage through mergers and acquistions.

M&A in the Pharma Industry

Blinded independent central review (BICR) is the process by which radiographic exams and selected clinical data, performed as part of a clinical trial protocol, are submitted to a central location for independent review. The Food & Drug Administration (FDA) advocates BICR of radiographic exams for registrational oncology studies when the primary study endpoint is based on tumor measurements, such as progression-free survival (PFS), time to progression (TTP), or objective response rate (ORR).

  Current FDA guidance recommends multiple independent reviewers evaluating each subject.

  One consequence of a multiple-reviewer paradigm is the potential for discordance between readers on the outcome of the subjects. Discordance between readers is adjudicated by a third reader to determine the final outcome. Adjudication rates concern sponsors and regulators because the reasons are poorly understood and there are few published metrics regarding the cause of discordance between BICR radiologists. This article discusses the causes of discordance between BICR readers, outlines the frequency of contributing factors, and suggests steps to mitigate preventable sources of discordance. This data was previously presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting.

Based on BICR data from 40 oncology clinical trials in 12 indications including 12,299 subjects, we determined that two readers did not agree 23 percent of the time when determining the best overall response and 31 percent of the time when determining the date of progression. In a subset analysis, data from only breast cancer clinical trials involving 876 subjects was blinded and pooled to identify cases wherein two primary readers were discordant in outcome. Discordance was defined as a difference in the overall best response, response date, or date of progression assessed between the two reviewers. There were 459 incidences of discordance identified. The radiographs were reviewed to determine the cause of discordance between readers and to establish if the discordance resulted from a justifiable interpretation difference where neither reader was incorrect in their assessment, or if it resulted from an assessment error by one reader. We acknowledge there may have been bias introduced into this process, as the "correctness" of the interpretation was judged by different radiologists from the same facility as the original reviewers.  

Table 1. Differences between readers in lesion selection was the leading cause of discordance.			

We identified the reasons for discordance including differences in lesion selection (37%), the perception of new lesions (30%), the perception of non-target disease progression (13%), image quality or missing image data (11%), differences in lesion measurements (9%), and missing clinical information (<1%). In total, 77 percent of discordant cases were deemed to be the result of justifiable perception differences between the two readers, while 23 percent of discordant cases were thought to be due to an interpretive error made by one of the readers. The distribution of reasons for discordance and the classification of justifiable perception differences versus interpretive errors is shown in Table 1 and Figure 1.  

Figure 1. The causes of discordance and classification of justifiable versus interpretive error.			

 When radiologists function as independent reviewers, they can potentially identify different target and non-target lesions that each considers representative of the subject's overall extent of disease. There is also the potential for the reviewers to identify the same lesions but classify them differently between target and non-target lesions. In a study by Hopper et al., two experienced radiologists identified the same lesions only 28 percent of the time.

 Since lesions do not respond or progress at the same rate, differences between reviewers with regard to response or progression of lesions can be observed. For example, in a RECIST (Response Evaluation Criteria in Solid Tumors) study, a percent change in the sum of the lesion diameters of target lesions may indicate an 18 percent increase (stable disease) by one reader and a 20 percent increase (progressive disease) by the second reader. In this example, it is likely both readers are correct and the results differ because the lesions chosen by Reader 1 changed at a different rate than the lesions chosen by Reader 2. Nonetheless, the outcomes are discordant, resulting in adjudication. There are multiple other examples where adjudication is forced by attempting to classify radiologist performance into categorical variables of complete response, partial response, stable disease, and progressive disease. One such example is illustrated in Table 2.  

Table 2. Discordance resulted from a justifiable difference between readers in lesion selection.			

In Table 2, there was discordance in the date of response between reviewers (R1 and R2) due to a justifiable difference in lesion selection. R2 chose more lung disease and R1 identified hilar adenopathy. Because the thoracic lesions, classified as target disease by R2, responded at a more rapid rate than the liver lesions, R2 confirmed a partial response (PR) one time point (TP) before R1. The best response and date of progression between reviewers were concordant, but a justifiable difference in number and classification of lesions resulted in a response date discordance by one time point.  

For registrational studies, current FDA guidance recommends the use of a sequential unblinding image presentation paradigm. In the sequential unblinding paradigm, each time point is read in sequence without access to future time points or knowledge of the number of time points available for review.

  At times, this paradigm forces the reviewer to make an assessment based on limited information, such as the assessment of progressive disease versus stable disease in the face of an equivocal new lesion.   

Due to the partially subjective nature of radiographic assessments, enforcement of the sequential unblinding paradigm, the presence of image artifacts, benign intercurrent diseases, and occasional image quality issues, some radiologists will determine that a new radiographic finding truly represents a new metastatic lesion, and therefore identify unequivocal progression earlier than others. An example of discordance resulting from a justifiable perception difference in the identification of new lesions is shown in Figure 2. Similarly, the threshold for assessing non-target disease progression may differ between reviewers as shown in Figure 3. Perception differences are unavoidable and are, in part, the rationale for the two-reviewer and adjudicator paradigm, where the adjudicator has the ability to review the outcomes and select the most correct assessment.  

