The CRO industry is on a course for continued rapid growth with the rise of genetics and genomics, as well as the push toward partnering and more postapproval research.


There is no question that the Contract Research Organization (CRO) industry has grown up fast. Revenues of about $50 million in the late 1970s have advanced to about $10 billion this year alone. After years of growth rates as high as 50 percent, we have "stabilized" at a healthy rate of approximately 12 percent. Last year, R&D spending in the pharmaceutical industry grew at about 8.5 percent. So the size of the outsourcing market to CROs is continuing to rise. By any measure, we are a healthy, growing industry that has a significant role in the drug  development process.

But we have a long way to go. Compare the size of our industry to the revenue generated by global prescription drugs sales, which is approaching $500 billion, according to the IMS World Review 2004. And while our industry now numbers over a thousand companies, only a relative few have true global capability.  

We are maturing. The number of things we do well as an industry is getting larger. When the industry was young, the companies were small and could provide services in only a few niche areas. Today, a number of companies have reached the critical mass needed to fully develop a drug candidate and even to maximize its success after launch. Still, I believe the size of the industry we see today is only the healthy sapling of the well-developed oak we will see a decade from now. Our growth will be fed by several factors.


Genetics and genomics hold the promise of more selective medicines, which will have a dramatic effect on drug development and the CRO industry. Different drug responses are being linked more and more to genetic variation. Genetic profiling is expected to increase, which may lead to smaller, faster trials. Genetics and genomics will enable us to address more complex and chronic diseases. Historically, we have had about 400 disease targets. In the future, it could be as high as 4,000 ("Genomics Moves On," Ann Thayer, 

, October 14, 2002, pp. 25-36). With more targets and greater selectivity of medicines, the number of trials needed will greatly increase.

Postapproval research is expanding (annual growth of almost 15 percent in 2003 according to Goldman Sachs) because of its increasing importance to the prescription drug industry. Regulators are re-questing more postmarketing safety programs. Doctors and patients are asking for more information about safety and efficacy in the "real world," a world significantly different from the carefully controlled environment of Phase II and III studies. More information is needed about the effects of drugs in special populations, particularly children. And companies are looking for new indications as they seek to improve the return on their enormous investment in new chemical entities.

The need to reduce the cost of developing a drug, which is now estimated at more than $800 million, is pushing forward the use of the Internet and informatics. The Internet allows rapid collection, ready access and faster analysis of data while protecting the confidentiality of patient information. Although we have had to learn as we go, we are finding ways to adapt drug development processes to the eClinical world in a way that can save money as well as time. Informatics helps us identify the best areas for patient recruitment, and our data bases are expanding every day.

Today, CROs have global scale, broad expertise, technological skill and a strong track record. While all of these factors will feed the growth of our industry, the real key may be in building partnerships with our customers. Partnering will assume many different forms, but the time for partnering has come. 


Partnering can help sponsor companies save time, increase productivity, and reduce financial risk, depending on the type of alliance. CROs have developed the capacity and expertise to take on an even larger portion of the drug development and commercialization processes. That enables sponsor companies-whether in pharma or biotech-to reduce or better manage costs, improve productivity, and maintain their focus on core capabilities.  

In the next decade, I believe, we will realize the enormous opportunity for partnering.  The pharma and biotech industries are building a potentially huge backlog of molecules for development. CROs will help move this backlog through the pipeline by helping to develop entire drug portfolios, perhaps even taking on portfolios as their own.

Because of rising development costs, biopharm companies have to become more productive. Partnering can increase efficiency, such as in the creation of infrastructure alliances, in which a partner assumes control of certain operations or facilities and absorbs employees. Partnerships in which risks are shared will be particularly helpful for smaller pharma and biotech companies, and for large pharma companies that have portfolios of new products moving to late development and launch. 

Certainly, there are hazards ahead as well. With responsibility comes more accountability. When we share risks, we must realize that not all projects will meet their financial targets. Additionally, regulatory scrutiny is increasing, and with it the cost of development is likely to rise. Taking full advantage of technology to control costs will be even more important. We can best serve our industry and regulatory agencies by protecting the interests of the people who volunteer for our clinical trials, and by delivering high quality safety and efficacy information in a timely manner.

