Human Drugs. The following table displays the funding and full time equivalent (FTE) staffing levels for FY 2011 through FY 2013.

Transcription

1 Human Drugs The following table displays the funding and full time equivalent (FTE) staffing levels for FY 2011 through FY Program Resources Table (Dollars in thousands) FY 2011 Enacted FY 2011 Actual FY 2012 Enacted FY 2013 Request +/- Enacted Program Level $956,160 $949,645 $978,705 $1,258,614 $279,909 Center $815,488 $811,869 $838,694 $1,063,869 $225,175 FTE 3,272 3,264 3,281 3, Field $140,672 $137,776 $140,011 $194,745 $54,734 FTE Program Level FTE 4,024 4,061 4,072 4, Budget Authority $477,018 $477,502 $477,810 $472,683 -$5,127 Center $345,929 $346,194 $347,817 $344,500 -$3,317 Field $131,089 $131,308 $129,993 $128,183 ($1,810) Budget Authority FTE 2,126 2,030 2,040 2,043 3 Center 1,423 1,284 1,301 1,304 3 Field User Fees $479,142 $472,143 $500,895 $785,931 $285,036 Center PDUFA $469,559 $465,675 $490,877 $501,334 $10,457 FTE 1,849 1,980 1,980 1, Field PDUFA $9,583 $6,468 $10,018 $10,231 $213 FTE Center Generic Drugs $0 $202,731 $202,731 FTE Field Generic Drugs $0 $51,811 $51,811 FTE Field Reinspection $0 $0 $0 FTE Field International Courier User Fee 0 $481 $481 FTE Field Medical Products Reinspection User Fee 1 0 2,749 2,749 FTE Center Biosimilars User Fee 15,304 15,304 FTE Field Biosimilars User Fee 1,290 1,290 FTE 5 5 User Fees FTE 1,898 2,031 2,031 2, Proposed User fee; the amount includes associated rent activity The FDA Human Drugs Program operates under the following legal authorities: Federal Food, Drug, and Cosmetic Act* (21 U.S.C ) Public Health Service Act of 1944 (42 U.S.C. 201) Federal Advisory Committee Act (FACA) of 1972 as amended Orphan Drug Act of 1983 (21 U.S.C. 360ee) Drug Price Competition and Patent Term Restoration Act of 1984 (Section 505(j) 21 U.S.C. 355(j)) (a.k.a. Hatch Waxman Act ) Prescription Drug Marketing Act (PDMA) of 1987 (21 U.S.C. 353) Anti-Drug Abuse Act of 1988 Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 201) Orphan Drug Amendments of

2 Generic Drug Enforcement Act of 1992 Prescription Drug User Fee Act (PDUFA) of 1992 FDA Export Reform and Enhancement Act of 1996 Food and Drug Administration Modernization Act (FDAMA) of 1997* Public Health Security and Bioterrorism Preparedness and Response Act of 2002 Best Pharmaceuticals for Children Act (BPCA) of 2002 Freedom of Information Act (FOIA) as amended in 2002 (5 U.S.C. 552) Pediatric Research Equity Act (PREA) of 2003 Project Bioshield Act of 2004 (21 U.S.C. 360bbb-3) Food and Drug Administration Amendments Act (FDAAA) of 2007 Public Health Service Act of 2010 (42 U.S.C. 262) Protecting Patients and Affordable Care Act of 2010* Allocation Method: Direct Federal/Intramural Program Description and Accomplishments FDA's Human Drugs Program is responsible for ensuring the safety and efficacy of prescription, generic, and over-the-counter (OTC) drug products that are available to the American public. The Program is also responsible for monitoring marketed drug products to ensure patient safety, and monitoring drug quality to ensure the safety of the drug supply chain. The Human Drugs Program, which consists of CDER and ORA's field drugs program, operates with funding from appropriations and user fees. Responsibilities and functions carried out by the Center for Drug Evaluation and Research (CDER) are a result of a series of statutory mandates beginning with the earliest days of the FDA and the Pure Food and Drugs Act of The Food, Drug, and Cosmetic (FD&C) Act of 1938 required that new drugs demonstrate safety before becoming available for public consumption. The Drug Amendments Act of 1962 (also known as the Kefauver-Harris Act) stipulated that a drug should be effective for its intended use. These statutory requirements contributed to the establishment of CDER's mission of assuring that safe and effective drugs are available to the American people. In 1992, Congress passed the Prescription Drug User Fee Act (PDUFA) which has, through a series of reauthorizations over the past 20 years, significantly increased FDA s resources to review human drug applications. The increase in funding from PDUFA has improved FDA's ability to review applications and increase access to drug products in a timely manner. The Food and Drug Administration Amendments Act (FDAAA) of 2007 reauthorized collection of user fees to enhance the review process of new human drugs and biological products. FDAAA expanded the Center s authorities and responsibilities for ensuring a more robust program for monitoring and managing drug safety after new drugs have been approved for marketing. *Authorities under this act do not appear in sequence in the U.S. Code. The authorities are codified as amended in scattered sections of 21 U.S.C. 164

