The New Drug Approval Process in the United States

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In the United States, the two points in the new drug approval process when the government mandates major submissions of scientific data are known as the investigational new drug (IND) application and the new drug application (NDA). In an IND, the investigational drug's sponsor (manufacturer or potential marketer) presents results of preclinical testing and describes protocols (detailed research plans) for initial trials in humans. Preclinical data include results of in vitro and in vivo tests to determine the compound's therapeutic potential, toxicity, and pharmacological activity (absorption, distribution, metabolism, and mechanism of action) in animals. The Food and Drug Administration (FDA) has 30 days to complete its review of an IND, after which clinical trials in humans can begin.

During clinical trials, drug sponsors report back to the FDA, on a regular basis, any information that will assist the government agency's ongoing assessment of the safety of drug studies in progress. Protocol amendments are often added as supplements to INDs. As a drug progresses through each of the three phases of clinical investigation, revisions in research plans are inevitable. For example, after Phase I first-time testing in (healthy) humans is underway, estimates of acceptable dosage and drug activity, previously based solely on extrapolations from laboratory data, often require adjustment. Phase II trials, when the investigational drug is first administered to patients with the target disease or condition, yield further data for preliminary evaluation of potential efficacy and how it can best be measured in Phase III trials. Although not a statutory requirement, this sequential approach to drug testing helps researchers devise rational plans for gathering sufficient evidence to support product approval.

Upon successful completion of clinical trials, the next step in the United States regulatory process is submission of an NDA. Applications for marketing authorization include not only voluminous data gathered from extensive clinical evaluation of the candidate product, but also formulation and production details, as well as proposed packaging and labeling (directions for safe use in specified conditions). Unless designated for "priority" or "fast track'' status (based on its therapeutic significance and chemical novelty), subsequent review of the NDA by the FDA can take as long as two to three years (see FDA Performance Reports cited below). This stage in the drug development process is known, in the international literature, as "preregistration" or "pre-registration."

FDA approval of the NDA is called "registration" and is officially conveyed in a letter to the applicant. This authorizes a company to market the product in the United States for precisely stated indications in specified dosage forms and strengths following tested regimens. Any proposed alteration in dosage form, strength, or conditions of use for a previously approved drug requires submission of another application to the FDA, known as a supplemental NDA (SNDA). Proposed changes in labeling, such as the addition of newly identified adverse effects or extra precautions information, require a "supplementary labeling NDA''.

Biological drugs, or biologics, defined in United States law as products composed of, or extracted from, a living organism, are subject to a similar approval process. Some classes of biologics, such as monoclonal antibodies, cytokines, growth factors, enzymes, and proteins intended for therapeutic use, require full NDA submissions. Other types of biologics are approved through a separate, but parallel, Biologic License Application (BLA) system. A BLA differs from an NDA in its greater emphasis on industrial processes and production methods. Pharmacological and toxicity data presented to support BLAs are typically more limited than that in NDAs, due to immunogenicity factors affecting long-term testing, as well as ethical issues. Biologics approved under the BLA system include gene therapies, allergenics, antitoxins, vaccines, in vitro diagnostics, blood, and blood-related products.

The abbreviated new drug application (ANDA) is another category of pharmaceutical product approval in the United States. Legislation enacted in 1984 authorized ANDAs in order to facilitate generic drug introductions and provide lower cost alternatives to original brands, once their patents have expired. For medications that copy drugs previously approved by the FDA (known as "me-too" products), preregis-tration data submissions need not contain full safety and efficacy test results required in initial NDAs. Instead, ANDAs focus on proof of bioequivalence to drugs already on the market and on verification of noninfringement of patent rights.

Regulations governing the drug approval process can limit the amount of publicly available information. The FDA is prohibited from announcing a new IND or NDA/BLA/ANDA filing before its approval, since disclosure could influence free trade marketplace conditions. There are competitive advantages gained by secrecy on the part of applicant companies. If the innovators themselves choose to announce news about drugs under development, information will be available from sources other than the FDA. Ironically, regulation of the pharmaceutical industry by another federal agency, the Securities and Exchange Commission (SEC), sometimes leads to conflict with FDA strictures on premarketing promotion. The SEC requires public disclosure by companies of all significant information likely to affect their publicly traded stock. Hence, some of the best sources of information on drugs still in the pre-approval investigation stage are investment analysts' reports and commentary in the financial press. Other sources for monitoring IND and NDA submissions are drug pipeline databases, discussed elsewhere in this book.

