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Human Drugs

<< Return to FY 2007 Budget Summary

 

  FY 2005 Actual FY 2006 Enacted 1/ FY 2007 Estimate Increase or Decrease
Program Level $482,134,000 $517,557,000 $534,961,000 +$17,404,000
Center
396,036,000,2,220
$431,705,000
$448,961,000
+$17,256,000
FTE
$86,098,000
2,360
2,382
+22
Field
698
$85,852,000
$86,000,000
+$148,000
FTE
664
659
(5)
Program Level FTE 2,918 3,024 3,041 17
Budget Authority $291,484,000 $297,716,000 $305,003,000 +$7,287,000

Center

$210,481,000 $217,797,000 $225,209,000 $7,412,000

Field

$81,003,000 $79,919,000 $79,794,000 -$125,000

Critical Path

  $750,000 $6,690,000 +$5,940,000

Drug Safety

$26,900,000 $36,531,000 $40,095,000 +$3,564,000

Cost of Living

    $4,874,000 +4,874,000

Strategic Redeployment

    ($7,091,000) ($7,091,000)

FTE

    (20) (20)
Budget Authority FTE 1,837 1,914 1,906 (8)
User Fees $190,650,000 $219,841,000 $229,958,000 +$10,117,000
Center PDUFA $185,555,000 $213,908,000 $223,752,000 +$9,844,000
Field PDUFA $5,095,000 $5,933,000 $6,206,000 +$273,000
User Fee FTE 1,081 1,110 1,135 +25

1/  Includes a one percent rescission.

 

 Historical Funding and FTE Levels
Fiscal Year Program Level Budget Authority User Fees Program Level FTE
2003 Actual $403,848,000 $274,073,000 $129,775,000 2,696
2004 Actual $396,491,000 $229,372,000 $167,119,000 2,190
2005 Actual $482,134,000 $291,484,000 $190,650,000 2,918
2006 Enacted $517,557,000 $297,716,000 $219,841,000 3,024
2007 Estimate $534,961,000 $305,003,000 $229,958,000 3,041

 

Statement of Budget Request

The Human Drugs Program is requesting $534,961,000 in program level resources for accomplishing its mission activities including:

  • Ensuring that prescription, generic, and Over-the-Counter (OTC) drug products are adequately available to the public and are safe and effective.
  • Monitoring the use of marketed drug products for unexpected health risks.
  • Monitoring and enforcing the quality of marketed drug products.

 

Program Description

 

The Human Drugs Program is responsible for ensuring that America's supply of brand name, over the counter, and generic drugs is adequately available, safe and effective, and of the highest quality.  The process for approving drug products begins with the companies who must first test their products.  CDER monitors their clinical research to ensure that people who volunteer for studies are protected and that the quality and integrity of scientific data are maintained.  CDER assembles a team of physicians, statisticians, chemists, pharmacologists, and other scientists to review the company's data and proposed use of the drug. If the drug is deemed effective and if health benefits outweigh its risks, the drug is approved for sale. CDER does not actually test the drug when the Center reviews the company's data. By setting clear standards for the evidence FDA needs to approve a drug, the Agency helps medical researchers bring new drugs to American consumers more rapidly.

Once a drug is approved for sale in the United States, FDA continues to monitor the use of marketed drugs for unexpected health risks. If new, unanticipated risks are detected after approval, steps are taken to inform the public and change how a drug is used or, if necessary, even remove a drug from the market. CDER also monitors product manufacturing changes to make sure that changes to the way drug products are made do not adversely affect the safety or efficacy of the medicine. CDER evaluates reports about suspected problems from manufacturers, health care professionals, and consumers. Sometimes, manufacturers run into production problems that might endanger the health of patients who depend on a drug. CDER tries to make sure that an adequate supply of drugs is always available.

In addition to setting standards for safety and effectiveness testing, CDER also sets standards for drug quality and manufacturing processes.  FDA works closely with manufacturers to see where streamlining can cut red tape without compromising drug quality. As the pharmaceutical industry has become increasingly global, CDER is involved in international negotiations with other nations to harmonize standards for drug quality and the data needed to approve a new drug. This harmonization will go a long way toward reducing the number of redundant tests manufacturers do and help ensure drug quality for consumers at home and abroad.

Accurate and complete information are vital to the safe use of drugs. Drug companies have historically promoted their products directly to physicians. More and more frequently now, they are advertising directly to consumers. While the FTC regulates advertising of over-the-counter drugs, CDER oversees the advertising of prescription drugs.

FDA conducts and collaborates on focused laboratory research and testing. Research maintains and strengthens the scientific base of CDER's regulatory policy-making and decision-making.  Most recently, and consistent with the Agency's Critical Path Initiative, FDA is focusing on new ways to review drug quality, safety, and performance; evaluate improved technologies; validate new approaches to drug development and review; and develop regulatory standards and consistency.

The field component, the Office of Regulatory Affairs (ORA), supports the Human Drugs Program by conducting risk-based domestic and foreign premarket and postmarket inspections of drug manufacturers to assess their compliance with Good Manufacturing Practices (GMPs).  Besides overseeing regulated products on a surveillance or "for cause" basis, ORA staff also respond to emergencies and investigate incidents of product tampering and terrorist events or natural disasters.  To complement the regular field force, the Office of Criminal Investigations investigates instances of criminal activity in FDA regulated industries.

During the latest performance period (FY 2005), the Human Drugs program successfully met seven of its center performance measures; expects to meet the other three when the data is reported; and met its one field performance goal.  CDER expects to successfully achieve the target for its Generic Drugs performance goal when data becomes available. For more information about these performance goals and results, please see the Performance Detail section.

Performance Highlight: 

FY 2007 Goal Target FY 2004 Results Context
Decrease the average FDA time to approval or tentative approval for the fastest 25% of original generic drugs applications by 0.5 months. FDA exceeded its goal for FY 2004 by acting on 91 percent of 563 original applications. Generic drugs are much appreciated for their cost-effectiveness.   The basic requirements for approval of generic and trade-name drugs are the same as new drug approvals, although the generic drug manufacturer does not need to repeat the safety and efficacy studies conducted by the developer of the original product.  Prior to approval, generic drug sponsors are required to demonstrate bioequivalence to the innovator drug product by showing that the active ingredient in their product is absorbed at a rate and extent similar to the innovator counterpart.  The approval time is measured from the date the application is received to the date a major action, either an approval or not approvable, is reached.

 

Program Resource Changes

 

Drug Safety: + $3,564,000 and +6 FTE

FDA requests an increase of $3,960,000 to improve drug safety through modernizing and expanding the existing drug safety system.  To improve drug safety, we will create an enhanced Adverse Events Reporting System and collaborate with the Centers for Medicare and Medicaid Services.  These activities will enable FDA to more efficiently and effectively track adverse events, analyze and interpret findings, take appropriate regulatory action and transmit critical drug safety information to health care practitioners and consumers.  This initiative will contribute to the Secretary's goal to reduce the number of preventable injuries and deaths among Americans.  The Human Drugs Program component of this request is $3,564,000 and 6 FTE.

Critical Path to Personalized Medicine:  +$5,940,000 and +6 FTE  (CDER)

Under the FDA Modernization Act (P.L. 105-115), Congress expanded FDA's mission to include the promotion of public health through review of clinical research and collaborations with partners in government, academia, and industry.  Coupled with these regulatory changes, the funding of basic biomedical research has doubled in the last few years.  Yet, the number of applications submitted to FDA for review has decreased.

Because the agency sees product development failures industry-wide, FDA, consistent with its public health mission, is in a unique position to identify priority hurdles to medical product development and the means to overcome them.  By facilitating communication between industry and the agency and providing guidance for modernizing the medical product development process (the Critical Path), FDA can overcome the bottlenecks to drug development and ensure that more people have access to the products they need.  

FDA can also assist medical product development by advancing new techniques that will identify product characteristics that make a drug, biological product or device safe and effective for particular individuals. This will allow Americans to benefit from an era of personalized medicine.

The amount requested for this initiative is $5,940,000 and 6 FTE.

Cost of Living:  +$4,874,000

FDA's request for inflationary pay costs is essential to accomplishing our public health mission.  Payroll costs account for more than sixty-percent of the FDA budget, and the Agency is not able to absorb this level of inflation on such a significant portion of its resources. The increase will allow FDA to maintain staffing levels, including a national cadre of specially trained scientific staff. The total estimate for pay increases is $20,267,000. The Human Drugs portion of this increase is $4,874,000. These resources are vitally important for FDA 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.

Human Drugs Reductions:  -$7,091,000 and -20 FTE

To fund FY 2007 priority initiatives such as Drug Safety and the Critical Path to Personalized Medicine, FDA re-deployed resources from base programs.  To accomplish this strategic redeployment and fund new, high priority initiatives, Human Drugs reductions include: generic drugs research contracts, animal care contract services, research/lab scientists, laboratory upkeep, and communications, staff for FOI requests, management services, and information processing modernization for the generic drugs program. 