3 CDER s mission is to promote and protect public health by ensuring that safe and effective drugs are available to Americans. This mission supports FDA priorities of improving health care quality and reducing health care costs. CDER regulates over-the-counter and prescription drugs, including biological therapeutics and generic drugs. CDER is also responsible for monitoring the safety and effectiveness of drugs once they are marketed and consumed, as well as assessing the quality of drugs in order to protect the supply chain. In addition, CDER regulates print and broadcast drug advertisements to ensure that health care providers and patients receive truthful, balanced information about drugs. The Office of Regulatory Affairs (ORA) supports the Human Drugs Program by advising FDA leadership on enforcement, import, inspection, and laboratory policies, and by assessing industry compliance with applicable regulations to protect the public health. To provide this support, ORA conducts risk-based domestic and foreign pre-market and post market inspections of drug manufacturers to assess their compliance with Good Manufacturing Practices (GMP). In addition to overseeing the regulated products on a surveillance or for cause basis, ORA responds to emergencies and investigates incidents of product tampering and natural or intentional disasters that may affect FDAregulated goods. In FY 2011, ORA working with CDER, established a staff of highly trained individuals primarily focused on conducting human and animal drug quality inspections of high risk firms. This joint effort between the Center and ORA to provide training and developmental experiences to drug investigators ensures the highest level of competence and professionalism in the drug inspection program. The Pharmaceutical Inspectorate will be maintained in coming years by providing continuing developmental and training opportunities coupled with opportunities to inspect establishments globally to sustain the level of competence. In addition, ORA will continue to develop all drug investigators to reach this level of competence. At the borders, ORA determines product admissibility by performing entry reviews, field exams, and sample collections to ensure that products coming into the United States are coming from approved sources and are properly registered. Through its laboratories, ORA conducts surveillance analyses of prescription and over-the-counter (OTC) products to verify compliance with labeled identity, potency and content uniformity. In instances of criminal activity, ORA s Office of Criminal Investigations (OCI) and the Forensic Chemistry Center complement the regular Field force activities by expanding efforts to develop cases that address the marketing of counterfeit products. The Human Drugs Program executes its regulatory responsibilities in five subprograms including New Drug Review, Generic Drug Review, Drug Quality, Post Market Safety Oversight, and Oversight of Drug Promotion. 165

4 New Drug Review Center Activities FY 2012 Enacted Amount: $440,970,000 (BA: $119,256,000 / UF: $321,714,000) Public Health Focus The New Drug Review function within the Human Drugs Program involves evaluating the safety and efficacy of medical products before those products are marketed to the public. Key functions in the New Drug Review subprogram include: Clinical Review - Pharmaceutical companies must conduct clinical research to test their products. Once the company has completed its research and submitted the findings and conclusions to FDA, CDER assembles a team of physicians, statisticians, chemists, pharmacologists and other scientists to review the company s data on the proposed use of the drug. If a drug is shown to be effective and if its health benefits outweigh its risks, FDA approves the drug for sale. By setting clear standards for the evidence required to approve a drug, FDA helps bring safe and effective new drugs to American consumers. Bioresearch Monitoring CDER monitors pharmaceutical companies research in clinical trials to ensure the safety of people who volunteer for studies and to maintain the quality and integrity of scientific data. CDER conducts on-site inspections of clinical trial study sites, institutional review boards, sponsors, study monitors, and contract research organizations. Pharmaceutical Science and Chemistry Review Evaluating the safety and efficacy profile of new drugs would be impossible without an understanding of how the chemicals involved act in the human body. CDER maintains a corps of highly talented scientists, clinicians and pharmacists who ensure that the new drug review process results in a thorough understanding of how drugs are designed, produced, and delivered to the patient in order to ensure that drugs available to the American public are safe and effective. Pediatrics CDER plays a major role in protecting children who need prescription or OTC drug products by working with companies to conduct studies of children s products. Due to the inadequacy of pediatric use information found in the majority of prescription medications, Congress enacted several legislative initiatives to promote drug development for children. As a result of these initiatives, the number of ongoing pediatric clinical trials and the number of drug products appropriately labeled for children have increased dramatically. Review of over-the-counter (OTC) Products CDER reviews and evaluates OTC drugs to ensure that they are safe, effective, and of high quality. CDER also informs consumers about how to best use OTC products by providing clear, easy-to-read drug information. These drugs play an increasingly vital role in America s health care system. The trend to self-medicate has increased greatly in recent years as health care costs have risen and consumers want to treat minor ailments with OTC drug products. Pre-Approval Inspections Before an application for a new drug product is approved, FDA inspects the product manufacturer to ensure that manufacturing and development 166

5 facilities meet FDA s standards for good manufacturing practices. FDA inspectors must ensure that a drug product is manufactured with reliable consistency and high quality. Public Health Outcome Efficient, accurate, and thorough reviews allow for the availability of safe and effective drug products to consumers. Without consistent dedication to conducting thorough reviews, the public might be at risk of adverse events resulting from unsafe drug products on the market. The pre-market activities associated with reviewing new drugs and inspections of facilities are conducted to pursue FDA s mission to promote and protect the public health. CDER s ongoing efforts to pursue modernization and efficiency, while maintaining safety and efficacy of its approved products, will make new medical treatments available to patients sooner, and improve patients confidence in new drug products. Promoting Efficiency Modernization is a critical component to improving efficiency at CDER. Developing and adopting standards for receipt and processing of electronic data will help to minimize the use of paper submissions which must be stored year after year, at increasing cost and take advantage of advanced computing techniques to review enormous quantities of data associated with a drug submission. Currently, CDER has a plan for developing data standards. The plan addresses challenges concerning the volume and complexity of drug-related information submitted to CDER for regulatory review. The lack of standardized data affects CDER s review processes by curtailing a reviewer s ability to perform integral tasks such as rapid acquisition, analysis, storage, and reporting of regulatory data. Improved data quality, accessibility, and predictability will allow more time for reviewers to carry out complex analyses, ask in-depth questions, and address late-emerging issues. This will improve the Center s ability to evaluate applications for new drugs and conduct in-depth reviews of drug products. New Drug Review Field Activities FY 2012 Enacted Amount: $35,684,000 (BA: $25,666,000 / UF: $10,018,000) Public Health Focus ORA s public health focus under the New Drug Review subprogram is to assess whether methods and facilities used for manufacturing, processing, and testing of products submitted under New Drug Application (NDA) are adequate to ensure strength, quality, and purity. ORA inspects establishments to verify their ability to manufacture products to the specifications stated in the application. ORA also confirms the authenticity of the data contained in the application and reports any information which may impact the firm's ability to manufacture the product in compliance with GMP. Inspectional coverage is 167

