Postmarketing Drug Safety Surveillance

Pharm Dev Regul 2003; 1 (4): 231-244REVIEW ARTICLE 1175-9046/03/0004-0231/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Postmarketing Drug Safety SurveillanceAn Overview of Regulatory Issues

Jasmanda H. Wu,1 Man C. Fung,2 Kenneth Kwong,3 Kenneth Hornbuckle2 and Edmundo Muniz2

1 Aventis Pharmaceuticals, Bridgewater, New Jersey, USA2 Lilly Research Laboratories, Indianapolis, Indiana, USA3 McNeil Consumer and Specialty Pharmaceuticals, Fort Washington, Pennsylvania, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2311. Safety Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

1.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2331.2 European Union . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2331.3 Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

2. Data Analyses and Safety Signal Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2353. Risk Management Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

3.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2383.2 European Union . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2393.3 Japan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

4. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2404.1 Medication Errors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2404.2 Pharmacogenomics and Pharmacogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

5. Conclusions and Future Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

Postmarketing drug safety surveillance has undergone many changes, especially over the past decade whenAbstractinternational harmonization on safety reporting and risk management strategies were adopted by regulatorsworldwide. It is important for readers in the field to keep abreast of the most recent occurrences and future trends.

This review provides an overview of the latest regulatory initiatives in postmarketing drug safety surveillanceand outlines major trends observed in three major economic regions (the European Union, Japan, and the US).The report encompasses regulatory developments in safety reporting, safety signal analyses, and risk manage-ment strategies. In addition, an overview of other important areas, such as medication errors, pharmacoge-nomics, and the future of pharmacovigilance, is also included. Overall, the most important initiative is theapplication of the concept of risk management programs. Regulatory authorities are currently developingguidance to the industry and healthcare providers through various concept papers and workshops. In addition,global harmonization of safety reporting has taken place within regulatory agencies for some time. Theseinitiatives could strengthen the ability of pharmacovigilance organizations to review and monitor the safety ofdrug products. Furthermore, automated data-mining techniques have been developed and used to systematicallyscreen adverse drug events for early safety signal detection.

The future conduct of postmarketing drug safety surveillance is likely to be evidence-based, technolo-gy-driven, and patient-focused.

232 Wu et al.

The safety of medication use is always an important issue in management strategies. In addition, an overview of other impor-public health.[1-6] Untoward effects of medicines and their asso- tant areas such as medication errors, pharmacogenomics, and theciated problems could lead to significant negative clinical out- future of pharmacovigilance is also presented.comes for patients. However, despite extensive research and largepremarketing clinical trials, the complete safety profile of a drug is 1. Safety Reportinggenerally not available at the time of product launch.[7] In addition,aging of populations and the associated more frequent use of An important aspect in postmarketing drug safety surveillancemedication as well as the common issue of polypharmacy have is the timely collection of appropriate safety data for assessmentcontributed significantly to the increased risk of occurrence of and decision-making. Internationally harmonized reporting re-adverse drug reactions (ADRs).[8-11] The problem is compounded quirements are essential for moving towards a more efficientfurther by a growing number of newly approved medicines and safety management system whereby data collected from variousmany new products with increased potency.[12] parts of the world could be quickly exchanged and compared.

Drug safety management places a significant burden both on Such a system also has the benefit of eliminating unnecessary andthe healthcare system and society. For example, ADRs are a undue reporting burdens on the industry as a result of regionalcommon cause of drug-related hospital admissions, especially differences.among elderly populations.[13,14] Many ADRs produce acute The working group of the Council for International Organiza-symptoms that impose costly emergency physician visits with tions of Medical Sciences (CIOMS) has developed several gui-subsequent hospitalizations.[15-21] The considerable direct and indi- dance documents for collecting safety information since the earlyrect costs associated with ADRs further support the need to 1990s.[43-47] For instance, the CIOMS I introduced the standard-employ effective means to systematically monitor and minimize ized reporting form used for expedited reporting of individualthe occurrence of ADRs.[22-26] Currently, the International Confer- cases of serious, unexpected ADRs.[43] The CIOMS II proposedence on Harmonization (ICH) and regulatory agencies worldwide standardized reporting requirements for periodic safety updateare adopting important initiatives that apply risk management reports (PSUR).[44] The most recent CIOMS report (CIOMS V),strategies to the early postmarketing period after product issued in 2001, entitled Current Challenges in Pharma-launch.[27-29] Their goals are to maximize drug benefits, minimize covigilance, covers other important issues in dealing with thedrug risks, and assess positive benefit-risk balance throughout a safety of post-marketed drugs, such as sources of individual caseproduct lifecycle. reports, good case management practices, PSUR issues, and deter-

