Contract Research Organizations and Outsourcing Strategies



Contract Research Organizations and Outsourcing Strategies






Science is a system of statements based on direct experience, and controlled by experimental verification. Verification in science is not, however, of single statements but of the entire system or a sub-system of such statements.

–Rudolf Carnap (1891-1970).


OUTSOURCING STRATEGIES

A strategy for outsourcing is an essential part of the overall clinical development plans created at the outset of a drug’s development. While outsourcing of nonclinical development also occurs to a large degree (e.g., scaling up of pilot production, packaging, manufacturing, synthesis of active material), the nonclinical aspects (identified in a Product Development Plan) will be covered in chapters on technical development and production in Section 9. This chapter focuses on clinical aspects of outsourcing.


Types of Clinical Outsourcing

There is a spectrum of outsourcing of a clinical trial ranging from one discrete service to virtually 100%. In all three investigational phases of development, almost all pharmaceutical companies will outsource the actual conduct of a clinical trial to one or more investigator’s sites. Two exceptions are companies that own their own Phase 1 unit (as Upjohn formerly owned) and companies that lease or have another legal agreement with a hospital or institution to operate (or have access to) a Phase 1 unit within that
institution. In addition, there are some business arrangements of financial support with universities or other sites for conducting part of their Phase 1 research at a specific place. It is an accepted fact that almost all Phase 1 clinical trials are outsourced, and therefore, this activity is rarely considered as a frequent issue to be discussed in terms of outsourcing.

The major activities that are part of what is referred to as outsourcing relate to any of the services of a contract research organization (CRO) listed in Table 74.1. Any other services (e.g., laboratory, radiology, pathology, ophthalmology, other specialized tests) provided by the same site where the trial is conducted may require a separate contract and budget and, therefore, would be outsourced to that group. In some cases, these or other services (e.g., a central laboratory, a central reader of the radiographs taken at the investigator’s site) are conducted by a different site, and a contract and budget are required with those groups.








Table 74.1 Services offered by many contract research organizations for a clinical trial





















































































































































































1.

Write a protocol, including all aspects from statistical, pharmacokinetic, quality of life, pharmacoeconomic, and other areas and have it reviewed and approved.


2.

Prepare a manual of operations.


3.

Prepare an investigators’ brochure.


4.

Develop a recruitment strategy and plan.


5.

Design and draft case report forms.


6.

Print and bind case report forms and distribute to sites.


7.

Prepare a prototype informed consent.


8.

Hold a scientific advisory board meeting to ensure that the scientific advisory board agrees with the plans.


9.

Meet with regulatory agencies as required and ensure they agree with the plans.


10.

Interact with the manufacturer to assure drug supply meets the protocol’s needs and the randomization code is generated, and set up a system for sites to obtain drug supplies.


11.

Package and label drug and supply to sites.


12.

Perform poststudy drug accountability.


13.

Return unused drug to sponsor for destruction.


14.

Find a laboratory to act as a Central Laboratory and contract with them.


15.

Contract with other laboratories as needed.


16.

Find specialists to act as central reviewers of radiology, pathology, electrocardiogram, or other data.


17.

Use an internal or external group to set up an interactive voice response system.


18.

Submit the protocol to a central Institutional Review Board/Ethics Committee or provide to each investigator to do this with a draft informed consent.


19.

Translate the informed consent and tests to be used into each language necessary and back-translate them to ensure they are consistent with the original.


20.

Identify investigators and a principal investigator.


21.

Interview investigators and their sites and make recommendations to the sponsor.


22.

Negotiate a budget and contract with sites.


23.

Prepare a contract for investigators.


24.

Pay investigators per contract.


25.

Collect all regulatory documents from investigators and sponsor.


26.

Submit regulatory documents to the regulatory agencies in each country as needed.


27.

Act as a US agent for a foreign-based company.


28.

Conduct site initiation visits.


29.

Conduct investigator meetings.


30.

Train investigators and study coordinators.


31.

Train monitors and others within the CRO.


32.

Assemble an internal project team within the CRO and meet as appropriate.


33.

Assemble an external project team of all vendors and the sponsor and meet as appropriate.


34.

Assemble a Data Safety Monitoring Board.


35.

Run the meetings of a Data Safety Monitoring Board.


36.

Maintain a telephone log of clinical questions, case report forms, and logistics.


37.

