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

BIOLOGICS

Historical Funding and FTE Levels

MISSION

The Biologics Program is responsible for ensuring that biological products, including whole blood and blood products, vaccines, and therapeutic products including cells, gene therapies, and tissues, are safe and effective.  The aim of the program is:

• Ensure the safety, efficacy, potency and purity of biological products including vaccines, cells, tissues, gene therapies, and related drugs and devices intended for use in the treatment, prevention or cure of diseases in humans;
• Ensure the safety of the nation's supply of blood and blood products;
• Evaluate the safety and effectiveness of biological products before marketing, and monitors the pre-clinical and clinical testing of new biological products;
• License biological products and manufacturing establishments, including plasmapheresis centers, blood banks, and vaccine manufacturers;
• Conduct regulatory research to establish product standards and develop improved testing methods; and,
• Assure the safety of marketed biological products through monitoring adverse experiences, lot-release testing and postmarket surveillance.

BACKGROUND

The products that the Biologics Program regulates are on the leading edge of technology.  Rapid scientific advances in biochemistry, molecular biology, cell biology, immunology, genetics, and information technology are transforming drug discovery and development, paving the way for unprecedented progress in developing new medicines to conquer disease. 

While scientific advances of new biological products promise great health benefits for U. S. consumers, FDA must ensure that these products are safe.  FDA is also responsible for ensuring the safety of the nation's blood supply by minimizing the risk of infectious disease transmission and other hazards, while facilitating the maintenance of an adequate supply of whole blood and blood products.

Biologics Program Increases for FY 2005
By FDA Strategic Goal

Cost of Living- Pay:  + $1,550,000

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.

The total Agency request for pay increases is $14,352,000. The Biologics program portion of this increase is $1,550,000. Without this, the FDA's ability to fulfill its mission to protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use will be significantly reduced.

Medical Product Countermeasures -- Counterterrorism:  + $2,000,000 and + 12 FTE

FDA, working with sister agencies such as CDC and NIH as well as DOD, and interacting with industry, health care providers and consumers, 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.  Resources are needed to continue to address the following essential activities:

• Assist in product development, review and testing, by supporting new product development teams to work with industry and other Agencies to develop key needed biological products;
• Assist in identifying, evaluating, and enhancing performance of manufacturing facilities for product production;
• Evaluate safety and efficacy of products, including those identified under the new BioShield provisions, and as a result of NIH and DOD funded research and contracts;
• Address new and emerging bioterrorism/chemical/infectious diseases threats to the blood supply and to tissues, and perform product testing and facilitate effective blood and tissue donor screening;
• Continue review, testing and appropriate use and ongoing safety/effectiveness studies of vaccines against bioterrorist threats, including site visits and manufacturer's assistance;
• Continue review, testing and appropriate use and ongoing safety/effectiveness studies of blood cells and blood products (e.g. clotting factors, immune globulins), stem cells and tissues to treat trauma and radiation injury, and new technologies such as blood "substitutes" and pathogen inactivation, including site visits and manufacturer's assistance;
• Establish a product risk assessment and safety/efficacy biostatistical, database development and surveillance team for products used to respond to bioterrorist and other threats, including vaccines, therapeutics, cells, tissues and blood products, collaborating closely with CDC, DOD and manufacturers pre- and post-licensure; and,
• Continue the development of policy initiatives and processes for improved application review.

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. 

Administrative Efficiencies: - $2,102,000 and - 18 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 Biologics Program portion of these management improvements consists of -$2,102,000 and - 18 FTE.

User Fees

Prescription Drug User Fee Act (PDUFA):  + $2,170,000 and + 7 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.

MDUFMA is patterned after the successful Prescription Drug User Fee Act, a successful partnership between the Federal government and stakeholders to improve the quality and timeliness of the medical device review process.  This multi-year effort authorizes the collection of user fees from those who submit premarket applications, certain supplements to those applications, and premarket notifications.  The funds continue the following FDA efforts begun in FY 2003 including:

• Acquire and train staff to meet a set of aggressive performance goals, for expediting the review of medical device applications;
• Promote public health with major improvements in review of expedited medical devices; and,
• Make major improvements in review performance in areas where fees are collected, while maintaining performance in other areas.