6 necessary to assure that NDAs are not approved if the applicant has not demonstrated the ability to operate with integrity and in compliance with all applicable requirements. ORA conducts Bioresearch Monitoring Program (BIMO) inspections of scientific studies which are designed to develop evidence to support the safety and effectiveness of investigational drugs. Physicians and other qualified experts ("clinical investigators") who conduct these studies are required to comply with applicable statutes and regulations intended to ensure the integrity of clinical data on which product approvals are based and, for investigations involving human subjects, to help protect the rights, safety, and welfare of these subjects. Public Health Outcome In an effort to increase public awareness and knowledge, FDA shares a series of lists on its website containing information on clinical investigators who: received notification from the Agency of the intent to initiate administrative proceedings to determine if the person should be disqualified from receiving investigational products are disqualified or 'totally restricted' and are no longer eligible to receive investigational drugs, biologics, or devices have been recommended for disqualification All clinical investigators who agreed to certain restrictions agreed to restrictions which have been subsequently removed provided FDA with adequate assurances of their future compliance with requirements applicable to the use of investigational drugs and biologics. FDA also makes available a separate list of firms or persons who have been debarred under Section 306 of the Federal Food, Drug and Cosmetic Act. Based on referrals from the OCI and other sources, ORA debarred fifteen individuals with criminal convictions from participating in certain aspects of human drug industry activities. Promoting Efficiency Through its pre-approval inspection coverage, ORA prevents unsafe and ineffective drugs from being marketed to the public while assuring the release of safe products into the US market. ORA also assures that a manufacturing establishment named in a drug application is capable of manufacturing a drug in compliance with Current Good Manufacturing Practice (CGMP), and that data that supports drug review are accurate and complete. These efforts also provide industry with assistance in addressing possible safety issues related to products as well as provide guidance through inspectional findings on current manufacturing processes. Through the post approval program, ORA audits drug manufacturing establishments to assure that any changes in manufacturing and process control comply with CGMP 168

7 regulations, to assure that all changes are documented in supplemental applications or annual reports, and to confirm that requirements concerning Adverse Reaction Reports, NDA Field Alerts, and Annual Reports are being met. Both foreign and domestic establishments are covered by this program. These efforts allow the Agency to provide guidance and assistance to manufacturers, through inspectional findings, to ensure product development is in accordance with FDA regulations and assurance of product safety for products currently in the US market. Performance Measures The following table lists the performance measures associated with this subprogram. Measure : Percentage of Standard NDAs/BLAs within 10 months. (Output) : Percentage of Priority NDAs/BLAs within 6 months (Output) Most Recent Result / Target for Recent Result FY 2010: 98% Target: 90% (Target Exceeded) FY 2010: 100% Target: 90% (Target Exceeded) FY 2012 Target FY 2013 Target FY /- FY % 90% Maintain 90% 90% Maintain Generic Drug Review Center Activities FY 2012 Enacted Amount: $87,936,000 (BA only) Public Health Focus CDER s generic drug review activities are part of the larger generic drugs program, which includes additional activities throughout the Center. The generic drug review subprogram concentrates specifically on the review function. Other non-review work (mainly post market work) within the generic drugs program is captured within other parts of CDER s budget. Generic drugs are widely known to be a cost-effective treatment alternative. According to generic drug industry estimates, generic drug products saved consumers approximately $931 billion between 2001 and In CY 2010,, generic drug products saved $158 billion, or an average of $3 billion per week. Further investments in FDA s generic drug program will generate additional savings for consumers in the future. Every year, FDA expands the availability of high-quality generic drug products and provides consumers and healthcare providers with information on both safety and effectiveness. With each new generic version of a brand-name drug FDA approves, consumers have an additional option to save money on their prescription drug needs. In FY 2011, CDER approved, or tentatively approved, 597 generic drug applications, the equivalent of more than two approvals or tentative approvals each business day. To measure its performance, CDER tracks the number of actions taken on Abbreviated New Drug Applications (ANDA). The total number of actions includes approvals, tentative approvals, not approvable actions, and approvable actions on applications. CDER took 2,276 actions in FY 2011 compared to 2,079 in FY

8 Key functions in the Generic Drug Review subprogram include: Generic application review The basic requirements for approval of generic drugs are the same as for 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 - that the active ingredient in a generic product is absorbed at a rate and extent similar to the brand name product. Medical reviewers from the Office of Generic Drugs (OGD) often consult with reviewers from the Office of New Drugs (OND) to address clinical questions regarding the referenced brand-name drug. Pre approval and Bioequivalence lab inspections As with new drug products, before an application for a generic drug product can be approved, FDA must inspect the product manufacturing facility to ensure that manufacturing and development facilities meet FDA s standards for good manufacturing practices. In addition, FDA inspects the laboratories where bioequivalence studies were conducted to ensure the accuracy and integrity of the data submitted in the generic drug application. Regulatory policy FDA frequently receives citizen petitions for or against an upcoming FDA action on a generic drug application. A citizen petition is a vehicle that stakeholders outside of FDA may use in order to suggest that FDA take or refrain from taking an action. FDA has received numerous petitions asking FDA not to approve particular generic drugs unless certain criteria set forth in the petition are met. In most cases, the petitions raise scientific issues relating to the standards for approval of the applications. CDER must evaluate and respond to each of these citizen petitions. Research into bioequivalence technologies Some types of drugs are very difficult for generic companies to duplicate. This is attributed, in part, to utilization of novel delivery technologies to which the human body s reactions are highly variable (for example, patches worn on a patient s skin, injections, etc.) In cases like these, FDA is eager to understand how to assess bioequivalence as a way to encourage development of generic alternatives, opening the doors to lower prices and better access to drugs for patients. All of the key functions listed above must be conducted in order to ensure the safety, efficacy, and quality of each generic drug. CDER s Office of Generic Drugs is responsible for conducting reviews of generic drug applications. The overall Generic Drug Review subprogram includes efforts from other offices within CDER and ORA to accomplish the key functions mentioned above. Public Health Outcome The availability of generic drugs directly impacts public health by making safe, affordable drug products accessible to the public. With increasing health care costs, many Americans face challenges in acquiring the drug products necessary for proper medical treatment. The availability of safe, effective, and affordable generic drugs supports the FDA mission of promoting and protecting the public health. 170

