Department of Health and Human Services
Food and Drug Administration
Fiscal Year 2005

HUMAN DRUGS

Historical Funding and FTE Levels

MISSION

The Human Drugs Program promotes the public health by assuring that all prescription and over-the-counter drugs are safe and effective. 

BACKGROUND

The Human Drugs Program evaluates all new drugs before they are sold, and serves as a consumer watchdog for the more than 10,000 drugs on the market to be sure they continue to meet the highest standards.  In addition,TV, radio, and print drug ads are routinely monitored to ensure they are truthful and balanced.  The Program also plays a critical role in providing health professionals and consumers information on how to use drugs appropriately and safely and conducts inspections of drug manufacturing plants, protects the rights of people involved in drug studies, regulates generic drugs, and determines when and if a drug should be available over-the-counter.

Human Drugs Program Increases for FY 2005
By FDA Strategic Goal

PROGRAM RESOURCE CHANGES

Budget Authority

Cost of Living- Pay: + $4,176,000

FDA's request for pay cost increases is essential to accomplishing its mission.  Without a specially trained national cadre of scientific staff, FDA's ability to adequately carry out the mission of protecting public health and providing consumer safety will be compromised.  FDA must maintain staffing levels and scientific capabilities that meet the demands of an increasing workload and new challenges.  Payroll costs, which account for over 60 percent of our total budget, significantly impact all FDA activities. 

Medical Product Countermeasures -- Counter terrorism:  + $3,000,000 and + 19 FTE

The Agency plays a pivotal role in counter terrorism preparedness and response and a combination of regulatory and law enforcement responsibilities mandated by the Food, Drug and Cosmetic Act.  The request will allow FDA to satisfy its mission and meet the goal to facilitate the availability of safe and effective biological products to prevent, diagnose, and treat sicknesses or injuries associated with terrorist attacks.  The Agency will be able to ensure the availability of safe and effective medical products, to support the development, maintenance and deployment of stockpiles of medical counter-measures; to assist in assuring that sufficient quantities of medical products are available; and, to support post-event follow-up and data collection initiatives for these products, some of which may be investigational. 

Working with sister agencies such as CDC and NIH as well as DOD, and interacting with industry, health care providers and consumers, FDA is at the forefront of the public health response related to countering terrorism.  We must have sufficient resources and the ability to employ all types of assets such as full time and contract employees and partnerships with contracting and academic organizations to continue to effectively and innovatively respond to the increasing and intensive level of activity required. 

The first therapy for those exposed to a biological, chemical, or radiological/nuclear agent is often a drug. FDA has been taking an aggressive and proactive approach to getting information on medical countermeasures into labeling of already approved drugs. We have also issued various guidance and regulation to help industry develop drugs and medical countermeasures for biological, chemical or radiological/nuclear.

Increased funding will enable FDA to continue critical efforts to identify new countermeasures in case of biological, chemical or radiological terrorist events. FDA will continue collaborations with the CDC and the NIH to conduct studies for infectious diseases.  Increases will fund additional staff who have specific scientific expertise, such as in infectious diseases and radiation and with staff who can focus time on application review of potential counter measure products, who can conduct product inspections, and who can ensure preparedness in case of emergency events.  Further, FDA will continue significant efforts to determine better dosing requirements for radiation-related countermeasures.

Administrative Efficiencies:  - $6,657,000 and - 57 FTE

To fully embrace the President's Management Agenda, FDA is delayering its organizational structure, performing competitive sourcing reviews, modernizing its financial management system, and consolidating its information technology infrastructure. The Human Drug portion of these management improvements consists of reductions of $6,657,000 and 57 FTE.

User Fee

Prescription Drug User Fee Act III (PDUFA):  + $22,748,000 and + 75 FTE

PDUFA authorized the FDA to collect fees from the pharmaceutical industry to augment appropriations spent on drug review.  These fees expand the resources available for the process of reviewing human drug applications including reviewers, information management, space costs, acquisition of fixtures, furniture, equipment and other necessary materials so that safe and effective drug products reach the American public more quickly.  The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 reauthorized the collection of user fees to enhance the review process of new human drugs and biological products and established fees for applications, establishments, and approved products.  These amendments are effective for five years and direct FDA to strengthen and improve the review and monitoring of drug safety; consider greater interaction with sponsors during the review of drugs and biologics intended to treat serious diseases and life-threatening diseases; and develop principles for improving first-cycle reviews.  The increases will contribute to meeting these mandated directives.

PROGRAM ASSESSMENT RATING TOOL (PART)

In the FY 2004 review, FDA was assessed as five distinct programs (Foods, Human Drugs, Biologics, Veterinary Medicine, and Medical Devices and Radiological Health) and was rated as "results not demonstrated" due to a  lack of long-term outcome goals.  To address this concern, long-term outcome goals were developed.   

For FY 2005, the Office of Management and Budget conducted a second program review that treated FDA as a single agency program.  In this review, FDA received a rating of "moderately effective" and score of 77 percent, up from 59 in FY 2004.  This was due to considerable improvements in developing long-term agency-wide outcome goals that will demonstrate its effectiveness and impact on the public health.  FDA also reduced the number of performance goals, and made various management improvements that further streamline its infrastructure while supporting core, mission-critical public health activities. 

The Program shares in an agency-wide outcome goal of reducing administrative overhead through the reduction of the number of administrative staff.  All of the Agency's outcome goals support the Department's priorities and Administration's initiatives with the intent to improve the health and well-being of the American public. 