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 Biologics 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 HEALH BANG FOR OUR REGULATORY BUCK

Use science-based efficient risk management in all regulatory activities, so that the Agency’s limited resources can provide the most health promotion and protection at the least cost to the public.

Cell and Gene Therapy

One of the most exciting and highly publicized areas in biomedical research today is human gene therapy "the replacement of a person's faulty genetic material with normal genetic material to treat or cure a disease or abnormal medical condition.  Over time and with proper oversight, human gene therapy might become an effective weapon in modern medicines’ arsenal to help fight diseases such as cancer, diabetes, high blood pressure and heart disease.  Also, for patients with presently incurable diseases, such as cystic fibrosis, hemophilia A and B, and other genetic disorders, human gene therapy offers the hope of a cure, or at least a measure of relief.

While FDA has not yet approved for sale any human gene therapy products, gene-related research and development is continuing to grow and FDA is very involved in overseeing this activity.  Since FY 2000, FDA has received over 400 requests from medical researchers and manufacturers to study gene therapy and to develop gene therapy products.  Presently, FDA is overseeing approximately 219 active investigational new drug gene therapy studies initiated in FY 2002 and FY 2003.

Regulation of Human Tissue Intended for Transplantation

The term "tissue" covers many products transplanted for medical uses, such as skin replacement following severe burns, tendons and ligaments to repair injuries, bone replacement, and corneas to restore eyesight.  Tissue transplantation is a rapidly growing industry.  The number of musculoskeletal tissue transplants increased from approximately 350,000 in 1990, to more than 800,000 in 2002.  Over the past decade advancing technology and improved techniques have expanded the therapeutic uses of tissue-based products.

FDA has three primary goals with respect to human tissues: (1) to prevent the spread of communicable diseases; (2) to ensure that safety and efficacy is demonstrated for cellular and tissue-based products that are also drug, biological, and medical device products; and, (3) to help enhance public confidence in these products so that, where appropriate, they can fulfill their great potential for improving and saving lives. FDA seeks to accomplish these goals in a manner that will not discourage the development of new products.  The Agency has published proposed rules on current Good Manufacturing Practice (GMP) regulations that apply to establishments of human cell, tissues, and cellular and tissue-based products as well as on donor-suitability procedures.

Pandemic Influenza

Preparation for the next pandemic of influenza requires action in the inter-pandemic period. This includes the production of the vaccines, which is unique among vaccine products in that the viruses in the influenza vaccine are changed on a frequent basis and the time for making each year's new vaccine and distributing the vaccine for use is fixed at 6-8 months. In order to ensure that vaccines can be produced in time to respond to a pandemic situation, infrastructure to permit support of manufacturing needs to be established.

• Collaborate with public health experts to determine the strains of virus to be used to manufacture the influenza virus vaccine that is to be administered each fall.  The recommendations are based on data provided from laboratories worldwide as the strains are continuously evolving or mutating.  As soon as the strains are recommended, manufacturers begin to grow virus strains in fertile hen's eggs.  The parent strains of vaccine, known as "seed strains," used by each manufacturer are tested to assure they are the same as the recommended strains;
• Expedite lot release of influenza virus vaccine through the manufacturing time period.  The process of manufacturing the influenza virus vaccine is a very complex one, complicated by the large number of doses administered in a very short time frame;
• Advise national and international public health groups such as WHO, CDC, NIH, and the National Vaccine Program Office (NVPO) for the purpose of selecting new influenza viruses to be used in vaccine manufacturing and in making preparations for a pandemic of influenza. Every year, FDA’s Vaccines and Related Biological Products Advisory Committee meets to make recommendations for the strains to be used in making vaccines and informs manufacturers of the choices; and,
• Work with manufacturers throughout the year to collect information on the capability of new influenza viruses to be used for large-scale production of influenza virus vaccines.