9 Promoting Efficiency CDER takes several steps to improve the efficiency of generic drug review. CDER expedites applications that, at the time of submission, are the first generic application for an innovator product that had no patent or exclusivity protection. The dramatic increase of generic drug applications creates a greater need for CDER s ability to process applications more efficiently. Steps to improve current processes and to improve the content and completeness of generic drug applications include: The Generic Initiative for Value and Efficiency, which focuses on using existing resources to help FDA modernize and streamline the generic approval process. Question-based Review to assist sponsors in providing information that demonstrates their understanding of the manufacture of the product. Posting bioequivalence information, including data tables, information about laboratory tests, and necessary studies. Focused hiring which will increase staff in critical review components. Holding joint meetings and workshops with academia and industry to improve knowledge of the submission process and quality of applications. Encouraging electronic submission of applications. Data standardization will also support improved efficiency in the generic drug review process, similar to how it promotes efficiency in the review process for innovator drug products. By converting to paperless, electronic data submissions and providing reviewers with standardized formats of data, the time to review and approve is likely to be reduced. This will improve the thoroughness and timeliness of the generic drug review process. Generic Drug Review Field Activities FY 2012 Enacted Amount: $8,029,000 (BA only) Public Health Focus ORA s public health focus under the Generic Drug Review subprogram is to assess whether the methods and facilities used for the manufacturing, processing, and testing of products submitted under an Abbreviated New Drug Application (ANDA) are adequate to ensure strength, quality, and purity. Public Health Outcome ORA supports the generic drug program through pre-approval and post-approval inspections to verify application data and assess the firm s ability to manufacture products in accordance with CGMP. ORA also conducts inspections of bioequivalence studies to substantiate source data and verify accuracy, completeness and regulatory compliance. Promoting Efficiency ORA achieves program efficiencies by ensuring through its inspection program that generic drugs marketed in the United States are shown to be both safe and effective 171

10 prior to marketing and widespread use in the general population, allowing for the marketing of lower cost generics to US consumers. In FY2011, ORA collaborated with CDER to develop a priority listing of Approved New Drug Applications (ANDA) inspections, aiding in targeting inspectional resources and creating Agency efficiencies by identifying generic drug manufacturing facilities for inspection to coincide with Center reviews of applications. Performance Measures The following table lists the performance measures associated with this subprogram. Measure : The total number of actions taken on abbreviated new drug applications in a fiscal year (Output) Most Recent Result / Target for Recent Result FY 2011: 2,276 Target: 2,000 (Target Exceeded) FY 2012 Target FY 2013 Target FY /- FY ,000 2,000 Maintain Drug Quality Center Activities FY 2012 Enacted Amount: $100,171,000 (BA: $44,020,000 / UF: $56,151,000) Public Health Focus CDER s drug oversight activities begin when sponsors test drug products in animals. This oversight continues in clinical development during the first human trials. CDER s role extends into post market safety activities after the sponsor receives FDA approval to market a drug product, and once the product is used by a diverse population. Generic drug products also receive CDER scrutiny to ensure that they have demonstrated equivalent performance to the innovator product. CDER is fully engaged in enforcement actions against drug products that exist outside of the FDA approval system such as counterfeit and marketed unapproved products. CDER provides comprehensive regulatory coverage of the production and distribution of drug products and manages inspection programs designed to minimize consumer exposure to defective drug products. CDER evaluates the findings of inspections that examine the conditions and practices in plants where drugs are manufactured, packed, tested, and stored. CDER also monitors the quality of finished drug products in distribution through sampling and analysis. In addition to setting standards for safety and effectiveness testing, CDER also sets guidelines for drug quality and manufacturing processes. CDER has a team of inspectors and quality management experts who ensure that any change to a manufacturing process does not adversely affect the safety or efficacy of the drug produced. CDER evaluates reports about suspected problems from manufacturers, health care professionals, and consumers. 172

11 Public Health Outcome Assessment of drug quality promotes the initiative to supply the public with drugs that are both safe and effective. This decreases risks of adverse events resulting from poorquality or defective drug products. As a result, consumers face fewer risks associated with unsafe drugs, and public health is protected from exposure to drug products that do not meet FDA standards of quality. Promoting Efficiency CDER s drug quality activities aim to eliminate production inefficiencies and undue risks for consumers by implementing improved policies that make better use of limited resources, and result in more targeted, effective inspections. The Drug Quality subprogram focuses on improving efficiency in critical pharmaceutical quality attributes, such as chemistry, pharmaceutical formulation, stability, manufacturing processes, bioavailability, and product performance. Long term goals include: Emphasizing quality by design in the evaluation of critical aspects of pharmaceutical quality. Focusing on manufacturing science. Integrating review and inspection functions. Using modern statistical methodologies. FDA inspections and sampling from clinical to manufacturing provide feedback to the firm on its state of compliance and result in corrective actions that the firm can bring forward to other relevant activities. Better compliance results in less waste and rework, fewer and less costly manufacturing changes, and fewer product recalls. Drug Quality Field Activities FY 2012 Enacted Amount: $91,884,000 (BA only) Public Health Focus ORA minimizes consumers risk of exposure to defective drug products by conducting inspections, monitoring imports, and collecting and analyzing product samples of domestic and foreign drug manufacturers. These activities prevent marketing of, or remove from the market, violative drug products, thereby ensuring the products do not reach the U.S. market. Early detection of contaminated or defective human drug products and their ingredients continues to be a priority within ORA. ORA field offices investigate and build enforcement cases using a number of enforcement tools such as seizures, injunctions, and prosecutions. ORA is also responsible for oversight and monitoring of recalls conducted by the drug industry, assuring that the companies recall efforts progress satisfactorily and are effective in removing defective products from commerce 173

