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BT-703-DLecture - 7 (NKJ)

DevelopmentOverview

1) Pre-clinical Data Package

2) Process Development/CMC/API3) IND Application

The decision to take a new drug candidate into the development phase entails asignificant commitment in terms of money, resources, and time.The attrition rate for making it to market is a disheartening nine in 10 compounds, anddevelopment costs per approved drug amount to $800 million, according to a study bythe Tufts CSDD (xyz, 2003, PoW link.) The average time to develop a new drug was 12years and 10 months in 2002.The number of new chemical entities (NCEs) gaining market approval has decreasedover the last decade down to 20 per year. At the same time, the estimated average ofnew NCEs needed for the pharmaceutical and biotech industry to sustain a 5 percentgrowth rate is 50.In terms of standards, drug development requires attention to the following:

GLP-Good Laboratory Practice refers to nonclinical laboratory studies thatsupport or are intended to support applications for research or marketing permits;

GMP-Good Manufacturing Practice, also known as cGMP ("current" GMP), is aset of regulations requiring that quality, safety, and effectiveness be built intofoods, drugs, medical devices, and biological products.

21 CFR-describing the code of regulations for food and drugs. Part 11 hasbecome particularly relevant describing the standards and regulations onelectronic data and electronic signatures.

Pre-clinical Data Package

o

UnderFDA requirements, a sponsor must first submit data showing thatthe drug is reasonably safe for use in initial, small-scale clinical studies.Depending on whether the compound has been studied or marketedpreviously, the sponsor may have several options for fulfilling thisrequirement: (1) compiling existing nonclinical data from past in-vitrolaboratory or animal studies of the compound; (2) compiling data fromprevious clinical testing or marketing of the drug in the United States oranother country whose population is comparable to the U.S. population;or (3) undertaking new preclinical studies designed to provide theevidence necessary to support the safety of administering the compoundto humans.

o During preclinical drug development, a sponsor evaluates the drug's toxic

andpharmacologic effects through in-vitro and in-vivo laboratory animaltesting.Genotoxicity screening is performed, as well as investigations ondrug absorption and metabolism, the toxicity of the drug'smetabolites,and the speed with which the drug and its metabolites are excreted fromthe body. At the preclinical stage, the FDA will generally ask, at aminimum, that sponsors: (1) develop a pharmacological profile of thedrug; (2) determine the acute toxicity of the drug in at least two species ofanimals, and (3) conduct short-term toxicity studies ranging from two

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weeks to three months, depending on the proposed duration of use of thesubstance in the proposed clinical studies.

Process Development/CMC/API

o Upon nomination of a development candidate, it becomes imperative thatthe highest-quality compound can be provided for preclinical and clinicaldevelopment repeatedly and consistently at reasonable cost and in a

timely manner.o The initial synthetic route will be revised and optimized to achieve:

Accessibility of readily available and cost-effective startingmaterial

Minimization of synthetic and purification steps Feasibility of scale-up from microgram to gram, and possibly to

kilogram scale. Reduced cost of goods (COGS)

o The FDA will require a Chemistry, Manufacturing and Controls (CMC)documentation package for any drug entering clinical trials.

o CMC: Active Pharmaceutical Ingredients (API) Description and characterization Manufacturer Synthesis/method of manufacture Process controls Specifications (list of tests, methods and acceptance criteria) Purity profiles Container/closure system for drug substance (DS) storage Container/closure system for drug product (DP) shelf life Stability

o Examples abound where quality or cost of compounds led to delays orfailure of clinical trials, underscoring the importance of processdevelopment for the overall success of a new drug.

IND Applicationo In many ways, the investigational new drug (IND) application is the result

of a successful preclinical development program. The IND is also thevehicle through which a sponsor advances to the next stage of drugdevelopment known as clinical trials (human trials).

o Generally, this includes data and information in three broad areas: Animal Pharmacology and Toxicology Studies: Preclinical data to

permit an assessment of whether the product is reasonably safefor initial testing in humans.

Manufacturing Information: Information pertaining to thecomposition, manufacture, stability, and controls used formanufacturing the drug substance and the drug product. Thisinformation is assessed to ensure the company can adequatelyproduce and supply consistent batches of the drug.

Clinical Protocols and Investigator Information: Detailed protocolsfor proposed clinical studies to assess whether the initial-phasetrials will expose subjects to unnecessary risks. Also, informationon the qualifications of clinical investigators to assess whetherthey are qualified to fulfill their clinical trial duties. Clinical

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investigators are professionals, generally physicians, who overseeadministration of the experimental compound.

Types ofINDs: "Commercial INDs" are applications that are submitted primarily bycompanies whose ultimate goal is to obtain marketing approval for a new product.However, there is another class of filings broadly known as "non-commercial" INDs,

which, in fact, account for the vast majority of INDs filed. Submitted by NIH and othersponsors, these INDs include "Investigator INDs," "Emergency Use INDs," and"Treatment INDs."

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