C O N T A I N I N G

An Inquiry into the Nature, Caufes, And Cure, of the Difeafe.

Together with

A Critical and Chronological View of what Has been published on the Subject.

Fellow of the Royal College of Physicians in Edinburgh.

The SECOND EDITION corrected, with Additions And Improvements.

Printed for A. M I L L A N in the Strand. MDCCLVII.

reaching the market is another day lost in the product's patent life—"time is money." Because of the complexity of a development program and the importance of time, planning is critical to the whole process including operational aspects of clinical plans and trials.

"Plan the work and work the plan." A plan is critical to ensuring efficiency in the complex research process (Fig. 8.4). Planning should be the first activity of the development and clinical team once the decision has been made to develop a new drug (i.e., file an IND or CTA). Thirty days after the IND has been filed with the FDA, the first clinical trial may begin if the FDA has not contacted the sponsor. The first clinical trial will need to be ready to begin on time and progress according to the planned schedule to ensure that all subsequent trials may begin according to schedule. Each trial at all phases (and its associated activities) fits into one plan. Therefore, the timing of the entire development plan begins with the first clinical study. The development team should spend an appropriate period of time planning the development strategy being sure to consider all aspects before the first study begins. As we will explain in more detail later, proper planning requires highly skilled resources, sufficient time, and proper follow-up to evaluate successes, delays, and failures so the plan may be modified as necessary. It is essential that members of the clinical team are part of this planning process.

The clinical trial is conducted according to the regulations and guidelines, as well as generally respected professional standards. Because the activities associated with the conduct of a clinical trial are regulated, they must be documented. An example of this documentation is the standard operating procedure (SOP), which describes in detail how r Planning - "Plan the work and work the plan": o A plan is critical to ensuring efficiency in complex process o Appropriate time is required to do it right! o Requires skilled resources c Each trial at all phases (and its associated activities) fits into one plan e Follow-up on successes / delays / failures are key elements to planning r Need clear objectives for each trial. Goal is to demonstrate following: c Drug is safe and efficacious c Drug can be manufactured safely and reproducibly c Both research & marketing plans are fulfilled r Clinical activities ongoing while development plan is being drafted:

r Review of studies completed to date

(e.g., pre-clinical studies) c Completing investigator brochure c Identifying potential investigational sites c Designing the trials c Determining timelines and costs to complete trials each specific activity is to be completed (e.g., study monitoring). SOPs help assure quality is maintained throughout the conduct of the clinical trial and demonstrate that processes exist to ensure that the regulations are being followed and scientific integrity is maintained. A company may audit itself through its quality assurance department to ensure and demonstrate that the SOPs are being followed. A clinical study plan may contain 5-10 or more separate studies (phase 1, phase 2a and 2b, phase 3 and 3b, economic studies, phase 4). Each trial at all phases (and its associated activities) fits into one integrated sequenced plan. Follow-up on successes/delays/failures are key elements to planning and operations, and such corporate learning is a key success factor.

A wide variety of clinical activities should be ongoing while the clinical development plan is being drafted in order to have efficient start-up of the clinical studies. Some examples include review of studies completed to date (e.g., preclini-cal studies), completing the investigator brochure, identifying potential investigators and sites, determining timelines to complete trials, designing the trials, and writing the protocols including the statistical analysis section.

Each clinical trial is complex in study design and clinical operations. Trials require study designing, protocol writing, evaluation and selection of investigators and sites, and internal/external agreements. The design and study procedures may require special population group(s) and specialized equipment or techniques, respectively. The many specialized people will be addressed below, which are both internal and external resources.

Clinical trial operations will require a large number of people from different departments and from outside the company with specific expertise (Fig. 8.5). One study often will engage multiple sites and investigators. For example, a single clinical trial may include the following 20-plus different

Investigative Institutions:

r Patients r Investigator Team o PI o Co-I

o Coordinators c Investigational pharmacist r Patient Care o Nurses o Laboratory & Radiology r Support Operations o Research Office o Institutional Review Board o P&T Committee o Information Technology

The Company:

r Clinical Operations o CRAs - Monitoring c Clinical managers o Safety group c Biostatistics c Clinical Data Management c Metabolism I Pharmacokinetics o Clinical Research Organization r Support Operations o Safety group c Quality assurance - auditing c Regulatory affairs c Medical writing c Information technology o Finance c Manufacturing - Clinical lots personnel at the institution and with the sponsoring company to perform all the functions dictated by patient care, the study protocol, company SOPs, and regulatory and legal requirements. All these research people need to be engaged but also directed and coordinated in the right ways at the right times.

In addition, some of the sponsor activities may be contracted out, which will present a number of further complexities. The aspect of clinical research organizations (CROs) will be discussed later in this chapter. The activities that each of these CRO personnel are responsible for must be coordinated and monitored by the sponsoring company to ensure that quality is maintained and timelines are met. Each clinical trial to be conducted will require good people, process management and leadership to ensure success.

For each clinical trial planned, it is critical that each study have clear objectives that meet the ultimate goal for the product, that is, its approval (Fig. 8.6). The goals of approval are to demonstrate that the drug is safe and efficacious, can be manufactured safely and reproducibly, and fulfills research, patient needs, and marketing plans. The goals as appropriate have a strong clinical focus. They require an understanding of the disease being treated, existing therapies (their benefits and limits), patient care and health care issues, and the product's potential benefit and value to the public 4-8 years before it is available. Therefore, it is essential that there is clinical representation, experienced in both research and patient care practice, on the project team who are involved in the development planning process. Ideally, a training and education session should be provided to clinical operations at the sponsoring company regarding this disease and therapies. Effective communication of information between all groups and within all groups of the project team(s) is critical to a successful project. Furthermore, the objective and study design need to be practical and match the needs of the development plan by answering k Each clinical trial is complex: o Requirements: study design, protocol writing, selection of investigators & sites, and internal/external agreements c Other design and study procedures possible:

> Special population group(s)

> Specialized equipment or techniques p Number of specialized people involved c Internal & external resources needed k Clear objectives & realistic design for each trial: c What is question to be answered?

o Is question relevant to the development plan/product profile? c Is trial affordable?

c Can we get it done, on time, on target? c Can the data be meaningfully analyzed and reported?

k Each clinical trial should answer at least one critical question:

c. Related to product's characteristics, as it relates to development plan.

key planning and operational questions. Five sample key questions should be asked during the planning process in assessing the fit of a study idea into the plan (Fig. 8.6). Also, each clinical trial that is conducted should answer at least one critical question related to the product's characteristics as it relates to the development plan, for example, Avastin® for lung cancer: primary or secondary treatment, concurrent cancer chemotherapies, dose-dose frequency (daily-weekly), administration of dose (bolus/infusion), lung bleeding, tumor shrinkage versus survival, secondary cancers.

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Project Management Made Easy

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