JUSTIFICATION OF BASE

EFFICIENT RISK MANAGEMENT: THE MOST PUBLIC HEALTH BANG FOR OUR REGULATORY BUCK

FDA conducts science-based risk management in all regulatory activities so that limited resources can provide the most health promotion and protection at the least cost for the public. Efficient risk management efforts for premarket activities include:

New Drug Application Review

The Human Drug Program is charged with reviewing and evaluating New Drug Applications (NDAs) to determine whether or not a new drug is both safe and effective.  Drugs for certain diseases (e.g. cancer, AIDS) are given priority status and evaluated through an accelerated approval process.  New Drug Application Review activities include:

• Regulate testing of Investigation New Drugs (INDs);
• Evaluate standard and priority NDAs received from sponsors; and,
• Complete review and action on standard and priority efficacy supplements - supplemental applications proposing to add a new use of an approved drug to a product's labeling.

OTC Drug Review

FDA is committed to providing consumers with safe, effective, and affordable drugs. Increasing the number of safe and effective Over-the-Counter (OTC) drugs that are available to consumers is consistent with this goal. The Program conducts the following activities:

• Reviewing OTC drugs to ensure their safety and effectiveness and assist consumers on how to best use OTC products by providing clear easy-to-read drug information;
• Providing funding for consumer behavior research to identify and manage the risks associated with the use of OTC drugs; and,
• Initiating a process and establishing timelines for completion of unfinished OTC drug monographs.

Generic Drug Review

FDA continues to support an active generic drugs program to complete review and action on Abbreviated New Drug Applications (ANDAs). Our focus continues to be expanding the availability of high-quality generic drug products to the public and providing consumers with information on their safety and effectiveness.  Generic drugs save consumers billions of dollars each year.  Accordingly, FDA is committed to bringing as many safe and effective generic drugs to market as possible by:

• Building consumer confidence in generic drugs by addressing specific scientific questions regarding bioequivalence and chemistry of generic products. This research will be directed at evaluating ways to enable approval of generic drugs in areas that currently lack generic alternatives, such as inhalational or topical drug products;
• Expanding the range of generic drugs available by targeting intramural and extramural programs, and helping to prevent adverse reactions involving generic drugs;
• Increasing efficiency and improving review times by evaluating ways to apply information technology solutions; and,
• Enhancing the Office of Generic Drugs (OGD) information technology capabilities to further refine and develop electronic submissions of generic drug applications to gain efficiencies in the review process; and train staff on the use, development, and expansion of electronic review efforts.

Biological Therapeutic Products

FDA reviews and evaluates biological therapeutic products, including establishing standards, conducting mission related research, participating in inspections, developing policy and procedures, and evaluating trial results and reports of adverse events. Biological therapeutic products include such products as growth factors, enzymes, monoclonal antibodies, and products prepared by genetic engineering and synthetic procedures.  Biologic therapeutic product drug review also includes:

• Monitoring production of biologics from the early stages all the way through postmarketing , with lot release testing to ensure the individual lots continue to meet safety, purity, potency and efficacy requirements;
• Engaging in compliance, lot release, surveillance, and standards development activities. Manufacturers are required to follow good manufacturing practices (GMPs) in the production of biologic products; and,
• Improving the safety of imported and domestic biological therapeutic products through the surveillance of imported biological products and coordination of domestic field investigational analytical compliance activities.

Pediatric Drug Studies

Working with sponsors to help ensure that useful new information on pediatric safety and effectiveness is included in drug product labeling in an efficient manner.  In December 2003, FDA's authority to require these studies was re-affirmed by the Pediatric Research Equity Act of 2003. This effort includes drugs both with and without patent protection and is accomplished by collaborating with sponsors, NIH, and academia to develop and issue written requests for pediatric studies.  Efforts to further build upon the gains shown in the following table include:

• Reviewing requested pediatric studies within six months of submission;
• Collaborating with NIH regarding funding for pre-clinical models for pediatric cancers and proceedings of the advisory committee established for pediatric issues;
• Working on the establishment of a research fund to study (in children) drugs that no longer have exclusivity or patent protection; and,
• Establishing a process to ensure revisions to labeling are made as a result of pediatric studies.

Prescription Drug User Fee Act (PDUFA)

The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 reauthorized PDUFA for a five-year period, allowing the collection of user fees to enhance the review process of new human drugs and biological products and established fees for applications, establishments, and approved products. Specifically, Congress directed FDA to strengthen and improve the review and monitoring of drug safety; consider greater interaction between the Agency and sponsors during the review of drugs and biologics intended to treat serious diseases and life-threatening diseases; and develop principles for improving first-cycle reviews. Performance monitoring of reviews is accomplished in terms of cohorts.  For example, the FY 2004 cohort includes applications received from October 1, 2003 through September 30, 2004. The FY 2005 cohort review performance goals covered under PDUFA for NDAs, Product License Applications (PLAs), and Biologics License Applications (BLAs) are:

• Review and act on 90 percent of standard original NDA and BLA submissions filed during fiscal year within 10 months of receipt;
• Review and act on 90 percent of priority original NDA and BLA submissions filed during fiscal year within 6 months of receipt;
• Review and act on 90 percent of standard efficacy supplements filed during fiscal year within 10 months of receipt; and review and act on 90 percent of priority efficacy supplements filed during fiscal year within 6 months of receipt;
• Review and act on 90 percent of manufacturing supplements filed during fiscal year within 6 months of receipt; and review and act on 90 percent of manufacturing supplements requiring prior approval within 4 months of receipt; and,
• Review and act on 90 percent of Class 1 resubmitted original applications filed during fiscal year within 2 months of receipt; and review and act on 90 percent of Class 2 resubmitted original applications filed during fiscal year within 6 months of receipt.

Product Quality         

Ensuring that the highest possible quality products are marketed is a large part of FDA's mission of protecting the public's health.  FDA ensures product quality by:

• Evaluating and analyzing inspection findings for trends in deficiencies by focusing on product quality standards and manufacturers' compliance with GMP regulations;
• Conducting criminal investigations of reported product tampering, counterfeit products, and other fraudulent criminal activities involving regulated drug products;
• Performing laboratory validation of analytical methods submitted to support premarket product applications;
• Verifying the reliability and accuracy of NDA data collected by regulated industry in animal and human studies; and,
• Evaluating approaches that may be used to facilitate the introduction of modern process analytical technologies and pharmaceutical engineering principles.

