preclinical development handbook || selection and utilization of cros for safety assessment

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979 28 SELECTION AND UTILIZATION OF CROs FOR SAFETY ASSESSMENT Joanne R. Kopplin and Ward R. Richter Druquest International, Inc., Leeds, Alabama Preclinical Development Handbook: Toxicology, edited by Shayne Cox Gad Copyright © 2008 John Wiley & Sons, Inc. Contents 28.1 Introduction 28.2 Historical Development of the Preclinical CRO Post-WWII 28.3 Role of the CRO in Preclinical Development Today 28.4 Locating Candidate CROs 28.5 Telephone Interviews for Initial Screening 28.6 Site Visit: The Key to Evaluation 28.7 Evaluation of the Process: Not the Final Report 28.8 Special Considerations in Selecting a Specialized or University Laboratory 28.9 Selecting a Single Laboratory Versus Spreading the Work Among Multiple Laboratories 28.10 Initial Selection of a CRO for a New Program or Single Large Study 28.11 Tactics for Developing a Relationship with the CRO Staff and Enlisting Them as Members of the Development Team 28.12 Dealing with Unexpected Compound-Related Changes or Technical Problems 28.13 Monitoring the Outsourced Work References 28.1 INTRODUCTION Outsourcing preclinical development and safety testing to Contract Research Orga- nizations (CROs) has become common in the biopharmaceutical, chemical, medical device, and food additive industries. It is important to understand the culture of the

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979

28 SELECTION AND UTILIZATION OF CRO s FOR SAFETY ASSESSMENT

Joanne R. Kopplin and Ward R. Richter Druquest International, Inc., Leeds, Alabama

Preclinical Development Handbook: Toxicology, edited by Shayne Cox GadCopyright © 2008 John Wiley & Sons, Inc.

Contents

28.1 Introduction 28.2 Historical Development of the Preclinical CRO Post - WWII 28.3 Role of the CRO in Preclinical Development Today 28.4 Locating Candidate CROs 28.5 Telephone Interviews for Initial Screening 28.6 Site Visit: The Key to Evaluation 28.7 Evaluation of the Process: Not the Final Report 28.8 Special Considerations in Selecting a Specialized or University Laboratory 28.9 Selecting a Single Laboratory Versus Spreading the Work Among Multiple

Laboratories 28.10 Initial Selection of a CRO for a New Program or Single Large Study 28.11 Tactics for Developing a Relationship with the CRO Staff and Enlisting Them as

Members of the Development Team 28.12 Dealing with Unexpected Compound - Related Changes or Technical Problems 28.13 Monitoring the Outsourced Work References

28.1 INTRODUCTION

Outsourcing preclinical development and safety testing to Contract Research Orga-nizations (CROs) has become common in the biopharmaceutical, chemical, medical device, and food additive industries. It is important to understand the culture of the

980 SELECTION AND UTILIZATION OF CROs FOR SAFETY ASSESSMENT

CRO industry and how to locate, evaluate, and work with individual CROs when outsourcing work. In this chapter, we discuss these processes based on personal experience working with and working for preclinical CROs. Our combined experi-ence is derived from outsourcing preclinical work as employees of a major pharma-ceutical company, a major chemical company, and a young biotechnology company and as consultants for these industries. We have also held senior management posi-tions in three different CROs during the course of our careers.

28.2 HISTORICAL DEVELOPMENT OF THE PRECLINICAL CRO POST - WWII

Contract Research Organizations (CROs) conducting preclinical testing provide services in pharmacology, pharmacokinetics, analytical chemistry, toxicology, pathol-ogy, and associated disciplines. Most were established and/or grew after Word War II as a result of growth in the pharmaceutical industry and because of increasing government regulations. The preclinical contract industry has been concentrated in the United States and the United Kingdom. Smaller laboratories are found in Canada, France, Italy, Japan, and other countries.

Early growth of the preclinical contract industry was fueled by rapid growth of the pharmaceutical industry when construction of new toxicology laboratories and animal facilities did not keep up with the number of new drug candidates selected for development. Surplus work was outsourced but sponsors outsourced only work that was deemed less critical and simpler to conduct because contract laboratories did not have the same level of scientifi c expertise, facilities, or equipment as the sponsoring companies. The scientifi c capabilities of the contract laboratories grew in quality and depth over the years and by the 1990s they were generally perceived as the equivalent of that found in the largest pharmaceutical fi rms. For many special-ized technologies they often were superior to the sponsoring companies because of extensive experience in technologies that were used only occasionally by a single company.

