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United States Government Accountability Office

GAO Report to the Ranking Member,

Committee on Finance, U.S Senate

November 2009 DRUG SAFETY

FDA Has Begun

Efforts to Enhance Postmarket Safety,

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BGA Oe GAO

Highlights

eee eee

Why GAO Did This Study There have been longstanding ‘cet Reger te Poel aed Drug Administration's (FDA) oversight of postnaret deus

PDA hat notclery defined the Toles aft ofc involved i (haking docs in the Of about point of New Druss

(OND) an me Omcw of Suneillanee and Epidemiology (OSE), GAO and others report ‘uiitonal conceme such

Tiiions in the dala FDA reion ‘onto Hendy postmarket drug Safety sus and the syste It fete trek mh fe At hat time, GAD made recommendations Including hat PA improve the dbpeilense of prota for reeoingslienic đeputes led to postmarket drug safety a 207, legion further expand FDA's

postmarket responsibil, This Terooxanlnes the tps that FDA ‘Staking (1) chhancel

processes for making đecions hoài the safety of marketed drugs (@himproveaccowsto data that Tiếp te agency enti drug cty ses and (S) bull ts caput to fu is pontarket deg salety ‘workload GAO reviewed FDA Poles and planing documents Ta

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(GAO recommends Aeselop a comprehensive that FDA plan Drepate OSE ford transfer of ‘Midna regulatory autores ftom OND FDA agreed recommendation ith GAO's

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DRUG SAFETY

FDA Has Begun Efforts to Enhance Postmarket Safety, but Additional Actions Are Needed

What GAO Found

FDA\is boxing to address previously ientified weaknesses in ts oversight of postmarket drug safety issues, but challenges rea The agency i ‘changing ta postnanketdeelalon-maling process as pat of ia Safety Fla Initiative, which includes formating interactions between OND and OSE and providing OS® with added responsiities The one authority FDA transferred fom OND to OSE fsa promarket review responsibilty PDA officals sal the agency plans to lane authority for two postmarket responsibilities for reviewing certain types of drug safety sti, but the agency doos not have a tine frame for thelr transfer Officials said that OSE mst sil gain experience leading the one transferred responsiblity nd expand ils aff before tea sume these sitions responsibilies While most ofthe OSE and OND “mployecs GAO interviewed indicated that OSE olen manaing safety {sstes has increased since 2006 most OSE employees GAO Interviewed sald that OND's perspective sil earrles more Weight indecision malin OND econly created safety management positions in each ofits 17 avisions; OSE ‘expanded itssmilar postions from 9 25, although an employee said fumover has made it dificult for the OSE managers to gain experionee, FDA {alo revising fs program fr esolsing cient dispute, bul these changes Ihave not inereasd its independence, as GAO recorumened

[PDA plans to implement new data systems and is increasing access to ‘exter daa sit with dra safety decisions FDA pans la plement new systems in 2010 to improve the timeliness, quali and analysis of reports bfaudverse evens associated with human drug use FDA has also increased fading for conteact with private companies andi nthe early stages of forming partnerships with federal data holders to acess external dat As ‘maniatel in the 2007 legislation, FDA is developing the Sentinel System, a network of external data providers intended to enhance dug safety surveillance, but the agency sn the early tages of developing it

[PDA faces challenges mecting an expanding workload The ageney indicated that expanded responsibiites resulting from the 2007 legislation increased is ‘workload and both OND and OSE employees described diulties meeting theie responsibilities, FDA indicated that since fisal year 2008, OND stall {ncreased from 726 t0 028 and OSE staf increased fom LH to HA, However, an agency Fevlew sugaests that OSE may’ sil nee to moe than double Hs ‘aff of 1 by fiscal year 2011 to mee its new responsibilities Alhonsh OSE

hha increase is sta, officals cited hiring challenges, such as competition ‘om the private sector, that may make it difiel to hie tft quickly enough {ommeet the increasing workload PDA also expects to complete a growing umber of drug safety stndes, bu technological and staffing challenges init ft capacity to conduct these studies, To assist its decision making, FDA as increasingly sought advice from members ofits external drug safely aviary committee However, the agency has encountered dficuly filing several ‘Somes vacancies An official sald FDA ts reviewing candidates with the ‘eal of fling these vacancle as acon as possible

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Contents

Letter i

Background DA Has Begun to Formalize is Postmarket Decision-Making Process and Recently Implemented Oxersighthtiatves, but ‘

Challenges Remain 6

BDA Plans to implement New Adverse Event Systems and Is Increasing Access to External Sources of Drug Safety Data Pn Although Stat Has Recently Increased, FDA Faces Challenges Meeting les Expanding Postmarket Safety Workload a1

Conclusions 30

Recommendation Agency Comments and Our Evaluation 40 an ‘Appendix I Recommendations Status of FDA Actions Related to Our 2006 “

‘Appendix IT ‘Comments from the Department of Health and

‘Human Services 4

‘Appendix IT ‘GAO Contact and Staff Acknowledgments 4

Table

‘Table 1c Selected Data Sources FDA Uses to Inform Its Drug Safety Decision Making ° Figure

igure 1: OSE and OND Funding, Fiscal Years 2004 through 200915

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‘Abbreviations

Adverse Event Reporting System

Center for Drag Evaluation ané Research MS DARRTS Document Archiving, Reporting and Reyalatory Centers for Medicare & Medleaid Sexiees Tracking Sysiem

pet data collection instrument bop, Depatanent of Defense

bea, DSakM difering professional opinion Dig Safety and Risk Management Advisory Commitee BSG Electronic Submissions Gateway

FAERS FDA Adverse Event Reporting System FDA ood and Drag Administration

FDAAA Foodland Drag Administration Amendments Act of 2007 HữS Departament of Health ard Human Services

om Institute of Medicine MOA memoranduns of azreement o1G OND, Diice of nspector General tee of New Drugs

OSE PDUFA Dies of Surveillance and Epidemiology —Pregeniption Drug ser Fee Act of 1502 REMS Risk Evaluation and bliigation Steategy va Department of Veterans Alfie

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i

& GAO

Taited States Government Accountability Offce Washington, DC 20548

November 8, 2000

"The Honorable Charles, Grassley Ranking Member Commitee on Finance United States Senate

Dear Senator Grassley

CConcenis about the Food ane Drug Administration's (®DA) management fof safety Issues for drugs approved for marketing have been fons

standing," Reviews dating back aver 0 years have identified problems related fo the agency's monioning of posimareet drug safety." In 2004, high-profile drug safety cases continued to raise concerns about FDA'S process for evaluating postnsarket safety and making decisions abont what Actions to take, For estmple, FDA was evitielzed or taking t00 long Inform patients of serious drug risks There were aso reports of Elsageeements within the agency about how to address certain safety ‘sues and reports that some FDA scientists were discouraged by Supervisors from ralsig questions aot the safety of certain dss

process for making postmarket drug safety’ decisions involves multiple ‘ffces including the Office af New Drags (OND) and the Ofice of ‘Surveillance and Epidemiology (OSE) OND is involved in drug review activities throughout the ie evele of deg (hat, premarkec and postmarked) For postnarket safety issues, OND's activities nelude Interacting with OSE,” whieh evaluates and monitors drug sk ad promotes the safe se of drs,

DAS

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‘Since these concems were raised, we and other organizations have

conducted reviews of FDA's process for monitoring the safety of marketed ‘rugs In 2006, we reported that FDA had not clearly defined the role of (OSE in postmarket drug safety and communication problems between (OND and OSE had hindered the decision-making process,’ We also found ‘weaknesses inthe data that FDA relied on to kdentify postnarket drug safety issues and in the systems it used 1 tack them once they were dented In addition, 2 2006 Institute of Medicine (ION) report identiied Similar weaknesses, 1OM also reported that FDA's resources for

postmarket drug safery were inadequate and that this could impede the Agency's ability to ldentify and take ations to address drug safety isses More recently, HHS's Office of Inspector General (O16) identified

