Procedures for Selection and Monitoring of
Contract Research Organizations
Duane B. Lakings, Ph.D., Principal, DSE Consulting
Once a decision has been made to outsource various studies of the drug development process, carefully selection and monitoring of CROs are necessary to ensure that these studies are conducted as designed and are completed on time and within budget.
The use of a CRO, or contract research organization, in nonclinical drug development programs, or outsourcing, is a common practice by many pharmaceutical and most biotechnology companies. Presently, over 450 CROs exist in the United States and Europe, with some offering a complete drug development support system, from synthesis of the drug substance to conducting Phase III safety and efficacy human trials. Others specialize in such areas as pharmacology animal model development and implementation, formulation development and stability testing, bioanalytical method development and validation, and clinical trial study support. The techniques commonly employed to select and monitor a CRO for nonclinical drug development studies are the subject of this white paper.
A company identifies a lead that mediates a human disease process and then needs to conduct the GLP-regulated research studies to first obtain an IND and then for a NDA submission. For a variety of reasons, corporate management may decide to have some or all these studies performed at a CRO. The drug development project team (DDPT) is commonly charged with coordinating the outsourcing program. For a small biotechnology firm, this responsibility may fall on the shoulders of a single individual, or at best a small group, who needs to have a good understanding of various scientific disciplines for which outsourced studies are being considered.
The first requirement for a successful CRO program is to identify which studies or aspects of the development program are to be outsourced and the projected timelines for the initiation and completion of these studies so the results and study reports are available for decision making and regulatory agency submissions. A drug development plan provides much of this information. Sub-project teams, consisting of DDPT members whose scientific expertises are needed for the outsourcing programs and the DDPT coordinator for contractual arrangements, first identify and then select the appropriate CRO(s) to conduct the desired research studies. These teams also are commonly responsible for monitoring the CRO(s) to ensure that the studies are being conducted as designed and that the generated results are appropriately recorded and documented in study reports.
CRO Identification and Selection
After a company, commonly referred to as the Sponsor, has decided to use CROs for some or all of their drug development needs, management or the DDPT assigns individuals to first identify and select the appropriate CROs. The steps in a selection process should include, but are not be limited to:
1.Preparing study designs for each of the research studies to be outsourced. The more details provided in the study designs, the better. CROs use the provided information to prepare a draft study protocol and a proposal with time and cost estimates. As an example, commonly included items for a nonclinical pharmacokinetic study design might include: Study Purpose; Test Species or Animal Model; Test Article or Drug Substance; Route of Dosing; Frequency of Dosing; Administration Technique; Number of Animals; Specimens to be Collected and Time of Collection; Bioanalytical Method; Stability of Test Article; Analyses; Projected Timeline for Study Start and Completion.
2.Determining which CROs should be considered as potential contractors. Most CROs have Internet web sites that describe the services they provide and give information on their expertises and qualifications. Even with the availability of this wealth of information, personal contact can provide a clearer understanding of a CRO's ability to meet the individual needs of a Sponsor.
3.Soliciting cost and time proposals for each study design from each CRO. Commonly 3 to 5 CROs who have the necessary expertise to successfully complete the study are requested to submit proposals for each study design or group of study designs.
4.Evaluating the proposals, which includes determining if the CRO understands the study design, and selecting those CROs to be considered further. At times, CROs will recommend modifications to the design, which may or may not improve the overall study and could provide additional information on the drug candidate. When this occurs, the Sponsor needs to critically evaluate the expanded study to ascertain if the increased costs and possibly extended study duration justify the additions.
5.Scheduling and conducting site visits to ensure the CROs are qualified and have the facilities and personnel necessary to conduct the studies. Commonly, these site visits include assessments of GLP compliance, SOPs, and computer validation.
6.Negotiating time and cost for completion of the research studies. The original estimate in the proposal is usually not the final cost of conducting a project at a CRO. Those CROs on the now short list should be asked to provide their 'best and final' cost and also the dates when they can actually initiate the study and the date when they project the draft final report will be available for review. The difference between original and final bids can be quite large, sometimes hundreds of thousands of dollars, for studies such as rodent carcinogenicity testing.
7.Selecting the CROs and awarding the contracts for each study to be outsourced.
The number of personhours required for the CRO identification and selection process depends on the size of the research program to be outsourced. Normally, a minimum of 1-2 person-weeks is necessary to effectively evaluate 3 to 4 CROs for each research study. This effort can be substantially reduced by placing more than one study at a CRO. Many firms utilize outside experts to assist them in the CRO selection process. However, these firms need to ensure that these experts or consultants have the necessary expertises in scientific disciplines for the studies to be outsourced and have knowledge of how CROs operate. A common mistake is to use individuals with expertise in the disease area but not in the nonclinical drug development process or in regulatory compliance but not in the scientific disciplines necessary to successfully characterize a drug candidate.