In 25 years, our industry has grown exponentially. We have expanded our capabilities, our capacity, and our expertise. We will continue to grow, becoming full partners in the process of creating better medicines to defeat more diseases.            

Articles

Guest Editorial

Progress and Potential: Evolution of the CRO Industry

The idea for this ACT CRO Retrospective came from the first SoCRA meeting I attended in 2003, just as I took over the position of Editor-In-Chief. I had the good fortune to hear PRA International's President and CEO, Patrick K. Donnelly speak about the CRO industry, and I was inspired by what he had to say. The CRO industry has exploded over the last 12 years. It has endured growing pains and it continues to develop. Therefore what better time than now to hear from the thought leaders who have been involved in the transformation taking place. 

I would like to thank the industry leaders who took the time away from their busy schedules to share their thoughts and insights. I enjoyed the opportunity to read their “grande mots.” They are a community of professionals who truly care about the work they do. -Toby Jane Hindin

Looking back, what makes the story of the clinical trials industry so interesting is its transformation over only a few decades. The CRO industry has seen an unprecedented growth rate in revenue. The future looks positive and the possibilities for expansion in the industry appear quite reachable as well as limitless. The industry's early development was as an offshoot of the pharmaceutical industry, and it can be traced back to the 1970s. At the 2003 SoCRA Annual Conference, Patrick K. Donnelly, President & CEO, PRA International spoke about the 1970s and 1980s as the "Formation Era." He explained that the "Formation Era" referred to a time when the industry was considered a relationship business. Many of the "new" outsourcers had relocated from the pharmaceutical companies. These outsourcers specialized in one particular area, stayed regional, and focused on clinical monitoring, data management or project coordination. Work was billed out as fee for service or time and materials. It was also a time when there was more than enough work to go around. 

In the 1980s the pharmaceutical industry came under a great deal of scrutiny. The FDA was looking closely at clinical trials conducted by pharmaceutical manufacturers. And within a 10-year period, the FDA had incorporated the principles of the Belmont Report into the Code of Federal Regulations, passed the Orphan Drug Act, Safe Medical Devices Act, and became an agency of the Department of Health and Human Services, with a Commissioner of Food and Drugs appointed by the President. The regulatory atmosphere at that time was putting pressure on the pharmaceutical industry to outsource. "FDA is taking an increasingly skeptical and adversarial stance regarding clinical trials and studies submitted by pharmaceutical manufacturers-regardless of how they are conducted," wrote Frederick L. Olmstead (

The last part of the 20th century witnessed aggressive mergers and acquisitions among pharmaceutical companies as well as SMOs and CROs (Figure 1). Donnelly aptly named this time period the "Consolidation Era." In addition, biotechnology came into the forefront of the pharmaceutical industry, work was billed as fixed-price contracts, and trial management became a global issue. Pharmaceutical companies continuously increased spending in research and development (Figure 2). And Sponsors continued to increase outsourcing to SMOs and CROs (Figure 3). As Donnelly noted, CROs are no longer "a Ma and Pa Industry," and he has dubbed the 21st century the "Efficiency Era." Several of the keywords he identified with the "Efficiency Era" are: quality, consistency, emerging markets, regulatory harmonization, research partnerships, and human subject legislation.  

As many CROs merged and grew larger, they became full-service global trial managers  (Table 1). "Looking back over the past 12 years, we have seen tremendous maturation of the outsourcing process, the emergence of truly global service companies with a strong track record of continued process and technological innovation by the CRO industry," notes PharmaLinkFHI's Executive Vice President, Rich Shea.  

PAREXEL's CEO, Joe von Rickenbach adds, "The CRO industry has advanced through global expansion, process improvement, and innovative technology. Increased efficiencies within clinical trials can be attributed to several factors. Tools for modeling and managing clinical trials have been developed and/or improved, thus accelerating patient enrollment. Additionally, project management solutions-better decision-making, leadership, and communication-provide significant client benefit."  

While pharmaceutical and biotech R&D spending is surpassing $36 billion today, blockbuster drug development is leveling off. Over a 10-year period, from 1992 to 2002, the CRO market grew from a $1 billion to a $7 billion dollar industry, and in that same period of time the number of CROs earning over $100 million jumped from 2 to 13. 

