during clinical studies. Manufacturing, stability, quality assurance, formulations, and package engineering are all groups that contribute to making sufficient and acceptable product available for clinical studies. Clinical operations will actually conduct the study with the outside investigators. Clinical-related groups such as biostatistics, data management, and medical writing support the study protocols, case report forms for study data, and report writing. Safety will analyze and report adverse events (AEs) about collected AE data. Regulatory oversees study operations and reports to guide protocols and studies with the regulations and NDA/CTD in mind, as well as liaison with the FDA as needed. Marketing provides research on marketplace data and helps create the best product profile and package insert to meet patient care needs and corporate marketing needs. They can serve as another perspective on provider and patient needs and disease opportunities compared to the competition.

The team will have a single leader, who may come from any department, calls and conducts the meetings, and fosters decisions. Team leaders are responsible to senior management and often are a separate management group within a corporate structure to foster planning and decision making independent from any one area. The project team will usually meet on a periodic basis (e.g., once a week) to track progress, discuss results, and modify the plan as necessary. Once the development plan is completed the clinical plan may be completed, and the clinical team may begin gearing up for the conduct of the clinical trials.

Within the drug development plan is the clinical plan. A clinical development plan is a description of the clinically related studies planned in order to assess the safety, efficacy, and value of the investigational product, leading up to an NDA/CTD. The usual studies in the clinical plan include efficacy and safety studies in phases 1 through 3, any special clinical trials, pharmacokinetic (ADME) trials, and pharma-coeconomic and quality-of-life studies. An example of a clinical development plan is provided in Fig. 8.11.

Note that the clinical development plan will include additional detail that is not provided in the overall development plan. In the examples provided above, the clinical development plan provides the timelines for the conduct of the trial and the time required to complete the report. It also provides a summary title describing each trial. As with the development plans, the clinical plan will also include budget information, but it is specific to each proposed study. It is broken down into its key components (e.g., per patient charges, overhead, lab charges). The above clinical development plan example also demonstrates the importance of planning to ensure efficiency. Looking at the phase 1.2 trial (Fig. 8.11), you will note that the conduct of the trial is completed, but the report is not when the phase 2.1 trial begins. The plan here may be that the project team has decided that sufficient pharmacokinetic information will be available before the report is completed to allow the initiation of the phase 2.1 trial.

To design and conduct a clinical trial, a thorough understanding of the disease area, the therapeutic area including competitive products, and the characteristics of the new drug known to date is essential (Fig. 8.12). In addition, a detailed understanding of applicable regulations, published guidelines, and generally accepted research practices (collectively referred to as good clinical practice; GCP) also is essential. Compliance with GCP ensures achieving three major goals of the clinical research: patient protection, acceptance of the study by the research community, and successful regulatory submissions around the world. Some key regulations and guidelines are provided in the Table 8.1; they have been promulgated by the FDA and found in the U. S. Code of Federal Regulations (CFR) and by the International Conference on Harmonization (ICH).

In addition, there is a large body of specific regulations, FDA guidances, "points to consider," and "guidelines" for clinical evaluations of many diseases (more than 100), as well as the full set of regulations available on the web at Fig. 8.12 [4-10]. The particular value of these documents for

Conducting clinical trial requires:

o Thorough understanding of therapeutic area and characteristics of drug.

c Also involves detailed understanding of applicable regulations, published guidelines, and Good Clinical Practices (GCP)

Regulations and Guidelines to have as references include c 21 CFR 50 Protection of Human Subjects e 21 CFR 56 Institutional Review Boards r 21 CFR 312 IND

o 21 CFR 314 NDA

c 21 CFR 201 Labeling o 21 CFR 202 Prescription Drug Advertising c ICH E2A-E Clinical Safety Data Management c ICH E3 Structure and Content of Clinical Study Reports c ICH E6 Good Clinical Practice: Consolidated Guideline c ICH E8 General Considerations for Clinical Trials c ICH E9 Statistical Principles for Clinical Trials

Basic Activities /Steps Required to Conduct Ciinicai Triais for regulations and guidelines

Protocol Concept/ Synopsis


Protocol Team Review

Statistical section Development

Protocol Development & ' Finalization .


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