As the pharmaceutical industry has expanded and matured, industry managers have become increasingly sensitized to the need to operate the clinical operations area as a scientific business in relation to the maintenance of large in-house clinical development organizations (Fig. 8.28). In response to these concerns, contract research organizations (CROs) began to spring up during the 1970s and to play a progressively more prominent role in the industry over the subsequent three decades. CROs have offered industry clients the ability to outsource various activities as the need arises. The contract concept has been applied to manufacturing, development (preclinical and clinical), and business (e.g., sales, market research) functions in the pharmaceutical industry [24-26].
Many CRO companies now operate on a global scale, which fits well with the global operations of sponsoring companies. The research-related CRO size has grown to over $9 billion by 2003, out of a $40 billion overall budget; growth has been occurring at varying annual rates (from 3% to 23%).
r Definitions r Functions / Services r Selection r Management of CROs r Characteristics
Fig. 8.28. Contract Research Organizations (CROs) Outline of Topics
While certain of the principles in the selection and management of CROs are applicable to other functional areas, the discussion to follow is specifically directed toward CROs offering clinical development services. CROs are used for clinical trials I, II, and III for more than 60% of the projects in the industry. The top five multiservice larger corporate CROs in the United States with operations around the world include Quintiles, Covance, Parexel, PPD, and Kendle, who have collectively 50% of the CRO revenues and are growing .
Discovery research programs are, by their very nature, sporadic in productivity. As a consequence, compounds emerging from these programs enter and then progress through clinical development sporadically. Clinical development organizations may exist in a "boom or bust" environment of alternating under- and overstaffing relative to current clinical development needs. This problem can be compounded in the small or start-up company with a small or single product portfolio, where failure of a single project can render a previously overworked and understaffed clinical development organization idle overnight. Companies will work with both fullservice CROs (about 80% of the time) and at the same time niche CROs with specific services (about 70%) to perform the various clinical development activities . Five topics will be addressed in this chapter for CROs as listed in Fig. 8.28.
Before beginning a detailed discussion of CRO functions and of the selection and management of CROs, definition of several key terms and consideration of the concepts underlying them is useful: The following Fig. 8.29 summarize some of the key terms and concepts, as well as in the text below.
Unbundling is dividing up the clinical research work into manageable and discrete portions. Contracting out discrete tasks is carried out within a particular clinical development program to one or more CROs, frequently with other tasks being carried out by in-house staff. This is essentially a "mix and match" approach in which specific areas of deficiency within the sponsor's organization are complemented by the resources of the CRO. This is in contrast with the approach of contracting for completion of a complete development program. An example of the latter might be a contract with CRO X to conduct all aspects of a study from investigator identification through the writing of a clinical report. The former might be exemplified by a study in which five research business arrangement are made: (1) the sponsor identifies r CRO Functions r Unbundling r Full service vs. Niche r Academic CROs r Domestic vs International k SMOs r CRO liaison/oversight Fig. 8.29. CROs: Key Terms & Definitions investigators and initiates and monitors some portion of the study sites, (2) CRO X initiates and monitors the remainder of the sites, (3) CRO Y is responsible for clinical data management, (4) an independent contract statistician carries out data analysis, and (5) a freelance medical writer writes the clinical report. Unbundling, by contracting out only where a truly complementary role for the CRO exists, can be the most cost-effective approach for the sponsor. However, this benefit may be offset by the complexities, cost, and risk of managing multiple vendors.
Certain CROs can justifiably claim to be "full service," a popular marketing term meaning that they have at their disposal the resources to take on a development project in any therapeutic area at the preclinical phase and take it through to an NDA. In essence, the largest of these CROs resemble large pharmaceutical companies with all the same types of staff and systems, only without discovery research or a pharmaceutical sales force. The reader should note that working with a full-service CRO does not preclude "unbundling" as discussed above for a specific (Niche) function. Other CROs, so-called niche CROs, may limit the scope of their activities to a phase of development (e.g., phase 1), a therapeutic area (e.g., oncology, dermatology), or a specific domain of clinical development activity (e.g., study monitoring, data management, biostatistics or patient recruitment or assignment).
As of this writing, domestic CROs exist in virtually all national environments in which clinical research takes place. In addition, many CROs have multinational capabilities. In certain instances, they have the same scale as those of major multinational pharmaceutical companies, which can be particularly useful for a pivotal global clinical trial being done across several countries. The choice of a domestic or multinational CRO is driven mostly by the required geographic scope of a development program.
Historically, biomedical research has been heavily dependent on contract collaboration with academic investigators. These academic researchers often are the thought leaders for a disease or therapeutic area, lead the development treatment guidelines/standards, and are looked upon in the medical community for innovations. With the growth of the contract research industry, some academic medical centers have determined that, with the addition of significant organizational infrastructure, hiring of some research coordinators, and improving of the business operations of their research offices, existing talent (practitioners and investigators) could be organized into and marketed as a CRO offering services beyond the traditional sponsor-investigator collaboration. A new revenue source for the medical centers, that is, CRO type research contracts, has been another driver for these academic CROs. Potential attractions to clients might include improved access to academic sites, access to high-level investigators, and the external perception of academic excellence in their protocols, study operations, and study reports.