‘oversight of drug safety as one of HHS's top management challenges and ‘earlier this year we added FDA's oversight of drugs and other medial products to our list of high-risk federal programs"

You raised questions about FDA's postmarket drug safety programa and asked that we follow up on our 2005 report to examine the role of OND and OSE in the postmarket monitoring of drugs Ths report examines the ‘steps that FDA Is taking o (1) enhance ls processes for making decisions about the safety of marketed drugs, 2) improve access co data hat help the agency identify drug safety issues, and (9) build its capacity to Full its postmarket drug safety workload

‘To desere the steps FDA is aking to enhance its processes for making {ecisions about the safety of marketed drugs, we reviewed FDA policies land planning documents and interviewed officals to identify specific actions being taken by the ageney.” We also interviewed all individuals ‘GAO, Drag Slt fmprosonent Need In FDI Postart Deion mag ed Oerig Pres GA 105 astngon, BC: Ma 3,8)

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who were members of FDA'S dg saeiy aavisory committee of external ‘experts, the Drs Safety and Risk Management Advisory Committee (DSakA), a8 of Jamary 2000 fr aldion, we examined policies reated co FDA's program for resolving professional seietife disputes and

interviewed EDA officials about its tliatson hy employees, To describe Steps FDA is aking to improve access ro data that help the ageney Weatiy Ang safely soues, we reviewed dacumentation deseribing the

{evelopment and plementation of systems the ugeney uses or collecting and monitoring drug safety data We also examined contracts FDA has entered into with extemal organizations and agreemtenis with federal agencies to access information about dg use an patient

‘outcomes To deseribe the steps that FDA is aking to bn it eapacity co Full ts postmarket drug savety workload, we reviewed staffing dara provided bythe agency and documents related to the agency's efforts to assess Workload We also interviewed FDA officials rezareing hising Iniaives ta meet ls postmarket dug safety responsibilities

In ation, to supplement our work foreach ofthe three abjectives, we conducted a series of interviews with small groups of OND and OSE ‘employees with responsibilities iwvolving postinarket dg safety Each Sinallgronp interview eansisted ofa group discussion to eapiure general ‘hemes about these aeiRlUes ALihe conehision ofeach slerview, we asker each exployee to complete a written data collection insrument

(DCF to document their responses to specific questions about the

agency's postmarketdecsion making process Ta select emplasees for our ‘small group interviews, ee obiained Nateh 2008 scaing data from FDA, nd confirmed te accuracy of these data through discussions ith ‘ffcils from OND and OSE, We also sed our discassions with the OND and OSE officials ro help us identify employees with no management responsibilities and a least d years of experience in the Center for Deg Evaluation and Researel (CDER}, We selected these employees heeanse they are directly engaged in postmarket safety activites and would bein a position 1o comment on changes made by the agency ince ou 2006 report

For OND, we selected employees from it four divisions with the largest ‘number of employees,” which we Mentiied using the March 2009 staring,

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Background

‘data, We determined that these data were wulicently reliable forthe parpose of our report Por each division, we ravdomy selected to Interview five medical reviewers, who are the indvials responsible for reviewing data on the snfety and efficacy of drgs In one division, we also spake with a second group of reviewers becatise that division has

‘stablished separate reams of general reviewers and reviewers with specific dua safets responsibilities Baved on these seleeton enteria a ‘he avallahilty of employees, we condueted five small group interviews Four or five employees, each of

For OSR, we selected all employees ftom each af the office's five divisions ‘who met our erteria to inerview: For one division, we divided employees Into io interview groups because ofthe large nutaber of employees meeting our seleetion eritera Based on these seletion criteria and the availabilty of enployces, we conducted Ss sal geoup interviews of| between three and six employees, each,

-Acrass al of the small zoups, we interviewed a total of 52 employees, «each of whom conypleted DCI The views expressed bs these employees ‘cannot be generalized to all employees working within these offices, ‘We conducted this performance avait from October 2008 trough October 2000 in aeeordance with generally accepted government auditing

Standards Those staudards requite that we plan and perform the aud lọ ‘obtain suiient, appropriate evidence (o provide a reasonable bes for ‘ou findings and conciusions based on our ait oectives, We believe thatthe evidence obtained provides a reasonable basis for our findings nd conchslons based on our adit ohectives

Before adrg an be marketed inthe United States, sponsor mnt emonatrate 1o FDA thatthe drug is safe and effective for its intended use FDA approves a deug for marketing when the aseney judges that ks known dhenefts outweigh ts known risks Hosrever, beeanse premarket «valuations are bnited in thei ability to always prediet safety an efficacy

‘with absolute cerainy, FDA continues to assessa drue’s isks and Denetis afer thas been marketed lí the agency Mentiies a postmarket safely ss, makes decision regarding whether to ake a regulatory

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action, seh as withdrawing the approval ofa drug, whieh ir rarely does, oF ‘comtnunieating new safely iaformation tothe public and healthcare providers

FDA Organization Related to Postmarket Drug Safety Decision Making

‘The decision-making process for postmarket drug safety is comple, rultidieiplinary, ad relies an a iterative interaction between OND, (OSE, and outer FD components." OND, whieh primarily eonducts premarket reviews of drug applications submitted by drug sponsors, also has postmarkel cr safety as one of is responsibilities Although

interacts with OSE and staff from other offices concerning the postnarket safety of drugs, OND tas ultimate responsibilty co decide whether co uke regulatory action regarding these issues The office is organized into U7 review divisions that gneraly reflect certain therapeutic ares, such as sastroenterology or oncology drugs The review of safety and efieac data Fron) ding applications is conducted by OND mesleal reviewers, who {ypcallyare physicians who have expertise in pecife therapeutie areas and are skilled in the review of cinta trials

(OSE’s primary focus is on postmarket safety, although i also involved in ‘eran premarker drug safety issues OSE has craditionally operated primarily iv a consultant eapacity to OND and has not ha any Independent decision-making esponsibility When a safety issue is ‘entsfied, OSE staff may conduct an analysis and produce n writen report called a “consi” to assist OND Safety consuls could inchnde analyses of adverse event reports and assessments of postmarket sty desis" In ‘contrat to OND onaanization by therapeutic area, OSE is onsanized ito five divisions thất cach reflect diftecent areas of is drug safety responsibilities Two divisions analyze adverse event reports, one division ‘eviews epidemiologic shes completed by drug sponsors and conducts ‘is oon stiles,” one division reviews risk management plans submitted "hy drug sponsors,” and ane division reviews proposed proprietary drs

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‘names submited by drag sponsors for thelr ew produets and postmark Studies of medication eerors completed by drug sponsors and others ‘Tohelp it provide oversight of important, hightovel safety decisions, EDA «established the Drug Safety Oversight Board in spring 2005." The boards ‘comprised primarily of FDA staf, nelnding OND and OSE officals, but also includes oficial from other federal ageneies, such asthe Nabonal

Tustitites of Health, It was established with the goal of providing independent oversight and making recommendations to the CDER Disector about the management of important drug safety issues”

ortant part ofthe drug approval and postmnarket monitoring process the advice the agency receives from CDER's 18 drug-related Scientife advisory committees composed of external experts." The

‘committees are generally organized into specific therapeutle areas, sch as ‘zastrointesinal digs or oncologic dtugs In 2002, FDA estalisted Saft, whi is ane ofthe 18 commiktees In contrast Lo the comaittees|

Focused on 2 specific therapeutie area, DSaRM was established to advise FDA on drug safety and isk management issues across therapeutic areas ‘The comnitee’s chatter states that DSaRM fs to be composed of 14 reniers 15 voting members with drug safety expertise ad I nonvoting rmeniber fo represent the drug industy, DSaRMC members ean also be asked o partcppate mother scientific advisory conamittee meetings when safety isstes are discussed OSE sets the agenda for DSalM meetings, tehereas OND sets the agenda for meetings ofthe ater 15 eanmnltees

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“Advisory committees nay’ make wecommendations to FDA that are nat binding on the ageney’s decision making,

individuals within CDER have differences of professional opinion or scientific disputes regarding a decision taken by the ageney, they are ‘generally expected fo try to resolve chem through their supervisory chain staff eannot resolve the dispute through this process, they ean access CDBR’sdfering professional opinion (DPO) program.” First

Implemented a a plot program in November 2004, it provides a process through which individuals can protest agency actions or inaction when they believe there isa rsk ofa significant negative impact on public neath Under this process, a dispute ied by @ CDER employee eould be reviewed by an ad hoe panel of three to four employees.” The panel chr, ‘who is appointed by the CDER Director, appoints the addtional members, ‘one of whom is nominated by the employee niating the dispute The panel would make a recommendation for resolsing the dispute tothe ‘CDER Director, Several elements ofthis process are overseen by the DER Ombuclsman’s Ofie, in consultation withthe CDER Director.”