Rapid growth of toxicology contract laboratories occurred during the 1960s and the early 1970s. Industrial Biotest (IBT) was an industry leader and was utilized by many major pharmaceutical and chemical companies in the United States, Europe, and Japan. IBT was favored because it turned out studies and reports on time and at low cost and was perceived to provide quality work. By 1975, it was learned that Industrial Biotest fabricated some of the data in its reports and the laboratory was eventually closed with several members of the management team convicted of criminal activity. The criminal behavior of this laboratory was one of the motivators for the establishment of the Good Laboratory Practice Act of 1978. Because so many large companies had relied on this laboratory and because some of the work was invalidated, there was a signifi cant backlash against outsourcing to contract laboratories. Pharmaceutical and chemical companies rapidly built new toxicology laboratories and established policies of conducting all preclinical testing in - house. The amount of outsourcing for preclinical safety testing leveled off or contracted in the 1980s, as a result.

Another unrelated event occurred in 1976 that was to have a major negative fi nancial impact on the preclinical contract laboratory industry when the Toxic

Substances Control Act (TOSCA) was passed, regulating an estimated 75,000 chemicals. Most people in the industry and government expected that TOSCA would mandate extensive toxicology testing of thousands if not tens of thousands of chemicals in industrial use. The contract laboratory industry viewed this as an opportunity and a major new source of revenue and expansion. Many of the labo-ratories, including the industry leaders, built new facilities, increasing their animal capacity by as much as 30 – 40%. The work predicted by passage of the Toxic Sub-stances Control Act never materialized due to the manner in which the law was interpreted by regulatory agencies and because of intense lobbying pressure by the chemical industry. By the early 1980s there was a serious surplus of animal rooms in the contract industry and most facilities were not fi lled. The industry became very competitive and companies cut prices to cost or even below cost to cover overhead. This oversupply of animal and laboratory facilities kept prices and margins depressed until the late 1990s when growth of the pharmaceutical industry caught up with capacity. Prices of studies remained at relatively fl at level for 15 years in spite of infl ation.

Starting in the 1990s, a series of factors dramatically improved the fi nancial outlook for preclinical toxicology laboratories. (1) The biotechnology industry, con-sidered as a subset of the pharmaceutical industry, matured and grew to spend sig-nifi cant amounts of money on development. (2) The contract laboratories achieved recognition that they were fully as capable as in - house laboratories of sponsors and they no longer carried the stigma of the Industrial Biotest incident. (3) Combinato-rial chemistry and new automated early screening technologies increased the number of potential drug candidates in development. (4) Financial administrators in the large pharmaceutical and chemical companies put more and more pressure on the corporations to outsource for economic reasons, because of the lower operating costs in contract laboratories. Purchasing departments became involved and they pressed for preferred provider agreements with one or more CROs.

Today the involvement of CROs is recognized and supported by the FDA. In a speech to the Association of CROs (ACRO) in October 2002, the FDA Commis-sioner, Dr. Mark McClellan, stated that “ CROs hold great potential ” to help the process of reducing development time for new drug applications and getting safe, critical products to market more quickly.

28.3 ROLE OF THE CRO IN PRECLINICAL DEVELOPMENT TODAY

The trends just described have fi lled the empty animal rooms in the major preclini-cal CROs in the last several years. Pharmaceutical companies have their own labo-ratories but contract excess or specialized work to CROs. We estimate the annual value of outsourced work (preclinical and clinical) to be in excess of $ 8 billion (U.S.). Of this $ 8 billion, an estimated $ 600 – 750 million was outsourced for preclinical testing in 2002. It is unclear whether analysts developing these estimates have included the potential outsourcing from the smaller biotechnology companies. Small biotechnology companies without their own internal capabilities exclusively use CROs to conduct their safety testing. Even the largest biotechnology companies have limited animal facilities, usually limited to effi cacy testing and pre - GLP safety testing.

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Testing procedures conducted by preclinical CROs are standardized by govern-ment regulation and all competitors conduct the same process. All of the major players in the marketplace produce a quality report on time, conforming to govern-ment regulations with the process being driven by experienced managers and tech-nical staff. Companies differentiate themselves by experience, unique technologies, automation, scientifi c expertise, and service. The product is the process rather than the end report.