In the 1980s, the need arose to identify progressively increasing numbers of qualified clinical investigators as discovery research activity and thus the volume of clinical research studies increased. It was recognized that large numbers of individuals with excellent clinical medical backgrounds, but little or no familiarity with clinical drug development research, were practicing in the community. These independent practitioners have an advantage, that is, large number of "typical" patients to be enrolled in clinical studies. Site management organizations (SMOs) typically represent a collection of sites, may act as the intermediary in identifying qualified sites for a given study, act as a business representative for sites in contractual matters, educate the practitioners regarding research practices, and also provide to each site required guidance in setting up the infrastructure and systems needed to carry out GCP compliant clinical research. Some practice sites will need some added staff support and space for study work. The practitioners see benefits of SMO participation in bringing new and innovative treatments to their patients, advancing medical practice, and creating a new revenue source for the practice.
Some large pharmaceutical/biotech companies have a specific group dedicated to interacting with CROs liaison/ oversight. Other companies may rely on different individuals, depending on the project, to interact with CROs. These groups or individuals are the primary liaison to the CROs in general, screen the potential CRO for the company, are familiar with who's who and what's what at the CROs, and lead the selection process and manage the overall relationship between the company and CROs. The primary liaison to the sponsoring company for a protocol or study conduct will usually be the clinical operations lead manager for a full-service CRO or the particular department lead for the product for a specific service, whether it's biostatistics, quality assurance, or regulatory affairs. A sponsoring company with a CRO department may benefit from a structure and process that provides for more fair, balanced, and knowledgable assessments of prospective CROs. The sponsoring company's CRO department will also be familiar with all the company's research programs and may try to create economies of scale by working with a particular CRO, if they can handle it, with several products.
As alluded to above, a sponsor may engage a CRO with appropriate resources to provide a narrowly defined or broad range of clinical development services (Fig. 8.31). These services may include creation of an IND, various regulatory affairs functions including initiating and maintaining IND-related contact with the reviewing division at FDA, performing any or all of the activities needed to conceptualize, execute, and report a clinical study or program of studies, and to create, file, and take an NDA through the approval process. A noninclusive list of 19 potential services of CRO is provided in Fig. 8.30.
The decision to engage a CRO can be driven by different considerations depending on the nature of the sponsor company. For fully constituted pharmaceutical companies, that is, companies with in-house staff representing the full set of skills required for clinical development, outsourcing has frequently been an ad hoc response to competing, unplanned for, resource demands at any stage in development. Examples might include the need to conduct an unplanned phase 1 mechanism of action study, receipt of an approvable letter from FDA conditioned on an additional unresourced phase 3 study, or the urgent need to do further source document monitoring against case report forms because of issues identified during NDA preparation. With increasing use of CROs by the industry, however, outsourcing by the larger companies has assumed a progressively more strategic role driven by long-term program and project planning and long-term staffing plans.
At the other end of the spectrum, the so-called virtual company, a business entity whose staffing may constitute a handful of managers who may have limited development experience, may require, at least for some stage in the company's development, outsourcing of the entire development process. For companies partially constituted by either chance or as the result of prospective planning, of course, task areas not represented in-house would be outsourced as a matter of practice.
Various business arrangements with a CRO may result in economies in both charges and administrative costs to the sponsor. Most common among these is a "preferred provider" scenario in which the sponsor places all work with CRO X for concessions on rates and does work under a single master services agreement rather than under multiple contracts.
There are numerous examples of CROs of all types doing outstanding projects of different types for industry sponsors.
• Training k Advisory boards k Patients:
• Assignment CRF design
- IRBs r Data entry r Biostatistics r Regulatory Services k Monitoring:
• Telephone calls k Lab services k Electronic data capture k Records retention k AE reporting r Drug Preparation,
Dispensing, Records k Audits @ site k Protocol and Report writing
Unfortunately, there are also examples of CRO-sponsor joint undertakings, which end in a less than satisfactory fashion for a variety of reasons (cost, quality, failure of execution, timeliness, etc.). In fairness, the successes and failures are both, in general, as much attributable to the management practices of the sponsor as to the qualities of the CRO.
The selection of a CRO or CROs is a critically important activity, which requires a systematic and reasoned approach (Fig. 8.31). Multiple CROs should be evaluated using a single set of prospectively defined evaluation criteria. The sponsor should begin with a top-level evaluation of each CRO in the following areas:
• organizational structure,
• overall quality and experience of management and staff,
• experience of CRO with the particular disease area,
• history of any regulatory actions including confirmation that no staff are debarred,
• financial stability,
• list of sponsor references,
• understanding of key elements of the contractual process,
• commitment by CRO of dedicated staff if possible,
• an understanding of the CRO's culture and values.
