The CRO market is going through major and unanticipated structural changes. Given high sponsor dependence on contract clinical services, it is essential that biopharmaceutical companies monitor and anticipate these changes in order to anticipate and manage them effectively. 

Financial analysts and outsourcing consultants predicted that niche and mid-sized CROs would steal a growing share of the market for contract clinical research services between 2000 and 2005. They anticipated that sponsors would increasingly seek higher levels of specialization and service quality that could only be offered by niche companies. The opposite occurred—according to the results of a recent study that Julia Wenger and I conducted at the Tufts Center for the Study of Drug Development (Tufts CSDD). 

In our study, we arranged CROs into one of three segments: Largest, Next 10, and All Other Companies, based on their annual revenues from clinical services. Tufts CSDD compiled and analyzed financial and headcount data on companies in the three segments. 

We found that the Largest CROs—primarily publicly-traded companies with the exception of Quintiles—have expanded their dominant position in the outsourcing market. The Largest companies captured nearly 80% of the market in 2005. Companies in this segment saw their revenues increase 15.7% annually—from $3.4 billion in 2002 to $5.2 billion in 2005 (see Table 1 for a list of companies in this segment). The Largest segment accounted for 76% of total headcount employed by CROs to provide contract clinical research services in 2005. 

Table 1: Leading CROs from the three segments for the years 2002 to 2005. 

The second segment, the Next 10 companies—also primarily publicly-traded entities—captured 11.5% of the total outsourcing market in 2005 and generated approximately $754 million, up from $495 million in 2002. Companies in this segment grew 14.9% annually between 2000 and 2005. 

Analysts projected that the middle market for contract clinical services would struggle the most to maintain revenue growth through its inability to dominate either full or niche positioning. These projections were mistaken. The Next 10 segment accounted for 11.9% of total headcount employed by CROs for clinical research outsourcing services in 2005 (Table 1 lists companies in this segment). 

Very little is known about the All Other Companies segment. This group is highly fragmented, comprising nearly 100 organizations of which most are niche service providers, founded in the mid-1990s or later. This segment is also comprised of more than 100 freelance consultants. Companies in this segment are privately-held, making it difficult to compile information about them. 

Tufts CSDD gathered data on 93 representative companies in this group. In 2005, the typical company in this segment generated average revenues of $3.1 million. This compares with average 2005 revenues of $568 million per company in the Largest segment and $42 million in 2005 revenues per company in the Next 10 segment. 

The All Other Companies segment captured an 8.5% share of the total market for contract clinical research services in 2005. 			

Contrary to analyst projections, this third segment is growing at a substantially slower rate than the other two. In 2005, companies in this segment generated a total of $561 million in revenue. This represents 6.6% annual revenue growth since 2002—less than half the average annual growth rate for the CRO market overall. This segment accounted for 12.1% of the total headcount employed by the CRO market for clinical research services in 2005. 

Since 2001, development sponsors ranging from biotech companies to mid-sized and large pharmaceutical companies have all become more dependent on outsourcing. In total, biopharmaceutical companies spent $6.6 billion on contract clinical services in 2005 (net of pass-through costs, such as central lab fees and investigator grants). The rate of growth in outsourcing spending by sponsor companies has outpaced the growth rate in overall global development spending—16% and 11% annual growth respectively since 2001. 

There are many drivers of demand for outsourcing drug development activities: Biopharmaceutical companies have largely frozen their global development headcount to contain rising fixed costs while maintaining earnings growth.  

Most of the headcount growth among sponsors has been in Phase IIIb–IV functions. Phase I–III headcount growth has been essentially flat during the period 2000 to 2005. During this same period, the volume of clinical trials conducted worldwide increased substantially, as did the number of geographically dispersed locations of clinical trials. 

There has been a dramatic proliferation of small- and mid-sized biotechnology and pharmaceutical companies engaged in clinical trials around the world. Smaller companies, many of them biotechnology firms, typically outsource greater proportions of their clinical research budgets, as they look to contract expertise that falls outside their core capabilities. And according to the results of a Tufts CSDD study conducted last year, high levels of CRO usage are translating into greater efficiencies for sponsors, including faster development cycle times with comparable data quality. 

Higher relative growth in sponsor spending on CRO services provided by companies in the Largest and Next 10 segments—typically more mature companies—is driven by a number of key factors. Whereas some sponsors are moving toward functional service provider models that may favor niche CROs, a growing number of biopharmaceutical companies are outsourcing broader combinations of contract clinical services that can be provided on a global basis. 

Leading full-service companies offer infrastructure and experience in conducting large-scale clinical trials worldwide. Demand has been particularly strong from sponsors currently engaged in multinational Phase III and Phase IV programs. 

Sponsor companies—particularly the largest biopharmaceutical companies—also strive to deliver continuous improvements in efficiency. Companies in the Largest and Next 10 segments may be well positioned to offer more favorable pricing, as they can spread their costs across scaled operations. Many sponsors have entered into preferred pricing arrangements with many of the larger CRO companies. 

In all, the CRO market is doubling the headcount capacity of clinical research personnel engaged in managing Phase I–IV global drug development programs. Tufts CSDD estimates that in 2005, there were a total of 50,877 people employed by the Largest, Next 10, and All Other Companies combined. This is up from 41,510 in 2002 and represents an annual headcount growth rate of 7% between 2002 and 2005, more than three times the rate of growth in clinical research personnel employed by PhRMA member companies during the same period. 