Figure 2. Discordance resulted from a justifiable difference in the perception of new lesions.			

In Figure 2, there was discordance in the date of progression based on a justifiable difference in the perception of new lesions resulting from image quality issues. At baseline (A), a poor quality color paper bone scan was received. At TP2 (B), a grayscale bone scan with slightly better resolution was received. At TP2, R2 identified increased uptake on the bone scan in three areas where CT correlation was not possible, and assessed progressive disease. R1 did not assess progression because, in their judgment, an adequate comparison with baseline could not be made. This represents a justifiable perception difference, as comparison between time points was difficult due to poor quality images and changes in scan technique.  

Figure 3. Discordance resulted from a justifiable difference in the perception of non-target PD.			

In Figure 3, there was discordance in the date of progression resulting from a justifiable difference in the perception of non-target progressive disease (PD). R1 assessed progressive disease at TP2 based on an increase in miliary disease (B). R2, however, did not believe that non-target disease progression was unequivocal until TP3 (C). This resulted in discordance of progression date by one time point.  

 There is a component of inter-reader measurement variability that can contribute to outcome differences between radiologists. As discussed by Hopper et al., when the same lesions are chosen by two different reviewers, the difference in measurements can be up to 15 percent, and greatest for lesions with poorly defined margins.

  The potential for measurement variability depends on many factors including lesion size, margination, conspicuity, phase of contrast enhancement, and measurement technique (manual, semi-automated, fully automated), etc.  

Figure 4 represents a justifiable interpretation difference in lesion measurements as well as an interpretation difference resulting from a lack of clinical information. Both R1 and R2 identified the same liver lesion as part of the baseline target disease (A-B, assessed as lesion 001 by R1 and 002 by R2). R1 and R2 measured the lesion on different image slices at baseline and subsequent time points (TP3, shown in C-D). At TP4, the lesion appeared to have increased in size (E-F). R1 measured the lesion which resulted in progression of target disease. R2 indicated the lesion had changed in appearance and decreased in density, and local treatment with radio frequency ablation was suspected. The lesion was therefore assessed as unevaluable by R2. This represents a justifiable interpretation difference, given the lack of clinical information.  

Figure 4. Measurement differences and an interpretation difference due to missing clinical data.			

 Given the global nature of large oncology studies and the limited technical equipment available in certain countries, independent reviewers may have to evaluate images they consider sub-optimal based on their local standards. Image variability can potentially impact discordance as indicated in Figure 5. Due to the potential for reviewers to identify different lesions at baseline, missing or poor quality image data may impact one reviewer's assessment but may have no bearing on the assessment made by the other reviewer. Similarly, as illustrated in Figure 4, missing or incomplete clinical data may affect the assessment made by one reviewer but not the other.  

Figure 5. Discordance resulted from an inconsistency in scan technique across time points.			

In Figure 5, there was a justifiable discordance in response between readers based on inconsistent scan technique between assessment points. Both readers identified the same target lesion (002) in the liver, however, inconsistent contrast administration made comparison between assessment points difficult. At baseline (A), the liver was imaged long after contrast was administered, resulting in delayed scans. At TP2 (B), the liver was imaged without contrast, making comparison with the baseline exam difficult. At TP3 (C), the contrast timing was similar to the baseline; however, the images were reconstructed with a different filter, further complicating the assessment. TP4 (D) was performed correctly, with the liver imaged in the portal venous phase. At TP3 (C), R2 attempted to follow the lesion. R1 did not believe reliable measurements could be made, due to the inconsistency in technique across time points, and assessed the lesion as unevaluable. At TP4 (D), both reviewers measured the lesion and R2 confirmed a partial response (PR). R1 was unable to confirm PR due to the prior unevaluable time point, and therefore assigned a best response of stable disease (SD).  

Additional factors affecting adjudication rates. 

Additional factors which can contribute to discordance between reviewers include the number of adjudication variables, tumor type, drug efficacy, duration of treatment, the number of assessment points, the complexity of the assessment, the subjectivity of the assessment, the types of imaging exams required by the protocol, the precision of the response criteria, and the dating conventions that are followed for assessing the date of progression or response.

Implementing processes to mitigate discordance

BICR reviewers should be qualified based on experience in the indication and response criteria specified in the clinical trial protocol and BICR charter. New BICR reviewers should undergo a certification process including training on BICR processes and reading paradigms followed by the completion of qualification test cases. In addition, each reviewer must complete dedicated protocol training according to BICR standard operating procedures for each clinical trial they are assigned to. Lastly, reviewers should be continuously qualified at a corporate level through ongoing monitoring of reviewer metrics.   

 BICR charters should detail the response criteria used, all modifications to the criteria, application of the criteria, approaches to qualitative assessments, dating conventions for response and progressive disease, and algorithms for handling missing radiographic and clinical data. Limiting the number of adjudication variables to only those that affect the primary endpoint is also recommended. For example, if a study has a primary endpoint of PFS or TTP, the only adjudication variable should be the date of progression.  

 Dating conventions that assign a single time point date are recommended in order to prevent date discordance within the same time point. This would be in accordance with current FDA guidance, which advocates the concept of utilizing a single time point date for the assessment of progression dates.