The rate of growth in the CRO industry has substantially increased: Today there are over 1000 CROs worldwide. In 2003, the number of CROs in North America was about 270. CROs are moving in the direction of becoming either niche or large service providers  

Along with an increase in growth, the CRO industry is faced with new challenges. As sponsors are consolidating they are looking for more efficiency and lower costs in the areas of technology, patient recruitment, and quality. "I do think there is more of a partnership attitude among sponsors as they realize they cannot get the job done on their own, and CROs have become more professional," observes Criterium Inc.'s President & Founder, John Hudak.  

Perhaps this is one of the many reasons for the paradigm shift to partnering and risk - sharing strategies in the pharmaceutical and CRO worlds ( Figure 4 ).

President & CEO, ICON Clinical Research-US, Bill Taaffe notes that over "the past 10 years there has been an initiative to develop the CRO-sponsor relationship as a partnership. This has not happened and it is unlikely to do so in the near future. I think that both sides now agree that it is not practical to have a true partnership between a CRO and a pharma company. What we have seen is a maturing of the outsourcing process and there are signs at last that the relationships will be strategic." 

Several themes that have emerged from recent conferences suggest that the challenges CROs will face are: quality, efficiency, the need for therapeutic expertise, the increase in the number of trials, difficulty in recruitment, the globalization of drug development, limitations on drug price increases, fewer blockbuster drugs, competition both within and outside the industry (witness the Wyeth and Accenture partnership), sponsors tightening budgets, the need for better sponsor-CRO communication, and the globalization of trials and EU regulations. 

Several thought leaders have expanded further upon the themes and challenges: 

Essential Group Inc.'s Chairman, President & CEO, C. Lee Jones explains "The challenge to drug sponsors and CROs is to collaboratively embrace the reality of outsourcing, but in the context of creating value and creating new core competencies of relationship and outsourcing management." 			

Medifacts International's Senior Vice President, Sales & Marketing, Vincent Lagrotteria adds that an increase in CRO and sponsor partnerships will lead to more efficiency. "If relationships start out with clear definitions of roles and responsibilities, there is a greater chance of both parties succeeding." He emphasizes that "CROs and sponsors must act as one to achieve study goals and objectives-from communication, execution, timeliness, even corporate culture. We believe that an outcome of working smarter together will be a reduction in cycle times and rework for many clinical trial tasks." 

The growing impact IT tools have on how CROs conduct business is a pervasive theme. "The increasing use of electronic information management systems is having a profound impact on the way clinical trials are managed," notes Brad Zaro, President & CEO, Clinimetrics Research Associates, Inc. He explains that EDC and CTMS tools "are adding to the speed, efficiency and economy" of clinical trials and he adds that "it is more expedient and cost effective to rely on outsourcing to provide support in these areas," since these tools require significant infrastructure and specialized skill sets.  			

"We hear much about the benefits of logistical tools such as EDC, about new scientific facilitators such as imaging, biomarkers, and proteomics and the benefits of intelligent and integrated program design. These are the drivers that can significantly improve the efficiency and value to the sponsors of drug development work," offers Alastair S. McEwan, President, Global Clinical, Inveresk. 

Several thought leaders have suggested that challenges can arise from poor communication and coordination. 							

"There are persistent challenges between contract organizations and clients because of changes in personnel and reliability, long decision-making processes and timeliness, ambiguous instruction and utility of work, quality of work, and changes to projects and costs. Pharma companies have CRO or contract departments that further lengthen the process for proposals and contracts, which makes it more difficult to choose CROs and more expensive for CROs to stay the course," explains Criterium's John Hudak. 

Peter T. Kissinger, Chairman & CEO, Bioanalytical Systems, Inc., notes that "poor coordination with preclinical history and laboratory work and the slow coordination and analysis of data on the fly as the trial proceeds," can be an issue, especially in the early phases of the trial. He adds, "This reflects the 'silo' nature of big pharma and may be inevitable, but opportunities exist for faster decision-making and perhaps even a reduced number of study subjects. Adding more and more subjects...doesn't improve matters all that much when in the first year after approval 2 million scripts are written." He comments that "The management and reduction of data when we have no industry standards for IT...makes it very difficult to do things better in our chaotic system. Hospitals and clinics have no standard database for even weight, blood pressure, cholesterol. A global standard would help enormously. Ending Islamic terrorism will be easier. I do not have an acceptable solution." 