Pharmaceutical companies generally do not feel comfortable with laboratories that appear to be too academic or culturally aligned with practices in government laboratories. These groups are perceived to pay less attention to timeliness and effi ciency and to have less understanding of the drug development process. Phar-maceutical companies contract work to laboratories that have familiar facilities and familiar cultural behavior. They contract to laboratories with a known track record or those laboratories that employ experienced staff familiar with the pharmaceutical corporate culture. David Cavalla [1] in Modern Strategy for Preclinical Pharmaceuti-cal R & D stated it in this way: “ Enduring added value can only come from a strong knowledge base of the core business. In this case this is the technical and scientifi c complexity of the pharmaceutical development process. CROs who can capture this knowledge through employing professionally experienced leaders, who can then cultivate the scientifi c culture of pharmaceutical development into their organiza-tion, will be the winners of the fi ght to capture increased market share. ”

28.4 LOCATING CANDIDATE CRO S

For new startup companies it is important to begin the identifi cation and evaluation of CROs early to enroll one or more in assisting development of their business plan. “ Before a company even has a drug candidate to test, when it is still devising its business plan and is concerned with matters such as fi nancing, infrastructure, and early - stage discovery, it should begin researching the services available for outsourc-ing, the economics of pursuing an outsourcing strategy ” [2] . For established compa-nies, it is important to establish an ongoing relationship with several CROs to allow them to move rapidly in outsourcing new drug candidate testing.

Colleagues who have worked with several CROs can be the single most useful source of locating companies that are candidates for your outsourcing requirements. They can provide the benefi t of their experience in working with specifi c companies and their positive as well as negative experiences. Frequently, they will have useful contacts on the staffs of the CROs they have worked with. An individual new to the preclinical development business may not have colleagues in the business. Attendance at local and regional biotechnology meetings is useful in making contact with new colleagues on an informal basis.

Consultants in preclinical development, safety assessment, or toxicology work with many CROs and they are usually in the business of assisting in evaluation of CROs and in outsourcing studies. While the major CROs all conduct a broad range of studies and have most technologies available, they are not all equally adept at conducting studies that are not part of the standard core of toxicology studies. Con-sultants can be very useful in assessing specifi c capabilities. Interviewing and getting the assistance of one or more consultants for suggestions on CROs helps develop

a useful relationship with the consultant early on in the preclinical development process. If problems develop or unusual fi ndings appear in safety studies, consultants can be invaluable in designing an approach to elucidate the problem and if neces-sary in working with the FDA to develop a strategy that will satisfy the agency ’ s questions when the data are submitted in an IND. The consultant may not be needed for anything further in the preclinical development program but an established relationship is invaluable, should a consultant ’ s assistance be needed.

Trade shows are a great place to review the capabilities of a large number of CROs, especially those with specialized technologies. The 2005 SOT meeting had 51 exhibitors who classifi ed themselves as CROs. In addition, there were specialty laboratories with a single technology who didn ’ t classify themselves as CROs. It is possible to meet scientists and scientifi c directors of the companies at shows such as the SOT Exhibition. It is possible to discuss a proposed development program and outsourcing requirements at the trade show and get a sense of the CRO ’ s approach to a relationship with a new client. Develop a fi le of candidate laboratories for future reference and keep it up to date. We maintain a library of literature from at least 12 companies that we are interested in utilizing. In addition to literature, web sites are useful in getting an overview of a company ’ s capabilities.

28.5 TELEPHONE INTERVIEWS FOR INITIAL SCREENING

Telephone interviews of candidate CROs save time and travel costs. They are useful in developing a short list of potential partners. The telephone will become one of the primary means of communication during the negotiating period and during study design, initiation, and conduct. The telephone interview will provide a sense of how easily the organization deals with you by phone. Determine if it easy to reach the scientifi c staff, whether you are routed only to marketing staff, and whether your calls are returned in a timely manner.