Import Monitoring and Inspections

FDA is responsible for ensuring the safety of nearly two hundred thousand import line entries for human drug products that annually cross the United States border. Products may enter the U.S. through one of approximately 300 ports throughout the country. The sources of these entries are diversified and include an increasing number of products from countries typically categorized as emerging economies, with start-up regulatory infrastructures. To make the majority of entry decisions, FDA relies on risk-based electronic screening of line-entry data produced by import filers in the Operational and Administrative System for Import Support (OASIS) system. FDA is also responsible for inspecting manufacturers to ensure that drug and therapeutic biologic manufacturers use current Good Manufacturing Practices.  Major efforts in this area include:

• Bringing a 21^st Century focus to the regulation of pharmaceutical manufacturing and product quality by providing high quality, cost-effective oversight of industry manufacturing, processing and distribution;
• Focusing on product quality standards and compliance by manufacturers with the GMP regulations to ensure that the highest possible quality products are marketed;
• Ensuring latest technological advances are encouraged, including application of the requirements of Part 11 regulations;
• Conducting field inspections and compliance actions, including post-approval human drug inspections, surveillance GMP inspections for human drugs, as well as appropriate follow-up to complaints or adverse event reports;
• Conducting criminal investigations of reported product tampering, counterfeit products, and other fraudulent criminal activities involving regulated drug products;
• Performing laboratory validation of analytical methods submitted to support premarket product applications;
• Review approximately 200,000 import entry lines representing different FDA regulated products for admissibility into domestic commerce;
• Develop rapid analytical methods of screening imports at the border and increase the number of import line entries review for admissibility into domestic commerce;
• Collaborate with the  U.S. Customs and Border Protection to monitor the importation of regulated products and follow-up on the status of products refused entry;
• Expand import surveillance at international mail facilities and courier hubs; and,
• Conduct about 600 bioresearch monitoring inspections to support the Human Drugs Program.

Information Technology

• Automated Drug Information Management System (ADIMS):  ADIMS is being developed as a fully electronic information management system to receive, evaluate, and disseminate information about investigational and marketing submissions for human drugs and therapeutic biologics. It replaces the Corporate Oracle Management Information System, Division Files System, and CDER Standard Letters system.  ADIMS includes electronic document receipt processes previously associated with the Electronic Document Room and Electronic Common Technical Document.  It includes therapeutic biologics per the OTRR Integration project.  ADIMS includes scientific tools that aid submission evaluation, such as tools to review structured clinical data, labeling data, and drug ingredients;
• Adverse Event Reporting System (AERS):  AERS encompasses the Drug Safety program along with all systems that rely on AERS data or functionality.  AERS remains the foundation of this program and was reported as a major system in the FY2004 Exhibit 53.  Significant requirements for AERS functionality related to Medical Errors are included, as is the AERS DataMart, which was reported under "small contracted projects" in the FY2004 submission. Also included are the following systems historically reported in the operating budget of the Office of Drug Safety: Look Alike and Sound Alike System and Adverse Events Data-Mining;
• Emergency Operations Network Project: An Emergency Operations Portal that will provide the front end for all EO applications and information;

EMPOWERING CONSUMERS: IMPROVING HEALTH THROUGH BETTER INFORMATION

FDA is committed to enhancing our communication methods in order to prevent any harm to the American public that may occur due to the lack of accurate and timely information about a drug product.  Base resources will be used to better enable consumers to make informed decisions weighing benefits and risks of FDA-regulated products.  These activities include:

• Collaborating with organizations such as the National Patient Safety Foundation on outreach activities targeting consumers to educate them about the safe use of pharmaceuticals;
• Developing education campaigns to disseminate consumer friendly information on drug products to promote the safety and quality of drug products;
• Collaborating with the National Library of Medicine to develop "Daily Med" to provide accurate and timely drug product information to the health care practitioner to help prevent medical errors;
• Maintaining and enhancing our web site to assure availability of information; and,
• Responding to consumer inquiries via letters, email, and telephone.

IMPROVING PATIENT AND CONSUMER SAFETY

Another important function of FDA is to promote improved patient and consumer safety through post-market activities by reducing risk associated with FDA-regulated products.

The practical size of premarketing clinical trials means that the Agency cannot learn everything about the safety of drugs or biologics before approval. Therefore, a degree of uncertainty always exists about their risks. This uncertainty requires our continued vigilance. FDA runs a risk management program of postmarketing surveillance and risk assessment to identify adverse drug events (ADEs) that did not appear during the drug or biologic development process by collecting, evaluating, and acting upon information on ADEs associated with marketed products. Maintaining drug and biologic product quality also helps assure the American public that drugs and biologics are safe.  Surveillance activities include:

• Processing and evaluating reports of adverse drug and biologics events via the Adverse Event Reporting System (AERS) database;
• Provide training for field staff to improve the information gathered through investigation of consumer complaints and reports of medical errors;
• Conduct investigations of reported errors to collect information program managers need to assess the error, and develop error reduction strategies with manufacturers and the medical community;
• Review adverse event and complaint files at manufacturers during inspections for compliance with FDA reporting regulations and to conduct follow up inspections on adverse event reports when information from the manufacturer is needed to evaluate the risks involved;
• Monitor promotion of drug and biologic products to assure the American public that information provided presents a fair balance of risks and benefits and is not false or misleading;
• Work with all interested governmental agencies and private organizations to coordinate collection of adverse event data;
• Operating the MedWatch Program, which permits health care professionals to voluntarily report observed or suspected defects and quality problems associated with marketed drug products. FDA reviews these reports to identify potential health hazards, initiates investigational follow-up, and takes appropriate enforcement action. The Agency reviews hundreds of thousands of reports per year and numerous reports result in product recalls and voluntary corrective actions by industry;
• Identifying health hazards associated with the manufacturing, labeling, and packaging of pharmaceuticals and biologics; removing unsafe and ineffective products from the marketplace;
• Coordinating with Medical Device contractors to continue implementation of drug products into Medical Product Surveillance Network (MeDSuN). MeDSuN is designed to train hospital personnel to accurately identify and report injuries and deaths associated with medical products. The MeDSuN model will be used for both medical device and drug products;
• Conducting product safety biomedical research in areas such as new cells used to produce drugs and biologics. Rapid advances in technology and the evolving HIV pandemic are stimulating a need in the field of biologicals to use new types of cell substrates and to develop new assays and assess the reliability of current assays used to monitor product safety. This is coupled with other public health crises of global proportions, such as hepatitis B/C infections, the constant threat of pandemic influenza, and the treatment of genetic defects;
• Developing new, specific, and sensitive techniques and assays for validation and the detection of a greater variety of known potentially infectious viruses. A prime objective of safe biological therapeutic products is detection, identification, and elimination of adventitious agents. One of the chief concerns inherent in biologicals is the potential for the presence of adventitious agents (infectious for humans) in the approved product;
• Maintaining reporting systems to collect biological therapeutic product deviation events that occur during manufacturing processes or storage of all biological products; and,
• Establishing contracts for safety monitoring data links that include data on product exposure and extensive patient information. Developing access to external database with other government agencies, states, academia, and independent health organizations such as hospitals, to enhance FDA's ability to monitor the public health impact of FDA regulated products.

Human Subject Protection

FDA's role in verifying the quality and integrity of data submitted is also an integral part of assuring safety. The following activities help us provide this assurance:

• Performing onsite inspections of clinical trial study sites, institutional review boards, sponsors, study monitors, and contract research organizations;
• Protecting human research subjects who participate in drug studies and assess the quality of data from these studies by conducting annual onsite inspections and data audits;
• Expediting development and licensing of safe and effective biological therapeutic products and ensuring patient safety through an effective, comprehensive BIMO program;
• Conducting inspections to increase oversight of high-risk IND applications; and,
• Convening conferences of investigators whereby the most experienced professionals in the field discuss appropriate monitoring practices.

Internet Drug Sales

At present, there are an exploding number of new web sites marketing FDA regulated products to the American consumer and medical professionals. FDA currently conducts only minimal levels of web-based oversight.  For example, FDA:

• Monitors potentially fraudulent Internet sites to identify targets for investigation and sampling of products;
• Conducts undercover purchases of prescription drugs from Internet sites suspected of engaging in illicit drug sales, distribution, and/or marketing; and,
• Provides oversight of mail and courier packages entering from foreign sources.

Premarket Activities

• Improve the quality and timeliness of product reviews by monitoring pre-approval inspections and expanding inspectional expertise in emerging technologies; and,
• Improve the scientific expertise of field investigators by providing training, information technology and contract support to improve the scientific expertise of field investigators.  This training enables investigators to conduct premarket inspections that are essential to meeting pre-market review time frames.
• Maintaining field staff hired to increase inspections of domestic and foreign firms. The staff will also be used to provide for team inspections (reviewer and inspector) to increase efficiency; and,
• Maintaining coverage of imported generic drugs so that FDA can better monitor the quality of finished drug products and bulk drug substances entering the U.S. from overseas.

PROTECTING AMERICA FROM TERRORISM

FDA plays a critical role in the war on terrorism.  Base resources will be used to strengthen the Human Drug Program's capability to identify, prepare for, and respond to terrorist threats and incidents.   The Program performs the following Counter terrorism activities:

• Prepares for defense against a bio-terrorist attack by reviewing new drugs to counter the effects of anthrax and other potential bio-terrorist toxins;
• Conducts GMP inspections of drug manufacturing sites whose products are stockpiled as part of the government's Counter terrorism efforts; 
• Assures regulated drug and therapeutic biological products are not used as vehicles of terrorism; 
• Supports the development, maintenance, and deployment of stockpiles of medical counter-measures;
• Establishes appropriate communications procedures for emergency situations to ensure FDA's ability to maintain vital operations and service throughout and following terrorist attacks;
• Maintains crisis management plans that are coordinated and reactive to the Agency crisis management plan, and ensures that personnel are trained in implementation; and, 
• Maintains procedures and plans to ensure the safety and security of personnel, physical assets, and information; maintains procedures and plans to ensure the safety and security of information technology assets, including essential databases, hardware and networking capacity.

STRONG FDA

Strong and sound science means Human Drug Program scientists stay on the cutting edge of new technologies. Our mission depends more than ever on a solid cadre of experienced physicians, toxicologists, chemists, statisticians, mathematicians, project managers and other highly qualified and dedicated professionals.  The following are examples of activities that fulfill this strategic goal:

E-Government

The program's information technology efforts go right to the heart of the President's Management Agenda for Electronic Government or "e-Government", by using improved Internet-based technology to make it easy to interact with the government, save taxpayer dollars, and streamline communications.  Primarily, the program's efforts target the following two President's e-Government Initiatives:

• Government to Business initiatives: to reduce burdens on business, provide one-stop access to information and enable digital communication using XML; and,
• Internal Efficiency and Effectiveness: to advance partnering and end-user focus and to reduce stovepipe systems.

As an example of "Government to Business", FDA has worked diligently with our partners in the International Conference on Harmonization (ICH) on the Common Technical Document (CTD) of the New Drug Application.  The CTD provides a harmonized format and content for new product applications in the US, the European Union, and Japan.  While the CTD is based on a paper paradigm, the FDA has also worked with our partners in ICH to develop the Electronic Common Technical Document (eCTD) to provide the electronic transmission of CTD applications from applicant to regulator.   The eCTD format will replace many of the current electronic submission formats and allow the electronic transmission of applications that currently do not have an electronic solution.  Leveraging a common technology across submission types will enhance the review process by allowing the FDA to build a common infrastructure and user interfaces for multiple submission types.