Data That Inform FDAS Postmarket Decision- Making Process

FDA uses evidence from multiple data sources to inform is postarket decision-making process, each of which has certain sirengths and

‘weaknesses, FDA uses randomized clinical tri data to assess drug safety prlor fo approval However, these data have inherent weakness

‘Therefore, the ageney uses other data to continue to asses drug safety ‘once drugs are on the market, One method of assessing postmarket deus safety is through the collection and analysis of reports of adverse events associated with drug use PDA requires drug sponsors to submit adverse

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‘ent reports forthe drugs they market In addition, healheare prewiders And patients ma voluntarily stint adverse event reports 0 FDA'S Medivatel program by telephone, by mailing or faxing a paper form, oF through a Web-based application on the Medhwatch Wel site In LM? CDER implemented the Adverse Event Reporting System (ERS) whic it uses to siore reports for posemarket safety etions: however, adverse event teporing has of adverse events Adverse events are alten a bass liitations that make it hard to establish the magnitude of a sets problem orto compare risks across similar drugs Therefore, once a safety signal is identified fora marketed drug,” FDA may nse data fom observational epidemiologic studies to further examine relationships between a drug's use and reported adverse events To conde these studies, the agency seeks data from large, external databases of eleetronie health information —ineluding claims data collected by heals wssurance companies and electronic medical records of care provided throng nese hheatheare systens (See table I Tors description of these dala sources used to inform deus safety decision making before and ater approval)

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Recent Reviews of FDA'S Postmarket Drug Safety Oversight

Te 2008, we reported that FDA'S process For overseeing posimaskee diz safety was limited by a lack of clarity about OSE's role in decision making For example, while OSE often made recommendstions:0 OND in the consuls that it completed, the sgeney had no poly explietly ating ‘whether this was part of OSE's role, OSE stasFalso reported that these ‘consult sometines fell ito a “lack hole” or “abyss” end OSE sta? would zo be informed of the reslts of ther recommendations, Also im 2006, 108 noted tat an imbalance in authority, formal role, and resources benween

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‘OND ane OSE constinated a major obstacle toa healiy organizations culture in CDRR Furtheriore, IOM reported that FDA's challenges reflective of how premarket ard postmarket Tunetions have been divided are historically OSE generally takes a population-based perspeetive in theit drug safety work by ulizing adverse event reparting and observational studies, while OND generally takes a einial perspective that focuses primarily on randomized clinic! tals They reparted that OND staff often view the observational data used by OSH as sof" and unconvincing, while (OSE staff view these data as informative and exmrying drest weight [OM noted thatthe inialance in roles and responsibilities denoted a

Suhservience ofthe safety finetion anda devaluation of OSE's asepline and approach by ageney management

‘We also identified several specific limlistions 10 FDA's postmarket {ecsion-making process Several years prior to the release of our 2000 report, FDA started drafting apoliey intended including those from OSE, in the decision making process However, the to cary the rle of taf, poliey had not been finalized and implemented bythe tne our 2006 report ‘was lesen adtion, we reported that the role of OSE staff in planning for and parceipating in advisory conunitiee meetings, other than hose involving DSaRM, was not clear, We aso Found that the DPO progra had nol been ustl and may not have been vested as saiicenly independent because it id not offer employees a forum for resolving disputes that was Independent of the CDER Dizector We reported, for example, that the DER Director would Help decide whether a dispute warranted review and would also make the final deeision about how the dispute would be resolved

‘We also found that OSE management had not effetively overseen

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whether or how inely dese sidies were progressing toward completion”

We also found in 2006 that FDA faced constraints in ts acces to data thet allow it to monitor the saeiy of marketed drugs For example, FDA staff dnd extersal drug safety experts told us that OSE dd not have enough funding to support the purchase of daca for postmarket drug surveance, ‘Sinilanly,IOM found tat funding for purchasing date was severely iced and had changed itl in over 20 years 1OM also Found that BDA devoted limited resources for sa taining and supportive technology that was needed to Tally utilze purchased data Furthermore, JOM concluded that ABRS was outdated and inefeient and the ageney had given tie Attention to using systematie methols for sereening AEKS for adverse

‘We made multiple recommendations to FDA in 2006 thar were tended 10 improve its oversight of postmarket deug safety We recommended that FDA revise and implement its draft policy on major postmarket drug safety —

clarify OSE's roleln FDA'ssclendlfe adtisorÿ contmitfee meetings "ráphing postmatket đrug satety issu

lptuve CDBIES dlSpute r+suÏulon process by re ling he DPO program {oinezease Is independence, and

‘establish a mechanism for systemadieall tracking OSE's recommendations and subsequent safely Setions

(See app or a summary of FDA actions taken in response to these recommendations

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‘Changes to FDAS

Postmarket Drug Safety Authority and Funding ‘The Food and Diag Administration Amendments Act of 2007 (FDAAA) provided the agency with zaldiional responsibilities intended to improve ins oversight of postmarket drug safely." For example, FDAAA provided! FDA with new authority to require drug sponsors to complete

osimarketing sudiesto identi a serious isk or assessa known serious risk.” Prior (othe ensetment of FDAAA, FDA only haổ the anthorty tụ limited circumstances to require deug sponsors to conduct a postmarket shrug Safety stady:” outside of these circumstances the agency could ‘request that rug sponsors voluntarily agree to condi such studies FDAAA also provided FDA with new authori to requie dri sponsors to complete risk management plans Previously, FDA ised guidance fo drug Sponsors to assist ne development of voluntary risk management plans FDA may now require drug sponsor to implements risk management plan through specifi approaches, known as a Risk Exauation and Mitigation Stztesy (REMIS).” FDAAA also prosided the agency with anthony to impose civ monetary penalties on dng sponsors who violate these requigements.”

FDAAA also requires FDA ta conduct several other postmarket drug safety activities For example:

FDA mst, in collaboration with publle, academe, and private entities, ‘develop a postnatket risk Wlenbiieation an analysis system that ean be tused to analyze safety data from maliple sources”

FDA Is required to screen ABRS bisceekely and publish quarterly reports of new safer information or potential signals of serious esks associated with these of drug.”

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FDA is required to use DSaRM io seek input on certain activites, such as| lements of REMS andthe analysis of das safety dat."