Slower relative growth among the small companies that make up the All Other Companies segment is indeed a surprise. Being relatively resource poor, many companies in this segment are pursuing a variety of strategies to stimulate growth and differentiate themselves. Based on our analysis of reports from companies in this segment, there are four primary strategies being pursued:  					

acquisitions of, or joint ventures with, site management organizations and managed site networks

acquisition and/or licensing of Phase I facilities

collaborations with software developers to e-enable development programs.

Based on the current and anticipated operating environment for drug development companies, over the next three to five years the Largest and Next 10 segments are expected to continue to grow at or near recent levels. Although the All Other Companies segment is the most difficult to forecast, we expect growth to accelerate as these companies reposition themselves and as biopharmaceutical companies become more adept at managing smaller full and niche service providers.

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

Articles

Clinical Trial Insights

A new study from Tufts highlights employee and fiscal growth in the industry from 2002 to 2005.

CRO Shifts in the Outsourcing Market

To improve informed consent comprehension, federal agencies such as the FDA, Office for Human Research Protection, and National Cancer Institute (NCI) recommend 6th to 8th grade reading level consent forms. But there isn't a single case of sponsors, researchers or institutions getting in trouble with regulatory agencies or IRBs for writing consent forms well above the 6th to 8th grade reading level. 

If they're serious about readability recommendations, sponsors and researchers should be required to certify the grade level of their consent forms, and IRBs should disapprove any forms that do not meet the 6th to 8th grade recommendation. This would bring clinical trial research to a complete halt for a long time, since writing consent forms at a junior high level is practically impossible. 

Federal regulatory agencies and IRBs can tell researchers to write consent forms at a junior high reading level, but they provide only generic templates of "readable" consent forms, leaving out most of the important—and complicated—details. If federal regulatory agencies want consent forms to be written at a 6th to 8th grade reading level, they should post examples of consent forms written at that level, not generic templates or plain language recommendations. 

Agencies should also follow their own advice. The NCI's (

) "Simplification of Informed Consent Documents" recommends writing forms at an 8th grade or lower reading level, but five NCI documents averaged a grade 14 reading level. 

Reading Grade Levels for Five FDA Documents			

PROSE The Readability Analyst software's grade level estimates are based on the average of eight readability formulas. Table 1 summarizes the readability of five FDA consumer-based clinical trial documents (

); none of the five were written at a 6th to 8th grade level. 

Let's briefly consider readability regulations in another industry: insurance. About 39 state insurance departments require specific reading grade levels for insurance policies sold in their states—usually a score of 40 to 50 (Difficult) on the 1948 Flesch Reading Ease Formula (0 = very difficult, 100 = very easy). 

Scores of 40 to 50 average about 25 words per sentence and 167 syllables per 100 words—the reading level of 1940 readers who completed high school or some college. Writing at a 6th to 8th grade level (standard to fairly easy) requires 14 to 17 words per sentence and 139 to 147 syllables per 100 words. 

If this is the federal and IRB goal, sponsors and researchers should have to certify consent form readability the same way that insurance companies certify their policy's readability. 

Although both the FDA and NCI recommend consent forms at a 6th to 8th grade reading level, their own clinical trial information for consumers is actually written at the college level. 

Since writing at lower grade levels is harder than it seems, federal agencies (and IRBs) should either require readability certification or eliminate readability recommendations entirely. Otherwise, federal agencies are hypocritically telling sponsors and researchers to: Do what we say, not what we do.  

A Closing Thought

When it comes to readability, do as the Feds say and not as they do. Federal agencies may recommend that consent forms be written on a junior high school level, but it's a daunting task even for them.

Consent Forms: No Easy Read

CTSD Version 2.5 provides improved data visualization and enhanced user interface

has released Version 2.5 of its Clinical Trials Signal Detection (CTSD) system. CTSD detects, evaluates, and tracks potential safety signals, which allows biopharmaceutical companies to analyze and classify potential safety signals, develop a product safety profile, and make more informed decisions earlier in the drug development process. 

CTSD 2.5 adds an enhanced user interface that features summary displays, data visualization tools, and access to trial data without programming. The user interface's interactive displays facilitate safety review workflow by including patient level drill downs, Lab Trend graphs, an Exposure Summary graph, and Kaplan-Meier plots. It also offers Hy's Law alerts and a full set of Standardized MedDRA Queries (SMQs). 

The product is integrated with Phase Forward's Web Submission Data Manager (WebSDM) platform and offers CDISC support. 

eShowcase

eShowcase: CTSD Version 2.5

The clinical development sector in India engaged in global clinical trials for product registration with international regulatory bodies is fast approaching an inflection point. Following a period when hype exceeded actual trial activity, the sector is expected to accrue revenues of about $150 million USD in 2006, continue enjoying a 25% to 30% annual growth rate, and perhaps even hit the much quoted $1 billion USD annual revenue target by 2010.

 Continued streamlining of the regulatory approval processes and the government's apparent commitment to enforce intellectual property protection to international standards has addressed two key sponsor concerns. Global CROs and multinational pharmaceutical companies are briskly building clinical operations capabilities in India. Consequently, recruiting resources able to meet the demands of the heightened clinical trial activity in India is a challenge, as demand outstrips supply. 

Numerous state- and industry-sponsored training initiatives are attempting to address this resourcing challenge with a degree of success. The expectation is that as India's vast and growing pool of biomedical graduates completes clinical research training programs and obtains clinical operations experience, the crunch will get ameliorated. However, resourcing and capacity constraints at investigative sites could prove to be a more thorny issue. This article discusses the role investigative sites play in enabling the Indian clinical development sector to attain its ambitions and explores effective approaches to building sustainable working relationships with them. 

Sponsors and CROs universally recognize the value of investigators who are able to recruit patients and provide quality clinical data in a timely fashion. They also recognize it is rare for the patient's physician, clinical investigator, and key opinion leader to be the same individual, and they strive to reach out to each of these groups. 

