Standards: Types, Uses, and Issues

Health is a complete state of physical, mental, and social well-being and not merely absence of disease.

–World Health Organization, 1947.

For the development of a drug to proceed smoothly, it is important to differentiate among the following terms: standards, regulations, guidelines, policies, principles, recommendations, and golden rules. Clear definitions facilitate and enhance communications. Nevertheless, many of these terms overlap, and distinctions among them are often unclear. As a result, the terms are frequently misused (e.g., principles are often called guidelines). This chapter discusses the definitions of multiple terms and explores the relationship between them. Its primary focus, however, is to describe the various types of standards used in drug development and to discuss the relationships among these standards. Chapter 50 describes the three main types of standards that can be used in developing drugs and focuses on the choice of one of these three types as most appropriate.

THE REGULATORY CASCADE

Legislators and regulatory authorities use specific definitions for the terms laws, regulations, and guidelines. The relationship among these terms is described here as a “regulatory cascade.” This relationship is shown in Fig. 4.1. The term cascade is used because the initial activity of government legislators passing laws often necessitates the development of specific regulations that the government agency involved [e.g., the Food and Drug Administration (FDA)] must issue and which interprets the law. Those regulations, in turn, often require the publication of specific guidelines to help people follow the regulations. This cascade continues in progressively less formal steps via points to consider, recommendations, and finally informal comments.

Other activities include podium policy (public statements made by regulators, often at professional meetings), hallway gossip, and comments made at meetings between the company and the FDA. Figure 4.2 shows that the ways in which compliance with laws, regulations, and guidelines are evaluated and assessed follow generally similar procedures within a regulatory agency.

Figure 4.1 The regulatory cascade and selected examples. Comments by FDA professionals at various meetings or public hearings are often referred to as “podium policy.” IND, Investigational New Drug Application; HIV, human immunodeficiency virus.

Regulatory terms described as part of the regulatory cascade have the same definitions within pharmaceutical companies. Other terms used in almost all regulatory and industrial institutions and organizations that deal with compliance with regulations are standard operating procedures (SOPs), policies, and standards. Each of these terms is briefly defined in Table 4.1.

Figure 4.2 Steps and procedures at a regulatory agency regarding the implementation of laws, regulations, and guidelines, and the assessment of compliance.

STANDARDS: WHAT, WHY, AND HOW?

What Are Standards?

Standards may be thought of as bars on a high jump that an athlete must clear to be successful in a particular endeavor (Fig. 4.3). Figure 4.3 also illustrates related metaphors for a few other terms discussed in this chapter. Numerous types of standards exist for the development of new drugs (Table 4.2). These include (a) ethical standards, (b) regulatory standards, (c) state-of-the-art technical standards, (d) practical standards, and (e) commonly used industry standards. In some cases, all of these standards are nearly identical, but in most situations, there are great differences among them. Adherence to one set of standards often leads to failure to meet others. Moreover, meeting or even surpassing one set of standards (e.g., regulatory) in a particular country (e.g., Sri Lanka) does not mean that (regulatory) standards for the same issue will be met in all countries. Great differences from country to country often exist for all types of standards, except for technical state-of-the-art standards, which are universal.

Why Create Standards?

Ethical standards, practical standards, state-of-the-art technical standards, and commonly used industry standards all exist for many particular aspects of drug development. Regulatory standards are the only type that do not a priori (i.e., necessarily) exist. Regulatory standards are established by a government to protect the health of a nation’s patients when taking drugs. Prior to the 20th century, few regulatory standards existed, and the overall control of drug composition, manufacture, and sale was often grossly inadequate to protect people’s health. Many dangerous drugs were widely promoted and sold for use in totally unethical ways (e.g., morphine was given as a pacifier to quiet “noisy” babies).

Table 4.1 Operational definitions of various terms

Term	Definition
Law	Principles and official codes established by an authority and applied to the people in a given area. In science, the description of thoroughly tested and accepted phenomena.
Rule	A principle, regulation, or guideline that is generally based on an accumulation of observations and tests. Prescribed or suggested guide for conduct or action.
Regulation	The specification of rules by a government or other official organization and issued by government departments to carry out the intent of the law.
Standard	An approved reference of a specific type or magnitude that is considered by an authority or by general agreement to be the accepted reference for comparison, control, or securing uniformity.
Guideline	A statement or rule to guide conduct according to an accepted policy to carry out a regulation, achieve a standard, or follow a rule.
Policy	General principles by which an organization manages its activities and makes its decisions.
SOPs	Methods and instructions of how various activities are to be performed to carry out policies of specific organizations in order to achieve the group’s goals and objectives. These are usually written documents and change over time to adhere to new regulations, company policies, or new technologies.

How Are Standards for Drug Development Created?

Each of the five general types of standards described in the following text is often applied to specific issues in toxicology, clinical trials, manufacturing, or any other aspect of the discovery, development, production, or marketing of drugs. This chapter cannot explore those detailed applications. Rather, a brief description is given of how each of the types of standards is created.

Regulatory standards are derived from laws that are initially created by governments (e.g., Congress in the United States, Parliaments in many countries) and interpreted and defined when possible through regulations, guidelines, and comments by the national regulatory authority that is charged with approving and reviewing the safety of drugs and determining which drugs may be allowed on the market.

State-of-the-art technical standards are created by innovative scientists and clinicians in the forefront of their fields and by those who influence thinking in the disciplines in which they work. Some of this latter group of people are methodologists who are concerned with refining established approaches and methods within their own discipline. These become known via multiple methods such as endorsement by professional societies, trade associations, or consensus conferences, or by common practice based on published studies.

Practical standards are created by the companies developing drugs. They determine what level of effort is feasible and cost effective to achieve the specific goals they set. Practical standards are often below state-of-the-art standards. Nonetheless, practical standards are often appropriate when studying certain topics or issues.

Table 4.2 Types of standards relating to various aspects of the pharmaceutical industry

Commonly used pharmaceutical industry standards	Those followed by most research and development-based companies
Pharmaceutical company standards^a	Standards of various types are reflected in the company’s SOPs and are reflected in the ways in which a company conducts its business
Regulatory standards	Sometimes approach the state of the art, but usually are at or near the level of the most advanced companies
Clinical methodology standards	Golden rules and principles followed in clinical trials
Legal standards	Laws of each country regarding the pharmaceutical industry
Ethical standards	Medical practice (community standards) and professional societies often establish these
Professional standards	Various medical, scientific, and other professional societies create or describe standards
Technical standards	Specification that must be met by the company in creating or producing a drug
^aMany of these standards (or others in this table) may be considered as practical standards.

Figure 4.3 Schematic presentation of metaphors of several types of standards and other terms (e.g., regulations, guidelines, and SOPs) using the high jump.

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