mination of population exposure data, and provides an overview ofThe thalidomide tragedy in 1961 led many countries to estab-worldwide clinical safety reporting regulations.[47]lish national and local agencies to conduct drug safety surveillance

in order to promote patient safety.[30-34] With further knowledge In recognition of the importance of a standardized and unifiedgained from new research as well as the availability of additional system for safety reporting and data collection by regulatorsresources and new technologies, regulators worldwide are refining worldwide, the ICH adopted several CIOMS guidance reports.and adopting several new initiatives to promote drug safety sur- Major progress made by the ICH is described as follows.veillance. The most noticeable amongst all the developments is the ICH E2A provides the standardized requirements for expeditedimplementation of the ICH guideline for safety reporting in the reporting; the CIOMS-I form could be used for such purpose.[48]

ICH regions.[35-42] The internationally standardized reporting re- ICH E2B standardizes data elements for safety reports of individu-quirements have many benefits including: promptly transmitting, al cases, regardless of source and location.[49] It serves as a base forexchanging, and comparing important safety information in vari- ICH E2B(M) which provides guidance on the development of anous parts of the world. Not only does the ICH guideline lead to electronic format that could accommodate direct database to data-changes in regulations in many countries, it also results in corre- base transmission using message transfers.[50]

sponding new changes in industry practice of safety surveillance. The ICH harmonization efforts of periodic safety reportingThis review summarizes the latest regulatory developments in primarily focus on adopting a unified content, format, birth date,

postmarketing drug safety surveillance in three major economic core data sheet, and periodicity across the three ICH regions (ICHregions: the European Union (EU), Japan and the US. This article E2C).[51] The important topics of ICH E2C include synchroniza-is focused on three main areas of development in pharma- tion of national birth dates with the international birth date (IBD),covigilance: safety reporting, safety signal analyses, and risk restarting the clock for PSURs, and incorporation of risk manage-

© Adis Data Information BV 2003. All rights reserved. Pharm Dev Regul 2003; 1 (4)

Postmarketing Drug Safety Surveillance 233

ment programs and benefit-risk analysis in PSURs. Recently, an regional-specific requirements for postmarketing expedited andaddendum to the ICH E2C guidance that clarifies the previous ICH periodic safety reporting.E2C and adopted CIOMS V recommendations was prepared.[47] Further descriptions of other regional-specific regulatory re-The addendum has proceeded to the Step 4 stage in February 2003. quirements and most recent changes in safety reporting are pro-This addendum should be used in conjunction with the prior ICH vided in sections 1.1 to 1.3.E2C guidelines.[52]

1.1 United StatesA new ICH guideline on expedited reporting for post-marketeddrugs proceeded to the Step 3 stage in Brussels on July 18, 2003

The US FDA has proposed amendments and additions to its(ICH E2D).[53] ICH E2A provides guidance on preapproval safetycurrent safety reporting regulations to implement definitions anddata management, while ICH E2D provides guidance on thereporting formats/standards recommended by the ICH.[60] Thedefinitions and standards for postapproval expedited reporting.main goal is to allow the industry to focus on more importantICH E2D is planned to reach the Step 4 stage in November 2003.spontaneous reports over those that are known or not medically

Another important advance is the adoption of the Medicalsignificant. This large US FDA document is nick named ‘TOME’.

Dictionary for Regulatory Activities (MedDRA) as the single andIn these newly proposed rules, the US FDA proposed a mini-

internationally acceptable medical terminology system for interna-mum data set (including an identifiable patient, an identifiable

tional electronic regulatory communication. MedDRA was devel-reporter, a suspect drug product, and an adverse event) for all

oped based on the Medical Dictionary for Drug Regulatory Affairssuspected adverse drug reactions (SADRs), and a full data set for

(MDDRA), which was originally derived from the UK medicalserious SADRs. In addition, the agency proposed active query (i.e.