In India's relatively nascent trial environment, investigators not only enable access to the large number of potential trial participants—the fundamental attraction to India—but they also are custodians of the data's scientific and ethical integrity. 

Obtaining data of the quality required to meet international regulatory standards and compliance with the spirit of GCP ethics, in particular the informed consent process, remains a concern for sponsors and CROs. The investigator and site staff play a key role in ensuring that patients are recruited, protocol is followed, and data is reported in accordance with the sponsor's expectations. Although universally true, this is much more relevant in a country like India with its limited track record of global clinical trial participation.  

Investigator selection is the first and perhaps most important step toward building a pool of high-quality investigators. India has over 500,000 qualified doctors, with 17,000 physicians graduating each year from the country's 210 medical colleges.

  Medical training is delivered in English and based on a curriculum that incorporates all of the elements of the Western medical system. India's leading specialists, with appointments at leading state and private hospitals, often have received part of their postgraduate training in either the UK or the United States. 

The vastness of the Indian medical education system with its many physicians and medical institutions poses a challenge because of the tremendous variation in the quality of training. Due to different governance structures, levels of state subsidy, and student motivation there are notable differences in the quality of training, research, and health care delivered at India's medical colleges. 

Although most physicians are keen to participate in global clinical trials motivated by the prestige, financial gains, and the opportunity to offer better medical care to their patients, only a few have the requisite mind-set and capabilities. Until recently, the clinical trial experience that most physicians in India have had was restricted to domestic postmarketing studies, usually conducted with minimal investment and rigor. 

In view of the variability of available physician talent and their limited clinical research experience there is an imperative to circumvent the large numbers of enthusiastic ill-suited investigators and identify those with the necessary mind-set, postgraduate qualifications, and patient access required for international clinical development. 

India's urban-centric health care system includes private and state funded hospitals and clinics. Primary health care is less organized, fragmented, and delivered on an ad hoc basis. 

Specialist health care in the state subsidized sector is delivered from large, moderately well-equipped hospitals often attached to universities and resourced by postgraduate physicians and research fellows. These hospitals offer a wide range of health care services to the inhabitants of the cities they are located in as well as to patients from the surrounding rural communities who travel for their secondary health care needs. Single specialty hospitals located in large metropolitan cities—cities with populations of around 10 million—serve as tertiary referral centers for populations of as many as 200 million. Lower labor costs, a no-frills approach, motivated academic staff, and large patient numbers make India's state hospitals an extremely cost effective health care vehicle. 

It is difficult to conduct clinical trials in a community setting in India and it is the state hospitals that are most attractive for global clinical trials. For trials that seek ambulatory participants, patients are recruited at the hospital's outpatient clinics, and often with a period of planned hospital admission for study treatments. Low hospitalization costs and the associated benefits of hospitalization for patients with limited financial resources mitigate the issues associated with hospitalization in a Western setting. Each hospital or group of hospitals has its own ethics committee that functions in accordance with the spirit of GCP whose approval needs to be sought in parallel with clinical trial approval from the Drugs Controller General of India. 

To date, relatively few clinical trial participants have been recruited from the private health care setting because of the relatively small proportion of the population served. Also, private physicians are not widely recruiting patients. This hesitance may be based on a fear of offending and losing the patient to a competitor. Only 12% of the population has any form of health insurance coverage; this is soon to change and India's health care industry is briskly growing to meet the needs of the country's 300 million strong affluent middle class, which is increasingly expanding. 

The Indian health care market, currently worth about $22 billion USD, is projected to triple in value by 2012.

  A large proportion of this will be within the private health care sector, including corporate private hospital chains. It is only a matter of time before such hospital groups serving middle class urban populations will become the setting of choice for global clinical trials because they will have the requisite equipment, qualified physicians, and access to well-informed patients. 

More experienced investigative sites and private hospital groups keen to attract global clinical trials have established clinical trial coordination cells that ensure availability of site resources and infrastructure and handle contractual matters. A handful has gone even further to set up in-house Site Management Organizations (SMOs). 

Building investigator & site relationships

Sponsors and CROs with medium- to long-term aspirations of working in India need to build investigator and site relationships suited to the therapeutic focus of their pipelines and peculiarities of their work processes. This exercise comprises three phases: identification and attraction of best-in-class investigators; facilitation of effective site working; and creation of sustainable goodwill. 

 Local relationships and insights are critical for navigating the myriad of professional bodies, formal associations, and medical institutions that house potential investigators. Thus, an insider to this world in the form of a well-connected Indian physician trained at one of the better medical colleges in the country is a key asset for seeking out quality investigators. As is the case elsewhere, individuals who belong to and are respected are able to gain access across the ranks of their community. 

Often physicians with the ability to be best-in-class investigators have heavy clinical workloads, commitments to academic research, and less financial motivation—thus, they're reluctant to participate in clinical research. An understanding of their working environments and personalities could enable the crafting of attractive proposals that include site support staff, academic grants, and/or international research collaborations. Proactively reaching out to this physician group and accommodating their needs could prove valuable for sponsors and CROs. 

 Site support by provision of ongoing training, staff, infrastructure, and streamlined contractual processes is essential to enabling mutually satisfactory and sustainable working relationships. One size does not fit all; hence, site support must be tailored according to the site's experience and available resources. Furthermore, certain investments may require a commitment that extends beyond the life of a single study. 

GCP compliant clinical trial training modules are essential for sites with minimal experience, and staff turnover may necessitate refresher courses. In addition, it is important to arrange training related to the peculiarities of a particular trial as well as the operational processes and systems of the sponsor or CRO. Training is best conducted at the site by sponsor or CRO staff. 