It would be useful if we could look into a crystal ball and predict what challenges CROs will face and what future trends there may be. 

 doesn't have that type of crystal ball in place, so we asked many of the thought leaders in the industry to comment on what they see as challenges and future trends. There are some common themes that have surfaced in our survey. 			

"The CRO industry today is faced with many large full-service organizations providing global capabilities," notes Kendle International Inc.'s Chairman & CEO Candace Kendle. "Biopharmaceutical companies are beginning to turn their focus away from these larger, full-service providers and to look toward more flexible organizations that can deliver proactive and innovative clinical development and life cycle management solutions on a global basis." She adds, "as a result, medium-sized global CROs providing access to specialized expertise and expanded patient populations are experiencing significant growth and capturing market share." 

"We see an increase in the need for CROs specializing in niche services...in addition to the ability and capability of managing complete drug development requirements," predicts Greg Holmes, Executive Vice President, SFBC International. 

 Stephen MacKenzie - Lawrie , Director , Sales & Marketing , Health Decisions , notes that sponsors " need to work with a CRO who not only offers global reach , but who can add value to this process and successfully integrate experienced people , with proven process and appropriate technology , that together can accelerate the drug development process and bring speed and efficiency to product development ."

"The generic pharma market has always relied heavily on Phase I/Bioequivalence CROs for expertise," states Marc LeBel, CEO & President, SFBC Anapharm. He forsees the early drug development CRO "becoming a source that is sought after for its expertise" by the biotech, small and large pharma and specialty markets. He adds "this new paradigm will facilitate the establishment of real and durable partnerships between CROs and their clients."  

 Brad Zaro of Clinimetrics states that the growth of the industry " has been driven by expanding product pipelines , movement of more biotechnology companies into late - stage development , economic considerations , and an increasing need to move products towards the market more quickly within an increasingly complex regulatory environment ." He expects these market drivers " to continue for the foreseeable future ."

Jules T. Mitchel, President, Target Health Inc. predicts that within the next three to five years Internet-based clinical trial (IBCTs) will have a major impact on the CRO business. "Already, those sponsors who use IBCTs no longer have the need for double key data entry and related services. The volume and scope of query resolutions, another cash cow, is also being dramatically reduced. Monitors are spending less time in the field with reduced travel budgets. Further into the future, when clinical research at the study sites becomes more and more a paperless function with direct data entry (eSource), source document verification will fall under validation and auditing, and monitoring as we know it will disappear. With appropriate controls to assure data accuracy, precision and quality, entering data will be like booking a hotel reservation." 

Rich Shea, PhamaLinkFHI predicts "looking forward to the next 12 years, the stage is set for an evolutionary leap as drug developers require their outsourcing partners to bring greater efficiencies in the planning and management of their clinical programs." He adds, "The companies that will be successful over the next 12 years will be those service providers that re-engineer their operating model in a way that enables transparency between sponsor and service provider." He notes "In the world of 'integrated outsourcing' the lines between sponsors and service providers will become blurred and perhaps disappear altogether. Technology will facilitate but will not drive this evolution. It is the process changes that CROs must implement that will enable our industry to consistently deliver higher quality, greater efficiency, improved information sharing, and an outsourcing model truly based on collaboration." 

Joseph L. Herring, President and COO, Covance Inc. cautions, "In today's ultra-demanding industry environment, CROs and biopharmaceutical companies face a critical choice...collaborate or stagnate.  To continue to be successful, our clients must get medical innovations to market more quickly than ever before. I believe the winning formula for expediting drug development is for CROs and sponsors to  work together in true strategic relationships. Given the many serious issues facing the pharmaceutical and biotech sector, collaboration is no longer a choice...it is a business imperative." 

