The Selection and Use of Contract Research Organizations

Shayne C. Gad

• Publisher: CRC Press
• Year: 2003
• ISBN:
  9781134424863
• Edition: 1
• Topic: Informatica
• Subtopic: Tecnologia dell'informazione

Choosing the right contract research organization (CRO) can make the difference between getting a product to market quickly and cost-effectively, and wasting valuable time and money. The vast number of available CROs is increasing all the time, and all of them make impressive claims. The Selection and Use of Contract Research Organizations is your

CHAPTER 1
Introduction

The research driven components of the global health care industry represent an enormous economic and societal force in the world, and are composed of an incredibly diverse set of component organizations. Ranging from huge multinational corporations to ‘virtual’ organizations which have only a few part time employees, while primarily in the private sector, there are also those which are partially or fully funded by various government organizations (there is probably even room for a separate volume on funding models and means for such organizations and the impact of such on development processes). There are ‘for pay’ directories of these available (DIA, 2002 for example), but these are by no means either comprehensive of objective.

For the purposes of this volume, the resulting products from all of the efforts of this sector of the global economy include drugs (pharmaceuticals, biologicals, vaccines and so forth), medical devices, and diagnostics. All of these are highly regulated both during their development and marketing. Though many of the service organizations referred to in this volume also do work for other industries, our focus will be on the more limited pharmaceutical and medical device industrial sector.

Contract research organizations (CROs) (also called CSOs – contract service organizations, or PDOs – pharmaceutical development organizations) span an amazing range of areas of expertise. Though there are some organizations which present themselves as turn-key ‘we do it all’ (none timely do), most offer distinct niche services. These include:

1. Biological: Pharmacology (in vitro screening, efficacy modeling, safety pharmacology), toxicology (genetic toxicology, animal toxicology – with many subsets), pharmacokinetics and metabolism.
2. Chemistry: Synthesis, active pharmaceutical ingredient (API) manufacture, radiolabeled synthesis, analytical methods, bioanalytical methods.
3. Clinical: Phase I centers, clinical research associates (CRA), statisticians, data and site management, report writing services. Centerwatch.com currently lists more than 730 of these for the US alone.
4. Dosage form aspects: Formulation developers, clinical test material (CTM) manufacturers (oral, topical and parenteral), labeling, patient kit preparation.
5. Regulatory: Investigative new drug (IND) applications, new drug applications (NDA), and annual update writers, regulatory advisors.

A more detailed breakdown of the scope and types of activities of CROs is provided in Chapter 4. Literally the services provided cover the entire range of activities involved in discovering, developing, getting market approval for manufacturing, distributing and marketing the products in these industries. I will limit this volume to those involved in taking an idea or molecule forward through development to the point of getting regulatory approval to market a product.

I must also state that most of my career has been spent in the aspects involved in insuring the safety of products, and therefore I will tend to use the CROs (‘toxicology labs’) and activities in this area as examples. While such have been the subject of limited directories in the past ( Jackson, 1985; Texas Research Institute, 1986 and Freudenthal, 1997), they have been limited to larger US facilities.

We should start by considering the history of such commercial labs. The oldest in the US (Food and Drug Research Laboratories or FDRL) opened in the 1930s, moved from suburban New Jersey to rural upstate New York, and went out of operation in the late 1980s, though the facilities are still utilized by (and some of the staff still work at) Liberty Laboratories, which specializes in felines (domestic cats) for and in research.