Considering the busy clinical workload at state hospitals, providing staff that are dedicated on a full- or part-time basis to the study is essential. For it is they who will support the investigator with regulatory document management, patient recruitment, patient and family counseling, record keeping, and patient follow-up. A clear definition of roles and responsibilities is valuable; indeed, it is good practice for the various site personnel (including investigator, research fellow, study nurse, study coordinator, and medical social worker) to clearly document their contributions and data entries on both the patient notes as well as the clinical report forms. 

At poorly resourced sites there will be a need to provide infrastructure such as a designated broadband connection, PC, refrigerator, and/or filing cabinets. The sponsor provides funding for staff and infrastructure either directly or via site fees. This should prove a worthwhile investment, and clear contractual arrangements should be made for timely payments. Excellent widespread Internet connectivity along with availability of IT savvy investigators and site staff offers compelling opportunities for the deployment of electronic data capture as well as other IT support tools. 

 Recognizing the critical role of investigators and sites, sponsors and CROs seeking to conduct increasing proportions of their clinical development programs in India over the medium to long term should build sustainable relationships with sites and investigators. It is unlikely that an organization will be able to negotiate exclusive access to a site or investigator network; however, efforts to develop sustainable working relationships could enable preferred access. Identification and elimination of the points of pain experienced at the site could help this endeavor. 

A good example is the feasibility assessment process. As sponsors build knowledge of the capabilities of sites in India, it is not uncommon for them to bombard multiple sites with detailed, tedious questionnaires. Sites keen to participate in global trials promptly respond but soon realize that a small portion of these convert to trials awarded—largely because sponsors have embarked on feasibility assessments when the inclusion of their site was a remote possibility. 

Of course, assessment of the feasibility of a protocol and projected patient accrual is an important part of trial execution. However, it is possible to conduct this exercise in a less painful manner. This could be achieved by fashioning an abbreviated questionnaire when a sponsor's intent is uncertain; archiving data received from sites so that tedious questions of a general nature need not be repeatedly raised; offering financial compensation; and by making the process site friendly. Personal investigator relationships often help overcome the frustrations of site staff and elicit responses. However, this goodwill can not be exploited on a long-term basis. 

Sponsors and CROs able to ameliorate such points of pain will enjoy a competitive advantage with respect to site access. Streamlined contractual processes and prompt site payments are other examples of points of pain often quoted by sites. 

Sites in India's leading metropolitan centers that have obtained a track record of contributing to global studies are already in demand. Although there presently remains additional capacity at these sites, farsighted sponsors and CROs have elected to develop sites located in India's second-tier cities, which typically have a population of around 1.5 million.  

Moreover, there is a tendency to overutilize the top 10 investigators and sites within each therapeutic area. As a result, there is already a build up of competitor trials at India's key oncology, neuropsychiatry, and cardiology sites. Continually identifying and developing new investigative sites will drive a balanced growth of India's clinical development sector. 

In addition, there is a strong case not just for attracting investigators working in India's second-tier cities but also for reaching out to more recently trained specialists and physicians. As more investigators mature toward key opinion leader status, the pool will continue to be replenished. 

As India's clinical trial sector grows, there will be a shortfall in the number of quality investigators and sites able to meet the increased demand. Therefore, stakeholders keen to ensure that India fulfills its potential as an important contributor to global clinical development are advised to make the necessary investments to build, nurture, and support a robust network of investigative sites across India. 

, MD, DPhil, MBA, is vice president of investigator relations, scientific & medical affairs with PRA International, Pacific House, Imperial Way, Worton Grange, Reading, Berkshire RG2 OTD, United Kingdom, +44 118 918 1025, email: 

1. Indian Clinical Trials Market, McKinsey Report, 2002. 

2. Handbook of Medical Education, Association of Indian Universities, New Delhi Edition, 2004. 

3. Indian Healthcare Industry, ICRA Report, 2005. 

Feature Article

India's investigators play a key role in helping CROs & sponsors recruit patients and meet global standards.

Investigative Sites Unlock the Door to Success in India

Legislation designed to encourage pharmaceutical companies to underwrite research on drug use in children requires Congressional reauthorization this year, generating talk of revising the system. Research sponsors say the current incentives are working fine and are needed to encourage more studies, but generic drug makers and some health care providers claim that added exclusivity for brands drives up the cost of medicines. 

Efforts to make prescription drugs more affordable also is spurring a campaign to authorize the FDA to establish a pathway for approving generic or follow-on versions of biotech therapies. Amidst the debate over costs and exclusivity, the need for clinical trials on follow-on biologics is emerging as a key issue. 

Incentives and requirements for pediatric studies expire September 30, 2007, and pressure is building to extend these programs. The Best Pharmaceuticals for Children Act (BPCA) grants an added six-months exclusivity to manufacturers that conduct postmarket research likely to generate new labeling on correct drug use in children. This 10-year-old policy is hailed as a great success, having generated some 800 studies that have resulted in labeling changes for more than 100 drugs. 

The legislation also established a program at the National Institutes of Health (NIH) to underwrite pediatric research on drugs with expired patents that do not draw manufacturer support, but this has been less productive. 

In addition to the BPCA "carrot," the Pediatric Research Equity Act (PREA) of 2004 provides a "stick" to spur research by giving FDA authority to require pediatric studies of some drugs under development. Sen. Chris Dodd (D-CT), who is the main proponent of both programs, has also introduced legislation providing incentives for developing medical devices designed for children. 