Prescription Drug User Fee Act:  +$10,117,000 and 25 FTE

PDUFA authorized 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.  Fee resources pay for the salaries of scientists and other professionals who review drug applications, and for information management, space costs, acquisition of fixtures, furniture, equipment and other materials necessary to conduct drug product reviews and to ensure that safe and effective drug products reach the American public more quickly. 

In 2002, the Bioterrorism Act included PDUFA III, which reauthorized FDA to collect user fees to enhance the review process of new human drugs and biological products.   PDUFA III also reauthorized fees for applications, establishments and approved products.  The reauthorization directs 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 directives. 

In FY 2007, FDA will work with Congress on the reauthorization of the Prescription Drug User Fee Act. This increase of $10,117,000 will cover inflationary costs, as well as overhead and rent costs, for additional staff associated with the Act. 

 

Proposed Fees (Reclassified as Mandatory - Non-Add)

Reinspection User Fee (Mandatory):  $2,009,000 and 16 FTE (Non-Add)

The Administration is proposing authorizing legislation that requires establishments to pay the full costs of reinspections and associated follow-up work when FDA reinspects facilities due to failure to meet Good Manufacturing Practices (GMPs) or other important FDA requirements.  Under this proposal, these activities will be reclassified as mandatory user fees in FY 2007.  FDA currently funds this activity through discretionary appropriations.  Imposing a fee would generate $22.0 million in revenue, an amount sufficient to fully fund reinspections.  The Human Drugs program component of this user fee is $2,009,000 and 16 FTE.

 

Justification of Base


FDA Strategic Goal: Enhancing Patient and Consumer Protection and Empowering Them with Better Information about Regulated Products

 

The practical size of pre-marketing clinical trials means that CDER cannot learn everything about the safety of a drug before approval.  Therefore, a degree of uncertainty always exists about the risks of drugs.  This uncertainty requires CDER's continued vigilance to collect and assess data during the post-marketing life of a drug. Once a drug is approved for sale, CDER monitors the use of marketed drugs for unexpected health risks.  If new, unanticipated risks are detected after approval, steps are taken to inform the public and change how a drug is used or even remove a drug from the market.  CDER also monitors manufacturing changes to make sure they won't adversely affect the safety or efficacy of the medicine. CDER evaluates reports about suspected problems from manufacturers, health care professionals and consumers, and tries to make sure that an adequate supply of drugs is always available. FDA also must be vigilant to protect Americans from injuries and deaths caused by unsafe, illegal, fraudulent, and substandard or improperly used products. Among the key functions performed by the Program are:

  • Monitoring the quality of marketed drugs and their promotional materials through product testing and surveillance.
  • Developing policies, guidance and standards for drug labeling, current good manufacturing practices, clinical and good laboratory practices and Industry practices to demonstrate the safety and effectiveness of drugs. 
  • Conducting 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. 
  • Reviewing 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.
  • Operating the MedWatch Program, which permits health care professionals to voluntarily report observed or suspected defects and quality problems associated with marketed drug products.
  • Working with interested governmental agencies and private organizations to coordinate collection of adverse event data.
  • Monitoring 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.
  • 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 MeDSuN, which is designed to train hospital personnel to accurately identify and report injuries and deaths associated with medical products.
  • Providing training for field staff to improve the information gathered through investigation of consumer complaints and reports of medical errors.

A comprehensive safety system for medical products is a critical priority. FDA's current systems are not intended to, and cannot, uncover the incidence of adverse events, their preventability, or the overall health and economic impact on Americans.  FDA has been partnering with others in DHHS to promote patient safety and prevent medical errors. To supplement CDER's adverse event data, FDA is working to establish contracts for safety monitoring data links that include data on product exposure and extensive patient information. CDER is developing 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.

 

Enhanced Communication

FDA is committed to enhancing CDER's communication methods to prevent any harm to the American public that may occur due to the lack of accurate and timely information about a drug product.  FDA's human drug program is engaged in a variety of activities designed to better enable consumers to make informed decisions weighing benefits and risks of FDA-regulated products, and is developing education campaigns to disseminate consumer friendly information on drug products to promote the safety and quality of drug products. Key activities include:

  • Continuing a Generic Drug Education Program aimed at both consumers and healthcare professionals to inform them about the safety, effectiveness and quality of generic drug products. 
  • Developing timely press releases that warn the public about potential hazards associated with purchasing particular products from stores or over the Internet.  For example, the Agency issued several press releases that advised the public not to purchase products promoted as alternatives to illicit street drugs (street drug alternatives) and not to purchase products with special safety considerations, such as Accutane, over the Internet.

 

Human Subject Protection

FDA takes its role of protecting human subjects involved in clinical trials very seriously, evidenced by its conscientious daily performance of the following:

  • Verification of the quality and integrity of data submitted to us to assure patient safety.
  • Protection of 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.
  • Performance of on-site inspections of clinical trial study sites, institutional review boards, sponsors, study monitors, and contract research organizations.
  • Conducting of inspections to increase oversight of high-risk IND applications and convene conferences of investigators who are the most experienced professionals in the field discuss appropriate monitoring practices.

 

Compliance Oversight of Marketed Prescription Drugs

FDA continues to protect the public health by assuring that marketed prescription drugs comply with the new drug approval and labeling requirements of the Federal Food, Drug and Cosmetic Act.  This helps ensure that drug products available to the consuming public are safe and effective and labeled correctly to assure their proper use.  Major functions include:

  • Review and support of litigation for recommended regulatory and legal actions, in both civil and criminal proceedings. 
  • Responding to requests for information from both internal and external stakeholders on new drug and labeling compliance issues.
  • Preparing assignments to FDA field offices for inspections and investigations, and coordinating case development and compliance actions with regard to new drug and labeling violations.

 

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.  Due to resource limitations, FDA currently conducts only limited levels of web-based oversight, of which the key components are:

  • Monitoring potentially fraudulent Internet sites to identify targets for investigation and sampling of products. 
  • Conducting undercover purchases of prescription drugs from Internet sites suspected of engaging in illicit drug sales, distribution, and/or marketing.
  • Providing oversight of mail and courier packages entering from foreign sources. 
  • Using a risk-based assessment protocol, prioritize and take enforcement action against firms that are illegally marketing products over the Internet.  Actions include warning letters, untitled letters, seizures and injunctions.

 

Research, Development, and Evaluation (RD&E) Activities

CDER research activities associated with patient safety include:

  • Analyzing specific immune deficiencies in animal models of bioterrorism-related radiation injury to clarify clinical problems that might be treated by therapeutic proteins.
  • Studying broadly-acting stimulators of the immune system in animal models to assess protective effects against various infectious agents that could be used in bioterrorist attacks. 
  • Developing new assays for anthrax toxin that more closely models toxin activity in humans than current mouse cell assays, and provide biomarkers for assessing anthrax toxin effects in vivo.
  • Clarifying normal function of novel proteins proposed as targets for cancer therapy, in order to predict adverse effects due to inhibition of these proteins in normal cells.
  • Studying novel cytokines to suggest new potential therapeutic strategies in autoimmune diseases for which current therapies have a poor risk/benefit profile.

 

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

 

The Human Drugs Program within FDA is responsible for ensuring the safety and effectiveness of drug and therapeutic biologic products.

 

New Drug Review

FDA reviews and evaluates New Drug Applications (NDAs) to determine whether or not a new drug is both safe and effective.  Drugs for diseases such as cancer and AIDS are given priority status and evaluated through an accelerated approval process.  Major activities associated with the process include:

  • Administering FDA's accelerated drug approval program to help make promising products for serious or life threatening diseases available earlier in the development process.     
  • Reviewing and evaluating 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.

 

Over-the-Counter Drugs

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.  Major functions of the program include:

  • Reviewing OTC drugs to ensure their safety and effectiveness and assists consumers on how to best use OTC products by providing clear, easy-to-read drug information.
  • Funding consumer behavior research to identify and manage the risks associated with the use of OTC drugs. 

 

Generic Drugs

FDA continues to support an active generic drugs program to complete review and action on Abbreviated New Drug Applications (ANDAs).  As a result, there are continuing efforts to  expand 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 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 inhalation or topical drug products. Key functions of the program include:

  • Assuring generic product conformance to manufacturing standards equal to the standards of the brand name pharmaceuticals.
  • Increasing efficiency and improving generic drug review times by evaluating ways to improve communications with industry.

 

FDA Approves First Pediatric Generic AIDS Drug for U.S. Marketing

September 2005: FDA announced approval for marketing several generic versions of drugs that treat HIV, the virus that causes AIDS. Previously, the products had been only tentatively approved and were not available in the United States because patent or market exclusivity blocked their approval. With the expiration of those patents, the following products today have receive full marketing authorization for the United States: (1) zidovudine (zye-DOE-vue-deen) tablets manufactured by Ranbaxy Laboratories Limited of Guragon, India; (2) zidovudine tablets and oral solution manufactured by Aurobindo Pharma LTD. Hyderabad, India; and (3) zidovudine tablets manufactured by Roxane Laboratories of Columbus, Ohio, U.S.A. These are the first generic versions of the already-approved Retrovir brand manufactured by GlaxoSmithKline to be approved for marketing in the U.S. FDA previously determined as part of a tentative approval action that these products meet all U.S. manufacturing quality and clinical safety and efficacy standards.

