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Table 2.7. Illustration of factorial design. In this example, any one of three potential interventions (placebo, drug 1, drug 2) are possible. Each participant will receive two of the possible three interventions
Participant group Treatment received
A Drug 1 and drug 2
B Drug 1 and placebo
C Drug 2 and placebo
D Placebo and placebo
Table 2.8. Typical issues addressed when designing a clinical trial protocol. The trial objectives should clearly define what questions the trial should answer. The study design section should contain comprehensive information detailing trial size, criteria used to choose the study population, and enrolment procedures. Description of intervention section should give the background to the intervention itself, its therapeutic rationale and how it is to be administered. Measurement of response should detail the data to be collected, how it will be collected and analysed. The organization and administration section should give full details of all the investigators, where the trial is being run, and its project management details
Trial objectives Study design
Description of intervention
Measurement of response
Study organization and administration
No matter what its design, a well-planned clinical trial requires development of a suitable trial protocol prior to its commencement. The protocol documents outline all pertinent aspects of the trial (Table 2.8) and should be made available to trial participants and other interested parties. A core prerequisite of any trial is that participants be fully informed regarding the intervention and any likely associated effects.
THE ROLE AND REMIT OF REGULATORY AUTHORITIES
The pharmaceutical industry is one of the most highly regulated industries known. Governments in virtually all world regions continue to pass tough laws to ensure that every aspect of pharmaceutical activity is tightly controlled. All regulations pertaining to the pharmaceutical industry are enforced by (government-established) regulatory agencies. The role and remit of some of the major world regulatory authorities is outlined below. In the context of this chapter, particular emphasis is placed upon their role with regard to the drug development process.
The Food and Drug Administration
The Food and Drug Administration (FDA) is the American regulatory authority. Its mission statement defines its goal simply as being ‘to protect public health’. In fulfilling this role, it regulates many products/consumer items (Table 2.9), the total annual value of which is estimated to be $1 trillion. A more detailed list of the type of products regulated by the FDA is presented in Table 2.10. Its work entails inspecting/regulating almost 100000 establishments in the USA (or those abroad who export regulated products for American consumption). The agency employs over 9000 people, of whom in the region of 4000 are concerned with enforcing drug law. The FDA’s total annual budget is in the region of $1 billion.
The FDA was founded in 1927. An act of Congress officially established it as a governmental agency in 1988, and it now forms a part of the USA Department of Health and Human Services. The FDA Commissioner is appointed directly by the President (with the consent of the US Senate).
Table 2.9. The main product categories (along with their annual sales value), which the FDA regulate
$500 billion-worth of food
$350 billion-worth of medical devices
$100 billion-worth of drugs
$50 billion-worth of cosmetics and toiletries
Table 2.10. A more detailed outline of the substances regulated by the FDA
Foods, nutritional supplements
Drugs: chemical-based, biologics and biopharmaceuticals Blood supply and blood products Cosmetics/toiletries Medical devices
All radioactivity-emitting substances Microwave ovens
Advertising and promotional claims relating to the above product types
THE DRUG DEVELOPMENT PROCESS 79
The FDA derives most of its statutory powers from the Federal Food, Drug and Cosmetic (FD & C) Act, legislation originally signed into law in 1930, but which has been amended several times since. The agency interprets and enforces these laws. In order to achieve this, it draws up regulations based upon the legislation. Most of the regulations themselves are worded in general terms, and are supported by various FDA publications that explain/interpret these regulations in far greater detail. The publications include: Written Guidelines, Letters to Industry and the Points to Consider series of documents. As technological and other advances are made, the FDA further supplements their support publication list.
A partial organizational structure of the FDA is presented in Figure 2.10. The core activities of biopharmaceutical drug approval/regulation is undertaken mainly by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).