The campaign to maintain incentives for pediatric studies has generated debate over a number of provisions. BPCA and PREA both have to be reauthorized every five years, and sponsors claim that uncertainty about the incentives deters some research. However, Dodd and most policy makers want to maintain the five-year sunset on the exclusivity program, but support legislation sponsored by Sen. Hillary Clinton (D-NY) to make the PREA pediatric rule permanent. At a hearing held by the Senate Health, Education, Labor and Pensions (HELP) Committee in March, Richard Gorman, MD, of the American Academy of Pediatrics (AAP) backed additional changes to increase transparency of pediatric study results and FDA's process for managing the research and exclusivity awards. 

The main issue, though, is whether the current six-month exclusivity program provides a big windfall to marketers of blockbuster drugs. Patient advocates, generic drug makers, and some medical groups want to reduce exclusivity to three months, particularly for products with sales over $1 billion or other thresholds. Democrats added such a change to legislation to continue the prescription drug user fee program. That provides critical support for the FDA drug approval process and is considered "must pass legislation" before it expires this fall. 

Gorman of AAP advised that any such change should be carefully analyzed to ensure it does not reduce the number of drugs studied in children. Dodd backed exclusivity for blockbuster drugs, despite industry cautions that "if it's not broke, don't fix it." 

Support for reauthorizing BPCA and PREA comes from a Government Accountability Office (GAO) report issued in March that documents the success of BPCA in spurring industry-sponsored pediatric research and important drug labeling changes. From 2002 to 2005, the legislation prompted FDA to issue more than 200 written requests for pediatric studies, and sponsors agreed to conduct the requested research on 173 of them. 

Although most of the studies were still ongoing, the program produced more than 50 exclusivity determinations during that period, and most (87%) of those exclusivity awards led to labeling changes for drugs that treat a wide range of diseases, including some life-threatening conditions for children.  

However, GAO noted that the FDA process of approving labeling changes resulting from the studies was often lengthy and cumbersome. 

Moreover, the analysts were critical of the NIH program to fund research on those drugs that fail to draw industry sponsorship. FDA had requested that the nonprofit Foundation for NIH study nine drugs that industry declined to take on, but only one research project may result. The problem is that NIH calculated it would cost more than $40 million to study six of the nine drugs and the Foundation had raised only $1 million for the program through 2005. The high cost of pediatric clinical trials appears to be taking a toll on the program. 

A March report from the Tufts Center for the Study of Drug Development documents a sharp rise in pediatric research costs from nearly $4 million in 2000 to $30 million in 2006, and a doubling in the time it took to conduct studies on children. FDA requests for more trials and longer studies increase research expenditures. And problems recruiting child volunteers for desired studies prompt sponsors to try to renegotiate the scope of requested research with FDA. 

An article by Duke University researchers published in the 

Journal of the American Medical Association

 in February similarly reported that pediatric studies for nine drugs cost from $5 million to $44 million. The article concluded that the pediatric exclusivity program may over-compensate a few companies that conduct pediatric research on blockbusters, but that most products gaining exclusivity realize only modest returns on their investment. 

The rise in research costs and user fees on pediatric study applications provides ammunition for those who claim that a reduction in exclusivity will curb industry enthusiasm for tackling pediatric study proposals, especially on small-market drugs. However, Congressional leaders appear intent on curbing any windfalls for drug makers from this program. 

In addition to limiting exclusivity for pediatric studies, generic drug makers also would like the user fee bill to include a measure that authorizes FDA to approve follow-on versions of biotech therapies. However, this more contentious issue may take more than a few months to resolve. A key issue is whether clinical trials are needed to bring a follow-on to market. 

Innovator drug firms claim that any biologic produced by a different company must submit data from clinical studies to demonstrate "sameness" and rule out clinically significant differences. Generic firms maintain that advances in analytical testing can ensure comparability and safety of similar versions of large molecules. This is important, they maintain, because the resulting market competition will greatly reduce the cost of important therapies for patients. 

FDA officials say that the extent of additional studies should be based on the complexity of the product and its clinical use and experience. Clinical trials are not always the best way to assess product structural changes, some experts point out. "But some degree of clinical assessment of a new product's immunogenic potential will ordinarily be needed," said FDA deputy commissioner Janet Woodcock at a hearing in March held by the House Oversight and Government Reform Committee. 

Such research requirements could range from small pharmacokinetic studies to larger randomized trials. However, if clinical trials are not needed, Woodcock commented, it may be unethical to require them. FDA requested additional clinical testing for Sandoz' Omnitrope follow-on, but not as much as provided originally by the innovator. 

A related issue is whether the manufacturer of a follow-on product could submit enough clinical trial evidence for the new drug to be rated therapeutically equivalent to an innovator biologic. Documenting comparability is quite challenging, but "ensuring interchangeability is essentially impossible," commented former FDA official Jay Siegel, now with Johnson & Johnson, at a hearing before the Senate HELP Committee. 

Even with many added studies, Omnitrope did not get a therapeutically equivalent rating from FDA. To demonstrate substitutability, Woodcock said that the follow-on sponsor may need studies showing that repeated switches between the innovator and the follow-on has no negative effects on patients. 

				FDA envisions a case-by-case approach to testing and evaluating comparability of follow-ons, similar to the approach adopted by European regulators for "biosimilars."

FDA is developing long-awaited guidance to clarify what data it recommends for developing new versions of fairly well-characterized biologics, such as human growth hormone and insulin. Evaluation of follow-ons will be complex and time-consuming, but Woodcock says FDA has the expertise to make the hard decisions that will arise, as policies governing follow-ons gradually evolve over the next decade. 

While policy makers have agreed on many of the core issues related to follow-on approvals, continued debate on exclusivity and testing may delay adoption.  

