September 1, 2006 (Vol. 26, No. 15)

Knowing Early On Exactly What Is Needed Will Save Headaches Down the Road

Understanding the requirements behind the FDA’s New Drug Application process can save substantial time in the development of biopharmaceuticals and allow companies in the life sciences sector to appropriately plan strategies that will maximize efficiency, control costs, and engage in clinical trials that provide real data on safety and efficacy while moving the product into the market much faster.

Upon discovery of a product and proof-of-concept, a company should begin thinking about what it requires to advance the product into clinical trials or to seek permission to begin marketing, where no trials are required by regulation. Preclinical testing and data lay the foundation for obtaining permission to commence human trials and therefore become an integral part of the FDA regulatory filings.

The approval process, where required, differs for each type of product. For example, approval of a pharmaceutical is different than approval of a device, which is different from approval of a dietary supplement. Understanding the approval process of a given product can be instructive in designing and implementing the development process.

Biopharmaceuticals are subject to rigorous preclinical and clinical testing and other approval requirements by the FDA under the U.S. Food, Drug, and Cosmetic Act and by comparable agencies in most foreign countries. Various federal, state, and foreign statutes govern or influence the manufacture, labeling, storage, record-keeping, and marketing of such products. Pharmaceutical manufacturing facilities may also be subject to regulation by state, local, and other authorities.

IND Application

The FDA imposes substantial requirements and conditions on therapeutic drug products, including lengthy and detailed laboratory and clinical testing procedures, sampling activities, and other costly and time-consuming processes. After preclinical testing, as required by the applicable regulations, an Investigational New Drug (IND) application must be filed with the FDA to obtain authorization for human testing through clinical trials.

This application includes a description of the overall plan for investigating the drug product and a comprehensive protocol for planned studies.

Pursuant to the regulations, the FDA usually asks companies to submit a description of the drug substance, including its physical, chemical, and biological characteristics, as well as a description of the general method of preparation of the drug substance and a list of all components, including inactive ingredients.

A section of the IND describes the composition, manufacture, and control of the drug substance. The drug company must provide sufficient information to assure the proper identification, quality, purity, and strength of the investigational drug.

The IND should also contain adequate information about pharmacological and toxicological studies of the drug, involving laboratory animals and other tests on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical trials. Where there has been widespread use of the drug outside of the U.S., it is possible in some limited circumstances to submit a well-documented clinical experience as part of the required preclinical work.

Once the FDA approves the IND, the sponsor is allowed to enter the clinic where certain reporting requirements, such as making progress reports on the study or studies covered by the IND, must be met and the sponsor must alert the FDA and clinical investigators immediately of any unforeseen serious side effects or injuries.

NDA Submission

When clinical testing has been completed and analyzed, final manufacturing processes and procedures are in place, and the company has ready other required information, it must submit a New Drug Application (NDA) to the FDA. No action can be taken to market any therapeutic drug product in the U.S. until the FDA has approved an NDA.

The data in the NDA must establish that the drug is safe for use under the proposed labeling conditions and is effective for its proposed use(s). Substantial evidence is defined by statute and FDA regulation to mean evidence consisting of adequate and well-controlled investigations, including clinical investigations by experts qualified by scientific training and experience, to evaluate the effectiveness of the drug involved.

The NDA must contain data-obtained outlines from the clinical trials of the drug, as well as a description and analysis of the drug’s pharmacokinetics. It must also include a description and analysis of any other data relevant to the safety and effectiveness of the drug product obtained from any source, foreign or domestic.

The NDA also includes an integrated summary of all available information about the safety of the drug product, including potential adverse effects and clinically significant potential adverse reactions with other related drugs.

A section of the NDA discusses the statistical, controlled clinical study and the documentation and supporting statistical analysis used in evaluating the controlled clinical studies. Another section describes bioavailability of the drug, including the data concerning the action of a drug in the human body over a period of time and the extent of drug absorption in the human body or information supporting a waiver of the submission of such data.

The NDA must describe the composition, manufacture, and specification of the drug substance, including a full description of the drug substance, its physical and chemical characteristics, and its stability; the process controls used during manufacture and packaging; and such specifications and analytical methods as are necessary to assure the identity, strength, quality, and purity of the drug substance, as well as the availability of the drug products made from the substance.

NDAs contain lists of all components used in the manufacture of the drug product and a statement of the specifications and analytical methods for each component.

The Legal Side

Attorneys for the life sciences industry oversee compliance with these regulations, including the data-collection process, while evaluating the risk of adverse events that may occur during the trial phase or post approval and while drafting and/or reviewing the informed consent documents to ensure that full and accurate dissemination of information is provided to the study subject. Attorneys also draft and review the clinical trials agreements between the sponsor and the clinical research organization and the sites.

In addition, it is often important to ensure that patent protections are in place prior to the FDA filings to maintain the highest level of protection for intellectual property.

Congressional hearings, pending high-profile litigation, or changes in the administration at the FDA may affect a company’s business strategy in terms of when to move a product into the clinic or into the marketplace.

A company can also learn to be proactive, based on events in the political or litigation arena. If litigation and politics are focusing on adequate warnings, an experienced life sciences attorney will advise clients to self-audit their labels and warnings in light of this activity.

Finally, even during the early stages of clinical development, a client should anticipate approval, think about market strategy, and understand the importance of product labeling.

The product label should be considered a live document that undergoes changes throughout the trial process to reflect new information. The company should also work on the detailing material and any direct to consumer advertising early on so as not to delay market launch.

While the NDA approval process is constantly in flux and at the discretion of political and social expediency, understanding restrictions and obtaining competent counsel to navigate the instabilities is vital toward expediting and controlling the trial process. Drug companies must always be prepared for changes to the new drug approval process and organize materials accordingly to anticipate constant transformation and amendments to the drug application system.

Diane Romza-Kutz is the managing partner of the Chicago office of Epstein Becker Green. Web: Phone: (312) 499-1422. E-mail: dromzakutz@

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