"The need for high-quality CRO services will continue to grow according to industry projections by 20% per year because of the increased drug company outsourcing. The reality is that drug companies cannot carry the large cost of clinical infrastructure to meet the full needs of an oscillating pipeline and declining earnings. This forces outsourcing to the forefront and demands two new competencies in R&D of outsourcing and relationship management if they are to succeed," offers C. Lee Jones, Essential Group, Inc. 

Paragon Biomedical Inc.'s CEO & Cofounder, Nicholas R. Reed anticipates "the industry's need for quality CRO services to increase.... We also expect to see a continued growing demand for more integrated services, technologies and multinational activities.... At the same time we expect continued price pressures." He suggests that, "Past response to these pressures has squeezed the inefficiencies out of the successful CROs, therefore future efficiencies will probably be gained by those sponsors that build integrated, mutually accountable processes with service providers." 

"We firmly believe that as imaging becomes more powerful it will play a greater role within clinical research," states Edward M. Aten, President & CEO,  Certus International, Inc., and "we have already seen significant changes in the way clinical research is conducted utilizing imaging and imaging endpoints." 

Quality, efficiency, niche or specialized providers, information technology, efficiency, improved communication between sponsor and provider, and new kinds of collaborations or partnerships seem to be the important issues that the CRO community will be dealing with in the coming years. 

Some of this growth will occur naturally. As PAREXEL's Joe von Rickenbach suggests, "Perhaps the most important advance in the CRO industry emanates from longevity. As the CRO evolves, its experience over time and across geographies allows the organization to pass learned efficiencies on to clients, minimizing time, cost and risk." 

 surveyed a number of CROs to find out some specific answers to questions about the present and predictions over the next five years.  			

Although the sample size was small, N=16, the respondents were an evenly divided cross section of Small, Small/Medium and Large CROs (Figure 5). All of the companies responded that they had grown over the last five years from 5% to 400% (Figure 6). This is reflective of what other sources have indicated with regard to the CRO industry. Projections for growth over the next five years appear to be extremely positive, with companies reporting projections of 5% to 500% (Figure 7). The respondents also noted that they are located globally, with Europe and the United States being primary areas (Figure 8). All respondents indicated that they were expert in all phases of clinical trials, however Phase I had the fewest amount of responses (Figure 9). Site selection, data collection, and data monitoring were indicated as the areas serviced the most in all phases of trials. The least serviced areas were metrics and pharmacoeconomics (Figure 10). Current clients were evenly divided among the pharmaceutical, biotech, and medical device industries (Figure 11). Six of the 16 respondents noted that they were niche providers and specialized in the following areas: Phase I/II trials, bioanalytical services, clinical imaging, devices, biotech, cardiovascular drugs and devices, ECG, Holter and ABPM monitoring, urology, gastroenterology, and women's health (Figure 12). 

Feature Article

The idea for this ACT CRO Retrospective came from the first SoCRA meeting I attended in 2003, just as I took over the position of Editor-In-Chief. I had the good fortune to hear PRA International's President and CEO, Patrick K. Donnelly speak about the CRO industry, and I was inspired by what he had to say. The CRO industry has exploded over the last 12 years. It has endured growing pains and it continues to develop. Therefore what better time than now to hear from the thought leaders who have been involved in the transformation taking place.

Looking Back, Moving Forward: A CRO Retrospective

's May 1992 inaugural issue. The author talked about the dilemma pharmaceutical companies faced with regard to oursourcing: legal and regulatory assaults if they kept clinical trials in-house, and major concerns about data quality, timeliness, overestimation of patient recruitment, research reports on time delivery, and cost overruns if they outsourced. The author's solutions included better communication of what the sponsor wants and expects, and improved computer technology applications. It has been 12 years since the article was published, and, as readers will find out, much has changed.-The Editors

Clearly, major pharmaceutical companies would conduct all trials in-house if it were feasible. Some pharmaceutical companies use hybrid systems, retaining certain elements while contracting out other elements. This most likely puts senior management of such firms in a bit of a quandary. FDA is taking an increasingly skeptical and adversarial stance regarding clinical trials and studies submitted by pharmaceutical manufacturers-regardless of how they are conducted. This attitude, coupled with the increasingly litigious nature of our society, makes it likely that FDA will attempt to "reform" the new drug approval process by imposing further time-consuming burdens on manufacturers. A likely avenue for such new regulation may lie in federal theories of so-called organizational conflict of interest.