View from Washington

Policy makers discuss incentives for trials on children and for generic versions of biotech therapies.

Trials for Pediatrics and Proteins Under Debate

Safety issues pinpointed earlier with Spotfire's interactive analysis data solution

 Clinical Trial Analysis software is built on its DXP enterprise analytics platform for pharmaceutical companies and can be used by physicians, scientists, analysts, and nontechnical staff to discover data relationships related to drug safety and efficacy. This allows companies to address drug design and discovery earlier in the process. 

Spotfire Clinical Trial Analysis provides querying capabilities of clinical and molecular data using graphs and charts. It analyzes data from various sources to identify trends, outliers, and exceptions; offers visual representations (charts, plots, graphs) of adverse event data, lab safety, demographics, and concomitant medications; allows for ad hoc data query; finds correlations between gene or protein expressions and safety profiles; and adapts to new technologies and methodologies. 

eShowcase: Clinical Trial Analysis

The contracting of trial activities to vendors is now commonplace in clinical research. However, determining what regulations are in place and how to develop a system of oversight is often difficult for sponsors. 

  can prove frustrating. There are no requirements for clinical quality assurance and no references to auditing vendors. Also, the FDA has well-defined expectations in some areas, but is less clear in others. 

Developing a program of quality assurance for vendor oversight is important for sponsors concerned about the quality of their trials. This article attempts to provide a regulatory context for managing three important GCP vendors: CROs, clinical labs, and site management organizations (SMOs). 

It is helpful to look at the FDA's two main concerns when conducting a GCP inspection at a sponsor of clinical research.

The integrity of the data submitted to the agency in support of an application

The protection of the rights and welfare of human subjects in clinical research.

A useful guidance for data integrity and human subject protection is the International Conference on Harmonization (ICH) document E6, Good Clinical Practice: Consolidated Guidance.

  We learn in section 5.1.1 that the sponsor should develop "quality control systems with written SOPs." And in section 5.1.3 we learn that "quality control should be applied to each stage of data handling."

In some ways, the data integrity portion of GCP compliance is that simple: "Each stage of data handling." Many GCP vendors are hired to do just that. They handle and process data from a trial. So, the first component of any GCP compliance activity is to determine data flow. Each entity, such as a statistician, that handles data from the time the subjects have signed the informed consent form until the time the database is locked needs consideration. 

Next, "each stage of data handling" needs to be determined. For example, a study coordinator enters a subject's blood pressure into a case report form. That is a stage of data handling. The sponsor contracts with a CRO to send a monitor to review the CRF. That is a quality control system. It all sounds pretty simple at first. However, the devil is in the details. Looking at the different types of organizations that handle the data shows why. 

The most common vendor performing work on clinical trials is the CRO. Most CROs provide a variety of functions. They are also the only vendor that is specifically covered in the regulations. FDA's regulations state: "A sponsor may transfer responsibility for any or all of the obligations set forth in this part to a contract research organization."

  This transfer must be in writing and all CRO responsibilities must be described in detail. 

However, the sponsor cannot just sign away its responsibilities and forget about them. Ultimately, the sponsor is always responsible. After all, it is the sponsor's investigational product, and it is the sponsor who submits the data to the agency. Thus, it is important for a sponsor to conduct due diligence by auditing the CRO prior to the enrollment of subjects. This is particularly true if it is the first time the sponsor is using the CRO. The sponsor's clinical quality assurance team or an outside contractor can conduct the audit. 

It is important for a sponsor to have written procedures for audits. A written plan for the specific vendor audit is highly recommended. The plan should cover each stage of data handling the vendor will be performing. Other areas to cover in a CRO audit include staff qualifications, experience in the therapeutic area of the study, written procedures, workload, and internal quality control and quality assurance activities. 

Sponsors should seek input from each department impacted by a CRO. Clinical development, data management, and drug safety departments can provide insight regarding CRO qualifications and should be consulted regularly. 

The most common responsibility transferred to a CRO is monitoring. An important component of monitoring is reviewing CRFs against source documents for data integrity. But is that the only stage of data handling? Were specimens or ECGs collected? These are also stages of data handling and need to be conducted under quality control with written procedures. 

A monitor will also have other responsibilities, including review of regulatory documents for submission of adverse event reports and IRB approval. A monitor will need to review informed consent forms. This is necessary for the protection of human subjects—FDA's second major concern—and should be a part of the monitoring plan and procedures. 

It is important to note that the medical device IDE regulations

  are silent about CROs. Although the FDA realizes that CROs are often used in medical device clinical trials, the regulatory responsibility always rests with the sponsor. 

If the regulations are clear regarding CROs, the opposite is true for contract clinical laboratories. There is noticeable regulatory silence when it comes to clinical laboratories. 

FDA does not have any specific guidance or regulations applicable to clinical labs that support trials. Consequently, many organizations look to the Clinical Laboratories Improvement Amendments (CLIA) for regulatory guidance. However, CLIA specifically states that it does not regulate research.

What to do? In spite of this, CLIA is still a very good place to start. FDA recognizes CLIA certification as the principle government standard for laboratories, and it is acceptable to FDA as a standard for diagnostic laboratory tests.

  In addition, many industry auditors use the Good Laboratory Practice (GLP) regulations, 21 CFR Part 58, as an audit guide. These regulations govern FDA's oversight of nonclinical laboratories, primarily animal laboratories, for toxicity and other safety testing. They are not, however, meant to govern all laboratories that perform analyses for FDA regulated products. 

There is no requirement for GLP, CLIA or any other lab certification for a clinical trial. The sponsor is pretty much on its own when it comes to qualifying a clinical laboratory. 