Blood Safety

The blood supply is critical to the nation's health care system, and the U.S. has the safest blood supply in the world.  FDA's goal is to continue this by ensuring the safety of the nation’s blood supply by minimizing the risk of infectious disease transmission and other hazards, while facilitating an adequate supply of whole blood and blood products.  FDA continues to strengthen its efforts to protect the blood supply, and to minimize any risk to patients of acquiring HIV, hepatitis, Creutzfeldt-Jakob Disease (CJD), and other blood‑borne diseases.  These efforts include:

• Promulgating and enforcing standards for blood collection and for the manufacturing of blood products, including transfusible components of whole blood, pharmaceuticals derived from blood cells or plasma, as well as related medical devices and screening tests. FDA also inspects blood establishments; monitors reports of product deviations and adverse clinical events; and, works closely with other parts of the Public Health Service to establish blood standards, and to identify and respond to potential threats to blood safety or supply;
• Continuing to reduce the number of exemptions to outdated blood regulations and the number of guidance documents lacking enforceability;
• Continuing to address emerging infectious diseases, ensuring compliance of plasma fractionation establishments, blood donor/recipient notification and look back, and FDA emergency and Class I recalls affecting blood safety response procedures.
• Responding to emerging potential threats to the blood supply, such as West Nile Virus, Severe Acute Respiratory Syndrome, new HIV variants; new hepatitis agents; human herpes virus‑type 8; and CJD, in a timely and coordinated approach.  A specific scientific and regulatory strategy must be developed for each identified threat.  The Agency, in collaboration with the CDC and the NIH, engages in scientific investigations of emerging infectious agents.  Actions include an assessment of the risk to the blood supply, diagnostic methods, standards development and regulatory controls; and,
• Continuing to emphasize the need to protect the nation's blood supply, and minimizing any risk to patients of acquiring Bovine Spongiform Encephalopathy (BSE) or CJD, and other blood-borne diseases.  No tests for the rapid diagnosis of either BSE or CJD or for detection of infected tissue have been validated as either sufficiently specific or sensitive to be used to screen the blood supply.  A reliable blood‑screening test for BSE is an extremely important goal and is currently the object of considerable activity.

Xenotransplantation 

The Biologics Program regulates xenotransplantation clinical trials conducted in the U.S. and establishes related public health policy.  Although the potential benefits are considerable, the use of live animal materials raises concerns regarding the potential infection of recipients with both recognized and unrecognized infectious agents, and the possible subsequent transmission to their close contacts and into the human population. Potential cross-species infection with persistent viruses, such as retroviruses, is of particular public health concern because they may be latent and lead to disease years after infection.  Moreover, new or emerging infectious agents may not be readily identifiable with current techniques.

Postmarket Monitoring

Engage in activities to ensure the continued quality and safety of previously approved biologic products. Because biological products are derived from living organisms, they do not have the same manufacturing consistency as pharmaceutical products derived from chemical combinations. FDA must engage in post-approval activities to develop and validate test methods and establish standards for biological products.

Imports, Import Monitoring and Foreign Inspection

Since the emergence of the "global marketplace" in the last 20 years, imported foods have grown to constitute more than 10 percent of the U.S. food supply. FDA data shows that the number of imported food lines has doubled over the past seven years. This explosion in the number of imported food lines combined with the security concerns raised by terrorism and counterfeiting incidents has increased the need to physically assess the status of imported products as part of the Agency's emerging import strategy. Base funding will enable FDA to:

• Improve the safety of imported and domestic biological products by increasing the surveillance of imported human tissues and other imported biological products and coordinate domestic field investigational analytical compliance activities.

Prescription Drug User Fee Act (PDUFA)

The Program has met or exceeded its PDUFA performance goals in FY 1994 through FY 2002. 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 a five-year period within certain technical improvements. 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.  Review performance monitoring is being done in terms of fiscal year cohorts. The FY 2004 cohort performance goals include:

• Complete review and action on 90 percent of standard original NDA/BLA submissions within 10 months; and complete review and action on 90 percent of priority original NDA/BLA submissions within six months of receipt;
• Complete review and action on 90 percent of standard efficacy supplements within 10 months; and complete review and action on 90 percent of priority efficacy supplements within six months of receipt;
• Complete review and action on 90 percent of manufacturing supplements within six months of receipt, and complete review and action on 90 percent of manufacturing supplements requiring prior approval within four months of receipt; and,
• Complete review and action on 90 percent of Class 1 resubmitted original applications within two months; and complete review and action on 90 percent of Class 2 resubmitted original applications within six months of receipt.

EMPOWERING CONSUMERS:  IMPROVING HEALTH THROUGH BETTER INFORMATION

Enable consumers to make smarter decisions by getting them better information to weigh the benefits and risks of FDA-regulated products.

