INDEnabling Studies

The discovery and early development process culminates when a decision is made to advance the product candidate into human clinical trials. To do so within a corporate setting, an Investigational New Drug (IND) application is filed with the FDA prior to initiating trials (Fig. 4.32). The IND summarizes many aspects of the discovery and development of the product candidate, as well as how the product is manufactured and controlled and how it will be used in the clinic.

From the preclinical standpoint, a number of IND-enabling studies are typically needed that each can take a year or more to complete. Such studies typically include animal efficacy studies related to the clinical indication and detailed toxicology studies conducted under GLP (good laboratory practice). To be considered GLP, a study must follow the guidelines outlined in Part 58 of the Title 21 Code of Federal Regulations (21 CFR Part 58) that are designed to assure the quality and integrity of safety data used in support of the application [34-36]. Much of the process for filing an IND and conducting clinical trial is also covered by Title 21 CFR documents (See Figure 4.33), and guidelines similar to GLP cover good manufacturing practice (GMP) and good clinical practice (GCP) [37].

For most small-molecule drugs, an extensive package of nonclinical information is needed to file an IND [37]. This includes five following topics:

• additional in vivo efficacy information in animal models relevant to the clinical indication

• toxicology studies in two species (commonly rodent and non-rodent)

• safety pharmacology (most commonly effects on the central nervous, cardiovascular and respiratory systems)

• Carcinogenicity/mutagenicity (potential to induce cancer)

• ADME (absorption, distribution, metabolism, and elimination)

Both the choice of study animals and the duration of the study are influenced by the product's characteristics and intended use in humans. Note that many drugs fail due to problems with ADME (the compound isn't absorbed, goes to the wrong place, is degraded too quickly [or into toxic components], or is eliminated too quickly) [37].

Because biologics are commonly recombinant proteins of human origin, they often require less safety information prior to filing an IND (Fig. 4.34). For example, most proteins are degraded by endogenous pathways into peptides and amino acids that are then reutilized by the host. As a result, some of the studies typically needed for small-molecule drugs (safety, pharmacology, mutagenicity, true ADME studies, etc.) can be less relevant for biologics. However, if the mechanism of action of the biologic is known to affect critical systems, then additional studies may be needed. Also note that for products like antibodies that are designed to bind specific molecular targets, cross-reactivity studies with a panel of human tissues are conducted in an effort to identify other tissues that may also be reactive. Such tissues may react with the antibody due to the expression of the specific target or because the antibody cross-reacts with epitopes on an entirely different antigen, either of which can reduce drug levels or result in unexpected toxicities. As noted previously, animal studies with proteins pose the complication of immune reactions by the animal to

Guidance for Industry

Contentand Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-characterized, Therapeutic, Biotechnology-derived Products

Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation And Research (CBER)

November 1995

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