Thus, the horns of an apparent dilemma for pharmaceutical manufacturers: contract out your clinical trials and suffer deficiencies in data quality and timeliness, or conduct the trials in-house and be subject to legal and regulatory attacks by interest groups and official regulatory bodies.

Contract research organizations must deliver the quality and reliability required by manufacturers on a timely basis and at a reasonable cost. This article summarizes the most commonly voiced complaints about their services and attempts to analyze the sources of such complaints and suggest possible remedies.


A number of articles and surveys have addressed concerns of pharmaceutical company research staff with the performance of their outside contract researchers.

 Based on both a review of some of the current literature and the author's experience, such concerns resolve themselves into four rather broad categories: credibility, responsiveness, quality of product, and cost.

 A consistent refrain in criticisms of  contract research organizations relates to the companies' tendencies toward what might charitably be described as excessive optimism. Sponsors complain that contractors

 overestimate or exaggerate the number of patients who will enter a study 


 exaggerate the resources and expertise available for the conduct of a clinical trial


 inaccurately estimate the time it will take to select sites, qualify investigators, and conduct recruiting


 provide excessively optimistic completion times or dates.

There are other complaints, but this list is sufficiently illustrative. Critics of a forgiving turn of mind ascribe such statements to "an excess of enthusiasm" on the part of the contract researchers. Others, of a more ill-tempered disposition, blame them on "sales hype" or worse. The essence of the problem, however, is that pharmaceutical manufacturers and CROs enter a trial or other clinical study with undue expectations of likely performance. Even if the study is eventually successful, the two parties will nonetheless be disappointed that it did not succeed as planned. Thereafter, the manufacturer will be skeptical of contractors offering research services.

 Once a study has begun, there is often the feeling that the contractor will plow ahead without regard to the sponsor's concerns. Sponsors fear that the contractor will

 fail to obtain enough sites to conduct the study, particularly if requested to expand the number of clinical sites by the sponsor


 depart from the study protocol, or resist modification of the protocol to meet the sponsor's needs


 not maintain adequate, timely data on trial status, and fail to report or respond to sponsor requests for data


 not prepare research reports on the schedule or in the format needed by the sponsor


 generally fail to maintain adequate, open, and responsive communications with the sponsor.

Of all of these, the last may be the most critical. The relationship between the sponsor and the contract researchers must be based on mutual trust, as well as the sponsor's confidence in the researcher's ability to perform.

 This is the area in which contract research is viewed with the greatest suspicion by sponsors. Quality problems run the gamut from delivery of sloppy, unclear, and technically inferior research reports to severe protocol violation. 

 enter patients in the study who do not meet the inclusion criteria, or who, indeed, even may meet one or more criteria for exclusion

 use particularly unreliable individuals, such as alcohol or drug abusers

 enter the same patient twice (or even more) in the same study

 enter data in the case report form inaccurately, under incorrect dates, substantially later than the performance of the experimental action, etc.

These examples are just a few of the many mentioned in various articles and surveys.

 The upshot of such activities is the marked degradation of the quality and usability of the clinical trial data. This may require the sponsor to conduct the trial a second or third time, delay the submission of an NDA, and lose time for marketing a new formulation, with the attendant consequences for pricing, revenues, and profitability.

 This is the least understood and most contentious of the problems presented here. Under the best of circumstances, developing full, accurate, fair, and reasonable pricing is difficult. In contract research, it may be more difficult than usual because there are a multiplicity of organizational actors-the research contractor, clinical centers or hospitals, laboratory, data analysis centers, etc.-all with their own cost and price studies. It is difficult to gain the cooperation required to determine all the costs and a fair price for conducting a trial under a given protocol. Indeed, some of the collaborating organizations may be quite competitive and seek to extirpate the participation of the other cooperating organizations over the course of the study. These problems may cause the contractor to 

 develop cost overruns, followed by requests for higher funding


 propose-or even invoice without prior discussion-costs not originally contemplated by the sponsor


 reduce the level of service (e.g., numbers of patients evaluated, quality of reports, and so forth) to stay within a fixed contract price


 substitute less-qualified and lower-salaried personnel on the study without informing the sponsor.

