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FDA guidance on early stage drug development

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The new drug development process is lengthy, costly and uncertain. Bringing a new drug from discovery to market may cost $800 million and take years of testing. Preclinical laboratory alone may take more than 10 years prior to submission of an Investigational New Drug (IND) application and commencement of the first human trials.

Even with this extensive testing, the outlook for ultimate approval of a new drug by the Food and Drug Administration (FDA) is far from certain. According to acting FDA Commissioner Andrew von Eschenbach, "nine out of 10 compounds developed in the lab fail in human studies ... in large part because they behave differently in people than they did in animal or laboratory tests."

Moreover, the number of new drug approvals (NDAs) has declined in recent years. In 2005, FDA approved only 20 NDAs, down from 36 in 2004 and 53 in 1996.

As part of an effort to make drug development more efficient, in January 2006, FDA issued a direct final rule and two new guidance documents addressing early stage clinical trials. These steps are intended to simplify the manufacturing standards for experimental drugs, and permit clinical investigators to test new investigational drugs in humans before beginning conventional Phase 1 clinical trials.

According to Dr. von Eschenbach, these measures "remove some of the hurdles from the earliest phases ... so that researchers can more rapidly establish whether or not a new compound truly has a real clinical benefit for people."

The direct final rule amends FDA's current good manufacturing practice (CGMP) regulations for human drugs. When finalized, the rule would exempt most investigational "Phase 1" drugs from the CGMP requirements although they would remain subject to the more general statutory requirement that drugs "conform with current good manufacturing practice." FDA simultaneously issued guidance that recommends approaches to compliance with the statutory CGMP requirements for exempted Phase 1 drugs.

FDA also issued a second guidance document that describes the IND requirements applicable to "exploratory" investigational new drugs, which may be tested in micro-doses in people before traditional Phase 1 trials commence.

Unlike traditional Phase 1 studies in which drugs are assessed for dose-limiting toxicities, these "exploratory" trials use much lower doses to identify, in humans, promising candidates for further testing and eliminate, early in the process, those that do not show promise.

The guidance describes how researchers can take advantage of the flexibility in existing regulations regarding the amount of data to be included in an "exploratory" IND. The guidance also recommends safety testing, manufacturing and clinical approaches that can be used in these early studies.

Direct final rule: CGMPs and INDs

The FDA published a direct final rule on Jan. 17 intended to streamline and accelerate the drug development process while ensuring the safety and quality of the earliest stage investigational drugs.

The rule exempts from the CGMP regulations the production of investigational new drugs for use in Phase 1 studies conducted under an IND. The FDA will continue to exercise oversight of the production of these drugs and regulate those drugs under its IND authority. The exemption does not apply to human cell or tissue products, investigational medical devices or investigational drugs used in Phase 2, 3 or post approval Phase 1 studies .

According to FDA, the issues presented by the production of investigational drugs for use in small Phase 1 trials are different from those presented by the production of drugs for larger Phase 2 and 3 trials or for commercial marketing. Many of the CGMP regulations do not apply to the production of small amounts of drugs for use in Phase 1 trials.

Thus, the safety of these drugs can be assured by measures to ensure their identity, sterility, quality and purity without requiring full CGMP compliance.

Guidance: Complying with CGMP during Phase 1

The CGMP Guidance, issued in conjunction with the direct final rule, outlines approaches that sponsors and producers of Phase 1 investigational drugs can use to comply with statutory CGMP requirements.

The guidance explains that the quality and safety of investigational drugs depend largely, on having adequate Quality Control (QC) procedures. During Phase 1 testing, QC procedures focus on: well defined written procedures; adequately controlled equipment; and accurate and consistent production and testing records.

The guidance recommends that sponsors and producers conduct a formal hazard evaluation of the production environment and take steps prior to and during production to minimize risk and safeguard product quality. It provides recommendations addressing specific areas of quality control, including: personnel; facility; equipment; components; production; laboratory controls; containers; labeling; distribution; and recordkeeping.

These recommendations are intended to "provide for flexibility to allow producers to implement controls appropriate for their specific situation and application ... based on a risk assessment for the product and manufacturing process."

Guidance: Exploratory IND studies The second FDA guidance clarifies the clinical approaches; chemistry, manufacturing, and controls (CMC) information; and pharmacology and toxicology data to be considered when planning limited, early exploratory studies in humans.

According to FDA, the "existing regulations allow a great deal of flexibility in the amount of data that needs to be submitted with an IND application, depending on the goals of the proposed investigation, the specific human testing proposed, and the expected risks."

However, FDA believes that sponsors have not taken full advantage of that flexibility. FDA observes that limited Phase 1 studies are often supported by more extensive preclinical data than necessary. According to the guidance, "depending on the study, the informational requirements for exploratory IND studies are more flexible than for traditional IND studies."

The guidance describes some approaches to early Phase 1 studies that are consistent with regulatory requirements, but that involve fewer resources than for a customary IND. The guidance discusses the content of an "exploratory" IND submission and clarifies the information to be included regarding the clinical plan; CMC; pharmacology and toxicology; and previous human experience with the investigational candidate or related compounds.

The guidance addresses the scope and nature of information to be submitted for particular study types, manufacturing scenarios and dosing regimens. It describes, for example, the preclinical safety programs recommended to support PK or imaging micro-dose studies, studies of pharmacologically relevant doses, and mechanism of action trials.

These initiatives are intended to reduce the time spent in early drug development on products that are unlikely to succeed and permit sponsors to more efficiently develop promising candidates. Companies engaged in the early-stage evaluation of drug candidates should explore opportunities to incorporate these potentially time and money saving approaches into their drug discovery and clinical programs.


Hathaway, a partner, has extensive experience in FDA regulatory matters and has represented pharmaceutical, device, biotechnology, chemical and agrichemical companies at various stages of product development.

Manthei, a partner, advises clients on all aspects of FDA's regulation of the development, testing, promotion and distribution of product.

Bloom is a corporate associate in the firm's Health Care and Life Sciences Practice Group. ??

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