Hire any consultants required for content expertise or other types of expertise.


38.

Create a comprehensive communications plan.


39.

Establish a 24-hour serious adverse event telephone line.


40.

Monitor the clinical trial and prepare reports for the sponsor, including study initiation and study closeout visits.


41.

Interact with the sponsor on an agreed-upon basis.


42.

Collect data as agreed (e.g., electronic submission, fax, paper).


43.

Query any outstanding issues, incomplete case report forms, or other matters.


44.

Enter data into database and quality assure it.


45.

Develop other databases (e.g., protocol deviations).


46.

Write narratives for serious adverse events and other events (e.g., overdoses, abuse of drug).


47.

Prepare a statistical analysis plan for the regulators and a more comprehensive one for the CRO to review with the sponsor and have approved (i.e., with draft tables, figures, and listings).


48.

Prepare all listings, tables, and figures agreed and have these reviewed by others for review by a Data Safety Monitoring Board or inclusion in a regulatory submission.


49.

Prepare a statistical report and have it reviewed by clinicians and others.


50.

Prepare a final medical report and have it reviewed and approved.


51.

Audit study sites.


52.

Conduct an audit of the sponsor’s files.


53.

Prepare a manuscript for publication.


54.

Marketing-oriented activities can also be considered depending on the status of the drug.


55.

Prepare the briefing books for meetings with regulators.


56.

Prepare a New Drug Application or other regulatory submission.


57.

Assist with planning and rehearsals for an FDA Advisory Committee meeting.


58.

Conduct the overall management and coordination of the entire project between sponsor and CRO/SMO.


Almost all of these activities can be divided into smaller segments or subactivities.


SMO, site maintenance (or management) organization.



Components of an Outsourcing Strategy

The following points apply most typically to a medium or large pharmaceutical company that has full internal resources of people and know-how. Smaller companies have to rely even more on CROs or other types of vendors (e.g., managed site networks). After the overall and clinical development plans are written, reviewed by various groups, and approved, the company will want
to create an outsourcing strategy. The main components of a clinical outsourcing strategy will consider the following:



  • When do we believe it is most appropriate to outsource (e.g., when in-house staff are inadequate or unable to take responsibility for the trial)?


  • What specific types of trials do we wish to outsource (e.g., pharmacokinetic, pharmacoeconomic, Phase 1 volunteer trials, every clinical trial)?


  • Which specific trials in the development plan do we wish to outsource and in which phases of development (e.g., pivotal Phase 3 trials, initial Phase 2 pilot trial)?


  • How much of each trial do we wish to outsource (e.g., protocol writing, data management, every aspect of the clinical trial, decide on a case-by-case basis)?


  • Will it be better for us to use a niche CRO, a full-service CRO, a global CRO, or a managed site network?


  • Do we wish to create a preferred list of CROs to go to for most of our outsourcing work (i.e., all or part of the clinical development plan), or do we want to start anew for each trial, phase, or segment of the program?


  • How much expertise should we maintain in-house through our staff, consultants, and scientific advisory board?


  • Will any regulatory activities be outsourced, and if so, which?


  • How will we develop general performance metrics and a strategy and plan for monitoring the CRO and other vendors to ensure that all vendors are performing their services in accord with our expectations?

A more detailed discussion of activities that are part of an outsourcing strategy, particularly to CROs, plus a variety of worksheets and useful pointers is presented by Vogel (2002). A broad overview of the area is given by Vogel and Getz (2006).


Although this chapter focuses on the outsourcing of clinical trials to CROs, it is also important for other functions within a pharmaceutical company to create their own outsourcing strategy for work in their areas. This includes toxicology studies (a large percentage of which are outsourced, even from large companies), pharmacokinetic studies (both preclinical and clinical), and preclinical efficacy pharmacology or other biological studies. Technical activities that are outsourced may include every step from chemical synthesis of compounds through manufacturing of the final product for study or sale. In other words, the outsourcing strategy should be part of the overall development plan for all part of the development effort.


What Phases of Clinical Development Are Outsourced the Most?

The investigational phase of drug development that is outsourced the most is Phase 3 (about 65% of all outsourced studies) followed by Phase 2 (25%). Phase 4 is less often outsourced (about 10% of the total), but there are likely to be exceptions to these figures in different companies that have their own strategies. (These figures were provided from the Tufts Center for the Study of Drug Development.)