  For example, if Reader 1 identifies progression of target disease on a CT scan and Reader 2 identifies new disease on a bone scan performed one day later, adjudication is required based on a difference in progression date by one day. If the BICR charter outlines a convention for using a single time point date for the assessment of progression dates, the date of progression assessed by both readers would be concordant, negating the need for adjudication. 

Corrections in the sequential unblinding paradigm.

 While current FDA guidance indicates assessments should be locked after each successive time point, more recent feedback in public meetings attended by officers of the FDA indicates assessments can be overturned based on data which emerges after the initial assessment. Response assessments at prior time points can be corrected based on information presented subsequently as long as the process is defined in the BICR charter, the process is driven by data which emerges after the initial assessment, and there are adequate audit trails that can substantiate the changes.

  Allowing for such corrections results in a data set more representative of the actual response of the subjects, while mitigating discordance associated with pseudo-progression, flare phenomenon of bone disease, and new radiographic findings that subsequently appear to be the result of benign intercurrent diseases. These issues are discussed in the updated RECIST 1.1 guidelines.

Best practices for qualitative assessments.

 Discordance often results from perception differences in qualitative assessments where detail and guidance are lacking in published response criteria. In our analysis, 43 percent of discordance was based on perception differences between readers in the identification of new lesions and the qualitative assessment of non-target disease progression. One way to mitigate these perception differences is to reach consensus within the reader pool on interpretation approaches and establish best practices for qualitative assessments. This can be accomplished through regular case reviews and training using data from past studies.  

As an example, the updated RECIST 1.1 guidelines provide additional detail and guidance regarding the assessment of non-target disease progression in patients with and without measurable disease.

  We presented data at ASCO in 2009 proposing additional rules for assessing non-target disease progression which can be used by the BICR as a supplement to RECIST 1.1.

  In addition, the RECIST 1.1 guidelines provide specific details regarding the handling of equivocal new lesions and an algorithm for using FDG-PET to identify new lesions.

  This additional detail has been particularly helpful in ensuring a consistent approach among readers. Additional areas where discordance can be mitigated through consensus of assessment approaches include: determining the threshold for when subtle findings represent unequivocal new disease, instituting thresholds regarding how a new bone scan lesion is unequivocally confirmed by subsequent modalities, and establishing thresholds to identify when an imaging exam is of inadequate diagnostic quality. The rules governing these approaches should be outlined in BICR charters. 

 Sponsors should consider contracting directly with imaging facilities to ensure imaging exams are performed according to the scanning parameters outlined in the protocol or BICR imaging manual. Just as investigator payment is tied to receipt of case report form (CRF) pages, payment to imaging facilities could be tied to receipt of images at the BICR and resolution of any quality issues.

Educating and training the monitoring staff on the complexity of clinical trials with imaging endpoints is imperative for enforcing site compliance and reducing discordance. Understanding the impact that different quality issues have on response assessments, and the probability of resolution at the imaging facilities, will allow monitors to focus their efforts on critical open issues.

 A well-controlled process for providing the independent review committee with clinical data relevant to BICR can reduce discordance rates. In oncology trials, clinical data such as prior radiation therapy, benign findings, cytology, local therapy, and physical exam findings often contribute to the assessment made by independent reviewers. As illustrated in Figure 4, missing clinical data can result in discordance between reviewers.  

It is important for clinical information to be collected in a manner that facilitates future BICR. The independent review committee can assist the sponsor during CRF development to ensure that all clinical data relevant to the BICR is collected consistently and is organized in a manner that can be effectively used during BICR (e.g., on a per-time-point basis).

  A process for providing clean clinical data and managing updates to data previously assessed should be prospectively defined and agreed upon in a BICR Clinical Data Transfer Plan. 

The overall adjudication rate and the causes of discordance should be monitored throughout the trial. In addition, reader-specific metrics (such as adjudication acceptance and rejection rates, error rates, and inter- and intra-reader variability) should be monitored on an ongoing basis. If outliers or significant discrepancies are identified, investigation, re-training and/or other corrective actions must occur. Monitoring reader performance throughout the trial can identify potential issues early in the process and mitigate unnecessary discordance resulting from those issues. 

Some factors which cause discordance are process-driven or due to justifiable interpretation differences, as was observed in 77 percent of adjudicated cases in our review. Examples include lesion selection, image quality issues, inter-reader measurement variability, perception of new lesions, and the assessment of non-target progression. Separate from these factors are reader assessment errors, such as those identified in 23 percent of adjudicated cases. This finding compares favorably to reports in the literature regarding radiologist error rates.

  The BICR process of adjudication by a third reader identifies and mitigates these justifiable discordances and interpretive errors. Discordance can be further mitigated by qualifying and training reviewers, detailing response criteria and any modifications in BICR charters, allowing for corrections in the sequential unblinding paradigm, establishing best practices for qualitative assessments, taking steps to increase site compliance, ensuring a well-controlled process for transferring clinical data to the BICR committee, and implementing processes to monitor reviewer metrics throughout the trial. 