terminology used in the Adverse Drug Reactions On-line Informa-direct verbal contact in person or by telephone with the initial

tion and Tracking (ADROIT) database.[54]

reporter of a SADR) to follow up on all SADRs. An additionalBefore the adoption of MedDRA, several medical terminology new requirement is that a licensed physician from a pharmaceuti-

systems existed including the COSTART system in the US, the cal company will be asked to be responsible for all the content ofWorld Health Organisation’s Adverse Reaction Terminology postmarketing safety reports submitted to the agency. Adverse(WHOART), Japan’s Adverse Reaction Terminology (J-ART), drug experience information obtained or received from any source,the International Classification of Diseases, 9th Edition (ICD-9) including the Internet, should be reviewed promptly by the phar-and the ICD-9 Clinical Modification (ICD-9-CM). Communica- maceutical sponsors. SADRs are required to be coded using thetion was often impaired among regulatory bodies as a result of ‘preferred terms’ in the latest version of MedDRA in use.delays or distortions caused by translation of data from one termi- For postmarketing periodic safety reporting, the new proposednology to another. Other limitations included restricted data re- reports include a Periodic Safety Update Report and an Interimtrieval, lack of specificity, and difficulty in cross-referencing data Periodic Safety Report. There are new requirements for enhancingthrough the product lifetime. To overcome these problems, the the content of the report narrative and changes in reporting fre-ICH called for adopting MedDRA as the universal standard quency. In addition, the agency proposed additional informationmedical terminology for the pre- and postmarketing phases of the be submitted as appendices to the standardized core safety reports.regulatory process (ICH M1).[55]

These would include information such as a copy of the current USapproved labeling, medication errors reports, consumer reports,Implementation schemes for these ICH guidance documentsSADRs with unknown outcomes, class action lawsuits, lack ofare currently ongoing in all ICH regions. National authorities areefficacy reports, resistance to antimicrobial drug products reports,adopting the ICH recommendations to instigate new regulations,etc.so that administrative laws can be enforced. For instance, when

Step 4 of each initiative is reached, the US FDA would publish anotice in the Federal Register. For the EU, the guidelines are to be 1.2 European Unionendorsed by the Committee for Proprietary Medicinal Products

The current European regulatory initiatives are as fol-(CPMP). In Japan, the ICH texts are translated into Japanese andlows:[29,63,65]notification is issued subsequently. Table I summarizes the imple-

mentation status of these ICH guidelines in the three major eco- 1. recommending electronic reporting based on the EudraVigi-nomic regions. Table II summarizes the ICH harmonization and lance network using MedDRA. Unlike the US, the ‘lower level


234 Wu et al.

Table I. Implementation status of International Conference on Harmonization (ICH) guidelines in three major economic regions

ICH Status Contents US European Union Japanguideline

EA2 Step 4 – October 1994/step Definitions and standards Published in Federal Adopted by CPMP in 1994 Adopted in March 19955 for expedited reporting Register 1995 Mar; 60 Nov (CPMP/ICH/377/95)[38] (PAB/PCD notification no.

(40): 11284-287[35] 227)[41]

E2B Step 4 – July 1997/step 5 Data elements for Published in Federal Adopted by CPMP in 1997 Not yet publishedtransmission of ADR Register 1998 Jan; 63 Sep (CPMP/ICH/287/95)[39]

reports (10): 2396-2404[36]

E2C Step 4 – November 1996/ Periodic safety update Published in Federal Adopted by CPMP in 1996 Adopted in 1997 Mar (PAB/addendum February 2003/ reports/addendum to ICH Register 1997 May; 62 Dec (CPMP/ICH/288/95).[40] PSD notification no. 32).[42]

step 5 E2C (96): 27469-476 Adopted by CPMP in March Adopted in April 2003addendum to be 2003 (CPMP/ICH/4679/ (PFSB/ELD notification no.notified[37] 02)[56] 0425001 and PFSB/SA

notification no. 0425001)[57]

E2BM Step 4 – November 2000/ Maintenance of the ICH Not yet published Amended guideline in Adopted in 2001 MarFebruary 2001 – Version guideline: data elements for November 2000 [CPMP/ (PMSB/SA notification no.4.4.1/step 5 transmission of individual ICH/287/95 correction – 30 and PMSB/ELD

case safety reports ICH E2B(M)][58] notification no. 334)[59]

M1 Version 2.0 – July 1997. Medical terminology – Proposed rules Adopted in 2002 Mar Adopted in 1999 DecCurrent version 6.1 MedDRA published in Federal (EMEA/H/31387/01/Final)[61] (PMSB/SD notification no.