" These approvals will now allow those infected with HIV more access to these life-saving drugs within our country. Some of these products have been available for purchase outside the U.S. as tentatively approved products under the President's Emergency Plan for Aids Relief," said Health and Human Services Secretary Mike Leavitt. "Generic products help reduce costs to patients and for the first time this antiretroviral drug will be available as a generic pediatric dosage form."

 

President's Emergency Plan for AIDS Relief (PEPFAR)

FDA plays a key role in the President's Emergency Plan for AIDS Relief (PEPFAR).  In May 2004, in direct support of PEPFAR, Secretary Thompson announced that the FDA would implement a new, expedited review process to ensure that the US could provide safe, effective drugs to developing countries. PEPFAR's major activities are:

  • Providing medical and scientific expertise necessary to fulfill the President's commitment to ensure the quality of HIV/AIDS drugs purchased by the US for developing countries.  
  • Performing outreach to pharmaceutical firms - including many foreign firms who are unfamiliar with FDA's regulatory processes.
  • Conducting its traditional drug product review activities for both new products and for generic forms of existing drug products to ensure product safety and effectiveness. 
  • Developing a program to conduct pre-approval inspections and pre-operational visits.

 

Protecting America's Children

CDER is responsible for fulfilling the requirements of recent legislation and for making significant progress in protecting children who need prescription or OTC drug products.  Due to the inadequacy of pediatric use information found in the majority of prescription medications in the U.S., Congress enacted several legislative initiatives to promote drug development for children.  In 1997, as part of the Food and Drug Administration Modernization Act (FDAMA), Congress enacted a law to provide marketing incentives to manufacturers who conduct studies in children.  This law, which provides six months exclusivity in return for conducting pediatric studies requested by the FDA, was reauthorized in January 2002 under the Best Pharmaceuticals for Children Act (BPCA)

As a result of these initiatives, the number of ongoing pediatric clinical trials in the last 5 years has increased dramatically.  The BPCA also established a publicly funded contracting process for studies of drugs that no longer have exclusivity or patent protection for which pediatric studies are needed. Finally, on December 3, 2003, Congress enacted the Pediatric Research Equity Act (PREA) which provides FDA the authority to require pediatric studies for certain new and already marketed drug and biological products. 

 

Research for Treatments of Orphan Diseases

Office of Orphan Products Development (OOPD) has been dedicated to promoting the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions since it was created in 1982. Major activities include:

  • Interacting with the medical and research communities, professional organizations, academia, and the pharmaceutical industry, as well as rare disease groups.
  • Administering the major provisions of the Orphan Drug Act (ODA) which provide incentives for sponsors to develop products for rare diseases
  • Administering the Orphan Drug Grants Program which provides funding for clinical research in rare diseases. 

 

Research, Development, and Evaluation Activities

Research CDER performs ensures that FDA has sufficient expertise to develop regulatory standards and risk assessment criteria to reach sound, science-based public health decisions. Important components of the research include: 

  • Clarifying mechanisms of cell death induced by cancer drugs in order to enable better bioassays to serve as markers for safety and efficacy of novel cancer drugs.
  • Characterizing differences between antibodies produced in vivo versus those produced by novel synthetic technologies to help assess potential adverse effects of synthetically derived therapeutic antibodies.
  • Identifying biomarkers of cancer development and progression to facilitate diagnosis and monitoring of treatment efficacy. 
  • Investigating novel ways to synthesize short pieces of DNA with proposed indications in treating and diagnosing diseases. 

 

Planning for Emergencies and Protecting Americans from Terrorism through Medical Countermeasures

Increased funding over the last five years has strengthened CDER's capability to identify, prepare for, and respond to biological, chemical, and radiological/nuclear threats and incidents.  

FDA is engaged in many efforts to promote the development of medical countermeasures, among which are:

  • Encouraging early and frequent interactions with sponsors, whether they are developing a novel compound or a new indication for a previously approved product
  • Expanding  the availability of safe and effective medical countermeasures for special populations (e.g., pregnant or lactating women, infants, elderly) through contracts that fund pharmacokinetic and safety studies of antibiotics likely to be used to prevent or treat illness following a terrorist attack.  
  • Assuring processes are in place if unapproved product is required in response to an event.   
  • Collaborating with other agencies on the development of INDs to allow access to investigational medical countermeasures. 
  • Conducting GMP inspections of drug manufacturing sites whose products are stockpiled as part of the government's counterterrorism efforts.
  • Assuring regulated drug and therapeutic biological products are not used as vehicles of terrorism.
  • Participating in committees to facilitate development of medical countermeasures and to provide recommendations on acquisition of products.
  • Interacting frequently with the Strategic National Stockpile to support the development, availability, maintenance, and deployment of stockpiles of medical countermeasures.

 

FDA Strategic Goal: Improving Product Quality, Safety, and Availability through Better Manufacturing and Product Oversight

 

Ensuring that the highest possible quality products are marketed is a large part of FDA's mission of protecting the public's health. The Agency ensures product quality by facilitating effective and efficient scientific assessment of relevant pharmaceutical and biotechnology information in regulatory submissions.  The Agency facilitates those scientific and technological innovations that improve understanding of product performance, quality and efficiency of development, manufacturing, and quality assurance processes.   Ensuring quality of products involves recognizing the level of scientific knowledge supporting product applications, process validation, and process capability.  In accomplishment of this strategic goal, CDER performs the following:

  • Applies a risk-based regulatory scrutiny that relates to the level of scientific understanding of how formulation and manufacturing process factors affect product performance and relates to the capability of process control strategies to prevent or mitigate risk of poor product performance.
  • Evaluates and analyzes inspection findings for trends in deficiencies by focusing on product quality standards and manufacturers' compliance with GMP regulations. 
  • Develops, deploys, and maintains risk-based compliance inspection models for prioritizing GMP inspections by risks to product quality.
  • Performs targeted drug quality surveillance studies to detect emerging threats to drug quality and develop baselines for risk-based drug quality monitoring by creating data resources and maintaining access to industry data resources for efficient and accurate assessments of drug products marketed and drugs consumed.
  • Conducts criminal investigations of reported product tampering, counterfeit products, and other fraudulent criminal activities involving regulated drug products. 
  • Performs laboratory validation of analytical methods submitted to support pre-market product applications.
  • Verifies the reliability and accuracy of NDA data collected by regulated industry in animal and human studies, and evaluates approaches that may be used to facilitate the introduction of modern process analytical technologies and pharmaceutical engineering principles.

 

Federal Authorities Cease Sale and Distribution of Counterfeit Lipitor

August 2005 FDA and the United States Attorney for the Western District of Missouri, Kansas City, Missouri, today announced the indictments of 11 individuals, a drug repacker, and two wholesale distributors in cases related to the sale of Lipitor, a popular cholesterol reducing drug.

The indictment alleges numerous charges including conspiracy to sell counterfeit, illegally imported and misbranded drugs as well as conspiracy to sell stolen drugs. The conspiracy involved the manufacture of counterfeit Lipitor at a clandestine facility in Central America, the purchase of genuine Lipitor intended for distribution in South America, and the illegal importation into the United States of both products.

 

Managing Quality by Industry Self-Compliance

FDA operates a comprehensive program to guide, assist, and manage industry self-compliance with manufacturing quality objectives of the Federal Food, Drug and Cosmetic Act. In support of the program, CDER organizes FDA experience and expertise into published guidance on how industry may meet requirements for manufacturing quality on focused areas of technology and procedures.  CDER also provides input on industry-generated voluntary standards and guidance documents to assure broad consensus for effective compliance.

Over the last few years, FDA has conducted a major effort to bring a 21st Century focus to the regulation of pharmaceutical manufacturing and product quality by providing high quality, cost-effective oversight of industry manufacturing, processing and distribution.  FDA focuses on product quality standards and compliance by manufacturers with the GMP regulations to ensure that the highest possible quality products are marketed.  CDER ensures the latest technological advances are encouraged, including application of the requirements of Part 11 regulations. Further CDER efforts include:

  • Providing inspection assessments of conformance with current good manufacturing practice requirements for self correction and improvement of operations.
  • Assisting Industry in voluntary recalls of products from the market and in the investigation, evaluation, and corrections of the conditions and practices which led to the recalls.
  • Certifying conformance with current good manufacturing practice by the Industry for use in facilitating export of US pharmaceutical production to countries with limited regulatory systems.
  • Consulting with industry and coordinating of FDA program activities to alleviate drug shortages in the US market.