Once a product is approved for marketing in the United States, the databases identified below are the most timely and comprehensive sources for answering questions regarding registration details. Typical information requests might focus on a specific type of approval (NDA, BLA, ANDA, etc.), qualified by factors such as company name, therapeutic category, specific indications, dosage forms, and/or time periods. Other frequently requested documents are Drug Review Packages, which summarize FDA analyses of data submitted in support of NDAs or ANDAs. They provide insight into the rationale underlying an approval and identify scientific evidence deemed acceptable to establish safety and efficacy.

Both retrospective surveys and ongoing monitoring of newly approved products are important in marketplace analysis and forecasting, as well as in gauging the relative productivity and potential profitability of individual companies. Documents associated with registration, such as copies of approved labeling and summaries of data submitted to support applications, can also provide useful models for companies planning clinical trials and subsequent submissions for comparable and competitive products.

Databases

[email protected]fda. URL: http://www.accessdata.fda.gov/scripts/cder/ drugsatfda. Introduced in May 2004, this database is the most up-to-date listing of drug approvals in the United States, posting FDA decisions within one to three days of official registration. Retrospective coverage dates from 1939 and includes NDAs, SNDAs, ANDAs, but not all BLAs (see complementary list of Biological License Application Approvals annotated below). On the [email protected] Web site, users can locate individual entries through browsable lists of product brand names (nonproprietary names for generic drugs). Alternatively, a targeted search interface enables access by drug name or active ingredient, FDA application number, and "action date'' ranges. Search results list pertinent product names, each of which is linked to a separate database record that identifies the drug's active ingredient(s), FDA application number, approved dosage forms/strengths and route of administration, designation of Rx (prescription-only) or over-the-counter (OTC, nonprescription) marketing status, and sponsoring company's name. Clicking on the product name shown in this initial entry leads to a "drug details'' screen that identifies the availability of therapeutic equivalents (if any) and provides a link to the drug's "approval history and related documents.''

The "approval history'' screen includes the FDA "action date'' (date of approval) and offers further links to the officially authorized label, the FDA's approval letter to the applicant company, and the agency's Drug Review (basis-of-approval summary), after each of these documents is released in PDF format. Letters and labeling typically appear in [email protected] within three months of product registration. Release dates of FDA Drug Reviews are somewhat unpredictable. For example, publication lag times ranged from 3 to 34 months after approval for Reviews posted in January-February 2003. Segments of these basis-of-approval documents, such as the Medical Review, Chemistry Review, Pharmacology, Microbiology, Biopharmaceutics, or Statistical Review sections, are available for downloading individually. Product entries in the [email protected] database posted prior to 1998 rarely offer direct access to full-text PDF Drug Review documents.

It's important to remember that this database is not accessible through the FDA Web site's general search engine (powered by Google). Instead, researchers seeking current drug approval information need to use the [email protected] targeted search form to locate pertinent data. Unfortunately, this form does not provide capabilities for isolating approvals associated with specified companies, indications, or application types (e.g., original NDAs versus SNDAs or ANDAs). Nor does it offer options to search on a combination of any of these factors coordinated with user-defined date ranges. When information requests involving drug approvals require more than a simple search on a product name or active ingredients, NDA Pipeline is a better, albeit less up-to-date, source of answers (see below).

FOI Online. URL: http:www.foiservices.com. Another complementary source for locating important documents associated with FDA product approvals is FOI Online. It provides access to a large, retrospective collection of Drug Review Packages, including those for products approved prior to 1998. Product name searches conducted on the FOI Online Web site often identify Summary Basis-of-Approval (SBA) documents or their counterparts available from FOI Services that are not part of the PDF collection of Drug Reviews currently hyper-linked from the [email protected] database.

Biological License Application Approvals. 1996- . URL: http:// www.fda.gov/cber/products.htm. The "Products" page at the FDA's Center for Biologics Evaluation and Research (CBER) Web site provides access to BLA approvals in separate annual lists. Each year's table, arranged in chronological order by approval date, lists brand names, indications for use, manufacturer name/address/license number, and official product registration date. Hyperlinks from individual product names lead to further information, including follow-up links to approval letters, labels, and SBA documents. The Products page also includes information on the recent transfer ofrespon-sibilities for regulating certain categories of biologics to the CDER, making them subject to full NDA (rather than BLA) submission requirements.