FDA is committed to developing an integrated, fully electronic internet-based or web-capable information management system for receipt, evaluation, and dissemination of human drug safety and effectiveness data coming into the FDA through investigational and marketing applications and related submissions.

This commitment supports both aspects of e-Government mentioned earlier.  Specifically, FDA processes an increasing number of electronic drug applications from businesses. Currently, approximately 75 percent of original NDAs received by the Program now include sections submitted electronically and a growing number of these are provided electronically, and this percentage is accelerating.  The Program is also committed to several efforts to improve internal efficiency and effectiveness.  The program is re-designing and modernizing its internal document and data processing systems used during the drug review process.  This modernization also includes consolidating functions, as applicable, with the review of biologic products.  The Program is also fully implementing Agency plans for consolidating information technology infrastructure Agency-wide to eliminate the stove-pipe network and desktop equipment and customer service within FDA.

SELECTED FY 2003 ACCOMPLISHMENTS

EFFICIENT RISK MANAGEMENT: THE MOST PUBLIC HEALTH BANG FOR OUR REGULATORY BUCK

Risk management is at the core of the Human Drugs Program's mission.  Almost everything we do in the review and approval of Human Drugs relates to weighing the benefits of a product to its risks.  We include the FY 2003 accomplishments of the Human Drug Review process here including new, generic, and OTC drugs.  In addition, we include here accomplishments of managing the risks of drugs in the pediatric population.

As the Agency Strategic Plan explains, "efficient risk management" requires using the best scientific data, developing quality standards, and using efficient systems and practices that provide clear and consistent decisions and communications for the American public and regulated industry.  Accomplishments toward objectives and strategies of the Agency Strategic Plan are included here as well.

New Drug Evaluation

The Human Drugs Program is held to strict performance goals and targets under PDUFA.  FDA met or exceeded all 15 performance review goals for the FY 2003 receipt cohort, and met or exceeded all review goals for New Molecular Entity (NME), a subset of the NDA category.  An NME contains an active substance that has never been approved for marketing in any form in the U.S.

FDA approved several important NDAs in FY 2003 as shown in the table below:

Significant NDAs Approved in FY 2003

NDAs Approved under Accelerated Approval in FY 2003

Generic Drug Review

There were many accomplishments in FY 2003 for FDA in its support of an active generic drug program, including approval of the following significant generic drugs:

• Ganciclovir Capsules and Ganciclovir Sodium for Injection - Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV). Ganciclovir Sodium for Injection is indicated for the treatment of CMV retinitis in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). It is also indicated for the prevention of CMV disease in transplant recipients at risk for CMV. Ganciclovir Capsules are indicated for the prevention of CMV disease in solid organ transplant recipients and in individuals with advanced HIV infection at risk for developing CMV disease.
• Paroxetine Hydrochloride Tablets - This is indicated for the treatment of depression, obsessive compulsive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder.
• Glipizide Extended Release Tablets - This is an oral blood-glucose-lowering drug of the sulfonylurea class. It is indicated as an adjunct to diet for the control of hyperglycemia and its associated complications in patients with type 2 diabetes.
• Quinipril Hydrochloride Tablets - This is a non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor that  is indicated for the treatment of hypertension and the management of heart failure as adjunctive therapy when added to conventional therapy.

FDA completed review and acted on over 90 percent of fileable original generic drug applications within six months after submission date and reduced the median month approval time from 18.3 months in 2002 to 17.3 months in FY 2003.

The Office of Generic Drugs is increasing communications with the generic drug industry with a goal of improving the quality of the generic applications thus increasing first cycle approvals and decreasing overall time to approval.  Some examples of our outreach to industry include: 

• Presented information to the Generic Pharmaceutical Association (GphA) technical committee on scientific review issues;
• Contributed to a GphA-sponsored technical session on impurities;  this session was an audiocast that allowed larger numbers of industry participants;
• Met with key GPhA members in June 2003 to discuss common problems seen in applications by FDA to help the industry look critically at their submissions;
• Participated in GPhA's Fall Technical Workshop; and,
• Developed and published an internal procedure document to provide guidance to chemistry reviewers on appropriate use of telephone calls in the initial review process to increase communication and speed the review process.

Much of FDA's efforts to reduce generic drug approval time involve research in bioequivalence, the key factor that demonstrates that a generic product is "equivalent" to an innovator drug product.  In FY 2003, FDA continued research endeavors to allow faster approval of certain products for which methods for demonstration of bioequivalence are not existent or are quite onerous, and:

• Let a contract for a study on in vitro methods to assess the structural similarity of topical products;
• Let a contract for a study on dermatopharmacokinetics to improve methodology for assessing bioequivalence of topical drug products; and,
• Researched the literature and current thinking on many issues related to approval of generic drug products to develop clear policy and scientific basis for regulatory decisions.

OTC Drug Products

The OTC Drug Product Program approved 12 new OTC NDAs in FY 2003.  They took 22 total NDA actions, 79 Chemistry, Manufacturing, and Controls (CMC) supplement actions, and 31 labeling supplement actions in FY 2003. 

Further, the Program held 59 meetings with drug companies and two advisory committee meetings.  They made 25 Federal Register publications, addressed 20 Citizen Petitions, acted upon four Time and Extent Applications, responded to 10 Congressional Inquiries; evaluated seven health hazards, and published two guidance documents.

FDA approved significant OTC drugs in FY 2003, including:

• Claritin Tablets, Syrup, Reditabs - for treatment of symptoms of hay fever and other respiratory allergies;
• Claritin-D 12-Hour and 24-Hour Tablets - for the treatment of fever and other respiratory allergies; and,
• Prilosec OTC Tablets - for the treatment of frequent heartburn.

In addition, the OTC Drug Program published several significant Federal Register notices including:

• Proposed rule on Warnings for Vaginal Contraceptives Containing Nonoxynol-9; and,
• Final rules on:
  • Reye's Syndrome Warning for Products Containing Aspirin and Nonaspirin Salicylates;
  • Ingrown Toenail Relief Drug Products;
  • Antidiarrheal Drug Products;
  • Skin Protectant Drug Products;
  • Antiperspirant Drug Products; and
  • Anorectal Drug Products.