So, what criteria should be evaluated in an audit of a clinical laboratory? Once again we start with quality control with written procedures at each stage of data handling. 

Follow the flow of a specimen from time of receipt to storage, destruction or return. There should be written procedures at each stage of data handling. In addition, the audit should determine that employees are qualified, the equipment calibrated, and that data can be attributed to a specific sample number. Labeling by subject identifiers is essential so that specimens throughout the analysis and final lab report are accurately correlated by data to subject. The data are worthless if you do not know which subject you are dealing with. 

Finally, just because a laboratory has analyzed a sample and generated a report does not mean the data have been successfully transferred to the sponsor. How does the lab send the data? By FedEx? By email? In what format is the report? Is it a printed form or a spreadsheet? This is a stage of data handling and needs quality control with written procedures. 

Clinical labs are often very large places. Therefore, it is important not to get lost when conducting an audit. To avoid getting lost, focus on the areas important to the specific study. 

It is worth noting that there is one place that clinical laboratories are subject to GCP regulations. The investigator is required to maintain adequate and accurate subject case histories.

  Laboratory reports are frequently part of those case histories, which is one reason why the investigator needs to list the clinical lab on Form FDA 1572 required by regulation.

If the laboratory is under the clinical investigator's direct control and supervision, it would be covered by the regulations. This is more often the case for specialized instruments such as echocardiograph machines or ECGs and the technicians who operate them than for actual clinical labs. 

Many sponsors are using SMOs in an effort to improve subject recruitment and GCP compliance. However, it is a mistake to think that SMOs are regulated the same way as CROs. In fact, the regulations treat them both quite differently. 

Why is this the case? It is a question of responsibility.

  Where the regulations allow the sponsor to contract certain responsibilities, they require the investigator to "personally conduct or supervise" the study.

  Since the SMO contracts with the investigator and not the sponsor, it assumes responsibilities assigned to the investigator in GCP regulations. 

Most SMOs provide study coordinators and other study staff. Staff members often participate in the recruitment of subjects and obtain informed consent.

  Study staff will maintain study records, including disposition of the study drug/device

  and subject case histories. These are specific regulatory responsibilities of the investigator. If the FDA has a problem with the conduct of the study, it is the investigator, not the SMO, who receives regulatory correspondence, including a warning letter, from the FDA. This should be understood by every investigator prior to subject enrollment. 

An SMO may have functions that are contracted responsibilities of the sponsor. These functions include the selection of a qualified investigator to conduct the study, test article accountability, and safety reporting.

  If an SMO has contracted with the sponsor or subcontracted with a CRO to perform regulatory responsibilities, then it can be held accountable by FDA. This certainly can be confusing. It's a question of responsibility—so the sponsor, investigator, and any contractors need to know exactly where responsibilities lay. This makes the auditing and qualification of an SMO a challenging task. Let's break things down into manageable portions. 

An SMO is going to be critical to both data integrity and the protection of human subjects. Sometimes both of these FDA concerns are addressed in the same function. When a study coordinator elicits adverse events from a subject, there is concern regarding whether the data are accurate. There is also concern regarding whether the safety of participants in a clinical trial is being reviewed and addressed by the investigator or some other individual. So a primary concern should be the qualification of study staff. 

Originally, most study coordinators were registered nurses. Nurses are trained to elicit adverse events from patients and know when to refer issues to a physician. Currently, study staff members are frequently not licensed medical professionals and there are no regulations that require an investigator to use nurses or other licensed health care workers. So it is important to examine how the investigator will delegate responsibility and supervise the trial. This should be established prior to subject enrollment and be periodically reviewed by monitors and auditors throughout the study. In addition, it still is important to have quality control with written procedures for each stage of data handling. 

The sponsor will also want to conduct quality assurance activities at clinical sites during and after a study regardless if an SMO is involved. Although not specifically required, quality assurance audits are recommended by E6.

  Surveys show that most sponsors conduct audits at sites during the conduct of the study. Additionally, sponsors audit nearly 90% of sites chosen by FDA for inspection.

 These audits occur between the time FDA notifies the site and the start of the inspection, which can happen within less than one week. Although it might not be practical to audit every site, the sponsor should consider auditing sites that are high enrollers, have a very large or small number of adverse events, or have compliance issues well before FDA phones to schedule an inspection.

Quality assurance audits should be separate from the sponsor's routine clinical trial activities. To encourage quality assurance activities, the FDA's Compliance Program Guidance Manual for sponsor audits

  prohibits review of QA audit reports under normal circumstances.

CROs, clinical laboratories, and SMOs are three of the most common GCP vendors. But there are a number of other vendors, some of which should be audited. 

In preparing procedures and audit plans, it is important to remember the two areas of FDA concern: data integrity and subject protection. Think about how the vendor will impact data and what steps need to be taken to ensure GCP compliance. In particular, determine whether there is quality control with written procedures at each stage of data handling. 

An important area to examine with any vendor is computerized systems. The FDA is currently reassessing its implementation of the Part 11 regulation regarding computerized systems (Electronic Records; Electronic Signatures). It has issued a draft guidance for clinical trials that is less stringent than previous enforcement efforts.

  The guidance states it contains "nonbinding recommendations." Although they may be nonbinding, they are the best we have until FDA determines how they intend to regulate computerized systems. 

In auditing computerized systems, one will quickly discover that everyone believes they have a validated system. However, by asking a few quick questions, the term validation takes on many different meanings. The FDA guidance document offers a framework for writing an audit plan that covers Part 11. The guidance offers the minimum, not the maximum, standard that should be applied. 