28.6 SITE VISIT: THE KEY TO EVALUATION

An actual site visit and inspection of the CRO ’ s facilities and staff is the most important single activity in evaluating a new company. Mid - size and large companies considering outsourcing will conduct site visits by their in - house staff, while small virtual companies and new startups may conduct site visits through a consultant. Consultants often have working knowledge of the CRO under consideration and may not need to conduct a new inspection in the detail outlined here. For small companies relying on a consultant, it is still benefi cial for a staff member to accom-pany the consultant on a site visit to meet the staff and begin to develop a working relationship. A site visit provides the opportunity to see work in progress and systems in action. It is the best way to evaluate security and the procedures to protect the confi dentiality of data. Breaches of confi dentiality can be very subtle and three examples follow. One of the authors (Richter) was alerted to a breach of security in his own CRO by a client. The client arrived at the laboratory early, 15 minutes before the front door was open for business. He walked behind some bushes adjacent to the front door to peer through the window. The desk of the director of

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pathology was next to the window and he saw the business cards of two of his col-leagues who had visited the week before and he could read pages of a report for his compound. He was very unhappy. One of the authors (Kopplin) inspected a GLP compliant CRO that was affi liated with a university, but operated as an independent agency. They were self - contained except for the ability to print reports and they used the university central reproduction facility in another building. Confi dential reports of safety studies were left on a table in the hallway for pickup after comple-tion. They were accessible to the general public walking by. This laboratory was not placed on a list of acceptable CROs. One of the authors (Richter) inspected a large well established CRO and was getting a tour of the facility. They were visiting the test material storage room when the host was paged to a phone call. The author was left alone with access to the stock test material from dozens of companies. The labo-ratory was not placed on a list of acceptable CROs. These examples provide insight into the type of things that can only be determined by a site visit. A checklist (Table 28.1 ) is provided to outline the conduct of an inspection of a new CRO.

28.7 EVALUATION OF THE PROCESS: NOT THE FINAL REPORT

While the checklist covers very specifi c items, the overall evaluation of the candidate CRO should depend on an evaluation of its culture and an evaluation of the process involved in conducting the work. Unlike the manufacturer of a widget, the process of conducting the research, interpreting it, and summarizing it in a report is critical to its quality and elegance. The widget manufacturer can tolerate mistakes by having a good quality control system that eliminates defective products. That simplistic approach to quality is not applicable to a highly regulated knowledge - based indus-try. Evaluating the process is fundamental to fi nding a CRO that meets your needs. All of the major CROs can produce a report on time that is free from error. The quality of the process is what differentiates them. Thus, the culture of the CRO, its systems, and its staff are critical elements in success. When inspecting a CRO, look for signs that the process has broken down, such as piles of work on a study direc-tor ’ s desk and fl oor or rooms full of materials that should have been archived or disposed of. One of the authors (Richter) discovered that a CRO ’ s inability to vali-date an analytical procedure occurred when a reference standard for another com-pound that should have been archived was left in the analytical laboratory and used by mistake.

The reliability and quality of the process infl uence the time to completion of studies and reports. Pharmaceutical companies are under strong pressure to cut the time from drug discovery to market. It is important to determine the CRO ’ s record for on - time reports. Late reports are an indication of failure in the processes or inadequate staffi ng.

28.8 SPECIAL CONSIDERATIONS IN SELECTING A SPECIALIZED OR UNIVERSITY LABORATORY

Working with university laboratories can require some extra effort. There are times when a specialized procedure performed only in a university setting is needed to

TABLE 28.1 Checklist for Site Visit Evaluation

Meet Key Personnel, Marketing, Management, Scientifi c and Technical

Marketing Representative Senior Scientifi c Management Study Director(s) Director of Pathology Director of Clinical Pathology Directors of Analytical and Bioanalytical Chemistry Director of Quality Assurance Director of the Pharmacy Managers and/or supervisors of other specialty services or laboratories

Staff Qualifi cations

Resum é s of key scientifi c and technical staff Certifi cations, scientists and technicians Training records, evidence of ongoing training Publication record and presentations at scientifi c meetings Consultant ’ s and part - time specialist ’ s qualifi cations Determine whether you would be comfortable working with this staff; go to lunch and/or dinner with some of them; ask to meet key people in their offi ce, view their work environment

Special Things to Observe or Determine During Visit

Determine in - house capabilities. Are any key services outsourced? Assess the morale of the staff Observe how busy the facility is. Are animal rooms mostly full or mostly empty? Find out their on - time record for delivery of reports Establish who will be your primary contact during negotiations and during conduct of

work Develop an impression of whether the laboratory management appear to be interested in

working with you or whether your visit is treated as a routine Evaluate the degree of automation for data capture and reporting

Physical Plant Areas to Inspect

Reception Conference room Offi ces Laboratories, chemistry, histology, clinical, specialty Necropsy room(s) Animal rooms Technician work areas, desks and facilities for data review and organization Pharmacy Information Technology Restrooms Cage washing Storage, clean and dirty cages, food, bedding, supplies