Generic Drug Approvals. 2000- . URL: http://www.fda.gov/ cder/ogd/approvals. This database, maintained by the FDA's Office of Generic Drugs, is designed as a supplement to the larger and more up-to-date [email protected] list cited above. Separate month-by-month summary tables, with entries organized chronologically by approval date, are available from May 2000 forward. Lag time from approval date to posting at this URL is typically four to six weeks. The Office of Generic Drugs database includes not only complete ANDA lists for specified time periods, but also offers the option to view either "first-time generics'' or "tentative approvals'' (awaiting patent or market exclusivity expirations of original NDA drugs that they will replicate). By completing the ANDA review process a few months in advance of the market exclusivity expiration for a brand name predecessor or equivalent ("referenced drug''), a generic preparation's manufacturer can prepare for more rapid product introduction after the innovator's legal monopoly in the United States marketplace ceases. Systematic surveillance of tentative approvals assists brand innovators in identifying threats to their future sales and helps generic drug companies assess their competition.

ANDA Suitability Petitions. 1999- . URL: http://www.fda.gov/ cder/ogd/suitabil.htm. The FDA Office of Generic Drugs also publishes a cumulative list of ANDA Suitability Petitions filed from April 1999 forward and their current status. Organized alphabetically by nonproprietary name, each entry in the cumulative table provides the dosage form and strength proposed for replication, the company filing the petition, the status of the petition, and the status date when the petition was approved, denied, or withdrawn. Under U.S. law, companies must submit a Suitability Petition to the FDA when their proposed generic product will differ in minor ways (dosage form, strength) from the original innovator drug on which their prospective ANDA will rely for proof of safety and efficacy. Suitability Petitions are, essentially, requests for permission to file an ANDA rather than a full NDA. Drug companies monitor these petitions in order to identify possible generic competitors.

Paragraph IVPatent Certifications. URL: http://www.fda.gov/ cder/ogd/ppiv.htm. Each year, products with previously approved NDAs are challenged by generic companies who submit ANDAs before the original drug's patent has expired. These ANDAs assert that the original drug's patent is invalid or will not be infringed by the proposed generic copy. This practice is known as a Paragraph IV Certification, in reference to a specific section of drug regulations. If the patent holder subsequently initiates an infringement lawsuit against the generic drug applicant, FDA approval to market the proposed "me-too" product is automatically postponed for 30 months unless, during that time, the patent expires or litigation is concluded. Why do generic companies invoke Paragraph IV regulatory provisions? If the courts support their certification, first ANDA applicants who use this legal device are entitled to 180 days of market exclusivity following FDA approval of their generic product.

The Paragragh IV database compiles, in tabular format, nonproprietary names of active ingredients in proposed generics, their dosage form and strength, and—most importantly—the brand name "reference drug" challenged. Cumulative tables are updated bimonthly, and new additions are highlighted in red. (Note: Names of ANDA applicant companies are not disclosed.) Industry watchers use this database, among many others, to assess product and company vulnerabilities. Other good sources of information about Paragraph IV filings and their basis/rationale are industry newsletters, particularly The Pink Sheet and Scrip (see below).

NDA Pipeline. 1991- . Chevy Chase, MD: F-D-C Reports. Monthly (online). Annual (in hardcopy format). The online version of this database is completely reloaded each month to provide a cumulative listing of new drug approvals in the United States from 1991 through the previous month. It provides separate records for each approval, searchable by applicant company name, product brand name, nonproprietary names of active ingredients, and date of approval. Online users can also limit retrieval to specific types of applications, such as original NDAs, SNDAs, ANDAs, or BLAs. Singling out records by FDA-assigned product and review types is another possibility. For example, users can limit output to approvals for products that represent new chemical entities (NCEs), new formulations, new combinations, or new indications, and can also segregate drugs accorded priority versus standard review or those officially designated as orphan drugs. Other searchable data elements include indications (keywords describing specific uses or authorized medical applications) and general therapeutic category headings from the U.S. Pharmacopeia (e.g., cardiovascular, cancer, respiratory).

FDA Performance Reports for the Prescription Drug User Fee Act. URL: http://www.fda.gov/oc/pdufa/reports.html. Appendices to these annual reports include retrospective lists of approved new drug applications and their review times (time elapsed from initial submission to final authorization).

FDA Approved Animal Drug Products. 1989- . URL: http:// www.fda.gov/cvm/greenbook/greenbook.html. Popularly known as "The Green Book,'' this compilation of approved new animal drug applications (NADAs) is maintained by the Virginia Polytechnic Institute. Cumulative product information for drugs registered from January 1989 forward is comparable in content to that provided for human drugs. The Green Book also provides access to abbreviated NADA (ANADA) Suitability Petitions, a directory of approved sponsors (companies), and a collection of pertinent regulations related to animal drugs. Online users can also search for patent numbers cited in approved NADAs. Subscriptions to the Green Book in hardcopy format include an annual, cumulative edition with updates issued each month.