Pediatric Drug Studies

As a result of FDA's efforts in the Division of Pediatric Drug Development, Health Care providers have 88 drug labels with new pediatric information.  In FY 2003, 21 labels out of 60 labels were approved for drugs granted exclusivity.  The other labels were from applications with completed studies and not associated with exclusivity.  FDA has worked hard to collaborate with the public and other government Agencies.  FDA published an article on pediatric drug labeling in JAMA, published four abstracts, published two  pediatric labeling articles in the AAP News, and participated in 27 presentations to various audiences.  FDA also has successfully collaborated with NIH as a result of the Better Pharmaceuticals for Children Act (BPCA).  Further, FDA implemented the off-patent process for contracting for pediatric studies and issued seven Written Requests for off-patent drugs.  FY 2003 accomplishments are as follows:

• Published lists of drugs for which pediatric studies are needed:  the first list of 12 drugs was published in Federal Register on January 21, 2003 and the second list of 8 drugs was published on August 13, 2003.  FDA also developed the Off-Patent Priority List with NIH, AAP, USP and other experts;
• Established the Office of Pediatric Therapeutics (OPT). OPT has worked with the Division of Pediatric Drug Development in a way that maximizes efficiencies and coordinates pediatric activities across the Agency;
• OPT and the Division of Pediatric Drug Development collaborated to implement the safety monitoring mandated by Congress in the BPCA legislation; and,
• OPT responded to and provided data to the GAO for 2 reports to Congress they were responsible for: "Substantial Increase in Studies of Drugs for Children, But Some Challenges Remain" and "Food and Drug Administration Should More efficiently Monitor Inclusion of Minority Children".

Actions to Improve the Management of Medical Risks

Several additional accomplishments that improve risk management include:

• Implementing new OTC drug facts label promoting the safe use of OTC medicines- May 16, 2002marked the date that most OTC drug manufacturers must display FDA's new easier-to-read drug facts label on their products. The OTC regulation FDA finalized in March 1999 requires a standardized format for the labeling of the drugs Americans use most often, namely OTC drugs. Most of the more than 100,000 OTC products marketed will now be required to display the new labeling;
• Modified Risk Management Program to include efforts to prevent birth defects caused by Accutane - FDA advised consumers and health care providers about significant changes to the Accutane risk management program for pregnancy prevention. The new program is called S.M.A.R.T. (System to Manage Accutane Related Teratogenicity). S.M.A.R.T. was developed in consultation with FDA by Accutane's manufacturer, Roche Laboratories. The program is designed to enhance the safe and appropriate use of Accutane by strengthening the existing Accutane Pregnancy Prevention Program (PPP), a comprehensive patient education program; and,
• Performing Drug Safety and Risk Management (DSaRM) Advisory Committee Activities --  Enhancing the safe use of drugs by adequately managing drug risks, adequately communicating drug risk information to patients and health care providers, and reducing the incidence of medication errors are topics that FDA's DSaRM may address. Discussion of these issues plays a significant role in FDA's overall evaluation of the risk-benefit balance of drugs and results in improved FDA public health initiatives. 

EMPOWERING CONSUMERS: IMPROVING HEALTHCARE THROUGH BETTER INFORMATION

FDA made great progress in its campaign to understand and inform healthcare providers and consumers about antimicrobial resistance.  Many significant accomplishments were made in FY 2003, including:

• Funding staff responsible for reviewing drug applications associated with antimicrobial drug therapy and antimicrobial resistance, and providing guidance for the development of these products;
• Coordinating the implementation of the final rule for the Labeling Requirements for Systemic Antibacterial Drug Products Intended for Human Use (Vol. 68, No. 25, February 6, 2003, page 6062), by providing information and guidance to the pharmaceutical industry regarding the new labeling requirements for antibacterial drugs to foster appropriate antimicrobial use and reduce the development of drug-resistant bacteria. The final rule goes into effect in February of 2004;
• Performing additional analyses of antimicrobial resistance in selected bacterial pathogens using data from Focus Technologies. This is year two of a five-year contract with Focus Technologies to monitor and identify current and emerging resistant organisms that pose a significant health threat to the public. The Focus contract allowed FDA to address several Action Items in the Public Health Action Plan To Combat Antimicrobial Resistance (http://www.cdc.gov/drugresistance/actionplan/2002report/index.htm), including developing a surveillance plan for antimicrobial drug resistance among clinical laboratory isolates to facilitate drug development; reviewing  private sector surveillance data to determine whether the data has potential to support FDA regulatory and scientific activity; and, identifying and evaluating methods for collecting and disseminating the surveillance data on antimicrobial drug use;

FDA has used several forms of outreach to work with Industry and the healthcare community including:

• Coordinating and hosting an FDA/Bacteriology and Mycology Study Group (BAMSG) workshop in late summer of 2003 to discuss issues affecting antimicrobial drug development and antimicrobial resistance in febrile neutropenia and combination antifungal therapy;
• Coordinating and hosting the FDA/Infectious Disease Society of America (IDSA)/ Pharmaceutical Research and Manufacturers of America(PhRMA) Public Workshop in November 2002 to discuss issues affecting antimicrobial drug development and antimicrobial resistance. This public workshop brought together the top national leaders and scientists from the IDSA, PhRMA, and U.S. academic institutions to address current topics of interest associated with antimicrobial resistance and antimicrobial drug development. Information on the 2 day workshop (including minutes) can be found at  http://www.fda.gov/cder/present/idsaphrma/default.htm;
• Co-sponsoring a FDA/PhRMA workshop on statistical issues in clinical trials in November 2002;
• Developing Outreach Programs, in cooperation with CDC and FDA's Office of Training and Communication to provide public education and information about the proper use of antibiotics and the dangers associated with excessive or improper use of drugs. A media campaign targeted towards health professionals and the general public was launched in the fall of 2003 at the Interscience Conference of Antimicrobial Agents and Chemotherapy in Chicago;
• Collaborating with the Center for Veterinary Medicine (CVM) in the publication of the Ranking of antimicrobial drugs according to their importance in human medicine section of the Draft Guidance for Industry "Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern"; and,
• Collaborated with CVM on an ongoing Public Hearing on the proposal to withdraw enrofloxacin use in poultry.