In addition ta increasing FDA'S authorities, FDAAA also reauthorized the Prescription Drag User Fee Act of 1002 (PDUPA)." Originally, PDUFA authorized FDA to collect user fees” from drug sponsors inorder ta ‘Support the review of drug applieations and i established performance goals, sch as tine fumes forthe review of applications, The inerease in Attention to timely dre approval decisions le to greater awareness ofthe need for EDA to strengthen its monitoring of postmarket drug sale, ‘which was reflected inthe 2002 reauthorization of PDUEA.” The most recent authorization of FDURA, i Septener 2097 a8 part of FDAAA, expanded the postmarker deug safety tivities for which FDA is futhorized to apply user fees" For example, the law identified the ‘development of adverse event dita collection systems as an activity that could be funded through user fees In addition to amounts authorized 1 be ‘used for al user fee acsiities, hoch premarkel ai postmark, the PDUFA -equtlorization identified specie ama Fee revenues to be used Tor postmarket drug safety activities In total, PDA reported that it plans to {nerease its allocation of annual user fees to support postmarket drug safety from about £54 milion in fiseal year 2008 to about 8102 mllion in fiscal year 2012." So ue Mo, WTI, 515, 24-4

A Proserpine a ct DUA TY Drag Sa

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‘Overall premarket and postmarket finding for OSE and OND nereased since fiscal year 2008." From fiscal year 2000 through fiscal year 2008, (OSE fouling inereased from about 331 million w abou $11 ralion Duin that samt period, OND funding inereased from about $115 milion to $141 mullion, For both OSE and OND, much ofthe increase oectared in fiscal year 2008 and ean be steed to increased user fees (See Ng.) Additionally, aevos all of CDER, fusing for postmark deug safely

Increased from about $54 milion in fiscal year 2006 1 $139 milion in fiscal year 2008, OF the $129 milion in ical year 2008, shout $84 milion tons and 856 million was from user fees

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Figo ¥ Oe and OND Furcing Pscal Years 2008 Teun 2009

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FDA Has Begun to Formalize Its

Postmarket Decision- Making Process and Recently Implemented Oversight Initiatives, but Challenges Remain

FDA has begun 1o implementa new process and iitaives intended to Clarify roles related to pasinarkel safety decision making, bal aces a ‘arity of challenges Several tities hase not heen fli implemented and the agen has not inerease the independence oft disrate

resolution program

FDA Has Begun to

Formalize OND and OSE's Decision-Making Process for Postmarket Drug Safety, but-a Time Frame for Implementing Key Elements Has Yet to Be Established

‘To enhance postmarket dug safes, FDA has begin to formalize

interactions between OND aad OSE, although some key elements new process have not been impleseented ln the past, FDA has nat of this forded the same focus and attention to postmarker drug safety 2st has tothe drug approval process For exaniple, an agency offical sald that, unlike for the premarket process, roles and responsibilities forthe postmuarket process have not heen clearly defined, Theeefore, tn Janey 2008, the ageney bean to establish a new framework for drug safety— ‘whicl calls the Safety Fest iniiative—hat is intended to provide this structure Under te nitatve, che ageney has adopted a maltiisesptinary approach based on te prineples the agency refers to as Bqual Voice, ‘whic are intended to ensure that all necessary parties eantsbate Lo ‘decision making, In aadition, OSE and OND signed a memorandutn of agreement (SOA) in June 2008 hat sates FDA's nteat for the two offices {o.ontibate equally determining regulatory actions related (o deus safes." However, im mast eases, OND retains the sothority to decide ‘whether to take regulatory aetion, According to FDA, OND retains these authorities beeause or most decisions related to posmarket drug safety (OND staff have the broadest expertise in evaluating and managing ebinicel sks andl benedts of drugs

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However, as par ofthe MOA, FDA has traneferred aulÖotlty for one regulatory responsibility related to premvarket drug safety from OND ro OSE aid plans to ranster allorit for to posimarkel responsibilities, bat has not se a time frame for doing so The MOA describes the ageney's intent to transfer (o OSE Lhe authority to make final decisions for those Activities in which the office has expertise Iitill, these include tree ‘drug safety activities that reside with OND» (1) review of proprietary drug ‘namics submitted by sponsors, (2) review af protocols aad findings of ‘observational epidemiologic studies, and (3) review of protocols and shies that assess mercation error risks In April 0%, OSE was

‘vansfereed authority for the fist regulatory responsibilty, the premarket review of proprietary drug names, whieh zives OSE fina decision-making authority forthe netivity and allows the office to commnicate directly ‘with the drug sponsor and issue letters approving or rejecting drug names ‘An OND official said that the transfer of authority for this esponsibility has been benefielal because proprietsey name review was not al area by

whieh OND had much expertise, An OSB offical said that, since the transfer, deeisions have been more consistent and the decison letters ‘sued to drug sponsors have been more transparent, Agency officials said they selected proprietary name reviews as the frst authority to transfer to (OSE because the process is well defined a self contained, adi wil ave OSE experience leading a significant drag safety activity while boiling ts expertise to assume ethority forthe adaitional

responsibilities named in the MOA Officials said the agency intends to ‘ransfer authori forthe two postinankes drug safety responsibilities 0 ‘OSE, hut it has not seca time frame for doing so Ageney officials added

‘hat coordinating some clement ofthe remaining responsibies will be sore complex and OSE sill needs to increas its staff 1 assume these Adeitional responsibilities,

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‘new poliey in July 200, but they could not provide an estimate numberof tears that have been formed ly addition, FDA established of the routine joint safety meetings between OND divisions an thei O

«counterparts In contrast to the safety issue teams, which are established to manage a specifi issue, the joint safety mectings focus on broader scientific matters and status updates of joint interes co both OND and (OSE The agency also continues co hold meetings ofits Drug Safety ‘Oversight Board, FDA indicted that the boar serves asa fora to fisciss emerging and often controversial drug safety issues: The board recently expanded its membership to nchide representatives rom Aeitional federal agencies, inchiding the Department of Defense snd HHSS Indian Health Service According to FDA, board members from ‘other feral sgencies allow FDA to hear perspectives om how ts drs safety decisions affect federal healthcare systems,

(OSE and OND employees n our sinall group interviews generally ileniied positive outcomes from FDA's initiatives, although most OSE ‘employees indicated that OND sill has more authority in te postmarket {ecision-making process Many ofthe OND and OSE employees who partelpated in our stall group interviews tod us thal the more formallzed process for managing safety issies has helped inpprove interactions between the cw offices since our last report For example, several OSE ‘employees sid that they now consistently receive m response front OND About their consults and recommendations evenif they are not aways Followed, snd these report no longer fall ncaa “black hole as we

reported in 2008, Employees also deserbed increased communieation between the two offices, which sonte said improved tracking of safety ‘sues bt others sud slowed the decision-making process, With rd to (OSE's influence inthe postmarket decision-making process, 75 percent (39 (0752) of OND and OSE emplosees who completed our DCT indicated that, (OSE's influence has mereased since 2006, Hoseever, ‘employees fered in whether they thought OSE eurronly serves as an OND and OSE

‘equal parinerin decision making OF the OND emplosees who completed ‘our DCE, 61 percent (14 of 22) iniated that OSE now serves an equal partner In contrast, 87 pereent (17 of 30) af OSE employees dicated that OND's perspective sill earies more weight, although 6 percent (18 of 3) Indicated that they thought OSE vould serve as an equal partner once the ‘new inidatves were fully implemented,

Despite changes to FDA's postmarket decision naling process, OND and OSE employees repor: that differences still exist in how the Hwa offices ‘ew information sed take decisions, For example, one OSE

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‘over the epidemioloaie deta ysed by OSE, and another OSE employee sald {hat OND Is generally wore resistant co accepting drug saely recommendations based on epidemioloye data Some OND employees also sid that physicians are better at identifying the dire clinical impact ‘ofa dmg than other types of staff, sich as epidemiologists, wha may be ‘nore silled in data aralysix OSE taking steps to address these

Aiferences, For example, an offical said tat OSE has provided training to ‘OND statf on the metho it uses to dois ark, nv adiion, of told tus that OSE plans to increase clinics expertise by hiring additional amedienl reviewers to assist it withthe review of adverse event reports