Register 2003 Mar; 68 164 and PMSB/ELD(50): 12405-497[60] notification no. 1843)[62]

ADR = adverse drug reactions; CPMP = Committee for Proprietary Medicinal Products; EMEA = European Agency for the Evaluation of MedicinalProducts; MedDRA = Medical Dictionary for Regulatory Activities.

terms’ are expected to be used for electronic transmission of well as loss of credibility with regulatory authorities. The enforce-adverse reaction data ment measures became effective in January 2002.

2. proposing renewing the first marketing authorization after five1.3 Japanyears, and the indefinite valid market authorization after this

renewalThe Japanese postmarketing surveillance system consists of a

3. recommending explicit requirement for continuous benefit-riskre-examination and re-evaluation period.[64] Re-examination is

assessment, especially in the PSURsmandatory for all approved drugs to reconfirm their safety and

4. recommending more rapid decisions for pharmacovigilance effectiveness after launch. Data are collected through surveys ofissues as part of the European risk management strategies. drug use, and surveys on special patient populations, including

infants, the elderly, pregnant women, and patients with kidney orThe European Agency for the Evaluation of Medicinal Prod-liver problems, who may not have been included in the preap-ucts (EMEA) has also identified a strategy for improving theproval clinical studies. The typical time period for re-examinationcompliance of postmarketing commitments to strengthen theis 6 years, but it could be as long as 10 years. Re-evaluation ispharmacovigilance process. According to the 2001 European Posi-undertaken every 5 years when the re-examination period is com-tion Paper on Compliance with Pharmacovigilance Regulatorypleted and potential safety issues have been identified for the drug.Obligations, a strict enforcement procedure for monitoring and

enforcing compliance for both quality and timeliness was adopt- In October 2001, a new compulsory postmarketing surveillanceed.[66] Initial noncompliance is judged on a case-by-case basis with system was introduced in Japan for collecting adverse event datapublic health impact considered. The most serious offences would on new products. The new system requires representatives frombe considered to be failure to notify changes in benefit-risk pharmaceutical sponsors to conduct frequent visits to medicalprofiles, deliberate noncompliance, or failure to improve the com- institutions in the first six months after launch of a new drug.[67] Inpliance. For the sponsor, these offences would result in potential addition, use of MedDRA and electronic filing began in Octoberrevocation of a marketing authorization, regulatory inspection, as 2003.[68] For enforcement, Japan has also adopted a rule, similar to



that in the EU, that regulation non-compliance could lead to fines ments. For example, there are different requirements for reports ofof up to 300 000 yen, withdrawal of the New Drug Application local origin, different definitions of seriousness and expectedness,(NDA), and removal of the product from the Japan National differences in the methods used in product licensure, and medicalHealth Insurance price listing and/or loss of product license.[69] practice differences in the country of origin. Nevertheless, al-

though much more work is anticipated in the future, the currentIn summary, the CIOMS guidance and ICH harmonizationharmonization efforts mark the first step in leading postmarketingefforts have led to many changes in safety reporting worldwide.drug safety surveillance systems towards more proficient modernAfter all, internationally standardized reporting requirements andpharmacovigilance practices.technology have many benefits. For example, multinational com-

panies could prepare centrally a standard periodic safety update2. Data Analyses and Safety Signal Detectionreport that could be submitted to regulators in all ICH regions.

Such a system could eliminate unnecessary and undue reporting After postmarketing safety data are collected in a timely fash-burdens on the industry because of regional differences. In addi- ion and transmitted to the regulatory authorities, the primarytion, there are common requirements for reporting serious unex- activities of pharmacovigilance personnel are to analyze and as-pected ADRs expeditiously, the use of MedDRA and electronic sess a large amount of spontaneously reported ADRs and identifyfiling in all ICH regions. Such requirements could allow important safety signals. Despite tremendous manpower having been invest-safety information to be promptly transmitted, exchanged, and ed in this area, the large volume of data has made manual reviewcompared in various parts of the world. Consequently, proper for individual case assessment and signal generation impossibleactions to minimize the occurrence of these ADRs could be taken and inefficient. The World Health Organization (WHO) and vari-in a timely manner. ous regulatory authorities have explored using automated data-