 MS, is Director, Medical Affairs, email: 

 MD, is Chairman, Scientific Advisory Committee, and Chief Medical Officer Emeritus, 

, MD, is Diagnostic Radiologist at CoreLab Partners, Inc., 100 Overlook Center, Princeton, NJ 08540.

* To whom all correspondence should be addressed.

1. US Department of Health and Human Services, Food and Drug Administration,

 Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 

2. US Department of Health and Human Services, Food and Drug Administration,

 Guidance for Industry: Developing Medical Imaging Drug and Biologic Products Part III: Design, Analysis and Interpretation of Clinical Studies 

3. K. Borradaile, R. Ford, M. O'Neal, et al., "Analysis of the Cause of Discordance Between Two Radiologists in the Assessment of Radiographic Response and Progression for Subjects Enrolled in Breast Cancer Clinical Trials Employing Blinded Independent Central Review." Poster presented at: 2010 American Society of Clinical Oncology Annual Meeting; June 4-8, 2010; Chicago, IL. 

4. K.D. Hopper, C.J. Kasales, M.A. Van Slyke, et al., "Analysis of Interobserver and Intraobserver Variability in CT Tumor Measurements," 

5. R. Ford, L. Schwartz, J. Dancey, et al., "Lessons Learned from Independent Central Review," 

6. R. Ford, D. Mozley, "Report of Task Force II: Best Practices in the Use of Medical Imaging Techniques in Clinical Trials," 

7. E.A. Eisenhauer, P. Therasse, J. Bogaerts, et al., "New Response Evaluation in Solid Tumours: Revised RECIST Guideline (Version 1.1)," 

8. K. Borradaile, R. Ford, "Analysis of the Rate of Non-Target Disease Progression in Patients with Stable or Responding Target Disease by the Response Evaluation Criteria in Solid Tumors (RECIST)." Poster presented at: 2009 American Society of Clinical Oncology Annual Meeting; May 29-Jun 2, 2009; Orlando, FL. 

9. S. Bates, K. Williams, "Effective Management of the Independent Imaging Review Process," 

Understanding the causes and implementing processes to mitigate preventable sources of discordance.

Discordance Between BICR Readers

Act Cover

The current regulations on the publication of clinical trial results require a major overhaul, according to a group of researchers from the German Institute for Quality and Efficiency in healthcare (IQWiG) in Cologne. 

Beate Wieseler, PhD, lead author of "Finding Studies on Reboxetine: a Tale of Hide and Seek," and IQWiG's Deputy Head of the Department of Drug Assessment, noted in the 

on October 12 that public access to regulatory databases  containing  trials of older drugs, more data sharing between regulatory authorities, re-evaluation of a drug if approval is declined elsewhere, and the legal obligation for manufacturers to supply all requested data to health technology assessment bodies without commercial restrictions to publication, are all necessary. 

Implementation of these measures, which should cover trials of both drug and non-drug interventions, would close the information gaps for post-approval decisions and enable adequate decision making in healthcare, she wrote. 

The Food and Drug Administration's Amendments Act of 2007 solves part of the problem over publication bias in drug research by requiring standardized data on protocol and results to be publicly posted at 

, except for Phase I. However, the act has loopholes, and does not cover trials completed before September 27, 2007 or trials of drugs that were never approved. 

"Although comprehensive information will in the future be available on newer drugs, published information on older drugs will remain biased, resulting in an unfair comparison of old and new treatment options," she stated. "It also means that negative findings on drugs never approved may not be made public, even if the drug is approved elsewhere." 

Furthermore, posting of results for trials of approved drugs tested in new, unapproved indications can be delayed for up to two years. Existing regulations are also insufficient to tackle the problem of reporting selected outcomes. Similar legislation to the FDA's Amendments Act is under way in Europe with the mandatory public disclosure of data from the clinical trials database, EudraCT. These laws should be expedited, and the loopholes must be closed, wrote Wieseler. 

The Cologne group assessed the benefits and drawbacks of reboxetine compared with placebo or other antidepressants, such as serotonin reuptake inhibitors (SSRIs), for treating adults with major depression. They also measured the impact of potential publication bias in trials, analyzing the results of 13 trials, including eight previously unpublished trials from reboxetine's manufacturer, Pfizer. They found the overall quality of the trials was good, but the data on 74 percent of patients were unpublished. A further comparison of published and unpublished trials showed that published data overestimated the benefits of reboxetine, an ineffective and potentially harmful antidepressant. 

Reboxetine was approved in several European countries in 1997. In 1999, the FDA granted preliminary approval on the basis of trials primarily conducted outside the United States, but after the results of later North American trials had been submitted, the FDA declined final approval in 2001 because of a lack of compelling evidence of efficacy.  

, Robert Steinbrook, MD, adjunct Associate Professor of Medicine and of Community and Family Medicine at the Dartmouth Medical School, Hanover, New Hampshire, outlined the problems of trusting drug companies to provide the complete picture about the clinical trials they sponsor. Journals should define full access to all the trial data and require that investigators and journal editors have full access, he pointed out. Editors should take appropriate action if concerns about data arise after publication. 