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986 SELECTION AND UTILIZATION OF CROs FOR SAFETY ASSESSMENT

What to Inspect Physical Physical Plant For

Organization of overall facility for effi cient work fl ow; user friendly HVAC, environmental monitoring system, review temperature records Cleanliness of the facility Cleanliness of uniforms Maintenance Organized work fl ow in laboratories Work fl ow into and out of animal rooms, clean versus dirty corridors Security and confi dentiality. Can you see any data left in open view during a tour? Availability of SOPs in work areas Availability of MSDSs in work areas

Security

Reception and visitor entrance Employee entrance Deliveries and loading dock Data security, hard copy and electronic Computer backup, stored on site or off - site Disaster recovery plan Compound and formulation security Background check on employees Is work left unattended on desks? Pathologists computers on or off while away from desk? End of work day security for active paper fi les? Backup generator Emergency planning: snow, sleet, or other event

Standard Operating Procedures (SOPs)

Review table of contents for general overview Review key SOPs and those for specialized procedures needed for proposed project(s) Are the SOPs reviewed and updated on a specifi c schedule? Are the SOPs accessible to the staff in the laboratories and animal rooms? Ask to see the

SOPs for a specifi c procedure during a tour of the laboratories. Is it readily available and does it appear that the staff are following the SOPs?

Is the format of SOPs user friendly? Is the process of SOP approval overly bureaucratic? Do you fi nd hand - written notes derived from SOPs in the laboratory — a GLP violation? Evaluate employee health and emergency medical assistance Review animal care program

Other Documentation

FDA and/or EPA inspections and audits, key fi ndings Maintenance records on equipment, view examples for critical equipment Sample contracts and confi dentiality agreements Sample protocols Statistical procedures Examples of reports — fi nal, interim, and periodic progress updates Facility certifi cations, local AAALAC accredited; date of last inspection, inspection report

TABLE 28.1 Continued

evaluate the safety of a drug candidate. Unless the testing procedure has a wide-spread demand by the pharmaceutical industry, the laboratory is unlikely to be in compliance with the Good Laboratory Practices Act. The requirements of full com-pliance are of such a magnitude that it is not economically practical for the univer-sity laboratory to meet all of the specifi c details. The FDA and EPA will accept studies from these university laboratories, if the procedures are not available from a fully compliant GLP laboratory and if the laboratory meets the spirit of the GLP requirements. University laboratories generally do not have access to help in setting up the major requirements of GLP compliance. It will be necessary for the sponsor-ing organization to work with the laboratory to meet minimum standards. An inspection of the facilities and an evaluation of systems is the fi rst step in outlining the defi cits for the laboratory director and staff. We have found that the fi rst and most glaring defi ciency in many university laboratories is control of the test material and its security. Often the laboratories are used by graduate students who have unlimited access along with their visiting friends in the middle of the night. It is not diffi cult, but it is necessary, to develop locked and secure cabinets or rooms for the test material, related materials, data records, as well as the appropriate logs of the materials. The extent of installing GLP procedures depends on how critical the labo-ratory procedure is to determining the ultimate safety of the test article. The sponsor should be prepared to provide QA inspection of the work. At a minimum, the sponsor should be prepared to assist in any or all of the following:

Outlining the SOPs needed Developing the protocols Advising and/or assisting in the preparation of SOPs Preparing forms for data recording, when not automated Documenting staff performing individual procedures Determining validation needs for instrumentation and processes Maintaining CVs and training of staff Defi ning raw data Establishing data security procedures

We have also found that an hour of time spent in reviewing the background and need for GLP standards is productive with an inexperienced academic staff. Most individuals grasp the concept of documentation and chain of evidence for forensic purposes as an analogy and this goes a long way in achieving compliance with the general concept of Good Laboratory Practices.

28.9 SELECTING A SINGLE LABORATORY VERSUS SPREADING THE WORK AMONG MULTIPLE LABORATORIES

Early in the evolution of the CRO industry, many in the sponsor industry worried about the stability of an individual CRO and placed their studies in different labo-ratories because they felt it reduced the risk. If anything were to go wrong, fi nan-cially, technically, or logistically in one lab and a study was compromised, the damage was limited. The rest of the development program would be safe.