Communications with Stakeholders and Consumers 

FDA is committed to carry out our mission in consultation with experts in science, medicine, and public health and in cooperation with healthcare provider, consumers, and industry. FDA is also committed to enhancing our communication methods in order to mitigate the risks due to the lack of accurate and timely information to the U.S. public about a biologic product.

• Collaborate with scientists to support regulatory decisions by assessing risks associated with regulated products; setting standards that minimize risk and testing products against those standards; improving the usefulness and precision of risk assessment methods; and developing methods to increase the accuracy of sample analysis and detection of biological substances;
• Provide information regarding research projects and scientific articles emphasizing the importance of our regulatory research as mission critical work underpinning regulatory decisions
• Maintain the program to increase access to new guidance documents, safety information and the opportunity to discuss important issues with Agency experts at numerous trade associations, scientific, and community meetings; and,
• Maintain outreach with industry and provide training as required by both the Food and Drug Administration Modernization Act of 1997 and the Small Business Regulatory Enforcement Fairness Act.

IMPROVING PATIENT AND CONSUMER SAFETY

Seek continuous improvements in patient and consumer safety by reducing risks associated with FDA-regulated products.

Medical Errors

The prevalence of avoidable health complications that involve the use of FDA-regulated products, presents a challenge for the Agency.  FDA's central public health role is to ensure that vaccines, blood and blood products, human cells, tissues, and cellular and tissue-based products are shown to be safe and effective.  FDA also ensures that quality standards are adhered to by the various biological product establishments.  FDA continues to:

• Conduct 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 the need 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;
• Develop new, specific and sensitive techniques and assays to validate and detect a greater variety of known potentially infectious viruses.  A prime objective of safe biological 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' agents that are infectious for humans-- in the approved product;
• Enhance the Vaccines and Biologics Safety Surveillance through ongoing programs for safety surveillance of cutting edge technology and its appropriate implementation;
• Maintain the system of post-marketing surveillance and risk assessment program to identify adverse event reports (AERS) that did not appear during the product development process by collecting, evaluating and acting on information of AERS associated with marketed products;
• Maintain reporting systems to collect biological product deviation events that occur during manufacturing processes or storage of biological products, including blood product manufacturers and blood‑banking facilities; and,
• Establish contracts for safety monitoring data links that include data on product exposure and extensive patient information. Develop access to external databases 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.
• Facilitate the development of reliable diagnostic tools, and safe and effective treatments for patients suffering from SARS including a SARS vaccine;
• Assure that adequate supplies of various medical products are available in the event of the broader spread of SARS in the U. S.; and,
• Safeguard the blood supply against the potential threat of SARS.

Severe Acute Respiratory Syndrome (SARS)

The CDC and the World Health Organization are investigating a worldwide outbreak of unexplained atypical pneumonia referred to as Severe Acute Respiratory Syndrome (SARS). In support of these efforts, FDA is supporting five specific areas by working with other government agencies, industry and academia to:

• Facilitate the development of reliable diagnostic tools, and safe and effective treatments for patients suffering from SARS including a SARS vaccine;
• Assure that adequate supplies of various medical products are available in the event of the broader spread of SARS in the U. S.; and,
• Safeguard the blood supply against the potential threat of SARS.

FDA is pursuing multiple potential vaccine development strategies and is working with other government agencies and the private sector to address many of the most difficult issues in early vaccine development.  In this process, guidance is provided on the use of animal test data and on safe manufacturing practices.  The FDA will also be a major participant in the design of clinical trials and in defining the needs of special populations, such as pregnant women.  As the SARS vaccine program is in its infancy, much painstaking work will be necessary to assure that the development and manufacturing processes meet the standards required to develop and produce safe and effective vaccines.

PROTECTING AMERICA FROM TERRORISM

The Agency strategic goal to Protect America from Terrorism focuses on preparation and response to a terrorist attack on the U.S. population.  This includes the ability to facilitate the development and availability of medical countermeasures to limit the effects of a terrorist attack on the civilian or military populations.