FDA Recently Inuplemented Initiatives to Facilitate Oversight of Postmarket Safety Issues, although There Have Been Implementation

Challenges

PDA implemented both staffing and tracking initiatives intended to Improve oversiht of postmarket drug safety issnes In January 2008, OND ‘reated two new safely management positions within each of ts 17 review divisions to reduce variabilig’ bs how the dissions oversee postiarket {rug safely.” ly addition to coordinating interactions between the offices, employees in these new management postions are to provide leadership and to ensure tha adequate OND resources and attention are Focused on Safety issues They also track postmaker safety ativites which may erduce the burden on indvidal medial reviewers, who ate sso responsible for reviewing a recommending whether co approve dew fnplicationss Several OND siedieal reviewers indicated during the siall {roup Interviews thatthe OND safety management postions have helped {osraek and cnordinate management of possmarket safety issues For ‘example, one medical reviewer noted th medical reviewers have

‘competing prensarket denlines related to PDUPA aii hep to fave Safety stadt who donot have these desilines and ean focus on pastmarket drug saety

In adaition, OSE reorganized ts existing safety projeet manaxer postions Jntoa single group in October 2006 co oversee the managetnent of safety Issues across OSE divisions These siety project manager positions serve ‘8s OSE counterparts to the OND managernent positions and are

responsible for among axher things, coordinating meetings with OND aud

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1nonitoring OSE activites These projeet manager posilons were each previously assigned ina specific OSE: division An OSE official sid this reorganization was intended to provide OND staf with a single point of «contact within OSE, rather thar having separate contacts fr eaca OSE sivsion Since the reorganization, the tora numberof safety project manager positions in this group has expanded trom 9 (0 25 However, several OSE employees in oursinall group incerviews cited challenges related to their interactions with those holding these OSE safety projec ‘manager positions Some sui individuals in these postions sil seem $0 be learning sheirnew roles and responsibilities An employee also said that turnover among the safety project manager postions has made i dificult Tor the iaividuals holding diose positions to gain experience As of July 2009, 20 ofthe 25 OSE safety project manager positions were filed, but an official stated that turnover has been 2 problem and only one of the Individuals has been in that position since Oetober 2005 The oficial sald ‘ha the expansion of responsible resulting from the reorganization ‘was challenging for some ofthe iia and noted that alaek of ‘raining and elear policies and procedures for these new positions may have contributed tothe high tamover The official said OSE is hoping 9 more retention by implementing talning and other suppor stems for these Saf

FDA is als implementing a new tracking system to assist OSE andl OND staff in overseeing identified safety issues, althoush the system has Timitatons: I Janary 2007, n response to on 2006 recommendation,

FDA hegan co incorporate a sitet) module within is Document Archiving, Reporting, and Regulatory Tracking System (DARRTS) co rack the agency's management of and response to significant safety issues ‘Mealfed with the use of marketed drugs." FDA requires that each Significant sate issue identified hy OND and OSE be tracked within DARRTS by creating 2 “tracked safety issue” fle As ofJuly 14, 2008, here ‘were 204 active issues, DARRTS suse, among other things, to generate # ‘Workplan and assign responsbiliies for managing these isues, as well as toprovide updates on the status of these isues Otel toid is that while the system contains documents deserbing specific recommendations and safety actions, it doesnot, as we recomended, allow FDA to

‘ystemtially trick how sues were resolved and whether OSE’

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‘ecommendations were implemented For example, an FDA offical old ws {hat DARRTS cannot provide the agency with a suramary ofthe

recommendations for safety actions that OSE has made to OND or how the safety issues were ultimately resolved FDA indicated that, due to Limited resources, it doesnot plan to incorporate this capably into DARRTS in the next year orto In addition, FDA has identified certain limitations with the system, such as problems of completeness and aaccuriey and the need fora mechanism to notify relevant staff when a new tracked safety issue is created, According to FDA, some ofthe ‘dentified problems have been corrected while others wil be addressed at later date An official sad that the agency expects that future problems ‘will be minimized by improved preimplemtentation testing, Por example, theofficial noted that the July 2009 update of DARRTS, which allows the spstem to be used for monitoring both postmarket studies and risk ‘management plans, was more rigorously tested by users prior to its Implementation

DA is also utilizing contractors to improve oversight of specific new authorities eeated by FDAAA We and others have identified problems in the agency's tracking of requifed and requested postmarketing studies, suc as OND reviewers not meeting their goals for reviewing in atmely ‘manner the annual satus reports submitted by drug sponsors." In 2008, PDA hired a contractor to monitor and provide support for postmarketing studies, including the review ofthese annual status reports." FDA officials ‘ald that this contract has been very productive because i allows the review of the annual status report to be completed, which is very time consuming, while allowing the agency to move ahead in its oversight ofthe ‘new postmarketing studies it is requiring under its FDAAA authority The Gao Ne Dew Approel FDA Nook Bhan i Overiht of Drags Approved om ‘he ato Surat Bmdecimh CAO Watington, De y3 ‘Shue Aen Haaton atretng Commie Sy Pa lọ

prepare Uattwewrescrpton a th eget of FD aaa Sb, pert gooey drag scteatc ent seems aly 2,20) “rhe cones aly eon te mua stu cated eh ‘aes, yoo, a1 Sa Aaa Coed a STUNT piES/gt2) Từ comncur ‘SSocesewing the anal pers bated by ra pore forme potatoe ‘hat have ben raed segue snee PDAAA sy, orexumple, Bae Ne Hanon, eqs of D8 Apr 1020, hep wen ibrogatidane opanesegaaery TP muinuPteceudelniaelXConnnmvngcnii0993lm Gecxetoet 280

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‘agency i also hiring contractor mansgehtenlplans to help oversee the required risk

FDA Is Revising Its Program for Resolving Scientific Disputes but the Changes Have Not

Sufliciently Addressed the Independence of the

Proc

PDA is revising CDER’s program for resolving seewtifi disputes raised by Individual employees, but the changes do not sufficiently address our prior "eeommendation or inprosing the independence of the process Beginning i 2007, FDA eondieted a review of each of centers’ dispute resolution processes, including CDER’'s DPO program,” Asa result of this review, FDA developed alist of mandatory elements forall enters to Implement during fiseal year 2013 anđ a ist of voluntary best practices for sclentife dispute resolution activites For exaruple, FDA now requires ‘Hat emplosees af eaeh center who file DPO have the otion to anpeal 10 PDA's Office of the Conissioner fora review ta eetermine ithe center fotlowed its own dispate resolution process correctly." CDER indicated that Hs DPO poly isbeing revised to reflec this "process reies™ and ‘other new ageneywide requirements bt noted thal CDR plans to make Fess other elianges As of October 2008, the revised poly had net been finalize

‘While DBR continues to make changes to is DPO pole, the planned changes do not address a weakness we \entiied in ont 2006 report—that ‘he program i established Lo resolve seieniie disputes my not be sewed as independent asa rest of the CDER Director's extensive involvenset ‘According (oa July 2000 draft ofthe revised policy, as was the ease in 2006, the Onburdsinan, sshom the polly designates as the focal poi for ‘overseeing the resolution of disputes, would consult with the CDBI Direetor before deciding whether a dispute warrants review An ageney official told us tar this corsultation is important because the Ombudsman does not have the same scientific expertise asthe CDER Director The ‘official acknovsledged tha, while the Ombudsman is included as & way 10 proce de independence of tre DPO program this psition does not eet the standards of independence establisied by the Coalition of

“the proceme revi wold ale nc an memento whee th cee onside

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Federal Ombudsiaen.* In addition, according to the draft DPO poles, the (CDER Director would sill appoint the ehair of the ad hoe review panel and decide how the dispate should be resolved, i consideration ofthe ‘panels recommendation, The draf PO poliey includes the required ‘option ofa process review by the Office of Hie Commissioner, whic ‘would not invalve the center dzector or other eenter staf indecision raking; However, this review is imived co determining whether CDER Followed its own processes correctly, andit does not consider the

scientific merits of the dispute Asa result, CDER's revised DPO program Stil may not be viewed as sufficiently independent forresoiving disputes