"Trust in the medical literature, not just in industry sponsored trials, is at stake," he concluded. 

editors agree that the medical evidence base is distorted by missing clinical trial data and that urgent action is necessary to restore trust in existing evidence. It is important to re-evaluate the integrity of the base of research evidence, and it is time to demonstrate a shared commitment to set the record straight, they noted in an accompanying editorial. 

Global News

Some believe that the medical evidence base is distorted by missing clinical trial data.

Pressure Grows to Publish Data

 from the European Medicines Agency, new rules have emerged on how it will be handling potential conflicts of interests of its scientific experts. The new rules, endorsed by the agency's management board in early October, aim at snuffing out some of the controversy that has become increasingly acute over the independence of advisors. 

The agency has been pushed into applying a more proactive approach by repeated suggestions that its scientific opinions can be tainted by its dependence on experts who carry out work for drug firms.  

It is promising to do more to identify potential conflicts, and to be more energetic in seeking alternative experts when the need arises—as is often the case with rare diseases, where the pool of experts is often small. It is going to screen all proposed members of its scientific committees prior to their formal nomination. 

The possibilities of conflicts of interest arising are classified as direct or indirect—or as zero, because of "no interests." The classification assigned to each expert or member of the agency's scientific committees is based on a signed individual declaration of interests, which details any financial or other interests that could affect impartiality. According to the risk level assigned, involvement of the expert may be restricted, in view of the nature of the interest declared, the time passed since the interest occurred, and the activity the expert will be involved in. 

The agency's line is that the new rules will balance out "the need to secure Europe's best scientific experts for the evaluation and supervision of medicines while ensuring that these experts have no financial or other interests in the pharmaceutical industry that could affect their impartiality."			

Noel Wathion, Head of Patient Health Protection at the agency, said as the new rules were announced: "We take this work seriously and review our processes continuously to be sure that we take all steps necessary to protect our scientific opinion-making against the influence of any improper interests." 

And so that justice is not just done, but seen to be done, the agency is boosting public access to information on experts' links to industry. Declarations of interests will appear on the agency website not only for all members of the scientific committees, but also for all the other experts included in the agency's database—who run into thousands. 

Putting the policy into place will take some time, because of the practical implications, so the new system is not expected to be up and running much before the middle of 2011. But it is yet another straw (a rather substantial one, at that) in the wind that is sweeping across Europe to shake up any cozy relations that operate against the public interest. 

The suspicions—which are not, in any case known to this columnist, proven—that have prompted the agency to this new move were in prominent view over the authorization of H1N1 vaccines last year, during the flu epidemic. Only weeks ago, French Green member of the European Parliament Michèle Rivasi staged a hearing in Brussels that bore something of the marks of a witch-hunt. She has repeatedly alleged that there might have been something inappropriate in the alacrity with which authorizations were rapidly given to expensive medicines that subsequently proved to be unnecessary—and even possibly to have unexpected side effects. 

She and fellow members of the parliament's health committee looked back at what happened, and forward to what lessons they thought could be drawn for the future. Rivasi said, "We need clarifications on transparency and expertise of the European institutions." The questions posed to the authorities at the hearing included how far the pandemic was properly managed, whether the risks and benefits were sufficiently taken into consideration when authorizing the vaccines, and whether there were any deficiencies with regard to the decision-making. 

 EU officials and diplomats responded robustly. There had been good cooperation, coordination, and synergies, said Andrzej Rys from the European Commission. Anita Janelm of Sweden, which held the rotating chair of the EU presidency at the time of the outbreak, pointed out that during a crisis, decisions often have to be taken even when not all information is available. "In such situations it is better to do more than do less and be criticized for actions taken, instead of being criticized for not acting when actions were really needed," she said. Georgette Lalis of the European Commission said the decision was made to give market authorization for vaccines even though the pre-clinical data was not always available because the World Health Organization raised the alert level. But, she added, "we pushed to the extreme what our scientists could give us." Thomas Lönngren, Executive Director of the EMA, said the risk/safety balance was good, since 45 million people were vaccinated with no serious side effects being detected. 

Members of the parliament also wanted to know what changes should be made to EU response planning, particularly to ensure independence, excellence, and transparency of decision-making. Lönngren acknowledged that healthcare professionals and patient representatives should be more closely involved, and, he went on, that a more flexible approach to pandemic flu vaccine authorization is needed. Paola Testory Coggi, director general for health in the European Commission, promised more coordinated measures to face cross-border pandemics, with a proposal for new regulation next year.  

The growing demand for reassurance that regulation is operating in the public interest have also spilled over into concessions from the authorities on greater access to documents. The European Medicines Agency also set out in October a new policy on how it will deal with written requests for access to documents related to medicines that the agency has originated, received, or holds. 

Readers of this column may recall that earlier this year the agency acceded to urgings from the European Ombudsman to release documents relating to Roaccutane, in what is something of a test case for the agency. 

The new agency policy explicitly takes into account the recommendations from the ombudsman, as well as input from a broad public consultation it organized. It says it "will ensure the widest possible access to EMA documents"—although it continues to insist that some documents, or part of them, may have to be edited prior to disclosure, to protect commercially confidential information and personal data.  