Obviously, despite these improvements, there remain other mining tools to analyze aggregate data for safety signal genera-differences in regional specific reporting needs and additional tion.[70-73] Such technology has revolutionized the field in terms offactors that contribute to the diversity of ADR reporting require- speed and accuracy. The most widely used signal generation and

Table II. International Conference on Harmonization (ICH) and regional-specific requirements on postmarketing expedited and periodicreporting[48,51,60,63,64]

Postmarketing expedited reporting Postmarketing periodic reporting

ICH Fatal or life-threatening unexpected ADRs should be reported within 7 Adopt a unified content, format, birth date, core datacalendar days and all other serious unexpected ADRs should be sheet and periodicity across the three ICH regions.reported within 15 calendar days Periodicity is based on multiples of six months

US For the current regulations, serious and unexpected ADRs, whether For reporting frequency, current regulations requireforeign or domestic, must be reported within 15 calendar days. In the quarterly reports during the first 3 years, followed bynew proposed rules, ADRs that must be submitted expeditiously to the annual reports. New proposed reporting frequency isFDA include: every six months for 2 years after US approval, every(i) serious and unexpected SADRs year for the next 3 years, every 2.5 years for the next 10(ii) unexpected SADRs with unknown outcomes years, and every 5 years thereafter. In the new proposed(iii) always expedited reports rules, nonserious expected SADRs are no longer required(iv) potential or actual medication errors in the report. Non-US serious, expected SADRs are

required for submission to the agency

EU For centrally authorized products, serious ADRs occurring in the EU For periodic safety reporting, PSURs should be submittedshould be reported to the member states within 15 days. Serious ADRs to the member states and the EMEA Secretariat at six-should then be forwarded by the Member States to the EMEA. All monthly intervals for 2 years after product approval, thenserious unexpected ADRs from outside the EU should be reported to annually for the subsequent 3 years, and 5-yearlythe EMEA and the member states within 15 days thereafter

Japan Serious and unexpected ADRs involving death, or serious infection due PSURs should be prepared annually for a drug within theto the use of a drug should be submitted to the MHLW within 15 days. specified re-examination periodPreviously known serious or unknown non-serious ADRs should besubmitted within 30 days

ADR = adverse drug reactions; EMEA = European Agency for the Evaluation of Medicinal Products; EU = European Union; MHLW = Ministry of Health,Labor and Welfare; PSUR periodic safety update reports; SADRs = suspected adverse drug reactions.


236 Wu et al.

data-mining tools that are currently the focus of the WHO and overall patient safety strategy that will shift the primary focus frommajor regulatory agencies are described as follows. voluntary reporting to automated systems for adverse event data

collection and analyses.[74]The WHO adopted the Bayesian Confidence PropagationNeural Network (BCPNN) method to screen for unexpected as- The proportional reporting ratio (PRR) is currently employedsociations between drugs and adverse reactions.[70,71] The BCPNN by the Medicines and Healthcare products Regulatory Agencyis now in routine use for signal detection in the WHO database, (MHRA) in the UK for routine screening of new data in itswhich contains over 2.5 million case reports. The information Adverse Drug Reactions On-line Information Trackingcomponent, a measure of the correlation between a drug and an (ADROIT) database, which contains more than 350 000 re-adverse reaction, and its confidence interval are calculated for all ports.[75,76] The PRR has an important computation ease advantagedrug-ADR combinations on a quarterly basis. Potential signals of and this makes it a valuable tool to detect signals of possiblethe drug event combinations that have a lower 95% confidence unrecognized hazards from the spontaneous reporting database.limit greater than zero, are highlighted for clinical review. The Currently, the criteria used to define a signal includes three orBCPNN approach is robust, time efficient, and produces reproduc- more reports, a PRR >2 and a chi-square value >4. In addition, inible results. Since more than 2000 potential signals were reported order to reduce the volume of potential signals for clinical assess-per quarter, additional signal selection algorithms have been im- ment, the agency employs the Strong, New, Important and Poten-plemented to fine tune the signals. Events that are of primary tially preventable (SNIP) criteria to focus on new signals withconcern are: serious and new events, events with a rapidly increas- strong intensity, which are clinically important and potentiallying frequency, events of special interest (e.g. rhabdomyolysis,

preventable. The intensity of each signal could be directly mea-agranulocytosis, and Stevens-Johnson syndrome), and events that

sured by the PRR. One limitation of the PRR is that large numbersare reported from more than one country.