4s of July 2008, CDER’s PO programs had not been used to resolve a diforence of opinion, The Ombudsman attributed the lack of use to the CDER Ombuudsman's Office's management of disputes so that they never each the level ofa formal DPO." FDA also inlcated thatthe DPO

program is narrowly focused on indiiduat disagreements that employees Ihave been unable to resolve within this supersisory chain if agreement 1has not been reacted between scientific disciplines, the principles of Equal Voice are intended to help different dseipines express differences ‘of opinion OND and OSE employees who completed on DCL xeported = ‘arity of reasons fr why they ehose not to file a formal DPO Or the 52 OND and OSE employees who completed our DCI, 38 maicated that they Inad not had a difference of opinion that would have qualified for fli dispute However, 1 ofthe employees did report having a difference of ‘opinion where they thought that FDA's action of lack of aetion had the potential fo have a sigoifiant negative impact on public health." When asked why thy did not use CLER's program to resolve ths ference, these employees most frequently indicated that they preferred to express

‘i'n tan len Si S9 leg 7e For Ph tan Operasons OF Ombuds ice Pree By The ne

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FDA Plans to Implement New ‘Adverse Event

Systems and Is,

Increasing Access to External Sources of Drug Safety Data

‘he opinion in written documentation (7) or were nat aware ofthe program (6)~ In addition, dof these 13 employees noted concerns about he fainess ofthe DPO program as one reason for why they did út ‘None ofthe 13 employees indicated that they prefered the option of| siseussing the differing opinion informally with the Ombudsman,"

DA plans to improve ils ienbiication of drug safely ves developing new adverse event systems (0 collect and store adverse event reporisand by increasing neces ( external sources of data However, the adverse event systens and a new network of external data providers have not yet been implemented,

FDA Is Developing New Systems to Improve

Collection and Analysis of Drug Adverse Event Reports, but

Implementation Is Not Expected Until 2010 Adverse Event Collection and Processing

FDA Is developing two new adverse event systems to help ently drug safely problems-one 19 impeove the colleetion and processing of adverse «event reports und another to store reports and provide FDA staff with Improved tools for analyzing them FDA's complete adverse event system for human drugs will not be implemented ntl tne end of 2010,

‘The new adverse event report collection and processing system, BeaWaichPIns, is intended to huetease the accuracy ail eles of reports accessible to FDA sai a fs shee tobe inplemenced for "homan drugs by sumer 2000." The current MedWatch Web ste collects

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adverse event reports about prescription drugs by providing fori that patienis and healthcare previders can suit online or dawnload and send 0 FDA im payer form,” Drug manufacturers may also use dis syste to ‘download form, although they may elet to submit eteetonically throng An altemative system, the Electronic Submissions Gateway (EG)

Although reports submited dhraugh BSG go direcly into CDER's database bf adverse events, ABRS, paper reports, and reports submitted using the ‘MedWateh online fonn must be processed and reanually entered into ABRS before they are available to FDA staff FDA estimates that reports ‘submited on paper may take from 2 weeks to 2 months from the tine of "eeeipt tobe entered Into AERS where they ean be analyzed by FDA stall ‘The new MedWaichPhssyscem wil allow online reports to be processed automatically and transferred directly into the agency's adverse event system,” reducing the need to process and enter reports manually

‘According o FDA, automatic processing will cut doxen on errors elated 10 data entty and should allow for more nanelyavalabiity of reports foe analysis FDA estimates that eleetronie submissions are genctally available Jn AERS within2 days oftheir receipt

FDA expects that MeaWatchPlas will enable the agency 10 inerease the electronic submission rate of reports, inerease the ntnber of reports accessible o FDA stat for analysis, ad improve report quality In fseal ‘year 2008, 61 percent of reports fran manafaetarers were submoieed ‘lectronicaly tn August 2008, FDA issued notice ofa proposed rule that ‘would require manufacnarers co subi adverse event repens ecironieally* whieh wold mean that manufacturers who đo nơi ‘currently subi reports electronically would either use BSG or would

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‘eed lo use the MedWatchPlus online form nreasing the eletzoale ‘Submission rate should allow for more reports to he available to FDA staf, Currently, FDA does not routinely enter all paper reports from

ranfaeturers into AERS,” which an official suid is becsuse ofthe cost so the ageney However, ll reports from manufetures submitied|

slectronlealy through MeaWatchPlus willbe automatially entered into ABRS, which should redace eos and allow for more poets to be available for analysis" FDA also expects o inerease the number of ‘leetronie submissions from patients and healtheare providers by making the stem easier 1 use As par of MedWatehPlus, FDA will use em Interactive questionnaire that will guide sbmiters through a senes of ‘questions which FDA expects will nerease the aeuracy and

completeness of reports For example, submitter errors, such as inaceurate drug names, create n burden for FDA." Through

‘MeaWatchPlus, he submitter will be provided with a menu of chotees for the name ofthe drag The questionnaire wil also anit the Inforntion received and prompt for missing information,

all er paper eps Gets aruacten FDA yee eps fo

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Adverse Event Storage and

Analysis {hey have been submited that should offer integrated data analvsis FDA is also developing anew database Features to feta the identification of safety issues, The new databese to store adverse event reports once the PDA Adverse Event Reporting System (PAERS), is expected to receive reports from MedtWetchPlus another FDS applications forall FDS regulated products and stare them in asingle location ® Ta addition to ‘voiding redandaney among the center daabases, FDA has sated tha a consolidated database wowd benefit dg set, for example, by {eiltating the sharing of aiverse event reports teross centers for

combination products." FAERS will place AERS and i intended to Agzess some curtent AERS litations that affect how OSE staf do thelr ‘work FDA officals told us that OSE staff view the current version of AERSa a lant “filing cabinet," which lacks integrated sofware for data ‘mining and signal management that eauld kelp the to monitor drs Safety more effectively.” FDA officals sad tat, ewrreny to use the softsare, staff have to periodically extract the data from AERS and fransfer them to another system for analysis, which means that analyses ‘anot be conducted in real time, In contrast, FDA plans ta include

integrated signal management and data mining sofware in FAERS, which ‘wll make these features easter tose and allow for analyses of safety signals closer to real tne

PDA oficial said thatthe agency plans to adress eter averse event ‘report quali problems by ineluding new features in FAERS For example, fan adverse event reviewer tld us that AERS lacks {such a8 a checkbox) ca indicate whether female patent deseribed in an 2 dedicated data fel adverse event report is pregnant ASa ges, reviewers mus nana review the narrative of reports for worsen age 15 t0 45 to determine ‘whether the patent was pregnant, FDA officials sald that FDA plans to Include a dedieated data Feld to indicate whether a report identified the patient as presgunt is FAERS An adverse event reviewer sso ieiied the lack ofa ink between an sdverse event report and FDA approved label

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information as @ problem because i Rinders taf in determining whether {he adverse event issiew or as already been identified ant inched inthe {Grug’slabe FDA ofetals said that linkage Co Label information isa goal for inclusion in PAERS, but itis complex and theageney does not have a time frame for its inclusion

FAERS development as experienced delass, bat FDA expects that it wil ‘ye partials implemented bythe el of 2010 EDA began developing an pre to AERS in 2004 Hovvever, ceording to 2006 report by an EDA contractor, deficeneies in FDA's procurement practices and the agency's {ecision o expand For all FDA-reguated products rested in delays.” The contractor the pret’ scope to develop an ageneswide database reported that these olistaces in development resulted in to Syeat lelay nnd an estimated $25 milion in addtional development costs ‘Curgently, FDA indicated tha it is prioritizing FAERS requirements to feermine what feanives and capabilities ate possible for che frst version ‘of FAERS FDA plans to complete he frst version of FABRS, for druss land biologics, by the end of 2010 However, this version will not inehuce fully integrated data mining and signal management software FDA does ‘not have an estimated tine trate for when these Feties wl be fully Snegrated