12 Public Health Outcome In FY 2011, ORA entered into a 3 year Cooperative Research & Development Agreement (CRADA) with the United States Pharmacopeia (USP), the worldwide recognized standard-setting authority for prescription and OTC drug products, to participate in the establishment of USP reference standards for drug quality assessments. This CRADA provides ORA with the ability to utilize highly advanced equipment to participate in collaborative standard assessments to ensure that both novel and existing drug standards and methodologies referenced by regulated industry meet required specifications, while bolstering and expanding efforts to promote drug quality, purity, and efficacy via ORA field laboratory support to USP. The CRADA allows for ORA and USP collaboration in the following efforts: USP Monograph Modernization revising and/or replacing USP monographs which require modernization in order to ensure the quality and potency for active pharmaceutical ingredients and their utilization in the manufacturing of drug products. Throughout FY 2011, select ORA field laboratories actively participated in a Pharmacy Compounding Validation pilot program. The program, which ensures specialized drug products are analyzed appropriately to ensure quality, consistency, and efficacy for pharmacy compounded products, called for ORA laboratories to perform method verification for 10 proposed USP pharmacy compounding monographs. The program resulted in the laboratories completing 9 verifications, and the findings and recommendations for issues to be addressed prior to final classification of the proposed monographs by USP were shared with USP. The tenth assessment is slated for completion in FY2012. In FY 2010, ORA began work with CDER to identify handheld portable analytical tools for use in the field for the early detection of contaminated drug products. ORA qualified a variety of tools and began a multi-tiered implementation program. The implementation program allows ORA to phase in each class of tool for daily use by ORA field investigators at specific U.S. ports of entry. To date, ORA has deployed 2 classes of portable analytical tools for use in limited pilot programs. The first class of tools allows for field staff to perform a limited analytical screen of drug products at the time they are offered for import into the U.S. to determine if toxic elements are present in the drug product. This tool has the capacity to test for additional elements as reference standards and methods continue to be developed within ORA. The second class of tools allows ORA import staff to detect suspected counterfeit drugs or packaging, providing ORA field personnel with advanced technology to assist in screening imported drugs and identify suspect shipments. As a result of the completed pilot deployment of one class of tools in limited locations, ORA has performed more than 230 field examinations. The second pilot program is ongoing. ORA will continue the phased development and deployment of the remaining classes of tools through FY ORA continues to see an ever increasing number of drug products being offered for import into the U.S through international mail and courier facilities. ORA works with other government agencies in joint operations to address these shipments. In FY 2011, ORA worked with Customs and Border Protection (CBP) through joint operations such as monthly Operation Safeguard blitzes to monitor these shipments through targeted blitzes 174

13 at various mail and courier facilities to detect counterfeit and unapproved versions of approved medications. Additionally, ORA participated in Operation Pangea IV, a global collaborative effort amongst government agencies in 43 countries, to perform targeted blitzes throughout the year targeting counterfeit drug products sold via the Internet. In FY 2011, ORA issued or updated 16 Import Bulletins and issued more than 110 identifying modifications to drugs related to Import Alerts encompassing numerous human drug products, combination drug products and drug firms determined to be manufacturing or shipping unapproved pharmaceutical products. These actions were a result of ORA import surveillance collections and testing of regulated drug products at the time they were offered for import into the U.S. as well as for cause sampling of imported products based on ORA findings of violations during inspections of foreign manufacturers. These notices serve to provide increased coverage at the border to assure these products are not available to the U.S. consumer. ORA exceeded the FY 2011 performance goal targets, and completed more foreign drug inspections than in the history of the program, for high risk foreign drug surveillance inspections by working with our Global offices and continued staffing of the ORA dedicated foreign drug cadre, consisting of 15 experienced drug investigators, which augments the existing foreign inspection program. In response to post-marketing complaints of contamination of purported sterile marketed products manufactured in India, ORA investigators in the Global office performed inspections of manufacturing establishments while ORA field investigators completed follow up inspections of domestic facilities involved in the issue. ORA investigations, both domestic and foreign, identified violations of post-marketing adverse drug experience reporting and resulted in subsequent recalls of three marketed products. In January 2011, FDA worked to stop importations of Fruta Planta, a product implicated in the death of a Florida woman. The product, labeled as a dietary supplement, contained the active pharmaceutical ingredient sibutramine, which can cause serious adverse reactions, including death. Sibutramine is known to substantially increase blood pressure and pulse rate and may present a significant risk for people with a history of coronary artery disease, congestive heart failure, arrhythmias or stroke. ORA subjected the product to detention without physical examination and also worked with our CBP partners to seize a number of shipments. FDA also issued a warning to consumers not to use the product. In FY 2011, ORA continued to staff the Commercial Trade Analytical Center (CTAC), a facility designed to identify safety risks in imported products by leveraging information sharing and data analysis by numerous government agencies. Once the risks are identified, the appropriate agencies work together to minimize the risk. ORA works closely with other government agencies on issues including products with undeclared active pharmaceutical ingredients and other unapproved drug products. ORA monitors recall of human drugs that have been found to present safety concerns, and assures the adequacy of the firm s recall to effectively remove defective products from commerce. Through the classification process, the Center determines the level of public health risk the product presents. Appropriate public notification is also a 175