As an adjunct to more formal inquiry, the sponsor should work the network to see what is being said about the CROs under consideration (as with all rumor monitoring, this should be done analytically). Essential criteria in CRO selection has been captured by CenterWatch in 2000; strong reputation 41%, therapeutic expertise 59%, and ability to deliver patients 59% .
The above should result in the generation of a "short list" of CROs with the desired characteristics to support further evaluation. The importance of a culture and set of values consistent with the sponsor's cannot be overemphasized. Because the CRO will really be part of the sponsor company during execution of the contract, the ability of sponsor management and staff to create a shared culture within which to work is essential and r Good and Bad CRO Outcomes r Evaluation Parameters (check lists): c People, experience base, & culture c Processes & systems r Company:
c Evaluation team C Visits to CRO
r Budgets: O RFPs c Standardized budgets r QA Audits to Qualify Fig. 8.31. CROs: Principles in Selection unlikely to be successful if great dissimilarities exist at the outset. CROs on the short list should be then evaluated in detail by a sponsoring company assessment and visit team led by the CRO department with representation depending on the services desired. Are any involved in competing projects? Are there systems (SOPs, IT, a quality assurance function) in place that are adequate to support the project? is training for assigned tasks performed and meticulously documented in training records? Is Staff turnover low? The CRO ideally should have had recent successful experience in the project therapeutic area or a related area. The sponsor must then very clearly define to CROs under consideration in a formal "request for proposal" (RFP) type document detailing what is needed of the CRO. The RFP needs to address this unambiguously at a truly "micro" level as the budget and timeline are directly determined from this. Responses to the RFP should be standardized in a sponsor-defined spreadsheet to facilitate comparison between CROs. The selected CRO should be subjected to an extensive QA audit by either the sponsor or a qualified independent entity contracted by the sponsor prior to contract execution.
CRO selection is a strategic activity. Bad choices made here will impact every aspect of a project and will jeopardize the ultimate success of the study and the NDA/CTD. CRO selection is a time consuming, often tedious process which produces large amounts of company data that must be rigorously analyzed (Fig. 8.32). Particularly in the case of the financial data, if you cannot really analyze it, don't be embarrassed to bring in someone from the business side who can. If the case of gross disparities in budgets from different CROs, step back and make sure that you have adequately communicated your requirements for the project and that all involved CROs have the same understanding of it, then ask them to re-bid. In making a selection remember that it is not only about price: "It is about value. value, which is a function of price x quality."
Once selected, CROs require intensive professional management by the sponsor from the top down to ensure successful business and research outcomes (Fig. 8.33). Sponsor management of a CRO is a demanding role requiring under-
r Strategic activity r Time consuming r Requires rigorous analysis - CRO:
r New business staff versus Coordinators & managers r Disease area experience r Reconciliation of disparities r Price and Quality Fig. 8.32. CRO Selection-Caveats r Intensive r Status reporting r Communications and decisions:
o Processes, systems, and people r Responsibility r Interfaces:
o CRO and Company o PI and site r Authority and chain of command r Change authorization
Fig. 8.33. CROs: Principles in Management r Culture r Finances r Conflicts of interest r Processes and Systems r Staff and Turnover r Experience base (Disease areas, Study types, Years, & Type of companies)
Fig. 8.34. Characteristics of Desirable CROs standing of the development process, planning skills, and a well-developed set of human relations and organizational skills. A specific and designated liaison team at the company may be created for this oversight, communication, collaboration, and management role. It bears repetition that the CRO is not responsible for the study to the investigators, the institutions (sites), the IRBs, or the regulatory authorities; they are a vendor for services, and the sponsoring company is the responsible party. Companies with limited resources should be particularly careful to assess whether they have the ability to manage the CRO they engage.
The CRO must be assimilated into the sponsor company. CRO staff working in a company culture, which they are conversant and comfortable with, will work smarter and be more productive (Fig. 8.34). Assimilation requires time and attention from sponsor staff. Loci of responsibility and authority and chain of command must be absolutely clear. The frequency, format, and contacts for status reporting to the sponsor should be defined prospectively as part of the contract. Staff need to be dedicated on both sides over the whole study time frame, and kept the same, to enhance communication and coordination. Turnover upsets the relationships and must be minimized. Compatible systems must be available at the CRO; they must be worked out between the CRO and sponsor, must be integrated as much as possible, and must appear seamless to the r Investigator Initiated INDs r Patient Access r Patient Expectations r Publications r Placebo Use r Quality of Life Endpoints r Compassionate Use r Pharmacogenomics r Outsourcing vs Internal Resourcing Fig. 8.35. Selected Issues in clinical Development investigative sites. Procedures for authorizing change from original contract work elements must be clear and must be followed without exception. The CRO to be successful and the company to be successful need CROs with sufficient years and types of experiences, regarding at least the regulations, therapeutic area, stage of research, research skills, and working clinicians focused multicenter studies.
Another important issue with CROs and a desirable characteristic is receptivity by the investigative sites. The CRO represents the company and gives them a good or bad name. The features that they find important are a collaborative team, supportive and responsive, professional monitors and staff and staff who are organized and prepared, according to a CenterWatch surveys of sites .
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