FDA Increased Funding for External Data Acquisition and Is Beginning to Access Dat from Federal Sources

FDA increased funding for anquring the external data that ¥ nsesto ‘examine dng saetyissies fro aut 85 milion in Rise year 2707, ta bout $28 milion in fiseal year 2008." FDA recently added additonal Funds to existing contracts with four private eompanies that conduet drug safety studies using their own databases of electronic health information, ince FDA inally awarded shout 85.4 milion in total to these companies

sca year 2008, these contracts have sled five completed epidemioiouie studies on drug saety, inclading a study on how

antidepressant use in pregnancy affects the health of newborns In fiscal Year 2008, FDA added about 89 milion in total to the four contracts However, FDA officials sid that under the current contracts is diicult ‘oexpand finding n response to che agency's needs and they will be

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“hanging 1 a diferent eantvaet type when these contracts end in 2010 ‘They said the new contract tye will make it easier co add funds the need arises for alditional epidemiologie studies to exansine previously ‘unknown drug safety issues

FDA has also used the increased data aequistion funds for contracts with Drisace companies that allow FDA sts divet access to data tat ean be ‘used to conduct drug safety studies internally, These contracts provide the Agency with access to drug ulation data, which are useful to FDA for Among other things, providing an estimate of how many people have beea exposed 1o a drug, which prorides context for adverse event analyses ‘These contraets allow FD to download the data onc Lhe agency's servers sshere staff ean access the data to conduct drug sfety studies In 20 FDA awarded contracts valued collectively at over 814 milion fora base yea and 3 option years The three new contracts replaced an existing

‘contrac with a sinale vendor and, according to an FDA offical, repeesent ‘an approximate tripling of funding for aceess to drug uiization data The official also sid ht contracts with three vendors allow shortcarinss in ‘ne data se 0 be compensated by information from another For

‘example, one contractor has mail order pharmacy cain dat, which are ‘ot available from the other Wo contractors

Inadeition to Fanding contracts with private companies, PDA isin the early stages of formmng partnerships with the Department of Veterans ‘Males (VA), the Department of Defense (DOD), and the Centers foe Medicare & Medicaid Services (CMS) to access thelr databases of ‘leetronie health information for drug saety research FDA signed memoranda of understanding with VA snd DOD in 2007 to enable these agencies to share information necessary to evaluate drug safery with FDA FDA allocated about 83.5 million to fad these agreements in 2008, which among other things, provided funding for research projects such asa ‘study ofthe relationship between the age of smoking cessation drugs and suicidal behavior, andl fundig for staff to support such sues.” In

“Then conus be nei delve contr wi do ot procure or pci

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addition, FDA signed an interagency agreement with CMS in August 2008 {oaccess hoth Medicaid and Medicare data, As patt ofthis agreement, DA transferred $1 milion to CMS in part to fund a project o ereatea ‘Medicaid database amenable to research on drug safety.” FDA is also "working on several pilot projects using Medicare prescription drug data ‘These data on Medicare beneficiaries provide the agency’ with aceess 0 ‘new information on the elderly and disubled—groups that are generally “underrepresented in traditional clinical trials that FDA uses to assess safety prior to approval FDA offiials said that partnering with federal agencies is beneficial because they have large databases of electronic ‘health information that may be accessed more cheaply than contracting ‘with private enities:

FDA isin the Early Stages of Developing a Network of External Data Providers Intended to Enhance Its Drug Safety Surveillance

FDA isalso taking steps to improve identification of safety issues by creating a network of external drug safety data providers, but te ageney Js in the early stages of developing i The FDAAA-mandated surveillance system, known as the Sentinel System, willbe a network of databases of electronic health information that can be wlized for safely signal

evaluation for drugs and other marketed medical produets FDA offcals| sald one of the purposes ofthe Seatinel System will be co provide the agency with an ative surveillance too! that willbe capable of generating safety signals that are not identifiable through ABRS For example, AERS relies on patients and doctors to submit adverse event reports, but if they do not recognize an event as being potentially drugerelated, they may not file an adverse System wl build on the current data contracts the ageney uses to conduct event report In addition, FDA expeets thatthe Sentinel

formal epidemiologic studies, which are generally used to confirm safety signals after they have been identified, by allowing researchers to specify potential safety problems in advance and monitor for these problems in ‘near real tie, The Sentinel System isin the early stages of development ‘nd as of June 2000 there were no established milestones" Thus far, FDA

Chetan nto aig, wea esis oak An FDA cea lo gery pled ‘oom fangs poet 23 and halos an dona lon

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‘Although Staff Has Recently Increased, FDA Faces Challenges Meeting Its Expanding Postmarket Safety Workload

tas established a Senlor management team, conducted a series of meetings ‘with stakeholders, and created a working group of federal agencies that are developing complventary initiatives FDA officials sad they have not Finalized funding oF staffing pans forthe system, In addition, many other

key decisions have yet to be made, including sources of data, an

information technology infrastructure, and methods of analysis la 2008, DA awarded eight contracts co investigate these and other issues Seven ‘ofthe reports fom these contracts have been completed and FDA expects thatthe remaining repor willbe completed by the end of 2000

FDA'S workload related to postinarket drug safety has increased as & resull of new authorities and other factors, While the agency received Inereased funding and is hiring staff to conduct postmarket drug safety Activites, t fice dificulties in recruiting the additonal staf and external ‘experts needed to meet lis increasing responsiilites

FDA Reports That New Postmarket Drug Safety Responsibilities Have Increased Its Workload and That It Is Challenged by Competing Priorities

DA reports that new posimarket drug safely esponsbiliies and other factors have led 1 an ineteased workload for which FDA has identified a need for inereased staff.” Of the OSE and OND staf that completed our DCI, 77 percent (40 of 52) indicated that thei workload had increased or treaty inereased since 2006, In addition, 00 percent (31 of 52) ofthe employees sald that they either were notable to meet their postmarket ‘drug safety responsibilities during an average workweek or were only able {omeet these responsibilities by working overtime Many employees told us during our small group interviews that one source ofthis inereased ‘workload has been the new postmarket drug safety responsihilties added by FDAAA FDA officials sald that requiring a drug sponsor conduct

= Snare Be por that Fe workload gre deo nee the necns tery eapnstdis at ming tube fed poe se {SEDA owraghe We ams oponed haan eased ans on a fe unig ha

GX 1 (Wangan, Deane 1,20,

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‘ostvarketing studies is more dine consuming for FDA staf than the past nrocess of requesting sch studies For example, to require a shy, bffcials sad the agency needs to document its raionale i a legal’ ‘enforceable contract wit a sponsor that may describe specific elements ofthe study design The agency also works with sponsors to establish anilestones forthe completion ofthese stds In addition, officials sid the process of overseeing the development and implementation of x drag sponsors required risk warsigernent plan fs led to ational meetings betveen OND and OSE, as well s adtfonal interactions with dng sponsors to review the propasal and discuss even minor madifiations to AC EDA officials sad thar the new FDAAA aluhoriies are espectaly time ceorsuring beeanse the agency i stl developing processes for how to ‘conduct this new work, Oeil said that proposals for requiring

posimarketing studies and REMS are being reviewed by oilers within EDA, {o ensure consisteney athe application of the authorities FDA officials ‘expect that some of this additional workload will decrease as the process

dheeaies more routine

‘OND medicat reviewers desered challenges meeting their premarket and posimarket responstbiles Several reviewers noted iat their peinary focus is an completing premarket Work within PDUFA tine franes, ad ‘sstes related to pastmarket safely receive lesser prion Two medical reviewers sai that iaportant identified sefety issies world take prionty ‘vermeeting PDUFA deadlines, but other reviewers told usthat thelr ‘workload prevents them from conducting reviews that sronléallow them {identify new postmarket safety issues For example, reviewers sad they are unable to fully eview the Periodic Safety Update Reports submitied by ‘dnug sponsors, which are comprehensive reports containing information ‘on serious and nonserios adverse events." According to some OND reviewers, medical reviewers do wot have the rine to fully analyze these