of reports of a particular signal of a drug would inflate the overallOn the other hand, the US FDA employed a new data-mining denominator, which could reduce the magnitude of the PRR for

tool called the Multi-Item Gamma Poisson Shrinker (MGPS) other signals with that drug. A possible solution is to exclude thoseprogram, which replaced the older Gamma Poisson Shrinker pro- reports and recalculate the PRR. Lastly, the sensitivity and speci-gram.[72,73] The MGPS program is used to screen over 2 million

ficity of the PRR method using various minimum criteria could beadverse event reports in the US FDA database. A unique feature of

further evaluated and refined.the MGPS program is that it can detect over-represented single

Table III provides a brief summary of these three most widelydrug-event combinations, higher-order combinations (e.g. drug-used signal generation and data-mining tools. Of note is that directdrug interactions and adverse events), as well as subgroup differ-comparisons of the tools may not be appropriate as they areences. In addition, specialized graphic visualization tools areapplied to different databases and are currently used differently byemployed to supplement the MGPS in identifying and interpretingdifferent parties. For instance, the BCPNN is employed to screenpatterns of potential safety signals. Signal scores, defined as thethe entire WHO database to search for any unexpected correla-lower 95% confidence interval limit of the adjusted ratios of thetions. The US FDA is still testing and validating the MGPSobserved vis-a-vis expected count for pair-wise combinations, areprogram prior to its full implementation in the Adverse Eventused to screen potential signals.Reporting System (AERS). The MHRA routinely uses the PRRA threshold of 2 is currently used, which means for any drug-method to screen new data in its ADROIT database.event combinations that have signal scores ≥2, the particular

Although data-mining techniques could provide a systematiccombinations are reported at least twice as often as expected. Theand efficient approach to screening large adverse event databases,MGPS emphasizes an overall ranking of signal scores for drug-limitations of the underlying data as well as the data-miningevent combinations. The US FDA is currently validating thetechniques employed must be fully scrutinized to avoid drawingMGPS program and the program is currently employed only on aimproper false-positive causality conclusions. After all, positivecase-by-case basis to assess specific safety issues as well as toscores serve only as an alert, and further clinical judgments areobtain further knowledge about data-mining tools. The agencyneeded to confirm the validity of the signals. It is generallybelieves that development of data-mining tools for safety signalaccepted by both the regulators and the industry that data-miningdetection in health maintenance organization records and militarytechniques should only be used as an adjunct measure to tradition-databases could further facilitate the systematic and independental pharmacovigilance methods.validation process. In the long run, the agency is working on an



Table III. Three signal detection and data-mining tools[70-76]

Characteristics Bayesian Confidence Propagation Multi-item Gamma Poisson Shrinker Proportional Reporting Ratio (PRR)Neural Network (BCPNN) (MGPS)

Organization/regulatory WHO Uppsala Monitoring Center US FDA UK MHRAauthority which hasadopted the tool

Year developed 1997 1997 1997

Usage In routine use for drug adverse reaction Experimental stage, Dr Szarfman, US In routine use for screening new data insignal detection in the WHO database FDA, is currently the exclusive user the UK ADROIT database

Statistical parameter Use information component (IC) where: Use empirical Bayes geometric mean PRR is a/(a+c) divided by b/(b+d) in a 2IC = log2[p(x,y)/p(x)p(y)] (EBGM) where: × 2 table. Criteria for possible signals: aBeta distribution was assumed to derive p (x actual >x expected) PRR of at least 2 and an associated χ2

prior probability Two-gamma mixture distribution was over 4, in the presence of at least 3assumed to derive prior probability reports

Strengths Transparent (easy to see what has Detects possible serious single-drug Simple, highly intuitive, and easy tobeen calculated). Robust (produces adverse event associations, drug calculate and interpretvalid results despite missing data). interactions and adverse events, andProduces reproducible signals. Time differences among subgroups.efficient Generates consistent, redundant, and

replicable signals while minimizingrandom patterns

ADROIT = Adverse Drug Reactions On-line Information Tracking; MHRA = Medicines and Healthcare products Regulatory Agency; p(x) = probability of aspecific drug ‘x’ being listed on a case report; p(y) = probability of a specific adverse drug reaction ‘y’ being listed on a case report; p(x,y) = probability thata specific drug-ADR combination ‘x’ and ‘y’, is listed on a case report; WHO = World Health Organization.