It is not only the authorities that are under closer scrutiny over their independence from big pharma. Patient associations are repeatedly and increasingly under attack for acting as front-men for drug firms as much as defenders of the sick. 

A number of recent exposés of supposed skullduggery have highlighted the failure of some well-known patient associations to observe the letter of the law in disclosing the interests of their officers. In consequence, the European Medicines Agency is contemplating another tightening up of its rules, so as to impose new criteria on admitting organizations of this type to its advisory panels.  

There is, indeed, a palpable sense of paranoia running through many parts of the European health machinery at present. The ruling presumption seems sometimes to be that scientists cannot make decisions independently, that authorities are too easily influenced by the drug industry, and that patient associations are untrustworthy advocates because they are often funded in part by drug firms. 

These sentiments are fed specifically in the health sector by energetic health activists who constantly question the current systems, and more generally by a growing range of what might be termed professional skeptics—not just the media (although they too have a role in this), but particularly by groups who monitor the work of lobbyists in the hothouse atmosphere of Brussels. There can be little doubt about the merits of skeptical questioning in principle: examples of abuses of position and trafficking of influence emerge almost every day across Europe, and it is a good thing that they are exposed and, in many cases, remedied. But in the health sector, the same risk/benefit equation applies to this sort of assessment as it does to any clinical trial protocol or indeed any medicine authorization. 

The best scientists may, in fact, occasionally—or even often—work on the trial of a new medicine, and be paid for doing so by a company developing the medicine. At the same time, regulatory authorities need the best scientists as experts to help reach the best decisions on new medicines. Rigorously excluding them from crossing that frontier will impoverish either medicines development or regulatory activity—and possibly both.  

Similarly, although many patient associations take money from pharmaceutical companies, they do not necessarily represent companies' interests rather than the interests of their members. To put an end to any link between the two would certainly bring the activities of many patient associations to an abrupt end. It would also probably have a negative impact on development of medicines—particularly for some of the niche diseases where patient associations play an important role.  

So some moderation is necessary to prevent excessive enthusiasm for purity—or rather enthusiasm for a purity that could be obtained only at a high cost. What the European Medicines Agency is doing on conflicts of interest and access to documents is a sensible response to current pressures. It might have been even better had it been a spontaneous measure. It is right that the European Parliament should question the authorities on controversial decisions—and suspicions and accusations are best dealt with by such open exchanges, so that they do not develop into widely-held but unsupported urban myths. Greater transparency over patient association funding is a legitimate demand—not to close them down, but to allow them to continue valuable work without being subject to constant allegations of playing for the other side. But it would be foolish to assume that scientists or authorities are so naive that they would be subverted by everything that came out of a patient association. 

Ultimately, balance is the only answer—and balance often has to change in the light of changing conditions. So as transparency rides again, it is, yet again, a new ride in new circumstances. Don't fall off.			

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium. 

View from Brussels

The European Medicines Agency responds to concerns over conflict of interest and openness.

Transparency Rides Again

It is a little known fact at the present time, but many investigative sites in the United States—particularly veteran sites supporting substantial clinical research infrastructure—are financially distressed and struggling. A small percentage of sites are managing to grow their revenue and profitability. However, nearly all investigative sites across academic, practice-based, and dedicated clinical research settings consider the past 24 months to be the most difficult they have ever faced. 

Throughout 2009 and 2010, principal investigators and study staff have reacted to a down economy and a tumultuous operating environment in a variety of ways. Some community-based sites have opted to increase their clinical practice revenue and to pass on conducting clinical research. Academic centers have focused more attention on government grant opportunities and limited but growing funding support from patient advocacy groups. This past summer, a handful of investigative sites established Phase I research facilities hopeful that they might enter this potentially lucrative market characterized by rapid relative growth in clinical trial activity, high per patient grant amounts, and intense competition from contract research organizations (CROs). Some investigative sites have closed their doors never to return to clinical research. 

The economic plight of US investigative sites demands closer scrutiny by sponsors, CROs, and the Food and Drug Administration. This fragile community of professionals faces increasing pressure from sponsors and CROs to perform more predictably, effectively, and efficiently. At the same time, the FDA is tightening its reins, expanding oversight, and conducting more frequent inspections of investigative sites. 

True, some of the recent decline in financial health of the US investigative site landscape can be attributed to the downturn in the global economy. Clinical trial activity—as measured by new clinical trials started—has declined by 40 percent since the second quarter of 2008. Numerous programs have been halted and cancelled. In many cases, investigative sites have invested substantial resources in getting trials started and under way only to learn that they have been terminated. 

The tenuous condition of US investigative sites is also a direct result of sponsors' drug development practices implemented over the past decade. Protocol designs, for example, have become far more complex. Research that I have conducted with my colleagues at the Tufts Center for the Study of Drug Development (Tufts CSDD) shows unequivocally that protocols have become unwieldy and are harming clinical trial performance.  