FDA improved its web program for faster posting of generic drug information including information regarding approvals, first generics, tentative approvals, suitability petitions, and other information, and increased our external collaborations to improve information for prescribers and consumers to ensure safe and effective use of generic drugs by:

• Developing and publishing new educational messages in English and Spanish;
• Recording a web-based continuing education program for health professionals;
• Partnering with numerous chain drugs stores (e.g.,Walgreens; Eckerds, K-Mart) and third-party payers (e.g., Blue Cross/Blue Shield, Medco) to further disseminate information about the quality and equivalence of generic drug products; and,
• Disseminating information to the public about the quality of generic products through magazine ads, radio spots, advertisements on buses, and similar settings.

IMPROVING PATIENT AND CONSUMER SAFETY

The review of adverse event and medication error reports to identify serious or potentially serious outcomes that might be avoided required substantial expenditure of effort. Staff utilized FDA's Adverse Event Reporting System (AERS) to detect signals.  AERS combines the voluntary adverse drug reaction reports from health care professionals and consumers, and required reports from manufacturers .  AERS offers paper and electronic submission options, international compatibility, and pharmacovigilance screening. As we discover new knowledge about a drug's safety profile, we make risk assessments and decisions about the most appropriate way to manage any new risk or new perspective on a previously known risk. Risk management methods may include new labeling, drug names, packaging, "Dear Health Care Practitioner" letters, education or special risk communications, restricted distribution programs or product marketing termination.

Electronic submissions of adverse experience reports provided FDA and the public with several tangible benefits. Specifically, automating the receipt and processing of safety reports will allow the Agency to be more responsive to public health issues, reduce resources associated with data management, and apply better data and better science to the drug regulatory process.

We estimate the cost of receiving a report is cut from $31 per paper report to $3 to $19 per report for those submitted electronically. Approximately 20 percent of expedited individual safety reports were submitted electronically in FY 2003. FDA implemented an Electronic Submission Product Test Pilot for AERS in October 2000. This pilot provided a mechanism for companies to test and send electronic submissions of expedited reports via physical media or gateway directly into AERS. The pilot moved to a production phase in FY 2002 and over 26,000 individual case safety reports were submitted electronically in FY 2003.

Electronic Submission of Individual Safety Reports (ISRs)    

Inspection and Enforcement Initiatives

Program staff play a key role in a major agency-wide initiative on "Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the 21st Century: A Risk Based Approach," a two-year program which applies to pharmaceuticals, including biological human drugs and veterinary drugs.   Two press releases were published in FY 2003 ( http://www.fda.gov/bbs/topics/NEWS/2003/NEW00872.html and http://www.fda.gov/bbs/topics/NEWS/2003/NEW00936.html).  A summary of the accomplishments in FY 2003 are provided below:

FDA issued five new guidance's designed to enhance the consistency and coordination of its drug quality regulatory programs. These include:

• A guidance for FDA regulated industry on the use of electronic records and signatures;
• A draft guidance on a process for resolving disputes arising over scientific and technical issues related to pharmaceutical current good manufacturing practices (cGMP);
• A draft guidance on the aseptic processes used in the manufacture of sterile drugs, emphasizing current science and risk-based approaches;
• A draft guidance on preparation and use of a comparability protocol for assessing chemistry, manufacturing and control changes to protein drug products and biological products; and,
• A draft guidance for Process Analytical Technology (PAT) - a framework for allowing regulatory processes to more readily adopt state-of-the-art technological advances in drug development, production and quality assurance.

FDA collaborated with academia, industry, and other government organizations to promote innovative approaches to drug development and regulation. These include:

• Collaboration with the McDonough School of Business (Dr. Jeffrey T. Macher), at Georgetown University, Washington, DC, and the Olin School of Business (Dr. Jackson A. Nickerson), at the Washington University, St. Louis. The collaboration should help the Agency identify the factors that predict manufacturing performance to further refine our pharmaceutical manufacturing risk-based assessment;
• Collaboration with the National Science Foundation's Center for Pharmaceutical Processing Research allowing FDA to expand its scientific foundation in the area of innovative pharmaceutical manufacturing technology;
• A Cooperative Research and Development Agreement (CRADA) with Pfizer, Inc., to research chemical imaging applications in pharmaceutical manufacturing and quality assurance;
• Renewed cooperative agreements for Internet enforcement with the Federation of State Medical Boards and with the National Association of Boards of Pharmacy. FDA issued 36 "cyber" letters and warning letters to firms promoting and selling fraudulent and unapproved products online. The "cyber" letters have about a 30% positive response rate from the firms that are targeted. Firms cited included ones found after a coordinated Internet "surf" selling products for protection against Counter terrorism and unapproved drug and dietary supplement combinations;
• Re-engineered FDA's Filer Evaluation Program which will provide a statistical based method to evaluate firms and individuals who offer FDA-regulated products for import; and,
• Improved OASIS to permit staff to track FDA changes to filer transmitted data; Filer Evaluation History; to rescind admissibility decisions; to set up work for Priority Exams; and, to receive Package/Can Codes across the Customs interface.