Such problems may be unavoidable by the very nature of the so-called conventional contract research process. Nonetheless, a contractor has an affirmative obligation to present the most realistic pricing feasible. To do otherwise is to fail to exercise the due diligence required of any professional.


The litany of sins set forth above could lead one to conclude that contract researchers are perhaps on a par with journalists, members of Congress, and others whom Twain once referred to as the "native American criminal class." It is not my intent to give or leave that impression. Following are some potential causes for the difficulties outlined above, focusing particularly on three areas: lack of consonance of organization purposes, lack of management authority, and complexity of communications. These are not the sole sources of difficulty; rather, they are those to which I ascribe the greatest importance.

Lack of consonance of organizational purposes.

 Contract research involves a multiplicity of independent organizations. Few of these organizations exist for the sole purpose of conducting clinical trials. For example, the clinical sites generally have multiple missions organized around provision of care. Whatever they may consider their driving goals, they are not exclusively or primarily research organizations in most, instances. Data analysis centers are often computer service bureaus, some more specialized in health care data reduction and tabulation than others. Pathology clinics and other laboratories are generally commercial ventures. Although they may appreciate the need for an exquisite precision in the analysis of research specimens, it is unlikely that they will direct any special attention to the research studies if there is no contractual requirement to do so and no provision for enforcement.

In addition to these disjunctions of purpose, consider that supporting clinical trials and studies is an adjunct activity for most of the organizational participants. Moreover, because these are autonomous organizations, it is difficult for a contract researcher, as an intermediary for a sponsor, to impose any realistically enforceable singleness of purpose on this multifarious gaggle of collaborators.

Some of the consequences of this diversity include

 nonstandard protocol execution among and between the various clinical sites


 vastly different rates of patient accrual and data collection (this may have implications for data validity and usability)


 data standardization difficulties attendant upon the wide variety of computer systems installed in the collaborating organizations.
In sum, the diversity of organizations potentially involved in any given clinical trial, while not totally random, may be said to verge on the chaotic.

 The contract researcher lacks the power to enforce procedural dicta across the collaborating organizations. The ability of a contractor to discipline personnel for material breaches or errors in protocol execution, for example, extends solely to his or her own staff. If a collaborating organization performs poorly, the contractor has three types of remedies available:

 attempts at persuasion, up to and including various threats


 financial penalties and withholding of payments on invoices, if contractually allowable


Clearly, these range from the trivial to the draconian. A far more focused approach would be desirable.

 The diverse group of organizations that collaborate on the clinical trial, whether implicitly or explicitly, are a communications network. Each potential combination of two autonomous organizations constitutes a "communications link." In any such network, the possibility for miscommunication is proportional to the complexity of the net, expressed as the number of potential links. The totals escalate very rapidly. Thus, for a trial that includes the sponsoring organization, a CRO, six clinical sites, a pathology laboratory, and a data analysis center (10 organizations total), there are potentially 45 communications links, each of which adds a potential for miscommunication. If five clinical sites are added to this trial, the number of possible communications links grows to 105. That is, a 50% increase in the number of involved organizations causes an increase in network complexity of over 150%. This is why attempts to speed trials by major expansion of the number of clinical sites and investigators often end in grief.

Pragmatically, not all the potential "links" are necessarily realized in particular trials. For one thing, not all clinical sites are necessarily aware of the other sites involved. This is most often true when there are more than 10 sites, widely geographically dispersed. Nonetheless, the more actors involved, the greater will be the difficulties in clearly and effectively communicating trial purposes and requirements and maintaining appropriate adherence to protocol requirements.

Perhaps of equal importance to the size of the communications net in a trial is the rather common lack of explicit communication rules and procedures provided by study coordinators to each participating organization. In physical computer networks, such rules constitute the communications discipline of the net and are enforced both by the hardware configuration and the network operating system-without overt operator intervention. Unfortunately, there is no equivalent of network software for clinical trial groups.

This potentially dysfunctional complexity may be as much of the source of the difficulties experienced in conducting trials as any other cause. So, the question to be addressed is: What solutions may be feasible?