 

Compliance Oversight of Marketed OTC Drugs

Enforcement of the OTC Drug Review regulations is tantamount to maintaining the integrity of the NDA process.  Those members of the regulated industry who market their OTC drugs in compliance with applicable monographs expect FDA to eliminate unfair competition from those who ignore monograph requirements.  Further, NDA holders for OTC drugs expect their investments to be protected by vigorous FDA enforcement against those who flaunt these NDA requirements.  This type of enforcement helps provide the consuming public with the assurance that they are buying safe and effective OTC drugs.

 

Pharmacy Compounding

FDA believes that a significant number of licensed pharmacies are engaged in manufacturing and distributing unapproved new drugs for human use in a manner that is outside the bounds of traditional pharmacy practice.  For example, some pharmacies make large quantities of unapproved drug products in advance of receiving a valid prescription for them, or copy commercially available drug products when there is no medical need for a compounded product.  Furthermore, some pharmacies have been found to compound drugs that are contaminated or that are dangerously subpotent or superpotent in a manner that can threaten public health.  In such situations, FDA may need to take enforcement action in accordance with the Act to protect the public health.   FDA continues to work with state regulatory authorities, providing support as needed for their regulation of pharmacy compounders. 

 

Import Compliance

FDA has worked with the Agency field import district offices and the U.S. Customs and Border Protection (CBP) to develop categories of drug products targeted for "blitz" operations scheduled at different major mail import centers.These "blitz" operations are held cooperatively with CBP to identify the type and origin of drug products being offered for import into the U.S. through the mail, with emphasis placed on counterfeit, misbranded, adulterated, and restricted distribution drug products.  CDER also responds to inquiries concerning import and export regulations and enforcement policy from the regulated industry, consumers, consultants, and health care professionals. Other inquiries come from field import offices concerning importation of unapproved and investigational drug products, and drugs being imported in advance of application submission and final approval.

 

Research, Development, and Evaluation (RD&E) Activities

CDER's research efforts associated with manufacturing quality include:

  • Studying the biology of prions (agents of "Mad Cow Disease") to facilitate development of detection procedures for prions in human- and animal-derived material used in manufacturing biological agents. 
  • Clarifying the mechanisms by which antibodies to interferons and cytokines can impact the safety and efficacy of these products.
  • Studying factors inducing some patients to mount immune responses against therapeutic proteins, responses that terminate effectiveness of these proteins and threaten patient safety. 
  • Studying the mechanism of action of therapeutic enzymes and cytokines to alert reviewers to potential adverse effects and facilitate improved potency assays.
  • Investigating a biochemical pathway of internal cell signaling in lymphocytes to facilitate novel therapies targeting lymphocytes in autoimmune and malignant diseases. 
  • Developing model systems to study interactions between drugs with anti-inflammatory effects (e.g. statins) and therapeutic proteins that modulate the immune system. 
  • Developing new tests and novel breast cancer cell lines for analyzing cell proliferation and potential for metastasis, to facilitate bioassays of proposed cancer therapeutics.
  • Studying cytokines that are secreted by HIV-infected cells and that act on HIV-infected cells, in order to facilitate development of surrogate markers to monitor therapeutic and adverse effects of new AIDS therapeutics.
  • Develop new strategies for downstream manufacturing processes to ensure the safety of biotechnology products from adventitious virus contamination.

 

Field Operations

ORA's field actions to ensure the safety and quality of the nation's drug supply include:

  • Operation Safeguard Pharmaceutical:  In a joint operation with Customs and Border Protection, FDA conducted blitzes of several international mail facilities across the country.  The blitzes revealed substantial numbers of shipments of unapproved drugs, and provided useful information for future targeting efforts.
  • Operation Bait and Switch:  FDA conducted a multi-district operation to detect import parcels which were shipped via postal service from a country other than Canada, and which contained pharmaceutical products labeled or identified as coming from a Canadian pharmacy.  FDA found that such products sourced from 39 different countries.  ORA drug laboratories analyzed 487 samples and found 28 products that were counterfeit (not consistent with authentic product) and one significantly sub potent sample.  In addition, label reviews found some products labeled entirely in a foreign language.  Operation Bait and Switch confirmed that U.S. consumers have no assurance of quality when purchasing medications from sources outside the normal distribution channels in the U.S.
  • State Partnership Program: The Agency and the States maintained and continued to develop new partnerships (e.g., compressed medical gas and drug GMP inspections) that have contributed to the exchange of inspection and sampling data and have facilitated the receipt of training and distribution of equipment to the states.  

 

FDA Strategic Goal: Transforming FDA Business Operations, Systems, and Infrastructure to Support FDA's Mission in the 21st Century

Strong and sound science means Human Drug Program scientists stay on the cutting edge of new technologies. CDER's 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. 

 

Information Technology

FDA is working to apply information technology by developing and managing systems that provide staff with the technical tools to manage the review process and to provide the means to evaluate post-marking drug safety.

  • Developing Automated Drug Information Management System (ADIMS) as a fully electronic information management system to receive, evaluate, and disseminate information about investigational and marketing submissions for human drugs and therapeutic biologics.  
  • Addressing, within ADIMS, its electronic document receipt and validation processes and efforts to develop scientific tools that aid submission evaluation, such as tools to review structured clinical data, labeling data, and drug ingredients.
  • Leveraging the wealth of data in its Adverse Event Reporting System to assist medical officers involved in the review process by providing a data mining tool to identify trends in adverse event data.

 

Selected FY 2005 Accomplishments

 

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

 

Risk management is at the core of CDER's mission.  Almost everything the center does in the review and approval of Human Drugs relates to weighing the benefits of a product to its risks.  CDER's FY 2005 accomplishments include new, generic, and OTC drugs as well as 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.

 

Significant NDAs Approved in FY 2005

  • Tarceva (erlotinib) - For the treatment of locally advanced or metastatic Non Small-Cell Lung Cancer (NSCLC) after failure of at least one prior chemotherapy regimen.  Approval was based on improved overall survival. 
  • Macugen (pegaptanib sodium injection) - For the treatment of neovascular (wet) age-related macular degeneration. Macugen was shown to slow vision loss in patients.  It is an alternative to traditional laser treatment and one of the first treatments to target the underlying biology of the disease.  This product was given Fast Track Status. 
  • Baraclude (entecavir) - For the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.  Baraclude slows the progression of chronic hepatitis B by interfering with viral replication. The virus can cause lifelong infection, liver scarring, liver cancer, liver failure, and death.
  • Increlex (mecasermin [rDNA origin]) - For the long-term treatment of growth failure in children with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone.  This is drug treats an Orphan indication.
  • Kepivance (palifermin) - To decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving high doses of chemotherapy and radiation followed by stem cell rescue.  Mucositis is an inflammation of the mucous membranes (lining of the mouth) that can be caused by chemotherapy and radiation.  Palifermin works by stimulating the growth and reproduction of the cells that line the mouth, speeding up the healing process.
  • Velcade (bortezomib) - Received regular approval for the treatment of multiple myeloma patients who have received at least one prior therapy.  Velcade was originally approved under the accelerated approval program in May 2003; approval was based on a decrease in the size of tumors.  Regular approval means that the FDA has determined that Velcade has demonstrated clinical benefit showing a survival benefit.  At the time of original approval, Velcade was the first of a new class of anticancer agents called proteasome inhibitors.
  • BiDil (hydralazine/isosorbide dinitrate) - For the treatment of heart failure in self-identified black patients.  BiDil is the combination of two older drugs, neither approved for heart failure.  Approval was based on a trial conducted in over 1,000 self-identified black patients based on results from previous trials which showed no benefit in the general population but suggested a benefit in black patients.  Hydralazine is an anti-hypertensive agent; isosorbide dinitrate is an anti-anginal agent. 

 

NDAs Approved under Accelerated Approval in FY 2005

  • Clolar (clofarbine) - For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) after at least two prior regimens or is unresponsive to other treatments.  ALL is responsible for 80 percent of all acute childhood leukemias.  This drug is for an Orphan indication.
  • Aptivus (tipranivir) - In combination with ritonavir, for the antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who had already used many HIV medicines, and had a type of virus resistant to currently available HIV therapy.  This new combination therapy provides a new treatment option for patients with limited options.  This is the only second drug approved for patients with advanced HIV disease.

 

Generic Drug Review

OGD continues to approve greater numbers of generic products thus helping to lower drug costs for millions of Americans.  The following are significant generic drugs approved in FY 2005 that will contribute to the goal and assure greater access to affordable health care:

  • Levofloxacin - A broad spectrum fluoroquinolone antibiotic used to treat conditions such as sinusitis, community-acquired pneumonia, and urinary tract infections.
  • Fentanyl Transdermal System  - The "patch" provides continuous systemic delivery of this potent opioid analgesic for 72 hours and is useful for patients with severe chronic pain, such as cancer sufferers.
  • Azithromycin  - This is an azalide antibiotic used to treat a number of infections including Disseminated Mycobacterium avium complex disease in persons with advanced HIV infection.
  • Fexofenadine  - As a histamine antagonist, it is used to treat seasonal allergic rhinitis and is used by large numbers of the population.
  • Zidovudine   - This is a pyrimidine nucleoside analogue that is active against the human immunodeficiency virus used in combination with other antiretroviral agents for the treatment of HIV infection.  It is also used for the prevention of maternal-fetal HIV transmission.
  • Ramipril  - An angiotensin converting enzyme (ACE) inhibitor used to treat hypertension and certain patients at risk of myocardial infarction and stroke.