PROTECTING AMERICA FROM TERRORISM

The Human Drugs Program plays a key role countering terrorism in the United States, especially in preparing the country to have medical counter measures readily available in the event of any chemical, biological, or nuclear attack.  In FY 2003, many accomplishments were made in the area of medical countermeasures.  Several new medical countermeasures were approved and doxycycline products received approval for revised labeling.  Approvals included:

• Lower doses of the AtroPen Autoinjector (atropine) were approved for use in children and adolescents exposed to certain nerve agents or insecticides. The AtroPen has been approved since 1973 for use in adults;
• Pyridostigmine Tablets were approved for prevention against the effects of Soman nerve gas poison.  This was the first drug product to be approved under the "Animal Rule";
• Radiogardase (insoluble Prussian blue) capsules were approved for the treatment of patients with known or suspected internal contamination with radioactive cesium and/or radioactive or non-radioactive thallium to increase their rates of elimination.  This is the first approval of a radioeliminator product;
• Doxycycline manufacturers received approval to revise their product labeling to include information on use for post-exposure prophylaxis of inhalational anthrax;
• Providing some funding, through an inter-agency agreement with NIAID, for a grant for the development of an oral product for smallpox treatment;
• Providing some funding, through an inter-agency agreement with NIAID, for a contract to evaluate animal models used to study Viral Hemorrhagic Fevers;
• Announcing in the Federal Register the conditions under which calcium-DTPA (Ca-DTPA) and zinc-DTPA (Zn-DTPA) can be found to be safe and effective for the treatment of internal contamination with plutonium, americium, or curium to increase the rates of elimination of these substances from the body. A guidance for industry was released to encourage manufacturers to submit NDAs;
• Establishing a Data Monitoring Committee for oversight of the human plague clinical trials in Uganda and Madagascar.  The Human Drugs Program and CDC continued development of the protocols for these clinical trials; and,
• Continuing efforts with NIAID and USAMRIID to evaluate the efficacy of several antibiotics in pneumonic plague in non-human primates.

The Program was involved in a number of collaborative efforts in FY 2003.   With the Device Program, we collaborated with the CDC on the efficacy evaluation of diagnostic kits for plague to be used in the CDC's human plague studies in Uganda and Madagascar.

FDA and CDC formed a Post-Event Surveillance Working Group to develop methods to collect data on medical outcomes and adverse events following the use of medical countermeasures during a terrorist event, as well as the processes by which such data would be collected and reviewed.  In follow-up to the first meeting, FDA is creating a template form for data collection, to be shared with the CDC in a December 2003 meeting.

FDA participates in a number of subgroups and working groups of the Weapons of Mass Destruction Medical Countermeasures Subcommittee, which reports directly to White House offices such as the Policy Coordinating Committee.  These subgroups and their working groups, with membership from a number of governmental agencies, have been tasked with providing and discussing information that will lead to the development of requirements documents for medical countermeasures to be procured under Project BioShield or other discretionary funds for placement in the Strategic National Stockpile. 

In addition, FDA is involved in the following partnership activities:

• DHHS Anthrax Risk Management Working Group to address development of anthrax interventions under Project BioShield;
• An Intercenter Nuclear/Radiation Countermeasures Working Group to facilitate progress of countermeasures by developing a list of potential products currently under development throughout FDA and by sharing common scientific issues across centers; and,
• FDA, CDC, and the Department of Homeland Security continued efforts to address issues on procurement and use of products in the Strategic National Stockpile.

Consolidation of Certain Products from Center for Biologics Evaluation and Research to Center for Drug Evaluation and Research

FDA completed the third phase of its work leading to implementation of the transfer of certain products reviews from CBER to the Center for Drug Evaluation and Research (CDER) on March 17, 2003. This third phase addressed larger logistical issues involved in the product consolidation.

Human Drugs
Program Activity Data

^1/ Total of approval, and complete decisions.  Does not include refuse-to-file decisions or withdrawals.

^2/ Includes IND, IDE, Master File and license master file receipts.

^3/  These Therapeutics activities were transferred from the Biologic Program to the Human Drugs Program effective FY 2004.

^4/ ANDA actions include total of approvals, not approvables, approvables, tentative approvals, and withdrawals.

^5/ CMC and Labeling Supplements, including global supplements. This figure also includes total of approvals, approvables, not approvables and withdrawals.

^6/ Over the next few years, as FDA makes progress in developing OTC Monographs, the number of drug product categories that qualify for having a monograph developed for them will decrease.  Over this same time, FDA increasingly will focus resources on finalizing monographs that have been developed.

^7/ FDA is in the process of developing a risk-based quality systems program.  The framework or model for this program will include basic elements, such as ensuring that there are process plans with written standard operating procedures, well-trained staff, record keeping and review, and process improvement.  FDA is in the early planning stages of developing its quality systems program and expects to make progress by implementing significant elements of the program in FY 2005.

^8/ FDA is committed to a collaborative effort with NLM and VA called the DailyMed.  The primary objective of DailyMed is to improve patient safety through improved access to medication information.  The primary source of medication information is the drug product label.  To successfully support the DailyMed effort, FDA must accomplish many significant tasks.  For example, FDA must develop structured product labeling, an electronic standard for representing the content of labeling.  In addition, FDA must publish rules to require firms to submit labels electronically and in the structured format.  FDA must also develop requirements for, design, and develop a repository to house all final product labels received electronically.  Toward these tasks, FDA published the rule for firms to submit the labeling information in electronic format.  The structure produce labeling standard is being balloted at HL7 as a draft standard for trial use and FDA has initiated the project to develop the repository for the labeling.  FDA expects to continue to make significant progress on many of the elements of the DailyMed effort in FY 2005.

^9/ The goal is to improve patient safety by increasing drug product surveillance capabilities by making it easier for healthcare providers to report adverse events and to automate linkages of their databases to our own.  Developing an internet solution to automate adverse event data submission and integrating access of external databases that house adverse event reports with our own adverse event reporting system is very complicated in that it has many complex elements.  For example, FDA must develop plans for and implement improvements to the MedWatch form.  In addition, FDA must accomplish all the steps necessary to make the MedWatch form available online and to link external databases to our adverse event reporting system.

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