TYPES OF CONTRACT RESEARCH ORGANIZATIONS AND THE SERVICES THEY OFFER

CROs are organizations that provide services to the pharmaceutical industry by functioning as middlemen to place studies and generally to run them in the same way that the company/sponsor would. While most of the (over 600) CROs in the United States are for-profit organizations, there are also medical schools and other academic institutions that have developed in-house CROs. A few examples include Mayo Clinic, Cleveland Clinic, Harvard Clinical Research Institute, and the University of Pittsburgh Medical Center.






Figure 74.1 The spectrum of CRO activities in terms of several characteristics of services offered and relationships with a sponsor.

Large CROs have a critical mass of staff and work, and the largest have revenues of over a billion dollars per year. Their margins range from about 1% to 12%, and although, in the past, their highest margin areas were in the areas of monitoring and data management, this is not generally true today.

Many small CROs specialize in a therapeutic area or a special function such as quality of life or pharmacoeconomics. Of all their fees, about a third comes from data management, a quarter from project management, and a third from site monitoring. Study initiation accounts for most of the balance. CROs typically invoice monthly for work performed, with agreed fees in the contract.

The various types of CROs described earlier offer different services (see Table 74.1 and Fig. 74.1). These range in general from providing a single service to being a “full-service” provider; the latter type of CROs can prepare a protocol, find investigators, initiate and monitor the trial, collect and manage the data, prepare statistical analysis plans and analyses, write the final medical report, and help represent the company at the Food and Drug Administration (FDA). Many additional activities/services could be listed. Some of these are shown in Table 74.1. The “deliverables” will depend, of course, on the specific services chosen by a sponsor, but some of the most commonly provided deliverables are case report forms, a statistical analysis plan, statistical report, final medical report, and forms that are part of the trial (Table 74.2). Such forms include numerous monitoring
visit reports, telephone reports, minutes of meetings, enrollment charts, project team minutes (or points of agreement and action points), and copies of e-mails. Additional information on CROs is found in Chapter 58 of Guide to Clinical Trials (Spilker 1991) and Vogel (2002).








Table 74.2 Selected forms used by contract research organizations in clinical trials
















































1.

Time sheets to track time spent on each project


2.

Training courses taken and evidence of passing the tests


3.

Company-specific policies


4.

Standard operating procedures


5.

Communications plan


6.

Lists of site investigators, liaisons, study coordinators, sponsor representatives, medical advisors, monitors, and contact information


7.

Call centers or interactive voice response system contact information


8.

Prestudy monitoring site visits


9.

Monitoring study site visits


10.

Telephone logs at sites


11.

Monitoring logs at sites


12.

Screened patients at sites with reasons for their not being enrolled


13.

Transmission of drug supplies to site, monitoring storage, security, and accountability


14.

Close of study site visit


15.

Serious adverse event reporting form



Types of Contracts

Contracts may take the form of Master Service Agreements that have specific project addendums for each clinical trial to be conducted under the Master Service Agreement, performance-based agreements, or risk-sharing agreements. Master Service Agreements do not bind a sponsor to only one CRO, but they do facilitate the contracting steps, and sponsors generally accept these contracts. Risk-sharing agreements are the least popular type of agreement for most CROs, but sponsors usually like them.


TYPES OF SITE MAINTENANCE ORGANIZATIONS AND THE SERVICES THEY OFFER

The site maintenance organization (SMO) was the mainstay for many years as the alternative model to the traditional CRO model. Although the scope of the SMO activities was always much smaller than the CROs, they seemed to have a place in the clinical trial outsourcing landscape. However, over the past decade, SMOs have progressively lost ground and are almost completely gone from the landscape of outsourcing options today. Even the term SMO has been replaced by the term managed site networks (Getz 2006).

Only gold members can continue reading. Log In or Register to continue

Related posts:

  1. Investigator-sponsored Research Proposals Submitted to Industry
  2. Collecting and Interpreting Life Events Data in Clinical Trials
  3. Corporate Issues Regarding the Medical-Marketing Interface
  4. Legal Activities and Issues

Stay updated, free articles. Join our Telegram channel
Tags:
Oct 2, 2016 | Posted by in GENERAL SURGERY | Comments Off on Contract Research Organizations and Outsourcing Strategies

Full access? Get Clinical Tree
Get Clinical Tree app for offline access