Figure 1, ANDA Approvals[D]

 

The Office has demonstrated full support for the President's Emergency Plan for AIDS Relief (PEPFAR).   CDER has approved or tentatively approved 12 applications for a number of products.  More firms have expressed interest in submitting applications and have provided OGD with their projections for future applications.  CDER views the applications as priority for review and provides extensive guidance to the firms, who are often from the developing countries that will use the products.

As seen in Figures 1, there were 467 abbreviated new drug applications (ANDAs) approved or tentatively approved in FY 2005, an increase of 13 percent.  There was a median approval time of 16.3 months seen this year. 

Figure 1, ANDA ReceiptsThere was a staggering 36 percent increase in receipts in FY 2005 as shown in Figure 2.  This increase  is in addition to the 24 percent increase in receipts from FY 2002 to FY 2003 and an additional 25 percent increase from FY 2003 to FY 2004.  With the continuing high numbers of submissions, mechanisms are needed to increase efficiency.  An emphasis over FY 2005 is working to streamline the review process.  The third division of chemistry is nearly complete and is functioning effectively.    The chemistry and bioequivalence review divisions are relying more on the project manager staff to triage supplements and information requests so that only those that require particular scientific expertise are put into the reviewers' queue.  Groups of applications for single products are reviewed by a dedicated team in order to capitalize on the knowledge gained about the product.

OGD has developed a question based review (QbR) for its CMC evaluation that is focused on critical pharmaceutical quality attributes.  The goal is to transform the CMC review into a modern, science and risk-based pharmaceutical quality assessment under the FDA's cGMPs for the 21st Century Quality and PAT initiatives. With the move to the QbR, there is more emphasis on moving towards the common technical document (CTD) format for generic drug submissions since the QbR is more closely aligned with that format.  Firms are also encouraged to move to the electronic format of the CTD. 

Finally, to address the advent of electronic prescribing, electronic health records, and interest in the computerized distribution of up-to-date medication information FDA adopted Structured Product Labeling (SPL).  By selecting this format, FDA hopes to provide labeling that is both human and machine readable, faster to disseminate, and improves patient risk management.  It will also allow easier review when changes are made and greater accessibility by prescribers and consumers through the National Library of Medicine.

 

OTC Drug Products

In FY 2005, the OTC staff approved a total of 2 NDAs (Reviewed 6).  Significant approvals included:

  • Loperamide Soft Gel Capsules (1 and 2 mg)
  • Highlights for other significant accomplishments include:
  • Approved three new efficacy supplements for new product uses;
  • Acted on 112 supplement submissions regarding changes to manufacturing procedures;
  • Acted on 28 labeling supplement submissions regarding changes to product labeling;
  • Conducted 52 meetings with drug companies;
  • Published 11 Federal Register notices for OTC monographs;
  • Responded to 9 health hazard evaluations;
  • Answered 8 citizen petitions;
  • Completed 7 time and extent applications; and
  • Published 2 guidance documents.
  • Significant new Federal Register Publications regarding OTC products included:  publishing six proposed rules,1 final rule and  3 notices of eligibility.

 

Pediatric Drug Studies

  • Reviewed 388 Proposed Pediatric Study Requests (PPSRs), issued 307 Written Requests (WRs) for on-patent drugs that asked for over 714 studies to be conducted in the pediatric population, and granted pediatric exclusivity for 114 out of 125 drugs that have had pediatric exclusivity determinations. Ninety-eight of these 125 drugs had labeling incorporating information from pediatric studies approved.
  • Determined pediatric exclusivity for 14 drugs, 13 of which were granted pediatric exclusivity.
  • Approved 16 labels for drugs responsive to WRs. 
  • Continued collaboration with NIH as a result of the Best Pharmaceuticals for Children Act (BPCA).  Further, FDA continues its implementation of section 3 of the BPCA (the study of drugs with no marketed protection in the pediatric population) and issued four Written Requests for drugs on NIH's annual list.
  • Collaborated on 2 Pediatric Advisory Committee meetings that presented post-pediatric exclusivity adverse events reports on 14 drugs.
  • Disseminated to the public 21 medical and clinical pharmacology reviews for supplements submitted in response to Written Requests.

 

Responding to Emergencies and Protecting Americans from Terrorism

CDER plays a key role in countering terrorism in the U.S., especially in preparing the country to have medical countermeasures readily available in the event of any chemical, biological, or radiological or nuclear attack.  In FY 2005, FDA approved several products for indications related to counter-terrorism:

  • Radiation Threats:  ThyroShield™ (potassium iodide oral solution) was approved as a thyroid blocking agent for use in radiation emergencies.  This oral solution is appropriate for use in children or in adults who cannot swallow tablets.  In February 2005, CDER assisted HHS in a BioShield procurement of ThyroShield™ for the Strategic National Stockpile (SNS). Tentatively approved were CIS-US's Ca-DTPA (Kelacal) and Zn-DTPA (Kelazin).and  Degussa's Manoplex (insoluble Prussian blue)
  • Biological Threats:  Levaquin (levofloxacin) was approved for an additional indication of post-exposure prophylaxis of inhalational anthrax.  Cipro (ciprofloxacin) tablets, IV solution, and oral suspension received approval for revised labeling for the Indications and Usage, Adverse Reactions, and Inhalational Anthrax-Additional Information sections of the package insert.  These changes were based on information obtained from the Centers for Disease Control and Prevention during the 2001 anthrax attacks.  FDA also released Bayer from its Subpart H commitment to report data from confirmatory anthrax studies. Four generic ciprofloxacin applications were also approved during FY05.

In FY2005, FDA also performed the following counterterrorism tasks:

  • Collaborated with NIH/NIAID to establish the animal model requirements necessary for development of medical countermeasures against nuclear/radiological threat agents and on the development of a non-human primate natural history model for inhalational anthrax disease.
  • Published the draft Guidance: "Internal Radioactive Contamination-Development of Decorporation Agents."
  • Coordinated emergency response activities, including non-CT incidents and natural disasters.  For eample, CDER assisted in response issues related to Hurricanes Katrina, Rita, and Wilma by coordinating web postings on the safety of medications potentially damaged by flooding or high temperature. 
  • Coordinated 25 urgent requests from the FDA Emergency Operations Center since March of 2005, addressing issues such as product quality, counterfeit products, mislabeled products, recalled products, product shortages, product theft / diversion, and severe adverse events. 
  • Prepared for pandemic influenza and avian flu by participating in intercenter and interagency working groups and developing the Center's response plan to pandemic flu.
  • Participated in TOPOFF 3 (Top Officials), a full-scale inter-departmental emergency response exercise intended to test the national preparedness to simultaneous terrorist attacks using multiple threat agents.
  • Published the draft Emergency Use Authorization Guidance in July 2005.

 

Information Technology

CDER accomplished several significant advances in applying information technology solutions to drug review processes:

  • Implemented the Electronic Labeling Information Processing System (ELIPS) was.  This system standardizes drug labels to improve patient safety by ensuring that medication information is readily available to health care providers, patients, and the public, in its most up-to-date form.
  • Implemented FDA Review, a product that provides greater eCTD submission processing and reviewer tools.  The implementation of this new product allows the FDA to process high volumes of eCTD submissions and allows the reviewer to see the cumulative lifecycle of a marketing application submitted in eCTD format.

 

FDA Strategic Goal: Enhancing Patient and Consumer Protection and Empowering Them with Better Information about Regulated Products

 

Patient and Consumer Protection

  • Approved a strengthened distribution program for isotretinoin, called iPLEDGE, aimed at preventing use of the drug during pregnancy.
  • In FY 2005 approximately 50 percent of expedited individual safety reports were submitted electronically CDER estimates the cost of receiving a report is cut from $34 per paper report to $20 per report for those submitted electronically.Approximately 30 percent of expedited individual safety reports were submitted electronically in FY 2004, an increase from approximately 20 percent the previous year.