FDA may be using enforcement discretion for the time being, but the day will come when FDA resumes enforcement of Part 11. If the computerized system is critical for the integrity of the data being submitted to the agency, then the system should be validated and Part 11 compliant. 

Using specialty GCP vendors is a necessity in conducting clinical research in today's research environment. By developing a strong, consistent program for quality control and quality assurance, a sponsor can ensure not only compliance with GCP regulations but also cost-effective quality research. 

Strategies sponsors can employ to ensure vendors are complying with regulations-even when none exist.

Vendor Quality Assurance Audits: A Formula for Success

As the established market for clinical trials becomes increasingly competitive in the United States and Western Europe, relatively new regions are becoming a popular location for clinical researchers. Health care systems, experienced investigators, a large population, cultural closeness to Western Europe, and comparatively lower costs make Eastern European countries attractive to pharmaceutical companies and global CROs. 

It is clear that the business climate in Eastern Europe has changed dramatically during the past decade. Many Eastern European countries, including several former Soviet republics, have entered into the European Union and are now perceived as equals to Western European countries—some of their neighbors have not entered the EU yet. 

The most important countries for clinical research from the first group are Poland and the Czech Republic. The clinical trials market is large there, and for many companies these two countries are part of the obligatory checklist for new study locations. According to CenterWatch,

  in 2006 there were 29.7 clinical trials per million people in the Czech Republic and 8.7 per million in Poland. 

From the second group (the non-EU Eastern European countries), Ukraine is worth everybody's attention. This country is a relative newcomer to the industry, but should be considered a potential country for clinical research development. 

Using Ukraine's geographic coordinates, the geographic center of Europe is located on Ukraine's territory, located near the Rahiv, Lviv region. The country borders Poland, Belarus, Russia, Moldova, and Hungary, and with an estimated population of more than 46 million

  is first among the Central and Eastern European countries, except Russia (see Table 1)

 Table 1. Population figures for Eastern Europe. 

Medical and pharmaceutical sciences are widespread. There are 15 medical universities and academies, four medical faculties of classic universities, three academies of postgraduate medical education, and 33 scientific medical institutes. There are also many pharmaceutical companies located in Ukraine that meet GMP standards, and 18,000 drugs (with 3411 active pharmaceutical ingredients) registered in the country.

The unique features of the Ukrainian medical care system help recruit patients for trials within a short time frame. Primary and specialist care is organized around large hospitals and covers a large population. The system has a centralized structure and vertical referral system, which means that principal investigators (who are at the top of the referral pyramid) can select patients from the regional population without any competition inside. 			

Often patients come from small cities to big centers for detailed diagnosis and treatment, which is advantageous for trials as well. Overall, more than 65% of inhabitants live in urban areas;

  in other words, clinical trials have easy access to more than 30 million Ukrainians. There are 30.16 doctors per 10,000 inhabitants—whereas, there are 22.43 in Poland, 34.03 in France, 34.02 in Germany, and 13.92 in Turkey.

There is no nationwide insurance system for health-related expense reimbursement in Ukraine. People need to pay out of their own pockets for treatment, and high-quality medications are rather expensive. Free of charge treatment guaranteed by the country's constitution and provided by most governmental hospitals is limited, uses generic drugs, and is often not up-to-date. Although there are some governmental and/or pharmaceutical company funded programs for certain types of diseases (e.g., cancer, HIV, tuberculosis, and cystic fibrosis), they do not cover the needs of the whole population. 

A study often provides a much better standard of care for a  patient than the national health services, since it incorporates not only study medication but a full set of health care services including free lab testing, instrumental diagnostics, deep medical observation, and in-patient care. For many people, the trial may be the only way to get modern diagnostic procedures and potentially effective treatment. This is likely to make potential Ukrainian patients motivated to enter a trial, and keeps them constantly compliant to the study protocol. 

Another relevant feature of Ukraine's medical care system:  poor efficacy of routine screening and prophylaxis activities. As a consequence, the rate of untreated or late-stage diseases is very high, which may make Ukraine attractive for projects with slow recruitment in Western European countries. Studies in late-stage oncology diseases, untreated hypertension, and L-Dopa naïve Parkinson disease have the potential to recruit the necessary number of patients on time in Ukraine. According to Ukrainian official statistics, there are approximately 32,000 new cases of different diseases per year.

  today the research-based pharmaceutical industry taps less than 15% of the clinical trials enrollment potential of the Russia/Ukraine/Balkans region. (Since the actual number of trials currently conducted in Ukraine is much lower than in other countries, that percentage is smaller for Ukraine and thus even more impressive.) The number of clinical trials in the country significantly increased during the past 10 years with development of modern legislation and gains in popularity. According to statistics,

  only six international clinical trials were conducted in the country in 1996. Nine years later, in 2005, there were 125 trials. In spite of such growth, the potential capacity is still huge. 

When comparing Ukraine's capabilities with key criteria used by sponsors during country selection for multinational trials

  (see Table 2), the Ukraine scores well in more than half of the criteria. Reasons for the good scores include: a lot of sites and investigators have conducted clinical trials and have extensive ICH-GCP training; the majority of principal investigators are professors or chiefs of departments and are very experienced in the field of medicine they specialize in; there is a Central Ethics Committee, which acts as an ICH-GCP compliant entity; and there are a number of possibilities for subject recruitment. In addition, most potential sites have good Internet access (or it can be established easily), and have experienced PC users on staff. Thus, there should not be any substantial problems using electronic data capture systems or conducting trials with modern approaches/methods. 

Table 2. Key criteria used by sponsors when selecting countries for multinational trials.			

Trials are on the rise in the country, where recruitment rates are high but custom procedures can pose a problem.

Applied Clinical Trials-05-01-2007