Typical IND-enabling studies include supportive animal efficacy studies and all GLP (Good Laboratory Practices) toxicology studies.

Toxicology studies seek to identify safe initial starting doses for human trials, potential target organs in humans, and ways to monitor these toxicities.

For both efficacy and toxicology studies, animal species tested, doses used, and duration of the studies are chosen based on indication, product, and intended use.

All IND-enabling work should involve regular review of theappropriate guidelines and frequent discussion with FDA.

Fig. 4.32. IND-Enabling studies the human protein, confusing the adverse effects and safety assessments.

As was stated previously, an IND summarizes many aspects of the discovery and development process, as noted on this slide in three areas: preclinical (toxicity, pharmacoloy, ADME), manufacturing, and clinical plans (the first human protocol) Fig. 4.35. Guidelines for the IND preparation are available from the FDA in guidance documents, which can be found at k Additional/confirmatory animal efficacy studies r Toxicology (typically two species) r Safety pharmacology r Carcinogenicity/mutagenicity r ADME:

O Absorption - How much of administered drug is really available?

O Distribution - To what tissues does drug localize?

O Metabolism - How is drug broken down in body?

O Elimination - How is drug cleared from body? r Most drugs in development fail to reach market due to problems associated with ADME

Fig. 4.33. Typical IND-Enabling Studies for Drugs r Additional/confirmatory animal efficacy studies k Toxicology (one or two species) k Tissue cross-reactivity (typically only for antibodies)

Fig. 4.34. IND-Enabling studies for Biologics r Document summarizes the drug and the intended studies: O General investigational plan C Trial protocol c Manufacture and testing of the drug (CMC section)

O In vitro & in vivo support for drug & indication

(Preclinical section)

C Essential toxicity data

>• Guidelines for INDs are published in Code of Federal Regulations:

O 21 CFR 312.22 and 312.23 k FDA has prepared guidance documents for IND submissions:

O Guidance for Industry - Content and Format of Investigational New Drug Applications (INDs) for Phase I Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products.

FDA website maintains guidance documents on many subjects

Fig. 4.35. IND Preparation their Web site [38]. Once submitted, FDA reviews the document and responds with questions or comments as appropriate.

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