 

Drug Safety

  • Initiated a contract with the Institute of Medicine (IOM) to study the effectiveness of the United States drug safety system with emphasis on the post-market phase, and assess what additional steps could be taken to learn more about the side effects of drugs as they are actually used. The committee will examine FDA's role within the health care delivery system and recommend measures to enhance the confidence of Americans in the safety and effectiveness of their drugs.
  • Conducted and completed a national search to fill the currently vacant position of Director of the Office of Drug Safety, which is responsible for overseeing the post-marketing safety program for all drugs.  
  • FDA issued three guidances:
    • "Premarketing Risk Assessment," which describes additional safety testing, monitoring, and interventions that may be helpful in selected circumstances and address pre-market risk assessment;
    • "Development and Use of Risk Minimization Action Plans," which outlines the development, implementation, and evaluation of risk minimization action plans (called RiskMAPs); and
    • "Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment," which illustrates good pharmacovigilance practices and assessment of reported adverse events.
  • Announced on May 10, 2005 the availability of draft guidance for industry entitled, "FDA's Drug Watch for Emerging Drug Safety Information."  This document provides guidance about how FDA intends to develop and disseminate important emerging drug safety information concerning marketed drug products to healthcare professionals and patients.  

Reforms Will Improve Oversight and Openness at FDA

February 2005:  HHS Secretary Mike Leavitt shared an emboldened vision for the FDA that included a new culture of openness, improved oversight and enhanced independence. In keeping with this vision, the FDA will create a new independent Drug Safety Oversight Board to oversee the management of drug safety issues, and will provide emerging information to doctors and patients about the risks and benefits of medicines.

"The public has spoken and they want more oversight and openness," Secretary Leavitt said during a meeting with FDA employees at the Parklawn Headquarters in Rockville, Md. "They want to know what we know, what we do with the information, and why we do it.  We will address their concerns by cultivating openness and enhanced independence."

 

Drug Safety Oversight Board

  • Created an independent Drug Safety Oversight Board (DSB)to oversee the management of important drug safety issues within the Center for Drug Evaluation and Research (CDER).  The DSB comprises members from FDA and medical experts from other HHS agencies and government departments (e.g., Department of Veterans Affairs) who will be appointed by the FDA Commissioner. The board consults with other medical experts and representatives of patient and consumer groups.

 

Better Communication to Consumers and other Stakeholders

  • Revised and expanded its presentation of consumer and patient education resources on the CDER web site.  This effort included adding or updating drug-specific information and regrouping educational materials more effectively for primary use by two targeted audiences: consumers and health care intermediaries.
  • Designed a new Patient Information Sheet that provides more information than the older-format Consumer Information Sheets and also places more emphasis on taking drugs safely. 
  • Review the Consumer Information Sheets already on the web site and updated the information in the form of Patient Information Sheets.
  • Redesigned CDER Internet home page to draw attention to drug safety information.  We also created a new page, the "Index to Drug-Specific Information," to help users locate Information Sheets and Drug Information pages.   The site also provides a link to Drugs@FDA, a searchable database of all FDA drugs and therapeutic biologics, and includes links to consumer and patient information materials, as well as approved labeling.
  • Updated many topical pages, such as the Influenza page,
  • Added a number of pages to provide needed hurricane recovery information promptly (http://www.fda.gov/cder/emergency/default.htm), such as the safe use of insulin when it can not be refrigerated.  . 

 

Public Service CampaignsA picture of a person’s intestine and stomach are shown with a caption entitled, “Exceeding the Recommended Dosage Can Do More Than Wipe Out Your Pain – Just Ask Your Major Organs.”

  • Developed a partnership with the United Health Foundation that produced a joint public service announcement (shown below) that appeared in a number of national magazines, including Parade, People, Better Homes and Gardens, Family Circle, Woman's Day, Ladies Home Journal, Ebony, Good Housekeeping, and Reader's Digest. The Foundation spent about 14 million dollars to run these ads.
  • Completed and disseminated radio, television and/or print public service announcements about buying drugs online; the safe use of OTC pain relievers; Know Your Child's Weight; Safe use of Prescription Pain Relievers; clinical trails; aging, medicines and alcohol; and antibiotic resistance (English and Spanish.)
  • Created the Generics and Aging, Medicines & Alcohol radio spots which garnered a total almost 63,000 plays reported by 233 AM and FM stations across the country. This equates to a little more than 526 hours of airtime worth an estimated $3.2 million.
  • Signed ten co-sponsorship agreements with healthcare organizations. These organizations combine to reach more than 240 million consumers with information about the safe and effective use of drug products.
  • Completed and disseminated six brochures: Buying Prescription Medicine Online, Kids Aren't Just Small Adults (Spanish-language version), Medicines in My House, antibiotic resistance; generic drugs (English and Spanish plain-language versions

As a result of meeting and collaborating with various health-related businesses and educational organizations, FDA-developed materials were disseminated throughout the world. Below are a few examples:

  • The New York State Patient Safety Center reprinted and promoted FDA's OTC pain reliever products. Nearly 5,000 retailers, hospitals, poison control centers, and county offices received copies. In addition, New York's Dept of Health announced to NY ENTs, pediatricians and family physicians the release of FDA's Kids Aren't Just Small Adultsbrochure.
  • Provided print PSAs to the Director of Pharmacy of the U.S. Army Europe Regional Medical Command in Germany. The materials were disseminated to U.S. Army personnel and families in Germany, Belgium, and Italy.  This involved 29 clinics and three medical centers.
  • Developed with the Consumer Healthcare Products Association a news release promoting the "My Medicines Guide." The release generated 188 newspaper articles in 23 different states with a readership of more than 4.5 million people.

 

Field Operations

ORA protected consumers from many sources of unsafe drugs, including:

  • Internet Storefront Drugs:  FDA obtained a preliminary injunction against one storefront operation facilitating the Internet sale and importation of unapproved prescription drugs from Canada. FDA also coordinated regulatory activities with state regulatory bodies and national regulatory organizations against internet and storefront operations that import unapproved prescription drugs.
  • Pharmakon Labs:  On July 27, 2005, FDA announced a permanent injunction shutting down operations at Pharmakon Labs of Florida. The company manufactured and distributed cough and cold liquids, tablets and caplets.  Following inspections by FDA, it was determined that drug products sold by Pharmakon Labs, Inc., did not meet current good manufacturing practice (CGMP) standards and other legal requirements. 
  • Genendo Pharmaceutical N.V:  On August 22, 2005, U.S. District Judge James F. Holderman entered an order of permanent injunction against Genendo Pharmaceutical N.V.; a drug importer located in Curacao, Netherlands, Antilles.  The Order held that Genendo violated the Federal Food, Drug, and Cosmetic Act when it imported name-brand drugs that were labeled in foreign languages and manufactured and/or packaged in facilities not identified in FDA-approved new drug applications (NDAs). 

 

FDA Strategic Goal: Improving Product Quality, Safety, And Availability Through Better Manufacturing And Product Oversight

 

Inspection and Enforcement Initiatives

Program staff played 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 that applies to pharmaceuticals, including biological human drugs and veterinary drugs.  FDA issued its final report on the cGMP initiative.  The report discusses:

  • The Agency's completed assessment of the current good manufacturing practice regulations, current practices and the new tools in manufacturing science that will enable a progression to controls based on quality systems and risk management.
  • Specific steps the Agency has taken and will take to develop and implement quality systems management and a risk-based product quality regulatory system.

FDA also took many other steps to enhance the consistency and coordination of its drug quality regulatory programs.  These accomplishments include:

  • Piloting a risk-based computer model for prioritizing cGMP inspections for domestic manufacturing sites, in order to further a systematic risk-based approach to inspectional oversight of pharmaceutical manufacturing.
  • Training and certifying a Pharmaceutical Inspectorate, a select cadre of field inspectors who will specialize in pharmaceutical pre-approval and cGMP inspections.
  • Issuing a final guidance on aseptic processing used in the manufacturing of sterile drugs, thereby encouraging the adoption of modern science and technology and risk-based approaches.
  • Actively collaborating internationally on pharmaceutical manufacturing issues, in order to move towards implementation of an internationally harmonized plan for a pharmaceutical quality system based on an integrated approach to risk management and science.