In early 2003, a Pharmaceutical Research and Manufacturers of databases, estimating sensitivity and specificity of different detec-tion tools, and comparing the utility of various data-mining toolsAmerica (PhRMA)–US FDA working group on Signal Evaluationin similar settings. Overall, further experience and guidance fromTools was formed. Its goal is to develop the ‘best practices’ forthe working groups and experts in the field are needed to betterdata-mining techniques to identify potential safety signals.[74] Im-define safety signals as well as in properly employing theseportant issues to be addressed by the group include, “what is thetechniques for routine safety signal detection in the future.best database; what are the best applications needed; and what are

the best practices for this tool?” The group also aims to understand3. Risk Management Strategiesthe strengths and limitations of safety data disproportionality

analysis. In addition, the group plans to explore applying data-The goals of overall risk management are to maximize drugmining methods to clinical trial data, which generally has better

benefits, minimize drug risks, and assess positive drug benefit-riskdata quality compared with spontaneous reports. Signals seen in

balance throughout a product’s life cycle. Although the concept ofclinical trials before product launch could be used in setting up

risk management has been around for sometime, its application toappropriate postmarketing pharmacovigilance plans.

postmarketing safety surveillance is relatively new. As a result ofIn summary, automated data-mining techniques are useful in the intrinsic limitations of clinical development (e.g. small sample

rapidly screening suspected ADRs in a systematic manner. They sizes, limited patient populations), the early postmarketing periodcould alert the industry early on about potential problems so that is important to further characterize the safety profiles of a drug. Infurther assessment could be conducted and risk management pro- addition, the safety profile of a drug may change over time,grams initiated. On the other hand, it is clear that data-mining is therefore evaluation of product benefit and risk profiles should beintended mainly to enhance current pharmacovigilance tech- viewed as an on-going process. Careful planning of effectiveniques, but not to replace them. Careful evaluation of individual pharmacovigilance and risk management activities, particularlycases using proper medical and scientific knowledge would still be for newly approved drugs, could minimize drug risks and promoteneeded. Future areas to be explored would include applying data- safe use of a drug. The ICH and regulatory authorities worldwidemining techniques to clinical trial data or automated claims are currently developing guidance on pharmacovigilance and risk


238 Wu et al.

management activities for the early postmarketing phase of new meantime, the agency has published concept papers on the follow-drugs.[27-29] ing issues: Good Pharmacovigilance Practices, Pharmacoepi-

demiologic Assessment, and Risk Management.[28]In its steering committee meeting of September 2002, the ICHendorsed an expert working group for developing a guidance In the concept papers for Good Pharmacovigilance Practicespaper entitled E2E: Pharmacovigilance Planning.[27] The paper and Pharmacoepidemiologic Assessment, the US FDA stated thatprovides guidance and standardized methodology for risk identifi- risk assessment by sponsors should comprise an estimate of back-cation, such that systematic approaches could be adopted to ground rates for the adverse event being investigated. These ratesachieve a more effective pharmacovigilance system across the should include an estimate of the background rates in the generalICH regions. The paper outlines the following components: population or in a subpopulation with characteristics similar topharmacovigilance specification, pharmacovigilance plan, and de- those of the exposed population. Although the agency recognizedsign and conduct of postapproval safety studies. The pharma- that reliable estimates of reporting rates in an exposed populationcovigilance specification that systematically documents the are difficult to obtain, it still suggested that the sponsor shouldknown and potential risks of a drug from preclinical and clinical attempt to provide them. The rationale is that the agency believesdevelopment provides the foundation for the pharmacovigilance that under-reporting is generally expected to be high, therefore aplan. The objectives of the pharmacovigilance plan are to better higher than expected rate might in fact reflect a strong indicatordefine the safety profile of a drug effectively and minimize prod- that the true incidence rate is sufficiently high to be of concern.uct risks when launching a new drug. The action plans could The papers also outline three primary methods to evaluateinclude conducting routine spontaneous reporting, preparing safety signals besides spontaneous adverse event reports, namelyPSURs, and performing postapproval studies. The amendment of the use of pharmacoepidemiologic studies, registries, and surveys.the pharmacovigilance plan could be based on several ‘safety These three tools could comprise a ‘pharmacovigilance plan’milestones’, such as product exposures, completion of safety proposed by a sponsor for the ongoing evaluation of identifiedstudies, or length of time on the market. The working group will safety signals. One of the US FDA’s criteria for recommending acontinue to meet in 2003 and a Step 2 document is expected to be pharmacovigilance plan beyond routine spontaneous reporting isreleased in November 2003. the presence of a ‘safety signal’. The agency stated that a single