The objective of this article is not to chastise the sinner but to seek means of redemption; that is, to suggest ways in which clinical trials can be improved, particularly when conducted on a contract basis.

 A solution obvious to some would be for pharmaceutical manufacturers to conduct all trials in-house. There are, however, two major disadvantages to doing this. The first is resources. The number of compounds being developed for which trials are needed is clearly outstripping the capacity of any one firm's resources. Perhaps of greater long-term importance is the growing hostility of FDA to free-market pharmaceutical manufacturers. For the foreseeable future, relations between FDA and companies submitting NDAs are likely to become more adversarial and contentious. The use of contract researchers seems to enhance FDA's perception of the objectivity of a trial. I believe, however, that all manufacturers should conduct at least some trials in-house, perhaps through the vehicle of a wholly owned subsidiary that retains a distinct corporate identity. This would allow development of baseline comparisons of product quality, operational efficiency, and cost, which could be used to evaluate extramural contract research. Such an entity could also provide a venue for testing compounds about which the developer wished to maintain a high degree of confidentiality.

 Another potential solution to the problems experienced with contract research lies in the legalistic approach. That is, pharmaceutical manufacturers should use rather explicit detail in contract terms and conditions to enforce certain performance standards on contract researchers. Doing so could have certain salubrious outcomes. It might well eliminate from consideration those contract researchers unwilling to apply the standards the sponsor feels are necessary. More stringent contracts might also clarify expectations and better define requirements among the parties involved.

Unfortunately, more complex contracts may at some point prove counterproductive. A telling example is found in federal government contracting. The laws and regulations enforced by federal agencies in their contracting practices are extremely detailed and one-sidedly onerous. This attempt to obtain quality by contract, however, is not particularly productive. The government experiences as many or more contractual problems as any private sector organization.

 Still another solution is the application of improved computer technology. This holds some real promise, particularly in the light of the growing power of microprocessors and the expansion of open systems architectures. Such approaches, at least in part, address the communications issues alluded to earlier. The disadvantages lie primarily in the implementation. Particularly in very large firms, there may be information services or records management departments that are wedded to obsolescent technology or at least resistant to the technology most effective for the types of problems faced in the contract research arena. Additionally, there is the problem of disseminating the desired technology through the various collaborating research organizations. Each may have distinct views as to the types of computer systems they can or will use. Moreover, if they are involved in multiple studies, which is a common situation, they may be besieged by demands to install and implement this or that system as a condition of a contract or grant.

 The most attractive solution, particularly because it rests in the hands of the contract researcher, is to markedly improve overall organization and management of the CRO itself. An explicit implementation of the principles of W. Edwards Deming, the leading proponent of statistical quality control, would be felicitous. Some of the specific actions that might fall within this rubric are

 creating an in-house data center and analytic capacity to control this critical element of the trial (some CROs have already done so)


 considering acquisition of clinical and laboratory facilities, and dedicating them to clinical trials and research (as opposed to ongoing patient care) 


 developing detailed costing models and financial planning systems, both to provide for better bids to sponsors and to improve internal management


 implementing a standard data communications process (e.g., a wide area network) throughout the organization


 focusing on active and aggressive accrual of trial patients, rather than passively waiting for them to present themselves at a clinical site


 emphasizing quality and timeliness constantly and building a focus on time and a "sense of urgency" into the corporate culture.

A number of CROs have implemented some of the approaches suggested above, though usually in piecemeal fashion. What is required is a comprehensive approach and strategy for improved performance. Karl E. Peace presented an interesting look at how such a research organization might be configured.

 In particular, strong emphasis on quality control and improved, automated data management are key elements of improvement.

There are no panaceas, but improved organization and management efforts on the part of contract researchers themselves will go far to reduce the most obvious difficulties.


1. Contract Research Organization Quality Assessment Study (Decision Research Corporation, April, 1991).
2. Karl E. Peace, "TMO: The Trial Management Organization-A New System for Reducing the Time for Clinical Trials," 

The very first article ACT ever published shows how many changes the CRO industry has seen in 13 years.

Supplements-08-02-2004

Progress and Potential: Evolution of the CRO Industry

Looking Back, Moving Forward: A CRO Retrospective

Improved Organization and Management of Clinical Trials