FDA plays a crucial role in protecting the public health by ensuring the availability of safe and effective medical countermeasures for mitigating the public health consequences of a bioterror event.  The biologics program is responsible for regulating the development and licensure of new biological products including vaccines, blood and blood products, human tissues and cells and gene therapies.  Working closely with industry and government agencies, FDA works to assure an adequate supply of these products which include products for immunization against anthrax, smallpox and other biothreats that might be used by terrorists as well as products to treat burn, blast and trauma injuries.  FDA collaborates closely with other federal agencies to develop protocols, conduct animal studies, and define reference databases on treatment and alternative therapies for infectious diseases caused by the intentional use of biological agents.  Applicable tests include those for bacterial and fungal sterility, general safety, purity, identity, suitability of constituent materials, and potency.  Adverse events are monitored to identify patterns of significant reactions to these new vaccines.  Support has been increased for the protection of regulated products from contamination and tampering to ensure availability of products.  FDA works to:

• Ensure the safety and efficacy of biological products, pharmaceutical, vaccine, and diagnostic countermeasures to support the development, maintenance and deployment of stockpiles of medical countermeasures;
• Ensure that sufficient quantities of medical products are available; and implement post-event follow-up and data collection for these products, some of which are investigational;
• Conduct and support active applied research programs directed towards optimizing the availability of safe and effective new products for the treatment, prevention or cure of diseases in humans;
• Evaluate the types of non-clinical data that may be acceptable for product licensure if pre-licensure clinical studies are not feasible or ethical;
• Evaluate over 100 active investigational new drug applications on products under development for use either to mitigate or prevent the pathological effects of terrorism-related pathogens in humans;
• Participate in activities to facilitate the availability of the currently approved vaccine for anthrax; and continue counterterrorism activities associated with the development of new smallpox and anthrax vaccines; vaccines for plague, tularemia, and Venezuelan Equine Encephalitis, as well as other encephalitis-causing viruses; and,
• Monitor production of biologics from the early stages all the way through post marketing with lot release testing to ensure the individual lots continue to meet safety, purity, potency and efficacy requirements.

STRONG FDA

The Agency strategic goal, More Effective Regulation through a Strong Workforce, focuses on the critical infrastructure that provides scientific support and administration to FDA's programs. This will ensure a world-class professional workforce, effective and efficient operations, and adequate resources to accomplish the Agency's mission. The managerial and operational efficiencies being pursued under this goal are aligned with the President's Management Agenda, the Secretary's FY 2005 Priority of strengthening management by creating a more streamlined, cost-effective, and accountable organization, and the DHHS strategic goal to achieve excellence in management practices

Information Technology

FDA supports the 24 President's Management Agenda E-Government initiatives and departmental enterprise information technology strategic initiatives.  This includes the enterprise approach to investing in key information technology initiatives such as the Federal Health Architecture, the Secure One HHS program, and Public Key Infrastructure.  These investments will enable HHS programs to carry out their missions more securely and at a lower cost. 

• Maintain the Electronic Document Room, EDR, a collection of systems that receives electronic transactions from industry.  The EDR stores, retrieves, and distributes electronic submissions to reviewers and is integrated with other regulatory databases allowing advanced searches. The EDR automates processing of submissions and automatically sends notifications to reviewers. The system also functions as an electronic library for CBER electronic submissions storing electronic submissions of IND, BLA, NDA, 510(k), PMA, regulatory correspondence, and other types of submissions.

SELECTED FY 2003 ACCOMPLISHMENTS

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

Prescription Drug User Fee Act (PDUFA)

PDUFA established performance goals for the evaluation of applications for marketing drug and certain biological products. Review performance monitoring is being done in terms of cohorts, e.g., the FY 2003 cohort includes applications received from October 1, 2002 through September 30, 2003.

Accomplishment of the cohort-year performance goals is not immediately measurable at the close of the fiscal year.  The outcome can be measured after the last submission received in the fiscal/cohort year, depending upon the category of submission. 

Performance goals of the Act began with FY 1994.  The Biologics program has met or exceeded its performance goals in FY 1994 through FY 2002.  The FY 2003 cohort review performance goals include:

• Complete review and action on 90 percent of standard original NDA/BLA submissions within 10 months; and complete review and action on 90 percent of priority original NDA/BLA submissions within six months of receipt;
• Complete review and action on 90 percent of standard efficacy supplements within 10 months; and complete review and action on 90 percent of priority efficacy supplements within six months of receipt;
• Complete review and action on 90 percent of manufacturing supplements within six months of receipt, and complete review and action on 90 percent of manufacturing supplements requiring prior approval within four months of receipt; and,
• Complete review and action on 90 percent of Class 1 resubmitted original applications within two months; and complete review and action on 90 percent of Class 2 resubmitted original applications within six months of receipt.