New Animal Drug Application FOI Summaries. URL: http:// www.fda.gov/cvm/efoi/foidocs.htm. The FDA's Center for Veterinary Medicine also maintains a database of SBA documents associated with original and supplemental NADAs. Known as "FOI Summaries'' because they are released under Freedom of Information Act provisions, these electronic files are accessible through index lists by date (NADA number), generic name, and brand name.

Over-the-Counter Drug Products. URL: http://www.fda.gov/ cder/offices/otc/industry.htm. In the United States, NDA requirements apply to both prescription and nonprescription drugs, although the latter are exempt from full premarketing clearance regulations when they simply reiterate products already long established in the marketplace. Since 1972, the FDA has been issuing results of a massive review of safety and efficacy data for active ingredients used in drugs already sold over the counter without a prescription. Published as separate "OTC Monographs'' for each major therapeutic category, the FDA's findings identify ingredients, dosage, and labeling proven to be safe and effective for use without the oversight of a qualified medical practitioner. New drug products that contain these ingredients labeled for use as described in the appropriate OTC Monograph require no premarketing authorization by the FDA. If, however, a proposed nonprescription product will use additional active ingredients, different dosage levels or recommended regimens, a new formulation or alternative delivery technology (e.g., timed-release), or therapeutic claims that deviate from Monograph standards, its manufacturer is subject to full NDA submission requirements. The Web page cited here links to the OTC Drug Review Ingredient Report in PDF format, covering more than 2700 ingredients.

Dietary Supplements. URL: http://vm.cfsan.fda.gov/~dms/ supplement.html. Like many OTC (nonprescription) products marketed in the United States, dietary supplements are also exempt from NDA regulations, provided that they make no claims, in labeling or promotion, about a preparation's ability to diagnose, prevent, mitigate, treat, or cure a specific disease or medical condition. Supplements marketed in pill, capsule, tablet, or liquid form for ingestion are also exempt from pre-market safety evaluations required for other food ingredients, as long as no information is available that points to significant or unreasonable risks associated with their use as directed. Since manufacturers do not need FDA approval to sell dietary supplements, there is no product database provided at this Web site. However, it is a useful source for background information on an often-controversial topic.

Inactive Ingredients in Approved Drug Products. URL: http:// www.accessdata.fda.gov/scripts/cder/ig/index.cfm. This database lists inactive ingredients (excipients) previously approved for use in specific drug formulations and identifies authorized dosage forms and strength (maximum potency). Developers of new drugs can, therefore, determine which excipients are likely to be safe for use in their own products and acceptable to the FDA. Ingredients in this source are not linked in any way to brands containing them or to therapeutic applications. Listings are accessible by nonproprietary or simplified chemical names. Queries lead to lists that show route of administration and dosage forms for marketed drugs containing the ingredient and its maximum FDA-approved potency.

Newsletters

Pharmaceutical Approvals Monthly. 1995- . Chevy Chase, MD: F-D-C Reports. Monthly. This newsletter provides thorough coverage of FDA deliberations and decisions related to prescription drug and biologic approvals in the United States. It includes not only news reporting, but also analysis and informed commentary. It is available by subscription in hardcopy format, as well as through a Web-based platform for searching. This newsletter is also incorporated into selected implementations of the F-D-C Reports database (see below).

Books

Mathieu M. New Drug Development: A Regulatory Overview. 7th ed. Waltham, MA: PAREXEL International, 2005. Mathieu guides the reader through every step of the U.S. drug development and approval process. Separate chapters provide in-depth discussion of key topics, such as preclinical testing and INDs, clinical trials, FDA Advisory Committees, postmarketing adverse experience reporting, the Orphan Drug development program, and recent changes in pediatric studies initiatives. Note: When issued as part of PAREXEL's "Worldwide Pharmaceutical Regulation Series,'' this book was published under the title New Drug Approval in the United States.

Mathieu M. Biologics Development: A Regulatory Overview. 3rd ed. Waltham, MA: PAREXEL International, 2004. This book was completely revised and updated to reflect the shift in responsibilities for oversight of many biologics from the FDA CBER to the CDER in 2003. Discussion covers all aspects ofbio-logical product development and approval subject to regulation in the United States, ranging from preclinical testing requirements to postmarketing surveillance and reporting.

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