Trang 37

‘eports ‘workload demands prevent then from reviewing these reports Given thar to look for potential safety isies." OSE salt Col us that nonserious adverse events nay not be entered into AERS, fale to fully review Period Safety Update Reports may result FDA missing safety signals for nonserious adverse events

OSE also reported that competing demands impact its abit Co met its posimarket responsibilities, such a its new premarket responsibilities for reviewing proposed proprietary dus names within PDUPA deadlines and ‘communicating is decisions to drug sponsors The staf involved in these reviews estimated that approximately 0 pereent of tel Une Is spent on seh premarket activites, sil leaves fie tine to spend on their other postmarket drug safety responsibilities, sth as analyzing reports of ‘medication errors, For example, an FDA employee told us tat they do ionitor AERS ro Menty safety signals, ut they do not hace time to

complete follow-up reviews of these signals Althongh employees agreed {ha te mast important safety issnes do get resolved, one employee said that follow-up reviews are often lower prority than falling prema responsibilities.” In addition, ether OSE staff identified competing fderaanls tht hampered their abiliy to canduet postmark safety work For example, OSE adverse event reviewers told us that consi requests Jon OND consumed the majority of hee time, leaving Lier les ne to

conduct seiniiated safety analyses of adverse event data According to FDA, each OSE adverse event reviewer receives an average of about At adverse events reportsper hy,” and recewers told us tha given ‘competing priorities, they are notable co review ther all

| contractor reviewing OSB's increasing worklosd found that sition staff will he needed inorder to full the ew responsibilities celaed to FDAAA and the MOA According tothe eantrsetar's December 208

‘OND stay eponite or sowing hee rept OND nical evi

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‘eport, OSE would need an estimated total of 158 fullalme equivalent employees by 2011 to meet its increased workload, more than double (OSE’s cureent staffing" While the contractor identified workload ‘increases throughout OSE, it found thatthe greatest increases vould be related to the review of risk management plans and pestinarket safety data, such as adverse events,

FDA Has Hired Some New Staff, but May Face

Obstacles Recruiting Additional Staff to Manage Its Increased Workload

‘OSE and OND officials described fiscal year 2008 as a very successful hiring year, due in part to specific hiring initiatives, FDA indicated that since the start of fiscal year 2008, OND increased its staff from 736 to 023, and OSE increased i sta fom 114 10195." The sal hited ineluded OND ‘medical reviewers who conduct premarket and postmarket reviews and OSE staff with postmarket drug safety responsibilities, such as

epidemiologists and risk management experts Agency officials attributed this success to speci hiring initiatives For example, officials told ns that bot OSE and OND used a sunamer 2008 job fai and directhire authority thie sta more quickly.” While the agency has had direct-hire authority {or medical reviewers since 2003, FDA indicated that i-temporarily ‘objained direet-hie authority from Apel 2008 through September 2008 for epidemiologists The OSE and OND Directors said thatthe’ ited

canlidates within weeks under the authority, rather than the 306 months itcan typically take to announce positions, Seren applications, conduct inerviews, and hire individuals The OSE Director told us chat without the authority, interested candidates have sometimes accepted employment

erp Peto Solitons, Of ý Sarco it Em tony Wout Avis Report report pepe he reget of FDA sve Spang MA Dccoicr Sit cack ama we ot ay a ch

{lnot we x conan ouematie roca or cllesting wore dats xeÌ ‘comme tthe ofr mprmsnt a ogg proces fr ecaing aing oe Soli we oe nt FA rp ae aed win “POA ori suf counts aso September 22,20 Accondig to FOA ol th seal sae 200 sing celing for OND wan wh or ONE was 21

‘apse hng of uae apts for crite sede pestons ty tat ‘catchy incor semen ni hag per te tt S0

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offer elsewhere before FDA could extend is own offer” Tn addition, an official sai that CDER’s ability to offer hiring bonuses, relocation reimbursement, and student loan repayteent contibuted cits hồng ‘success during fiscal year 200% 3

Atthoush OSE significantly inereased its taf in fscal year 2005, hiring and Saffing challenges could make it tfcult forthe office to meet the

‘workload! generated by its new postmarket drug safety responsibilities, ‘While the contractor estimated that OSE woul need 43! fulltime equivalent employees by 3011, the OSE Director el not know if the agency planned ta increase O5E's nocal year 2009 staf celing of 211 ie Tiseal sear 2010, However, officials sai that eeruiing the right people ‘with the desired drug sets expertise difficult For example, an OSE

official sat that ifs hat o ind candidates who have experience with the specife epidemiologic activities conducted by FDA, and the agency therefore looks for candidates with epdemiologie skills who ean then be tained by the agenes ance they ae bred Officials indicated that while the new hires cun bring up-to-date sll, er lack of experience means thar it ean take up to years hefore newly hired exployees ean seoxk independently addition, an offical said it ls dificult for OSE to

compete with drug companies, who ean offer higher compensation, for the ‘same pool of talent Given the estimated workload inereases identified i the FDA contractar's Deceriber 2m review, OSE may be challenged to Inve staff quiekly enough to meer its increasing workload,

FDA Faces Technological and Staffing Challenges That Limit Its Capacity to Conduct a Growing

Number of Postmarket Safety Studies

"PDA officials sid tat they lack adequate computational pacity and ‘noth staf to male fll se of external sources of dats for drug saety studies, and FDA expects the number of such studies to grow OSE has ‘creased funding for acquiring external data and areeent workload planning report prepared Ly an FDA contractor inleates tat OSE intends to tripe the numberof epidemiological studies t conducts using such data {omy £3in 208 to in 2011 An OSE oficial tod ws that currently, most

ofthe epidemiologic studies are conducted by contractors, bat tha OSE ‘would lke to conduct more studies internals The offical said that intemal studies afford EDA more control aver the analses, 2 well a8

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provide Inereased professional opportunities (o OSE sai, whieh may lead {o.reater staff retention Hoscever, the oficial sid that conducting more internal stuies would require greater computational eapzeity and more safe” OSE officials (old us for example, that the curtent technoloical Infastructare limits stato running a single analysis ata tine and that the ‘computer servers in CDER “routinely erash” when dealing with arg data sets, OSE officials also saa that they lack programmers who ae needed to ‘extract data from databases and prepare data sets for analsis OSE officials sl that the office has facet eificlies hiring progransmers because the position deserptions that it would use to ire these programmers are currently only svallble Information Management, whieh has meant Uns sc stall may not be ta the agencs’s Office of hired by OSE," They indicated that, without enough programmers, (his \Workis shifted to epidemiologists, who mst then spend more time on teach study and have less tine to devote to developing and carrying out adatiional studies

CBIR is developing.2 computational science center that is intended addzess some ofthese challenges, hu this ceater sin the early stages of ‘evelopment FDA hleated thatthe center is intended to support both pre-and postnarket quantitative analyses ofthe safe, effeaey, ad ‘quality of drugs." FDA officals sald it should address current problems by providing inereesed computational expacity nd more sal, nelodin£ programmers and dita managers ai cạn be utilized by OSE However, {hey sad thal the center I currently in the developmental stages, and that there js no tie frame fr its completion In the interim, OSE is using shor-term fixes, such as increasing the memory capacity of existing servers, OSE officals nord that OSE may also contract out some