FDA also took many other compliance and enforcement steps to protect the American public, including:

  • Providing regulatory support to the work of the Strategic National Stockpile (SNS) which is charged with delivering critical medical assets to the sites of national emergencies.  Agency support for the SNS included reviewing the labeling and approval status of stockpile drugs;.ing a risk-based selection process to choose establishments for inspections to assess compliance with regulatory requirements for adverse drug safety event reporting.,
  • Increasing industry awareness of post-marketing adverse event reporting requirements through an industry education program and development of a public website.
Human Drugs
Program Activity Data (PAD)
PROGRAM WORKLOAD AND OUTPUTS FY 2005 Actual FY2006 Estimate FY 2007 Estimate
New Drug Review      
Priority New Drug Application (NDA/BLA) Reviews 41 30 30
Standard NDA/BLA Reviews 141 165 165
Priority NDA/BLAs Approved 27 16 16
Standard NDA/BLAs Approved 82 72 72
Time from Receipt to Approval (mo.s)(mean)-Priority NDA/BLAs 10.1 (8.5) (8.5)
Time from Receipt to Approval (mo.s)(mean)-Standard NDA/BLAs 20.6 (18.0) (18.0)
Time from Receipt to Approval (mo.s)(median)-Priority NDA/BLAs 6.0 (6.0) (6.0)
Time from Receipt to Approval (mo.s)(median) -Standard NDA/BLAs 12.9 (13.5) (13.5)
NDA Supplemental Reviews (NDAs only) 2,793 3,300 3,300
INDs (Active) (Drugs and Biologics -Commercial+Research) 13106 13,000 13,000
Clinical Pharmacology/BioPharmaceutic Reviews 1,875 1,600 1,600
Biologic Therapeutics Review      
Total Original License Application (PLA/ELA/BLA) Reviews 3 7 7
PLA/BLA Approvals 3 5 5
License Supplement (PLA/ELA/BLA) Reviews 318 220 220
Commercial IND/IDE Receipts (Biologics Only) 68 80 80
IND/IDE Amendments Receipts
(Biologics Only)
9,772 8,800 8,800
Generic Drug Review      
Abbreviated New Drug Application (ANDA) Actions 1496 1,553 1612
ANDA Approval Actions (both Tentative and Full Approvals) 467 450 470
Average Review Time from ANDA Receipt to Approval (median in months) 16.3 16.9 17.5
ANDA Supplemental Actions (Labeling and Manufacturing) 4,566 5,406 5,610
Over-the-Counter Drug Review      
OTC Monographs Under Development 17 25 20
OTC Final Monographs Published 8 5 5
Best Pharmaceuticals for Children Act      
Approved Labels with New Pediatric Information 16 22 22
Patient Safety      
Adverse Reactions Reports 462,284 508,512 559,364
Percentage of Adverse Drug Reaction Reports Submitted Electronically (% of total) 29% 36% 40%
Percentage of Serious/Unexpected Adverse Drug Reaction Reports Submitted Electronically 51% 66% 75%
Drug Quality Reporting System Report 2,933 3,400 3,500
DRUGS FIELD PROGRAM OUTPUTS- DOMESTIC INSPECTIONS FY 2005 Estimate FY 2006 Estimate FY 2007 Estimate
Pre-Approval Inspections (NDA) 149 130 130
Pre-Approval Inspections (ANDA) 81 135 135
Bioresearch Monitoring Program Inspections 562 520 520
Drug Processing (GMP) Program Inspections 1,365 1,500 1,440
Compressed Medical Gas Manufacturers Inspections 125 155 150
Adverse Drug Events Project Inspections 106 135 135
OTC Monograph Project Inspections and 11    
Health Fraud Project Inspections 1 53 45 45
State Partnership Inspections: Compressed Medical Gas Manufacturers Inspections 85 110 110
State Partnership Inspections: GMP Inspections 57 50 50
Total FDA and State Partnership Inspections 2,594 2,780 2,715
Total Domestic Reinspections (Non-add) 220 220 220
Domestic Laboratory Samples Analyzed 1,446 1,735 1,600
PROGRAM OUTPUTS-IMPORT/FOREIGN INSPECTIONS  
Foreign Pre-Approval Inspections (NDA) 163 180 180
Foreign Pre-Approval Inspections (ANDA) 77 60 60
Foreign Bioresearch Monitoring Program Inspections 85 65 65
Foreign Drug Processing (GMP) Program Inspections 217 195 195
Foreign Adverse Drug Events Project Inspections 10 25 25
Total Foreign FDA Inspections 552 525 525
Total Foreign Reinspections (Non-add) 17 17 17
Import Field Exams/Tests 4,288 4,400 4,400
Import Laboratory Samples Analyzed 1,045 355 300
Import Physical Exam Subtotal 4,850 4,850 4,700
Import Lines 264,559 317,471 380,965
Percent of Import Lines Physically Examined 1.83% 1.53% 1.23%
Note:
1.  The OTC Monograph and Health Fraud Inspections will no longer be planned separately in FY 2006.

 


 Office of Orphan Products Development

1/Includes a 1 percent rescission. 

2/The Office of Orphan Products Development is shown for illustrative purposes and is not contained as a separate line item in the All Purpose Tables. 

3/The Grants piece is part of the aggregate amount of budget authority contained in the CDER budget line item of the All Purpose Tables. 

4/The Program Administration piece is part of the aggregate amount of budget authority contained in the Other Activities budget line item of the All Purpose Tables. 

  FY 2005 Actual FY 2006 Estimate 1/ FY 2007 Estimate Increase or Decrease
Program Level 2/ $16,959,000 $17,378,000 $17,378,000 0
Grants 3/ $14,277,000 $14,696,000 $14,696,000 0
Program Administration 4/ $2,682,000 $2,682,000 $2,682,000 0

 

Historical Funding
Fiscal Year
Program Level
2002 Actuals $13,364,000
2003 Actuals $16,002,000
2004 Actuals $15,895,400
2005 Actuals $16,959,000
2006 Estimate $17,378,000
2007 Estimate $17,378,000

Does not include GSA Rent or Other Rent and Rent Related Activities.

 

Statement Of Budget Request

 

The Office of Orphan Products Development (OOPD) is requesting $17,378,000 in program level resources for accomplishing the four functional activities of its mission:   

  • Review and designate qualified drugs and biologics as Orphan Products;
  • Review and designate qualified medical devices as a Humanitarian Use Devices;
  • Award and administer grants for clinical research studies of promising new orphan drugs, biologics, medical devices and medical foods for rare diseases and conditions; and,
  • Outreach to advance the development of orphan products; includes determining whether a request for formal research protocol assistance (research on a treatment for a rare disease) qualifies for consideration.

 

Program Description

 

The Orphan Drug Act (ODA) (P.L. 97-414) amended the Federal Food, Drug, and Cosmetic Act, as of January 4, 1983, and established that the Federal government would provide incentives to assist and encourage the identification, development, and availability of orphan drugs. Under the ODA, the law guarantees the developer of an orphan product seven years market exclusivity for a specific indication following the approval of the product by FDA. 

Orphan drugs, as defined by the ODA, are drugs for the safe and effective treatment of rare diseases/disorders affecting fewer than 200,000 people in the U.S., or affecting more than 200,000 persons but not expecting to recover development and marketing costs.  There are an estimated 6,000 rare diseases that affect more than 25 million people in the U.S.; between 85 and 90 percent of which are serious or life-threatening.  Orphan drugs provide important breakthroughs for patients who would otherwise be left lacking therapy.  One example is the approval of Fabryzme for the treatment of Fabry's disease, which is a rare life-threatening genetic disease.  Another is approval of Orfadin for the treatment of Tyrosinemia, a fatal metabolic disease affecting children.

In 1982, FDA created the Office of Orphan Products Development, which continues to assist the private sector in producing orphan products (drugs, biologics, medical devices, and medical foods) necessary to treat a patient population that otherwise would be considered too small for profitable research, development, and marketing. 

 

Justification of Base

 

The Office of Orphan Product Development program is responsible for promoting and advancing the development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.  The OOPD administers an orphan product designation process, provides research study design assistance to sponsors of orphan products, encourages well controlled clinical studies, and manages clinical research grants program. The OOPD supports FDA's strategic goals by improving the efficiency of translating new discoveries into safe, effective and accessible treatments for patients. 

 

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

Grants

Orphan product grants are a proven method of successfully fostering and encouraging the development of new safe and effective medical products for rare diseases/conditions in a timely manner with a very modest investment.

Number of New Orphan Product Grants Awarded by Fiscal Year
2003 2004 2005 2006* 2007*
15 15 15 16 16

* estimated

The table above shows only new grants funded.  Grants generally are funded for three years.  Typically there are 45 to 60 ongoing grant-funded projects at any one time.  So a major portion of the appropriated funds for a given year go towards continued funding of prior approved grants.  The rapid increase in the cost of individual clinical trials in recent years has precluded an increase in the number of new grants.

The major grant management activities include:

  • Review of solicited grant applications by OOPD staff to ensure program requirements are met.
  • Coordinate and convene peer review panels to provide technical review of grant proposals to ensure the best scientific proposals are funded.
  • Select grant applications for funding.
  • Monitor the grant-funded products to satisfy regulatory and program requirements. 

 

Program Administration

Besides managing the Orphan Grants Program, the OOPD manages an orphan drug designation process, a Humanitarian Use Device designation process, and provides research study design assistance to sponsors of orphan products.  The major activities include:

  • Review and designation of orphan drug and humanitarian use device[1] designations;
  • Serve as an intermediary between sponsors and FDA medical product review divisions in the drug development process to help resolve outstanding problems, discrepancies, or misunderstandings that often complicate review division/sponsor relationships;
  • Provide expertise in clinical trial design and outcome review.

The anticipated workload for the orphan designation requests is expected to continue to increase as noted by the trend in the table below.

 

* estimated
Orphan Drug Requests, Designations, and Market Approvals by Fiscal Year
Activity 2003 2004 2005 2006* 2007*
Designation Requests 154 160 187 200 210
Designations 93 102 109 115 120
Market Approvals 15 13 15 15 17

 

* estimated
HUD Requests and Designations by Fiscal Year
Activity 2003 2004 2005 2006* 2007*
Designation Requests 25 25 13 25 25
Designations 6 6 5 10 10

 

FDA Strategic Goal: Enhancing Patient and Consumer Protection and Empowering Them with Better Information about Regulated Products

 

OOPD assists patients and advocacy groups on issues addressing rare diseases and orphan products.