14 component of the agency s recall program. In FY2011, FDA classified and issued recall numbers for 91 Class I; 1,279 Class II; and 246 Class III recalls of human drug products. ORA created and successfully launched a searchable FDA webpage and database for recalls in April Additionally, a process and tracking system was developed to ensure timely posting of firm recall notices on the intranet within 24 hours of receipt. In support of the President's Transparency Initiative, ORA started posting the most common inspection observations of objectionable conditions or practices that are made during inspections as well as a searchable database of inspected facilities with FDA inspection classifications. This website premiered in May 2011, and included data for FY2009 and FY2010 inspections. The Agency is committed to updating the data periodically, but at least twice per year and has already updated the data to include the first six months of FY2011. This action will provide the public and regulated industry with more information about company practices that may jeopardize public health, as well as about companies that are complying with the law. In FY2011, the agency s MARCS-Compliance Management System has indicated three approved CDER injunctions and two seizures for drug products. These actions helped protect patient safety by assuring that manufacturers comply with laws and regulations. An example of recent enforcement actions include FDA s March 2011 filing of a consent decree of permanent injunction against a large manufacturer of over-the-counter drug products and two of the firm s officers. The manufacturer failed to comply with current good manufacturing practice (cgmp) requirements as required by federal law in the manufacture of multiple liquid drug products. Inspections at multiple manufacturing facilities of this corporation, beginning in CY 2009, found violations of cgmp requirements. Deficiencies at these facilities resulted in several extensive recalls, including an April 30, 2010, recall of lots of several liquid products indicated for children. The consent decree required the firm to destroy all drugs under their control that have been recalled from multiple facilities since December In February 2011, FDA seized all lots of a drug solution used to treat pain and inflammation associated with ear infections. Sale of the product in the United States violated federal law because the product does not have FDA approval and its labeling did not include adequate directions for use. The seizure, estimated to be worth more than $16 million, was the final step in a regulatory process stemming from a 2009 inspection of the manufacturer and a Warning Letter that was issued in In FY 2011, ORA inspected several firms potentially involved in the manufacture of drug products of concern in an outbreak of Bacillus cereus. ORA s inspection at a manufacturer of multiple human drug and medical devices found multiple violations of cgmp requirements, including failure to adequately investigate drug products that did not meet specifications. The inspectional findings led to the recall of several drug products and the seizure of more than $6 million in products. A variety of drug products were seized, including povidone-iodine and benzalkonium chloride antiseptic products, cough and cold products, nasal sprays, suppositories, medicated wipes, antifungal creams, hemorrhoidal wipes, in-process drug products, and raw materials. FDA sought an injunction, and a consent decree of permanent injunction was entered in June

15 In FY 2011, ORA issued 108 warning letters to prevent the continued distribution of adulterated human drug products in U.S. commerce. In FY 2011, FDA issued numerous press releases citing concerns about dietary supplements that contained active pharmaceutical ingredients. The press releases warn about potentially harmful marketed dietary supplements, citing the product lots of concern when the information is available and providing guidance to consumers on possible interactions with other medications. The releases also provide a next step if a consumer has a product of concern. In December 2010, FDA issued a warning to consumers to avoid a dietary supplement because the product contained a variation of an active drug ingredient. In May 2011, FDA identified a dietary supplement of concern that was deemed to be counterfeit and containing active pharmaceutical ingredients. FDA s analysis of the product identified two lots of counterfeit dietary supplements. ORA and CDER co-led an FDA and FTC joint enforcement and outreach initiative targeting fraudulent products to treat and prevent sexually transmitted diseases (STDs). FDA and FTC issued 12 joint warning letters and FDA issued one independent letter to internet and retail firms marketing supplements and external products to treat STDs. A national roll-out for the initiative featured a press call led by ORA and a public health physician, consumer education materials, a podcast and a video. In September 2011 in coordination with ORA s Health Fraud communication campaign, ORA launched the Health Fraud website to help raise awareness and educate consumers, many of whom include vulnerable and underserved populations, on scams that can lead to ineffective or delayed treatment and cause serious or even fatal injuries. Videos and print materials have been developed in both English and Spanish and can be accessed through the FDA website. In cooperation with CDER, the Office of Criminal Investiagations (OCI), the Office of Regional Operations (ORO) and CFSAN, ORA initiated and implemented a strategy to monitor the marketplace, conduct undercover purchases and investigations as part the "Operation Shady Supplement" enforcement initiative. An updated strategy emphasizes the development of criminal cases against distributors of tainted supplements by OCI. In addition, a CDER-issued sampling assignment to intercept and analyze imported samples at international mailrooms is being conducted in several districts. A white paper that describes the results of the sampling assignment will be presented at the Bilateral meeting with China in December At the meeting, CDER and ORA will again convey to the Chinese government the serious health threat posed by tainted supplements and ingredients from China and will attempt to gain cooperation from the Chinese authorities to combat the problem In collaboration with Canada s Competition Bureau, FDA issued two ORA -recommended warning letters to US firms marketing dietary supplements in the US and Canada on the internet and Facebook with unapproved disease claims. The warning letters were intended to target the rapidly expanding promotion of health products with illegal and deceptive claims on social networking media sites such as Facebook. The Competition 177