Sponsors have vied to conduct more robust early stage studies and to collect more clinical data throughout the pre- and post-approval clinical phases. The average number of procedures per protocol and the typical effort required of study staff to execute these procedures, for example, have each increased by more than 50 percent from the early to the late 2000s. The number of eligibility criteria for protocols conducted in 2007 and 2008 grew by nearly 60 percent over levels observed in the early 2000s. The average number of amendments per protocol has increased in step with the growth in design complexity. Yet grant dollars per procedure per protocol paid to investigative sites declined by 7 percent annually, when adjusted for inflation, during the decade. 

The migration of FDA-regulated clinical trials overseas during the past decade—primarily into emerging markets including India, China, and Central and Eastern Europe—has been motivated in large part by economic advantages there. Sponsor companies have found a high volume of eager, treatment-naïve patients, and large numbers of well-trained professionals willing to perform at half the cost of their counterparts in the United States and Western Europe. These economic advantages have prompted sponsors to place 38 percent of their clinical trials among investigators in emerging markets in 2010. Indeed, some sponsors have set and implemented plans to recruit as much as 65 percent of their investigative sites in global regions outside the United States and Western Europe. Globalization has helped commoditize study conduct services and inspired pharmaceutical and biotechnology professionals to continue to pursue low cost investigative sites. 

Facing highly-unpredictable investigative site operating performance, sponsors and CROs have pursued a practice dubbed "hedging" since the early 2000s. Clinical trials are routinely placed among a larger number of sites where each one is contracted to recruit a smaller number of patients. This approach hedges operating risk by spreading the number of patients across more individual sites. But the overall number of patients recruited per site per study is declining, making many trials economically unattractive to US-based sites—especially those with substantial infrastructure. Under the practice of hedging, sponsors and CROs have further encouraged novice investigators, those with little to no experience and infrastructure, to enter the fray as they can accept unattractive grant amounts more easily, often a result of their naïveté. 

 During the past year, how easy or difficult has it been for your site to be profitable? 

Sponsor and CRO grant management practices are particularly at fault for facilitating a more fragile community of investigative sites. In a study jointly conducted by 

and Tufts CSDD this year, 60 percent of nearly 3,000 global investigative sites reported that the past 12 months has been difficult to maintain profitability.  Sites face major cash flow challenges: In a study conducted two years ago, we found that it takes on average nearly 120 days for sites to receive payments from sponsors and CROs for work already performed. Most sites operate on a cash basis where their expenses are paid net 45 days.  

Sponsor payment schedules favor  allocating large portions of the grant to the end of the study, with funds held back until the data has been locked (e.g., after all sites have completed enrollment and the clinical data has been cleaned).  

Research conducted by, and presented at, the Site Solutions Summit this past October depicts a particularly shaky and alarming period for US-based investigative sites:  					

Fifteen percent of annual site revenue is older than 90 days.

One-third of sites are writing off aged accounts receivables. This is up from only 15 percent who wrote off uncollected receivables in the prior year.

Dedicated, experienced investigative sites have been forced to borrow money in order to survive. On average, each site is carrying a debt-load of almost $400,000.

Natural market forces across the global economy are based on products and services that offer superior value. Within the clinical research enterprise, it is a rational behavior for sponsors and CROs to seek lower cost for faster study conduct. 

But in the current operating environment, sponsors and CROs are arguably driving the most experienced US-based investigative sites out of the clinical research enterprise at a time when they are needed most. Forces alienating these investigative sites are not purely market based, but rather they are due to short-sighted drug development practices that are unintentionally preventing collaborations that hold the greatest promise in delivering higher performance and efficiency in the long run. 

The most experienced US-based investigative sites play an integral role in delivering a high level of professionalism, integrity, and expertise. They are a most vital link to study volunteers in the United States, offering patients quality care and essential access to investigational treatments. Veteran investigative sites and those with established clinical research infrastructure hold unprecedented promise in forging progressive relationships with sponsors and CROs that integrate communications, study management processes, and clinical and health information technology systems.  

Some companies and organizations (e.g., CTTI) are already looking at this growing problem. But much more needs to be done and quickly. As a start, each sponsor and CRO must open a dialogue with its experienced US-based investigative sites. This dialogue must include a review of practices contributing to the onerous regulatory compliance burden placed on clinical investigators; of the rising complexity of study protocols and how to simplify and streamline designs in order to improve study conduct feasibility; and of the fragile financial health of many investigative sites and the grant management practices contributing to this dangerous condition. Ultimately, this dialogue will assist in prompting sponsors and CROs to identify concrete ways to change their drug development practices in order to support the success of their US investigative sites... not their demise. 

 is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: 

Clinical Trial Insights

Why investigative sites are at financial risk and how it may effect sponsors and CROs.

Chasing Veteran US Sites Out of the Enterprise

2008 Salary and Satisfaction Survey of Clinical Research Professionals

The 2010 Salary and Career Development Survey for the clinical trials professional featured new directions and challenges over the previous survey in 2008. First and foremost were the economy and the mergers and acquisitions within the pharmaceutical industry. The data and results gathered should prove insightful, and helpful for professionals navigating the terrain over the next two years, when the next survey will be conducted. 

 collaborated with CenterWatch, an information services leader in the clinical trials industry, to broaden the audience of the survey; develop a more robust survey instrument; and to bring its wealth of research and analysis of the industry to bear on the results. CenterWatch will feature its own article based on the survey data in the December issue of its monthly newsletter. 