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With the maturation of the CRO industry, the individual companies have become fi nancially stable, they have well established and reliable procedures, and they main-tain a staff that is just as stable as that of the sponsoring organizations. With that change, it is usually wiser to place all of the development outsourcing with a single company once a working relationship has been established. The company will have experience with the compound, its formulation, and expected compound effects. Dose setting studies do not transfer well from one lab to another because of subtle differences in animal environment and care. A second lab will almost always insist on repeating dose - ranging studies before undertaking the next step in a develop-ment program even though dose ranging was done earlier at another laboratory. They will have learned from experience that they risk running a study that may not meet regulatory guidelines for establishing dose levels. It is critical to place major studies in the same laboratory that did the dose - ranging studies in the same species and strain of animals.

There are distinct fi nancial advantages to placing all of a safety testing program at one laboratory in addition to eliminating the need for several dose - ranging studies. CROs will negotiate favorably on packages of all of the studies needed to reach an IND. Even those sponsors who only outsource one or two studies from a development program will get favorable treatment in pricing if they are repeat clients. However, it may be necessary to use several CROs because the laboratory of choice may not offer all types of studies or may be relatively inexperienced in a specialized study such as reproductive toxicology or genetic toxicology.

28.10 INITIAL SELECTION OF A CRO FOR A NEW PROGRAM OR SINGLE LARGE STUDY

For budget purposes, CROs will provide general prices for specifi c types of studies. The fi nal price will depend on the specifi c protocol and variations of the protocol related to the type of compound, mechanism of action, and clinical indication being tested. CROs will also provide templates of protocols for sponsor review and modi-fi cation or they will modify a protocol to meet the sponsor ’ s specifi c requirements. Once the protocol is close to the fi nal version, it is time to get specifi c prices for the work. This may involve submitting a single study for pricing or submitting a whole series of studies for pricing.

When outsourcing a new development package or a single large study such as a carcinogenicity study, it is useful to get prices from at least three different labora-tories that have met your criteria during the screening process. The favored labora-tory may not be able to start the projected studies on a realistic schedule because it is busy. Laboratories that are busy and fully booked usually do not negotiate on price. By letting the CRO know that you are getting three bids on the program, it will be sure to quote its best price for fear of being underbid by a competitor.

When getting bids from several laboratories and comparing prices, it is important to be certain that all are bidding on the exact same protocol. Rather than asking for the price of a 28 day rat gavage toxicity study, a specifi c and identical protocol should be submitted to each of the CROs. In that way, prices won ’ t be affected by variations in the several laboratories standard protocols for that type of study. Inform the bidding companies that the protocol may be modifi ed in fi nal negotia-

tions but that the initial protocol will be the basis for selection based on price. It helps to build future relationships, if you agree to share the pricing information after bids are returned. It is not necessary to disclose the bidding laboratory, only the range of prices from them.

Since the laboratories are competitive, bids usually are quite similar. If they are, the choice should be your favorite providing they all meet your time frame for completion of the work. Occasionally, there may be a laboratory that is especially high and out of range. The high price may indicate that the lab is booked and over-worked or that it didn ’ t review the protocol carefully, both bad signs. Bids that are signifi cantly lower than the rest may indicate that the laboratory is having diffi culty marketing or that it did not review the protocol carefully. If awarded the contract, the lab could be tempted to cut corners to keep costs down. When we were outsourc-ing studies for our respective employers, we never recommended accepting a price that was signifi cantly below others or that was well below the expected range based on previous experience.

28.11 TACTICS FOR DEVELOPING A RELATIONSHIP WITH THE CRO STAFF AND ENLISTING THEM AS MEMBERS OF THE DEVELOPMENT TEAM

Nothing is more important to the success of outsourcing than developing an effec-tive working relationship with the staff of the CRO. They should be considered part of the development team with just as much invested in the success of the project as the sponsor ’ s staff. They should share the agony of failure and the elation of success. Decades ago, many sponsors felt it necessary to develop an adversarial relationship with a CRO to ensure due diligence in the conduct of the project. Nothing destroys a successful outcome more than a paranoid attitude over the conduct of a study. It is possible to exercise proper quality control over the outsourcing process without making it an adversarial relationship. The staff of the CRO expect that the sponsor will be looking over their shoulders and evaluating their work as it proceeds but this process does not need to be confrontational.

Developing a relationship that makes the technical staff as well as the scientifi c staff feel part of the team helps ensure success of the project. A good sponsor will present one or more seminars on the drug candidate and the development progress for the CRO staff. Progress reports on the development program keep enthusiasm high for the testing project and encourage careful work on the part of the technical staff. CRO management usually encourages such inclusion of the staff as part of your development team. It helps morale of the staff to have a stake in the outcome of the drug candidate ’ s progress through the development process.