16 Bureau also issued warning letters to the firms. One of the firms has complied and follow-up continues with the other firm. For the 2011 Internet Week of Action, the ORA Office of Enforcement (OE) reviewed nearly 1,700 websites identified by OCI that sell unapproved prescription drugs with or without a prescription. OE captured more than 1,000 violative websites to be used as evidence to support CDER warning letters to website operators. This annual international enforcement initiative was announced in a press rollout in late September ORA drafted a new Compliance Policy Guide (currently in final clearance status with the Department) describing policy for refusing imports of foods and medical products exported from facilities that have refused an FDA inspection. This CPG will facilitate the Agency s ability to prevent the introduction of foods and medical products in US commerce from facilities that have delayed, denied, or moved to avoid an FDA inspection. In instances of criminal activity, ORA s OCI is expanding efforts to develop cases that address the marketing of counterfeit products. The increasing globalization of crime has created new challenges to law enforcement. OCI coordinates counterfeit drug investigations with several foreign counterparts, especially those in China, Israel, Canada and the United Kingdom. These efforts continue to produce positive outcomes for both OCI and its foreign counterparts. OCI continues to aggressively pursue counterfeit drug investigations with law enforcement partners in foreign countries as well as with Federal, State, local, tribal, and territory law enforcement here in the U.S. During FY 2011, ORA s OCI made 258 drug related arrests, and secured 214 drug related convictions with fines, restitutions and other monetary penalties in excess of $981 million. A sampling of some of the specific case activity that led to these positive public health outcomes are as follows: Misbranded drugs sold over online search engine GOOGLE Inc One of the largest forfeitures in the United States - In August 2011, OCI successfully completed an investigation involving illegal sales and marketing over the Internet conducted by online search engine Google Inc. Google agreed to forfeit $500 million for allowing online Canadian pharmacies to place advertisements through its AdWords program targeting consumers in the United States, resulting in the unlawful importation of controlled and non-controlled prescription drugs. The OCI investigation revealed that Google took steps to block pharmacies in countries other than Canada from advertising in the U.S. through AdWords. Google continued to allow Canadian pharmacy advertisers to target consumers in the United States. Google was aware that U.S. consumers were making online purchases of prescription drugs from these Canadian online pharmacies, and that many of the pharmacies distributed prescription drugs, including controlled prescription drugs, that were based on an online consultation rather than a valid prescription from a treating medical practitioner. At the time, Google was also on notice that many pharmacies accepting an online consultation rather than a prescription charged a premium for doing so because individuals seeking to obtain 178

17 prescription drugs without a valid prescription were willing to pay higher prices for the drugs. In addition, Google also provided customer support to some of these Canadian online pharmacy advertisers to assist them in placing and optimizing their AdWords advertisements, which assisted with improving the effectiveness of their websites. Counterfeit Drug/Misbranded Products - In June 2011, a foreign national from China was sentenced to serve 87 months in federal prison for trafficking and attempting to traffic in counterfeit goods, namely counterfeit versions of the pharmaceutical weight loss drug known as Alli. In addition, the defendant was ordered to pay restitution totaling approximately $505,000 to the victims of his crime, including an emergency room doctor who suffered a mild stroke from ingesting the counterfeit medication. The OCI investigation was initiated in January 2010, to target the manufacturer of tainted weight loss products and counterfeit drugs that were the subject of a series of FDA public alerts issued in 2008, 2009, and The OCI investigation determined that a foreign national from China was responsible for illegally manufacturing and importing the counterfeit Alli. The foreign national was arrested in March As a result of the investigation, FDA warned the public about counterfeit Alli, a popular over the counter weight loss drug manufactured by Glaxo-Smith Kline. The counterfeit versions of Alli were being sold in the United States, among other ways, through internet auction websites. Misbranded and unapproved imported drugs - Sentencing in major fraudulent dietary supplement investigation In March 2011, an individual was sentenced to three months in prison for importing and distributing more than four million diet pills that contained a controlled substance, an anti-seizure medication, and a chemical solvent that is considered a possible carcinogen. This individual pled guilty to an 18 count superseding indictment, including 11 counts of mail fraud, one count of conspiracy to smuggle illegal merchandise, and six counts of distribution of a Schedule IV controlled substance known as Sibutramine. The OCI investigation led to the conviction and sentencing of the defendant who owned and operated a business which imported and distributed a variety of beauty products, including diet pills. The defendant attempted to smuggle the pills using packages with customs declarations that falsely described the capsules as gifts worth minimal amounts. The defendant was also ordered to pay a fine in the amount of $5,000, complete three years of supervised release including eight months of home detention, forfeit $250,000, and pay a special assessment of $1,800. Misbranded drugs - Former CEO sentenced to prison In March 2011, a former CEO and Chairman of the Board of a Missouri-based drug manufacturer pled guilty to two federal charges of misbranding drugs and was sentenced to a one month term of imprisonment and fined one million dollar fine. In addition, the defendant was also required to pay $900,000 forfeiture to the United States. 179

18 The defendant admitted that during the summer of 2008, the company shipped oversized morphine tablets to retailers in San Francisco, California and Canada. The drugs labeling was false and misleading because it stated that the drugs were of uniform strength when the tablets of the drugs were oversized and contained more of the active ingredient of the drug than what was specified on the labels. The California morphine tablets weighed over twice the specified amount, while the Canada morphine tablets were 65% stronger than what the label claimed. Both of the misbranded morphine tablets had the same color and engraving as a normal and correctly sized tablet. The company conducted a safety assessment in May 2008 concluding that oversized morphine tablets raised potential safety concerns for patients, including the possibility of acute overdosage, respiratory depression, stupor, coma, and even death. Doctor Sentenced in Foreign-Sourced IUD Investigation In September 2011, a doctor in Arkansas was sentenced to five years probation, fines and community service after an OCI investigation led to a conviction on one count of misdemeanor misbranding of a drug and one count of health care fraud. The doctor obtained, and implanted in patients, Mirena IUDs (Intrauterine Devices) from foreign sources that were not approved for use in the United States. The IUD s were labeled in Scandinavian and Turkish languages. The doctor committed health care fraud by billing a state Medicaid program, TRICARE and private insurance companies as if he were providing the beneficiaries with the FDA approved IUD s instead of the unapproved versions he had obtained at a lower cost. OCI Proactive Ongoing Initiatives: Operation Pangea - For the past four fiscal years, OCI has participated in Operation Pangea, which is an International Internet Week of Action (IIWA). For FY11, OCI coordinated with the FDA Office of Enforcement (OE) and Center for Drug Evaluation and Research (CDER), to target approximately 1,000 websites for illegal activity associated with prescription drugs. This year, both CDER and OCI sent representatives to INTERPOL in Lyon, France to provide hands-on assistance at the command post. As in previous years, CDER issued warning letters against approximately 700 websites. Additionally, OCI worked directly with the domain name registrars, Internet service providers, and payment providers and was successful in getting approximately 600 of the approximately 1,000 websites permanently shut down. The project received positive press, and was highlighted in the IIWA Reports prepared by INTERPOL and distributed worldwide. (Operation Pangea is led by Permanent Forum on International Pharmaceutical Crime (PFIPC) in cooperation with INTERPOL) Internet Investigations - Drug investigations involving the Internet are conducted by OCI and provide some of the most egregious threats to the public health. OCI is responsible for conducting criminal investigations of internet pharmacy sites and other internet drug sites whose operations involve potential criminal activity. These complex and resource intensive investigations have become increasingly global in nature as criminals based in foreign countries masquerading behind the anonymity of the internet offer counterfeit and unapproved drugs to U.S. 180