Providing the backdrop for this year's survey is the state of flux characterizing the pharmaceutical industry. While clinical development talent has traditionally moved between pharma and its outsourced brethren, M&A activity driven by a postmarket world is affecting the R&D industry like never before. M&As and the need to strengthen pipelines is determining the way that pharma is doing business, with many choosing to cut internal clinical and research development in favor of outsourcing to the CROs. This is leading to changing relationships within the industry. 

For example, the late September announcement from Sanofi-Aventis and Covance. The $2.2 billion agreement calls for Covance to purchase two sites from Sanofi for $25 million, maintain employment at those sites for at least five years, and perform laboratory tests for Sanofi, in order for the pharma to "transform its R&D model and discover new medicines through the use of novel technologies and innovative partnerships." In return, Covance will receive between $1.2 billion and $2.2 billion during the 10-year contract, which is viewed largely as a positive by the investment community because of the guaranteed rather than periodic income typical of a transactional relationship. 

Figure 1. The majority of respondents work for a pharmaceutical sponsor, biopharmaceutical, or biologics.  

The Sanofi-Covance agreement follows a similar one struck between Covance and Eli Lilly in 2008. In that $1.6 billion arrangement, Covance purchased a US-based Lilly business facility, as well as agreed to provide clinical testing services to Lilly over a 10-year period. 

Covance is not the only CRO with more strategic or functional service provider (FSP) relationships. i3 also has similar types of agreements with various pharma, including a recent agreement with Lilly for its US-based medical writing, biostatistics, and biostatistical programming functions. Parexel and PPD were recently chosen by GlaxoSmithKline as its two sole providers for clinical development and trial services. GSK specifically cited it was reducing the number of CROs it worked with to increase efficiency and productivity. Bristol-Myers Squibb also chose Parexel and ICON in June to pare down its outsourcing relationships in order to better manage volume and risk mitigation. 

Figure 2. When considering a job change, over 50 percent of those surveyed cited professional advancement as the main motivator.   

How do these strategic moves between pharma and CROs translate on the hiring front? 

Large pharmaceutical companies have eliminated approximately 64,000 employees since 2008. ZRG Partners reported that Outsourcing and Services has 500% more current hiring than Life Science and Pharma. ZRG's Global Life Science Hiring Index, which was launched in January 2010, uses confidential hiring numbers from selected benchmark companies in Medical Devices, Pharma, and Outsourcing/Services. Pharma has a broader base of $357 billion and 804,000 employees comprised of companies including AstraZeneca, BMS, Lilly, GSK, and Merck, among others. Outsourcing/Services comprises in its index $11 billion in revenues, 80,000 employees, and includes Quintiles, Covance, PPD, Parexel, Kendle, ICON, PharmaNet, and others. 

According to ZRG's Life Science Hiring index, regulatory, quality, and clinical roles were the most in demand hiring roles globally for the second quarter of 2010, with 27.2% of all opportunities in these areas. ZRG believes there is a "fight for talent" among the industries for these regulatory, quality, and clinical roles, as 63% of the opportunities come from the Outsourcing and Services sector. This echoes what may be playing out with the change in strategy in pharma outsourcing. For Life Sciences/Pharma, ZRG reports the top area for hiring is in the area General, which includes accounting, finance, and IT. 

Table 1. Respondents were asked how their workload changed in the past three to five years.  

Specifically by worldwide region, ZRG reports that the regulatory, quality, and clinical roles are in the highest demand in the Europe/Middle East/Africa region, with 33% hiring. This is followed by Asia-Pacific at 24%, and the Americas at 22%.  

For our survey, respondents were most likely employed in the pharmaceutical and biotechnology industry, where we had 38.4% of the respondents. CRO respondents were the next largest segment at 21.6%, followed closely by the clinical study/investigative site at 17%. The breakdown is listed in Figure 1. 

Figure 3. Participants were asked to share their reasons for joining a professional organization.   

The hiring markers listed by ZRG indicate at least a comfortable feeling of job security, which is comparable to what our survey of clinical trial professionals said. For example, to the question "How secure do you feel your job is with your current employer?" the majority of our survey respondents across all industries felt somewhat to very secure. Breaking that down by industry—this time not combining biotechnology with pharmaceutical sponsors—is as follows:  

Applied Clinical Trials partnered with CenterWatch on the biennial review of compensation and fulfillment.

Applied Clinical Trials-11-01-2010

Applied Clinical Trials Digital Edition - November 2010

Compliance: Suicidality Monitoring

Tis the Season, For the Flu

M&A in the Pharma Industry

Discordance Between BICR Readers

Act Cover

Pressure Grows to Publish Data

Transparency Rides Again

Chasing Veteran US Sites Out of the Enterprise

2010 Salary & Satisfaction Survey

Act supplement cover

Business and News Update November 2010

Researchers Grapple with CER Challenges

A Comparison of Protocol Characteristics Over Time Shows Complexity is on the Rise