28.12 DEALING WITH UNEXPECTED COMPOUND - RELATED CHANGES OR TECHNICAL PROBLEMS

It is human to immediately assume that errors were made in the conduct of a study when there are unexpected adverse effects. It is in the best interest of the CRO to detect errors if they occur and the staff will assist in resolving the cause of

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990 SELECTION AND UTILIZATION OF CROs FOR SAFETY ASSESSMENT

unexpected results. One of the authors (Richter) worked with a sponsor on an intravenous infusion study that caused the death of all animals at the high dose level with severe damage to the veins. Studies on vein irritation had shown that the com-pound was not especially irritating. The sponsor immediately accused the laboratory of misdosing the animals, hired several consultants, and spent 3 months reviewing all of the records, interviewing technicians and scientifi c staff in an attempt to prove that the laboratory had made a serious error. The CRO staff had determined that the problem was related to the formulation within days of the deaths. The compound was only minimally soluble in the formulation and it precipitated out in the veins during infusion, actually obstructing them. It took the sponsor 3 months of lost time before the sponser accepted this interpretation and, working with another consul-tant, went back to the drawing board and reformulated.

28.13 MONITORING THE OUTSOURCED WORK

Monitoring of the work is a key to a successful outcome. Under GLP regulations, a study monitor is specifi ed by the sponsor and this individual is the primary contact with the CRO ’ s study director during the initiation, conduct, and reporting of the outsourced work. The study monitor should be in contact by email or phone at least weekly to review progress. The contract with the CRO should specify regular letter reports on a periodic basis, weekly or monthly, depending on the complexity of the study.

It is very helpful for the study monitor and/or additional sponsor representatives to visit the CRO laboratory site and review the work during the course of a study. The frequency and depth of these inspections depends on the complexity of the study. Short - term dose - ranging studies usually do not need a physical inspection unless the dosing procedure is unusually diffi cult. For defi nitive studies, such as 28 day, 90 day, or longer toxicology studies, it is desirable to have a sponsor representa-tive on - site for at least the fi rst day of dosing and the necropsies. Interim on - site inspections of the data on a monthly or quarterly schedule reduce the amount of time needed in reviewing the fi nal report and in detecting problems. These visits are helpful in nurturing a sense of team work with the CRO staff and lets them know that they are part of the team. When unusual parameters are being measured or when a routine parameter is critical to the mechanism of action of the compound, the sponsor will want to be present for the event. Urinalysis is usually considered to be a very routine analysis in toxicological studies. We worked with a compound that was expected to cause changes in urinary parameters and this was so critical to the outcome of the study that sponsor representatives at the vice presidential level were on site to observe the urine collection and processing in the clinical pathology laboratory.

The best CROs occasionally make mistakes and sometimes these are not obvious to those who observe the work on a daily basis. A sponsor representative may look at the progress of the study with a different viewpoint. One of the authors (Richter) worked as a consultant for a carcinogenicity study at a CRO in which more than half of the female rats in all dose groups, including controls, developed uterine car-cinomas. The spontaneous incidence of uterine carcinomas in rats of the strain used was less than 5%. The staff of the CRO were unable to determine the reason for

the increased incidence after detailed review of all records. After the author found that there was light - induced damage to the retinas, he suggested that increased estrogen levels were responsible and that excessive exposure to light could increase estrogen. The CRO staff carefully checked the timers for the animal rooms and found that they were correctly set to go off and on at the protocol specifi ed times. After the author insisted that the timers be checked again, the building engineers revealed that they had disconnected the timers from the lights and although the timers were running, they had no effect on the lights. The rats had been exposed to light 24 hours a day for 2 years! No one had checked to see if the lights actually went off every night. The book by Gralla [3] covers many issues in monitoring toxi-cology studies.

REFERENCES

1. Cavalla D. Modern Strategy for Preclinical Pharmaceutical R & D 1997 ; 131 . 2. Glaser V. Outsourcing Drug Discov Dev 2005 ; 25 ( 15 ): 23 – 26 . 3. Gralla EJ. Scientifi c Considerations in Monitoring and Evaluating Toxicological Research .

Bristol, DA : Hemisphere Publishing Corporation ; 1981 .

REFERENCES 991