From the second half of the 1970s a number of toxicology laboratories [Industrial Biotest (IBT), the University of Miami operated lab, Cannon Laboratories, Bioassay Systems, Lilton Biometrics, Tegaris Labs, Bushy Run (for years called the Chemical Hygiene Fellowship of Carnegie Mellon Institute and perhaps the second oldest contract toxicology laboratory), Borriston/Midatlantic Laboratories, Primate Research Institute (PRI), Utah Biomedical Testing Laboratory (UBTL), HTI, and Oread Laboratories – to name a few] of significant size have gone out of existence. Additionally, just as in the industries they serve, there has been a continued series of acquisitions and mergers (the current Charles River Laboratories includes what were once Sierra Biomedical, Pathology Associates Incorporated, Argus Research, Redfield Laboratory, Springborn Laboratories and TSI Mason among its parts) and of renamings (Hazleton becoming Corning becoming Covance, for example). These same trends and forces have been active in the other types of CROs. As has continued shifting (and generally) expansion of services offered to expand market, revenues and profitability. In extreme cases this has led to the evolution of some organizations (such as Quintiles, Covance, and MDS Pharma) which offer to ‘do it all’ for the pharmaceutical industry.

Few companies seeking to develop a new regulated product (though the focus of this book is on drugs, devices and diagnostics, this also applies to dietary supplements, pesticides, cosmetics and many other products) have the capability to perform the required technical (and in many cases, regulatory) work needed to bring the product to market. From this point such companies will be generally referred to as clients or sponsors. Alternatively, although some or all of the capabilities may exist, the company’s laboratory schedule may not be able to accommodate all required works in the desired time frame. At some time, for various reasons, industry will need to contract work to external facilities, whether they are commercial contract laboratories, university laboratories, or even a member company’s laboratory as in the case of a consortium study. As with all contractual arrangements, careful planning and coordination coupled with thorough preparation is required in order to obtain the desired product or service, to avoid confusion and misunderstanding, and to produce a timely and cost effective result. This is a practical guide for those organizations that need to outsource some or all of their activities at external facilities. Here I shall attempt to present both the how of such activities and a source book (directory) of those that are available.

The needs for (and means of accessing) CRO support services are different for the majority of client organizations (smaller companies which have no or only one marketed product) and larger organizations (sometimes referred to as ‘big pharma’, comprising truly fully integrated companies with multiple products on the market). Issues of timing, cash flow and objective (get the product to a point where a ‘partner’ will buy or at least heavily support the continued development of a product versus taking products all the way to market) as well as what contract resources are needed and how they are to be managed as part of a development program tend to be very different. But the majority of the concerns and issues of individual contractory selection, monitoring, and management as presented in this book are common (FDA, 1984).

DEFINING THE PROJECT

Development of the study record

The objective of a study or any research is to evaluate theories and produce results. The written record of this work is called the study record and includes all records, documentation, and results of the development effort. Let us now consider the logical progression of such research activities and the development of the study record.

Research plan

The development project begins with developing the study or project plan, or simply thinking through what needs to be done and when. Whether the worker is performing internal research, concept evaluations, or works in support of regulatory requirements, this plan should be written down. When written, the research plan becomes the framework for the protocol or contract for the project and includes the hypothesis, the proposed methods, observations to be made, and the expected results. Researchers should pay special attention to the level of detail in this plan. For example, in regulatory research environments there are mandated requirements for inclusion of particular details in the protocol and a specified format. Optional experimental methods may be included in the protocol or amended into it as needed, but (again) must be recorded. Even if a written protocol or detailed contract is not specifically required for the project, it is useful to develop the habit of producing a protocol because it requires you and your colleagues to think clearly through the experimental design and potential issues. It also provides guidance for the actual conduct of the work and promotes consistency in performance (Figure 1.1).

General considerations

There are a number of general aspects to be considered in the operations of a CRO in the regulated industries that we are concerned with. Most of these, of course, have to do with how things are documented. I will generally use US FDA Good Laboratory Practices (GLPs) (FDA, 2002c) as my model in this volume, but the principles are the same internationally (Gad, 2001) and for Good Manufacturing Practices (GMPs) and Good Clinical Practices (GCPs).

Figure 1.1: Progression of a contracted study or project.

