Tài liệu drug safety fda has begun efforts to enhance postmarket safety potx

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United States Government Accountability Office

GAO Report to the Ranking Member,

Committee on Finance, U.S Senate

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

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

[ST

(GAO recommends Aeselop a comprehensive that FDA plan

Drepate OSE ford transfer of

‘Midna regulatory autores

ftom OND FDA agreed recommendation ith GAO's

NHI p2 ươm vơi

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

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

uta states covenant Account onan

Recommendation Agency Comments and Our Evaluation 40 an

‘Appendix I Recommendations Status of FDA Actions Related to Our 2006 “

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

‘ou ut peascn fh GRO arr ner fs wo ay ta ecteser you wah optics ie mato eepxrte

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,

‘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)

‘Arann, Commie on he Axes oft US Dr ay Spt, Te Pa of nating ane Protecting he Helo te Pui Wasting D.C

‘its, Pace Yar 2008 Agony PoancialRoprt Monet 2008)

‘hts ie ge (ase ie 1, 08) AD ih ak Sin Ups,

(Wshingon Des aay 200)

“our works Foci on an drags rte seme such an acne Seed on ing sures wh x bana anal tr by CDER apd to noe Bilge

‘ticrorganans, Some bilge are watt CDE an uh profs nc Ik

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,

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

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

‘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

"Os provides premascing reef propor dena to mini say poten

‘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.”

‘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

"ir roe epor, we eared depute "uate ston poco tee eal Atm DFO prog, o wltile FDA proce for ring scenic X9 0A 10 or the pupae tiepon, wea the tem pte reson 1

‘siete clean of poteees ented ameter cenife dayton el

‘horevow othe dapat the aperebony hai and DRO pogen

esterase agony eos bechosen

in aan she des, COB Oana sien sl meets

‘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)

eeion Ss asa pois Popes crate oanacnad dee Wich pana

Use To asaos dug sley and oicay To gavarate ale pans wih To con stety signal rer

‘Beenie Sateen ne goups atime oust,” rae, nexpeced amv evans, patere one lange perooa Five, fandariaton rnin erent Prades valle Wlomai an Vly iva lege groupe oT aT

“= no

AE ab en oe ttn oes oA aces ae

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

‘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 posimarket drug stew and lacked s)stematic information on this process Speeiialy, although OSE maintained a database of eansalt requests received from OND, the database didnot incl information abort

‘whether OSE staff had made recommensistions to OND regarding safety actions I also dd not inchide infoemation on how the safety ies were resolved, ineliing whether OSE's recommended safely setions were Implemented! by OND In addition in 2006, O1G found weaknesses i the

‘extent to which FDA tracked another element of postiarket drug safety, the progeession of postinarketing studies that FDA had requested dz sponsors to conpleie O16 found that FDA could not readily identify

‘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

‘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.”

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."

‘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

‘was fom fseal year approps

year Sh sy ant ee

FDA Has Begun to

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

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,

PDA tas established liple opportunities fr stat from afferent isciplinesto discuss drug safety fsues As part ofthe MOA, postmarket safely sites would be managed by an inerdiseplinay (eam process tat,

ss similar to FDA's process for managing drug approvals FDA iesied aa snterin policy deserbing these safety Issue cans in May 2008 Teams ‘woul be ereated as needed and inede the OSE, OND, and other salt necessary lo evaluate a given safety issue and make a decision about any needed regulatory actions As par ofthis process, the teans Would establish ratgct dates for evaluating the safety issve and later monitor the Inplementation of an regulatory actions FD ails said that teams nave been formed in the past to discuss safety issues, but this new poiey Formalizes existing team-based review practices to provide consistency in resolving safety issues Officials said that they began taining seaffon the

‘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

‘employee said that OND staf trust the results of randomized chaleal tals

‘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

Postmarket Safety Issues,

although There Have Been

‘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

‘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’

‘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)

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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

‘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

‘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