Medical Device User Fee and Modernization Act (MDUFMA)

MDUFMA provides the biologics program important new responsibilities, resources, and challenges.  In exchange for user fees, the Agency to pursue a challenging and comprehensive set of device review performance goals that will significantly improve the timeliness, quality, and predictability of FDA’s review of new devices.  These performance goals were developed collaboratively by FDA, stakeholders, and Congressional staff.

Through its implemented changes, the biologics program has demonstrated that it has the ability to provide timely review of device submissions, consistent with the MDUFMA goals.  Additionally, the biologics program has shown improved performance in review and approval of HIV-related diagnostic tests.  However, it must be noted that, without the additive resources provided by the MDUFMA program, these results would not have been possible. 

Significant Biologics Approvals in FY 2003

Several important new Biologics Licensing Applications and one very important Device application were approved in FY 2003 as shown in the table below:

Blood Safety

In January 2003, much of the country experienced blood shortages with supplies at less than 2 days, largely due to the fall off in donations that often accompanies the winter holidays.  The shortage resulted in a request by the American Association of Blood Banks (AABB) inter-organizational task force to the Department of Health and Human Services to make a public appeal for blood.  Secretary Thompson issued a statement in early January asking all eligible Americans to donate blood, and a joint appeal was issued by all the major blood organizations.  DHHS is working with Public Health Service agencies to develop a uniform system for collecting information on the blood supply.  The shortage abated in February.

FDA also worked very closely with industry to prepare for the West Nile virus season and encouraged industry to develop blood donor screening tests.  In June 2003, blood-testing centers began testing the blood supply for West Nile virus, using experimental test kits that FDA evaluated and permitted to be used.  The Agency also developed guidance to industry recommending procedures to assess donor suitability, and to retrieve and quarantine potentially contaminated blood products.  FDA approved the first test for use as an aid in the clinical laboratory diagnosis of West Nile virus in July 2003. 

During FY 2003, the following final guidance and proposed rules were published:

• Final Guidance: Streamlining the Donor Interview Process: Recommendations for Self-Administered Questionnaires, (July 7, 2003); and,
• Proposed Rule: Revisions to Labeling and Storage Requirements for Blood and Blood Components, Including Source Plasma, (July 29, 2003).

Tissue Action Plan

FDA has made significant progress towards completing the tissue action plan deliverables.  FDA published the third of three proposed rules intended to implement the tissue action plan. This rule would require establishments that recover, process, store, label, package, or distribute tissue, or that screen or test donors, to follow current good tissue practice requirements. The proposed rule also contains provisions for FDA inspection of establishments and enforcement of the regulations. In addition, FDA published a final rule requiring human cell, tissue, and cellular and tissue-based product (HCT/P) establishments to register and list with the Agency. The FY 2003 significant accomplishments include: 

• Initiated electronic registration for HCT/Ps.  Registration can be accepted via a web-based system; and,
• Completed establishment registration and listing for over 1,000 human tissue establishments.

Improving Patient And Consumer Safety

West Nile Virus

On October 25, 2002, FDA issued guidance designed to protect the safety of the blood supply against West Nile Virus (WNV).  This guidance for industry, which was revised in May 2003, provided recommendations for assessing the suitability of potential donors and for the proper handling of blood products from donors known or suspected to have WNV infections.  The guidance provides detailed information to help blood establishments decide which potential donors should be deferred; it also sets forth recommendations about the retrieval and quarantine of blood and blood products from donors who develop WNV illness or infection after donation or are suspected of having WNV infections.

The guidance builds on existing blood safety regulations that require blood establishments to defer donors who are not in good health. Approximately 20 percent of persons with WNV have mild symptoms ranging from fever to other flu-like symptoms. Donor-screening procedures already in place should identify these people. FDA reminded the blood industry of these existing provisions in an alert on August 17, 2002, which was updated October 3, 2002. 

Severe Acute Respiratory Syndrome (SARS)

On April 17, 2003, FDA issued guidance to the nation's blood establishments on measures for further safeguarding the blood supply against SARS. This interim measure was taken to assure the safety of the blood supply while more was learned about the disease. Scientific studies are being conducted to determine whether SARS could be transmitted through blood.