Standard operating procedures

Some of the procedures performed during the study are routine for the laboratory. Formalize the documentation of these routine procedures into written standard operating procedures (SOPs). SOPs are detailed descriptions of such things as equipment operation, methods for taking and recording data, and procedures for reagent receipt, storage, and preparation – the types of procedures that are common to all laboratory operations. Write SOPs in sufficient detail to promote consistency in performing the procedures. Having SOPs and insisting that they are followed provides the researcher with a measure of control over potential variables in the experiment.

A good place to initiate an evaluation of any regulated facility is to examine its record of previous inspection results. For the FDA, these are easy to obtain (FDA, 2002b).

Data recording

The study begins. You perform a procedure, write down what you did, and record the observed results. The level of detail of any written record should enable someone else with equivalent technical training to perform your experiment exactly as you did. Why? Reproducibility. That experimental results must be reproducible is a basic rule of science. It is the process through which scientific conclusions and discoveries are confirmed. Reproducibility is promoted by the specific data-recording requirements for data that are submitted to the FDA and equivalent non-US regulatory agencies. Reproducibility is also required in research performed to support a patent request.

For now, I wish to introduce you to the concept of ‘if you didn’t write it down you didn’t do it’. You, the researcher, have the burden of proof in regulated research, in protection of patent rights, and in defense of your work in professional circles. The issue is completeness of your records. The study record must be a complete record of all data and procedures performed. If you didn’t write it down, you didn’t do it. In the experimental record, there are some accepted shortcuts. Here some of the hard preparatory work pays off. In your written record, you may include references to previously described methods and SOPs, state that they were followed exactly, or describe deviations from them. And efficient ways of collecting data may be developed to encourage the complete recording of all required data. Later in this chapter, methods for recording procedures and observations will be discussed in detail.

The accuracy of recorded data is another important consideration because any observed result, if not recorded immediately, may not be record accurately. Don’t lose data because of some rationalization about time, money, or your ability to remember what happened. All data should be recorded directly into a notebook or onto a worksheet at the time of the observation. Also, transcribed data – data copied by hand or entered by a person into a computer – often is subject to errors. If data are copied to a table or a spreadsheet, the entered data should be checked against the original data to ensure accuracy. In a regulated research work, all such work and data will also be audited and the accuracy and conformance to procedure verified.

Analysis of the data

When the laboratory work is done, the analysis of the data begins. Observed data are entered into formulas, calculations are made, and statistical analysis is performed. All these manipulations must be carefully recorded, for from these data the conclusions will be drawn. The manipulations of the data are the link between the original observation and the conclusions. Consistency between the data and the result is controlled by monitoring all transcription, manipulation, and correlations of the data in generation of the final manuscript.

Reporting of results and conclusions

Finally, the draft final report is provided for review, to the client and/or their agent. It will receive critical review before acceptance. The final version will then be provided to others and again will receive critical re...

Table of contents

• COVER PAGE
• TITLE PAGE
• COPYRIGHT PAGE
• DEDICATION
• PREFACE
• CHAPTER 1: INTRODUCTION
• CHAPTER 2: THE PHARMACEUTICAL DEVELOPMENT PROCESS
• CHAPTER 3: THE MEDICAL DEVICE DEVELOPMENT PROCESS
• CHAPTER 4: FUNCTIONS AND TYPES OF CROs
• CHAPTER 5: SELECTION OF CROs
• CHAPTER 6: CONTRACTING, PRICING, AND COST OF WORKS PERFORMED BY CROs
• CHAPTER 7: MONITORING ONGOING STUDIES AND WORK
• CHAPTER 8: COMMON PROBLEMS AND THEIR SOLUTIONS
• APPENDIX A: TOXICOLOGY LABS
• APPENDIX B: MISCELLANEOUS LABS AND SERVICES
• APPENDIX C: ANALYTICAL LABS
• APPENDIX D: GMP CONTRACT FACILITIES
• APPENDIX E: FORMULATION
• APPENDIX F: DOSAGE FORMS
• APPENDIX G: CLINICAL TESTING
• APPENDIX H: REGULATORY SERVICES
• APPENDIX I: CONTRACT LABORATORY AUDIT CHECK LIST