19 consumers, circumventing U.S. Customs and FDA regulations. Suspect websites are researched and possible violations identified. OCI field offices receive investigative assignments which often include undercover buys and other resource intensive activities. OCI continues to foster strong working relationships with other law enforcement agencies in the U.S. and overseas to identify and prosecute violators who use the internet to sell drugs that threaten the health and safety of the American public. OCI has been identified by our domestic and foreign law enforcement peers as an expert and global leader in Internet investigations. Additionally, in FY11, OCI provided multiple Internet investigation training courses (both domestic and foreign) to our regulatory counterparts from many countries, including: Canada, Italy, United Kingdom, Ireland, Israel, Romania, Estonia, Poland, Czech Republic, and others. H1N1 Epidemic - During the H1N1 epidemic, OCI conducted a significant number of test purchases of Tamiflu products from internet pharmacies. None of the test purchases required a prescription. As a result of these efforts, FDA issued an alert to consumers after it was determined that a potentially harmful product represented as Generic Tamiflu sold over the internet did not contain Tamiflu s active ingredient, oseltamivir. Instead it contained cloxacillin, an ingredient in the same class of antibiotics as penicillin, which could result in injury or death for consumers who are allergic to it. Pharmaceutical Fraud Program (Health Care Fraud and Abuse Control Investigations) - In FY 11, OCI continued the coordination and communication between criminal investigators, regulatory components of FDA, and the United States Attorney s Offices investigating health care fraud-related investigations. As a result of the investigative efforts during FY 11, OCI secured two indictments; a physician and clinical research coordinator were indicted on charges of falsifying study data in a clinical trial. The indictment alleges the defendants falsely stated physical examinations had been conducted on two unqualified test subjects, signed false statements to FDA indicating the clinical study was being conducted in accordance with proper protocol and arranged for the unqualified subjects to have office visits while the executive director was at lunch to conceal the fact the test subjects were ineligible. The ineligible test subjects were employees of the research institute and under the required age to participate. In addition, sixteen criminal investigations were initiated including the following: 1) four investigations involving allegations of off-label drug promotion by different manufacturers of brand name drugs; 2) one investigation involving allegations of off label drug promotion and other violative promotional issues by a manufacturer of brand name drugs including unsubstantiated superiority claims and omission of risk information; 3) one investigation involving a medical device manufacturer pertaining to issues involving a recalled device product; 4) one investigation involving allegations that a company withheld nonclinical studies from FDA regarding Investigational Device Exemption applications because the studies demonstrated that the products in the applications could be hazardous to patients, and; 5) nine investigations involving allegations of clinical trial fraud and/or application fraud. 181

20 National Document Center - In FY 2011, OCI received special funding from the Department of Justice (DOJ) to apply towards the completion of the recently established OCI National Document Center. This center supports OCI criminal investigations in order to obtain substantive data relating to fraudulent activity involving FDA regulated products in order to maximize monetary recoveries related to illicit proceeds. Many OCI investigations are complex and very document intensive which require a scanning and optical character resolution (OCR) solution, in order to search, identify, extract and analyze key information relating to fraudulent activity involving FDA regulated products. This information is often required by United States Attorney s Offices (USAO's) who are accepting the cases for federal prosecution. The OCI Document Center is being used for, but not limited, to OCI criminal investigations such as those that include the Off-Label Promotion of FDA approved drugs and medical devices, application fraud, clinical investigator fraud, healthcare fraud involving FDA regulated products, and import investigations involving any criminal investigations national in-scope or document intensive cases involving FDA regulated products. Promoting Efficiency The Predictive Risk-based Evaluation for Dynamic Import Compliance Testing (PREDICT) tool allows ORA to focus resources on high risk commodities, providing greater assurance that imported products are safe and effective for use by U.S. consumers. Expedited clearance of low risk products helps ensures that products are available in the U.S. market providing consumers and health care providers with the commodities of necessity. ORA continues to identify violations during inspections of foreign facilities to establish pre-emptive import controls. These internal actions provide for the increased surveillance of products regulated in the violative firms to ensure a higher level of scrutiny if products are offered for import into the United States. In May, 2011 a new streamlined enforcement process for seizures and injunctions was implemented. The new process increases collaboration at an early stage in the process of case development; reduces paperwork by removing redundant and unnecessary documentation; removes a bias toward inaction by making the process less daunting and more collaborative; provides a mechanism for continuous improvement in case development; and shortens approval times. In order to achieve these changes, the Compliance Management System (CMS) was modified to capture milestones and allow concurrent review; the RPM was updated to incorporate the significant process changes; and a training video was developed on the new procedures. ORA coordinates information sharing with the Veteran s Administration (VA) regarding the regulatory compliance of drug establishments. This collaboration has resulted in the VA s removing products from its hospitals that violate safety standards. Because of this information sharing, the VA has implemented stricter policies to ensure products purchased are produced in compliance with FDA s GMPs, thereby ensuring the quality of medical products available on the Federal Supply Schedule. 182