The new SARS guidance set forth measures for temporarily deferring potential donors who may have been exposed to SARS or have experienced acute SARS. These measures included limited additional questioning of potential donors to help ascertain if they may be at elevated risk for SARS, due to recent travel to known high risk areas as defined by CDC or due to exposure to a person with SARS or suspected SARS.

This guidance also calls for blood establishments to actively encourage those who have already donated to report any SARS-related exposure that occurred within 14 days before donation or SARS illness or treatment occurring within 28 days prior to their donation. Donors are also encouraged to report SARS illness or treatment that occurs within 14 days after donation. Donated units identified as having come from potentially SARS-exposed or infected donors will be quarantined and indefinitely kept out of the general blood supply.

Gene Therapy Clinical Trials

As a precautionary measure, on January 14, 2003, FDA placed on "clinical hold" all active gene therapy trials using retroviral vectors to insert genes into blood stem cells.  The Agency took this action after it learned that a second child treated in a French gene therapy trial had developed a leukemia-like condition. Both this child, and another who had developed a similar condition in August 2002, had been successfully treated by gene therapy for X-linked severe combined immunodeficiency disease (X-SCID), also known as "bubble baby syndrome."

While FDA believed the two leukemia cases reported from that clinical trial were likely related to the gene therapy, a continuing review of adverse events from all U.S. studies involving similar retroviral vectors found no evidence of leukemia believed to be due to the gene therapy.  The Agency reviewed the discussions and advice of the Biological Response Modifiers Advisory Committee, and continues to work closely with sponsors to help them develop innovative new treatments while working to do everything possible to better understand and prevent any adverse events.  While this process continues, FDA actively considers specific requests for retroviral gene therapy trials involving fatal or life-threatening disorders for which there currently are no viable alternative treatments.

Gene Therapy Patient Tracking System Development (GTPTS)

This integrated system for the collection and analysis of information to assess and promote gene therapy product safety.  The GTPTS represents a comprehensive evaluation and re-engineering of FDA approaches regarding data pertinent to the safety of recipients of gene therapies, including collection of data from gene therapy recipients; and use of the data and analyses to make informed regulatory decisions and increase the understanding of researchers, subjects, and the public. 

The Genetic Modification Clinical Research Information System (GeMCRIS) is one of several databases that will be part of the GTPTS.  GeMCRIS is designed to provide protocol and adverse event information, and is designed with a browser function to review specific gene therapy trial information.  Other databases in the GTPTS are the Biologics Investigational New Drug Application Management System (BIMS), and the Gene Therapy (GT) Access system.  The BIMS has been enhanced to include clinical trial information, and the storage of investigators, subinvestigators, clinical sites, Investigational Review Board and clinical trial protocols.  The GT Access System is a gene therapy adverse event repository that contains both historical and current gene therapy adverse event information. 

White Particulate Matter in Blood and Blood Components

On February 7, 2003, FDA announced that it has issued recommendations to the blood industry for additional blood inspection measures and will issue interim guidance recommending enhanced visual inspection of all blood and blood components. This interim guidance was a precautionary measure as the FDA continues to actively investigate reports of units of blood and blood components containing white particulate matter. 

If abnormalities were detected, FDA requested that blood establishments quarantine the products and report their findings expeditiously to the Agency. Adverse events potentially related to the presence of particulate matter should also be reported.  Early reports of adverse events in patients who received blood that might have conceivably contained such particles raised the question of whether they could be harmful. However, follow up investigations by the blood centers failed to provide any evidence of any increase in adverse reactions among patients who might have received potentially implicated blood transfusions.

Numerous investigations by blood bag manufacturers, FDA, NIH, CDC, and the American Red Cross focused on the nature of the particles and the possible cause of their formation.  Epidemiological investigations by the Georgia Department of Public Health, in conjunction with CDC, blood centers that may have received affected products, found no evidence for an increase in the frequency of adverse events from transfusion. FDA regulations call for visual inspection of blood and blood components during storage and immediately prior to distribution. Based on studies mentioned, FDA believes that there is no additional value provided by the enhanced visual inspection and blood establishments should discontinue that procedure.  Although the cause of the particulate matter was not fully explained, there is no evidence it posed a threat to blood safety at that time.  The Agency emphasized that blood donation is a safe procedure. Continued donations are critical to maintaining a safe and adequate blood supply. For patients who need a blood transfusion, the benefits of transfusion are far greater than the risks.