Sponsors commonly employ one of three strategies, designated virtual company, pre-selected, and special study, to identify CROs. The virtual company strategy is employed by Sponsors, mostly biotechnology firms, which do not have the infrastructure or resources to conduct GLP-regulated studies. The primary benefit of this approach is that the various expertises, such as toxicology, pathology, pharmacokinetics, and drug metabolism, and the infrastructure, such as facilities, Quality Assurance, and GLP compliance, needed to support GLP-regulated studies are available to the Sponsor without having to build the in-house groups. A primary limitation is that the Sponsor can be vulnerable to poor CRO selection or to mismanagement by the CRO. However, by appropriately using experts to assist in the identification and selection process and in the monitoring aspects, the Sponsor can usually avoid this limitation. In the pre-selected strategy, the first choice of many mid-sized and large pharmaceutical houses, a limited number of CROs, usually 3 to 6, are pre-qualified to support a company's possible nonclinical needs. The qualification process includes a detailed site visit to review the CRO's facilities, staff, and GLP compliance and to determine which types of nonclinical studies can be placed at the CRO. This strategy can provide a synergistic working relationship between the Sponsor and the CRO. A major drawback is the unnecessary limitation of outsourcing. If a fairly large number of CROs, say 30, have the necessary expertise to conduct a study but the Sponsor pre-qualified list contains only 3 CROs with the required expertise, the other 27 are not considered even through some may be able complete the studies faster and cheaper or may have superior expertise in the drug candidate's therapeutic area. The final strategy, the special study approach, is used by some companies to place single or a few nonclinical studies with a CRO. If a company's internal resources are usually, but not always, sufficient to meet their nonclinical needs, this strategy can be used in order to have an important study completed to meet a critical timeline on a drug development plan. However, some companies employ the special study strategy for all their nonclinical needs and then attempt to integrate the results for the individual studies into a drug development story. For a company with substantial drug development expertise, this approach may work but requires considerable effort in identifying and selecting CROs, in monitoring the various CROs, and in synthesizing the results from the various studies. CROs are generally not in favor of this strategy because they become only 'a pair of hands' and can not provide the sponsoring company with their considerable expertise and experience. Whichever strategy is employed, the Sponsor should carefully select the CRO. One poorly conducted study can effectively delay the drug development process until the study has been repeated and the results integrated into the overall story. If this delay is for a study on the drug development critical path, the projected time for regulatory agency submission has to be changed, thus delaying the projected date of approval for marketing and resulting in lost revenue for the Sponsor.
CRO Monitoring
The identification and selection processes are only the first step. The second aspect involves monitoring the CROs to ensure that the research studies are conducted according to the study protocol, that the results are obtained using appropriate techniques and procedures, and that the generated data are correctly recorded and documented in the study report. Monitoring studies at CROs should include, but are not be limited to:
1.Reviewing and approving the study protocols, prepared by the CROs and detailing the procedures to be followed to successfully complete the study designs. The study protocol should provide information on all aspects of the study. For example, commonly included items in a nonclinical drug safety animal study protocol are: Protocol Title; Objective; Study Location; Sponsor Designation; Study Monitor; Personnel; Study Dates; GLP Compliance; Test Article or Drug Substance; Test Species or Animal Model; Study Design; Test Species Assignment; Dose Preparation; Route of Dosing; Clinical Observations; Body Weights; Food Consumption; Physical Exams; Blood Collection; Hematology; Clinical Chemistry; Toxicokinetics; Euthanasia; Moribund or Found Dead Animals; Necropsy; Organ Weights; Histopathology; Statistical Analysis; Reports; Raw Data; Approvals.
2.Monitoring various aspects during the research phase of each study. Most items listed above are possible points for potential study monitoring. Monitoring will ensure that the data collected is appropriately documented and does not contain 'surprises' that can prevent the results from being used to support submissions to regulatory agencies.
3.Assisting in the evaluation and interpretation of results to ensure the data is analytically acceptable and correctly correlated to tell the story of the experimental results.
4.Reviewing the study report to ensure that the information provided accurately reflects the generated results, documents any deviation from the study protocol, and gives appropriate conclusions.
The number of personhours required to appropriately monitor a research study conducted by a CRO again depends on the size of the research program. Normally, a minimum of 1 personweek for each in-life phase month of a research study is required and includes the time necessary to review and approve the study report. As noted above, some firms employ consultants or consulting firms to assist with CRO monitoring and to ensure that the studies were conducted according to GLP guidelines. These consultants should also be specialists in the scientific disciplines for the conducted studies. Having a toxicologist or pharmacologist consultant monitor the bioanalytical chemistry program to support a pharmacokinetic research study could result in an assay that is inappropriately validated and thus not capable of analyzing specimens for drug and drug metabolite concentrations.
Conclusion
This white paper discusses some aspects for CRO selection and monitoring. By carefully evaluating CROs and then effectively working with these organizations during and after the study, the Sponsor can obtain the desired information needed to successfully characterize their drug candidate and prepare the necessary submissions to regulatory agencies. A close partnering between the Sponsor, or its designated agents, and the CRO is very important to ensure that the outsourced research studies are conducted as designed, within the desired time frame, and for the budgeted amount.