  • OOPD staff members are trusted sources of expertise in the patient community, which is why OOPD pays special attention to patient support and advocacy groups. 
  • OOPD staff members respond to many invitations to attend meetings and conferences to speak about the FDA process, Orphan Products Program, and the science of developing a therapeutic product for rare diseases/conditions.

 

FDA Strategic Goal: Transforming FDA Business Operations, Systems, and Infrastructure to Support FDA's Mission in the 21st Century

 

OOPD continuously strives to improve the efficiency and effectiveness of its IT infrastructure systems used to support it operations and in turn review grant and designation applications in a shorter amount of time.  Current ongoing initiatives include:

  • Efforts to modernize the transmission of applications and other review information through full electronic submissions and paperless reviews for quicker designation and grant application reviews.
  • Improvements to the OOPD database system for more efficient and effective retrieval of information and other internal management practices. 

 

Selected FY 2005 Accomplishments

 

FDA Strategic Goal: Increasing Access to Innovative Products and Technologies to Improve Health

 

OOPD continues to encourage the development of therapies for rare diseases by administering the Orphan Drug Act and other programs that provide incentives to companies willing to develop drugs, biologics, medical devices, and medical foods for rare diseases. 

 

Program Administration

  • Orphan Drug Designations:  Of the 1,539 orphan designations issued by OOPD, as of December 30, 2005, 282 have resulted in marketing approval with orphan exclusivity.  Since the Orphan Drug Act passed in 1983, more products are now available to treat a potential patient population of more than 14 million Americans.  In contrast to this current pace of designating orphan drugs to treat rare diseases, and subsequent market approval, the decade prior to 1983 saw fewer than 10 such products come to market.

The number of Orphan Product designation applications continues to increase dramatically.  In FY 2005, there were 187 applications, a record number, representing a 40 percent increase over the average (133/year) of the prior four years.  These include potential treatments for many kinds of cancers, Crohn's Disease, cystic fibrosis, and tuberculosis.  In FY 2005, 109 drugs were designated and 15 orphan designated drugs were approved for marketing.  These numbers are expected to increase in future years as more new drugs are developed that are targeted at specific genetic disorders.

 

 List of FY 2005 Orphan Product Approvals
Sponsor Generic Name Trade Name  Indication
Serono Laboratories, Inc. Recombinant human luteinizing hormone Luveris For use in association with recombinant human follicle stimulating hormone for the treatment of women with chronic anovulation due to hypogonadotropic hypogonadism.
Medicis Pharmaceutical Corp. benzoate/phenylacetate Ammonul Treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle.
Schering-Plough Research Institute temozolomide Temodar Treatment of malignant glioma
Genzyme Corporation clofarabine Clolar Treatment of acute lymphoblastic leukemia
DynPort Vaccine Company LLC Vaccinia Immune Globulin (Human) Intravenous   Treatment of severe complications from the smallpox vaccine
Mutual Pharmaceutical Company, Inc. Quinine Sulfate   Treatment of Malaria
CoTherix, Inc. Iloprost inhalation solution Ventavis Treatment of pulmonary arterial hypertension
Tercica, Inc. Mecasermin Increlex Treatment of growth hormone insensitivity syndrome
BioMarin Pharmaceutical, Inc. N-acetylgalactosamine-4-sulfatase, recombinant human Galsulfase Treatment of mucopolysaccharidosis Type VI (Maroteaux-Lamy syndrome)
Bausch & Lomb Pharmaceutical Company, Inc. Fluocinoline Retisert Treatment uveitis involving the posterior segment of the eye
Boehringer Ingelheim Pharmaceuticals, Inc. Mexloxicam Mobic Treatment of juvenile rheumatoid arthritis
Millennium Bortezomib Velcade Treatment of multiple myeloma with prior therapy
DynPort Vaccine Company, Inc. Vaccinia Immune Gobulin (Human) Intravenous   Treatment of severe complications from the smallpox vaccine
Novo Nordisk, Inc. Coagulation factor VIIa (recombinant) NovoSeven Treatment of bleeding episodes in patients with congenital factor VII deficiency
Novo Nordisk, Inc. Coagulation factor VIIa (recombinant) NovoSeven Prevention of bleeding episodes in patients with hemophilia A or B, with or without inhibitors
Novo Nordisk, Inc. Coagulation factor VIIa (recombinant) NovoSeven Prevention of bleeding episodes in patients with congenital factor VII deficiency
  • Updated regulations for designating orphan products were drafted in order to produce more consistent, understandable, and predictable outcomes, which benefits sponsor companies who invest in developing these products.
  • Humanitarian Use Device (HUD) Designations:  Since the HUD regulations took effect in October 1996, OOPD has received 163 applications and designated 109 devices.  Of the 109 designated devices, 39 have been approved for an Humanitarian Device Exemption.  In FY 2005, 13 HUD applications were received and 6 of these have been designated, including a monitor for phenylalanine in the blood.
  • Outreach:  In FY 2005 OOPD continued its outreach activities to increase the feasibility and level of sponsor interest in orphan products development.  For example, in FY 2005 presentations were made at the:
    • University of Salerno (Italy) on the development of drugs for rare diseases emphasizing in enzyme replacement therapy as a result of the U.S. Orphan Drug Act. 
    • University of California, Irvine (UCI), to discuss development of orphan products through a joint venture between the Octane Group and UCI.

    OOPD staff members also met with representatives of the European Union, Japanese government, and Australian government and their rare disease groups regarding their orphan product programs.

  • Facilitation:  OOPD acts as a facilitator for small companies in their dealings with various FDA centers. For example, in FY 2005 a presentation was made to MannKind Corporation and other small biotech firms who are interested in developing orphan products.

 

Grants

OOPD supported new and continuing extramural research projects that test the safety and efficacy of promising new drugs, devices, and medical foods for rare diseases and conditions through human clinical trials.   OOPD conducted site visits to grantees to ensure extramural funded studies, which involve human subjects, are consistent with grant agreement terms and minimize FDA's exposure to risk of violations in human subject protection requirements.  A peer review process was used to select the highest quality scientific research projects.

  • The $14.696 million appropriated in FY 2006, an increase of $419,000 over FY 2005, for research will be used to fund 11 to 14 new grants and maintain approximately 60 ongoing grant-funded clinical study projects.  The number of grants awarded has been decreasing year-by-year as a result of continued increases in the cost of clinical trials. 
  • In FY 2005, there were 89 grant applications received.  Although the number of grants awarded is slowly declining, the number of applications to be reviewed and scored has steadily increased since 2000.
  • Since its inception, 40 orphan products have been approved using data obtained from OOPD grants.  Most recent was an expandable rib prosthesis for previously fatal thoracic insufficiency syndrome in children. 
  • Another benefit from the OOPD grant funded studies has been the hundreds of publications in peer-review journals that has come about that have changed the state of medical care for Americans with rare diseases/conditions. 

 

FDA Strategic Goal: Enhancing Patient and Consumer Protection and Empowering Them with Better Information about Regulated Products

 

OOPD partnered with other HHS organizations and national and international non-governmental organizations to increase awareness and create similar orphan product development programs in other countries.   For example, presentations were made at the:

  • Israel Medical Association Conference to discuss orphan product legislation in Israel.
  • First International Conference on Rare Diseases and Orphan Drugs in Stockholm.
  • Tenth Asian European Workshop on Inborn Errors of Metabolism in Egypt.

OOPD increased patient and provider awareness of available orphan products.  For example, presentations were made at the:

  • Annual Meeting of the Society of Inherited Metabolic Disorders.
  • International Federation of Associations of Pharmaceutical Physicians on the topic: Orphan Drugs: Current Issues and Activities.
  • Annual Meeting of the National Organization for Rare Diseases.

 

FDA Strategic Goal: Transforming FDA Business Operations, Systems, and Infrastructure to Support FDA's Mission in the 21st Century

 

In FY 2005, OOPD made improvements to the OOPD database, which is used to effectively and efficiently review applications for orphan and humanitarian device designations, grant applications, and funded grants.  Improvements included:

  • Linking Business Objects software for easy data mining.
  • Improving compatibility with the IMPAC II grants management system managed by the National Institutes of Health.

OOPD is also working on the Critical Path Initiative and FDA's contractor, C-Path, to enhance the methodology using orphan drugs programs as a prototype for faster drug development without compromising safety and efficacy.

 


 

[1] A Humanitarian Use Device (HUD) designation from OOPD is required for a device prior to applying for a Humanitarian Device Exemption (HDE) from CDRH.  An HDE for a specific device allows the sponsor to bring the device to market for a very small patient population (less than 4,000 patients per year in the U.S.) after demonstrating the safety and probable benefit of the device. 

 

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