Xenotransplantation Action Plan

Highlights of significant regulatory and policy accomplishments in FY 2003 are:

• Final Guidance: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans, published on April 3, 2003;
• The Xenotransplantation Product IND Reviewer Focus Group, consisting of the review staff responsible for the review of xenotransplantation submissions (clinical, product, and pharmacology/toxicology reviewers, and veterinary staff) meets regularly to discuss application of the principles set forth in relevant FDA regulations, to review and discuss current scientific and medical data and literature relevant to transplantation, to review and discuss the current status of xenotransplantation applications submitted to the agency, to discuss the unique issues that these products may present and to highlight areas of concern where further expert advice may be needed;
• The Secretary’s Advisory Committee on Xenotransplantation held a meeting on February 3-4, 2003;
• FDA in collaboration with the CDC worked on the development of a proposal for a National Biological Specimen Archive for Xenotransplantation to be administered by the CDC; and,
• Continued Agency involvement in international activities for the regulation of xenotransplantation products.

Blood Storage and Container Labeling Requirements

Rules were proposed  on July 29, 2003, to revise the labeling and storage requirements for blood and blood components including source plasma, which combines, simplifies, and updates regulations related to blood container labeling and  the storage and shipping temperatures of frozen blood components. This rule will make it easier for the blood industry to comply with existing regulations and manage the supply of plasma to further enhance the safety of the blood supply while reducing the cost of regulatory compliance through greater efficiency.

Protecting America From Terrorism

FDA plays a crucial role in protecting the public health by ensuring the availability of safe and effective medical countermeasures for mitigating the public health consequences of a bioterror event.   The Agency’s responsibility is to regulate the development and licensure of new biological products, including vaccines, blood and blood products, human tissues and cells and gene therapies.  FDA also collaborates closely with other federal agencies, such as DOD, NIH, and CDC to develop protocols, conduct animal studies, and define reference databases on treatment and alternative therapies for infectious diseases caused by the intentional use of biological agents. 

• In October 2002, FDA approved a license supplement for a 100-dose kit of Dryvax, with a new supply of diluent (the liquid that's mixed with dried vaccine before it's administered) and needles for administration. Before the approval of this supplement, Dryvax was available only under an investigational new drug, IND, application. This action allows the vaccine to be distributed and used as any other approved product. Along with Dryvax, there are several other smallpox vaccines that are being evaluated under INDs.
• The FDA issued guidance for the blood industry regarding potential blood donors who have recently received the smallpox vaccine, vaccinia virus, or those who may have had other direct exposure to smallpox vaccines. The recommendations were developed in collaboration with smallpox experts at the CDC and DOD. The FDA issued the guidance as a precautionary measure because the presence of vaccinia virus in transfused blood or plasma could be harmful to some recipients.

In addition, FDA:

• Consulted with sponsors of new smallpox vaccines to enable production of hundreds of millions of doses of new smallpox vaccine;
• Worked with HHS and industry to develop a new generation smallpox vaccine intended to be safer and appropriate for use in certain special populations, for instance those who are immuno-compromised or who are contraindicated for the currently licensed class of smallpox vaccine; and,
• Collaborated with CDC and NIH on development of a new recombinant vaccine for anthrax.

STRONG FDA

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.

Electronic Document Room (EDR)

The Electronic Document Room (EDR) is a collection of systems that receives electronic transmission of information from industry and FDA. The EDR stores, retrieves, and distributes electronic submissions to reviewers, and is integrated with regulatory databases to allow for advanced searches based on data in CBER databases.  The EDR automates processing of submissions and automatically sends notifications to reviewers, and serves as a repository for generated final documents.

Three software upgrades were made in FY 2003, including the addition of electronic routing of amendments to the IND and BLA electronic submissions process, and Smart PDF forms containing business rules that ensure that forms are completed appropriately and allow information to be extracted automatically into the EDR.  These capabilities have also made it possible for industry to reduce the time and cost to create a regulatory submission, and allows the Agency to review these documents on-line, reducing the time to decision. 

Biologics
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