In addition, other risk management activities have been devel- well-documented case report could be viewed as a signal if theoped in each of the three major ICH regions. These are described information contained is clear-cut, e.g. the report describes ain sections 3.1 to 3.3. positive rechallenge. In addition, preclinical findings or experi-

ences with similar products may also be sufficient to generate asafety signal. Lastly, a pharmacovigilance plan could also include3.1 United Statessubmitting adverse event reports in an expedited or more frequentmanner, performing active surveillance on certain events in select-In June 2002, the amendments of the Prescription Drug Usered patients or populations, and conducting more controlled clinicalFee Act of 2002 (PDUFA III) were adopted in the US.[28] Thetrials.PDUFA III proposed the following: (i) risk management plans

Further, in the concept papers for risk management, the USmay be included in the pre-NDA meeting package; (ii) risk man-FDA proposes four levels of risk management programs. Figure 1agement tools (e.g. medication guides and stickers that give in-depicts the details of such a proposal. Level 1 is the package insert.structions on the the correct use of the medication, and restrictedLevel 2 would include education and outreach to health profes-distribution) may be treated as labeling for purposes of NDAsionals and patients. Level 3 would include all of the elements ofactions; and (iii) outcomes of risk management may be included inthe first two levels, plus systems that could guide practitionersthe periodic reports for the first 2–3 years postapproval.and/or patients to prescribe, dispense, or receive a product proper-In addition, in exchange for receiving user fees under PDUFAly under different circumstances. Level 4 specifies a restrictedIII, the US FDA agreed to provide guidance for the industry onaccess system to the products. However, guidance was not pro-risk management activities. The US FDA proposed that a completevided on what circumstances would constitute programs beyondrisk management plan should include risk assessment, risk con-level 1.frontation, risk intervention, risk communication, and risk man-

agement program evaluation. The agency intends to produce gui- Evaluation of the success of a risk management program isdance documents on these issues by September 30, 2004. In the essential for ensuring that effective communication of a product’s



Package insert Education and outreach

Systems that provide guidanceRestricted access system

(product could be prescribed only by registered physicians, dispensing only by registered pharmacists or practitioners, or dispensing only to

patients with documentation of safe use conditions, such as laboratory results)

Package insertEducation and outreach

Systems that provide guidance (informed consent, certification programs for practitioners, enrollment of physicians and patients in a safety educational program, limitations on supply of the product of concern, specialized product packaging, and

specialized systems, records or stickers)

Package insertEducation and outreach

(healthcare professional letters, trainingprograms, continuing medical education, public notices, patient package inserts,

and medication guides)

Package insert

Level 4

Level 3

Level 2

Level 1

Fig. 1. Risk management tools proposed by the US FDA (contents adopted from the 2003 FDA Concept Paper on Risk Management).[28]

safety profile has been disseminated to healthcare providers, pa- early postmarketing period. The risk minimization toolkit is de-tients, and the general public. The US FDA stated that the evalua- signed to complement the pharmacovigilance plan to minimizetion could include process measures that reflect desirable safety product risks and protect patient safety. A detailed list of eachbehaviors, such as the use of a product as labeled. The evaluation element is presented in figure 2.could also include health outcomes, e.g. hospitalization data, anddeath certificate surveillance.

3.3 Japan

3.2 European UnionIn Japan, Early Phase Postmarketing Vigilance (EPPV) was

introduced into the Japanese regulations for postmarketing surveil-In the EU, the European Heads of Agencies formed an ad hoclance in October 2001.[67] The Ministry of Health, Labor andworking group to develop a European strategy for risk manage-Welfare (MHLW) is asking pharmaceutical companies to conductment in July 2002. A summary report was issued in Januaryfrequent visits to medical institutions and adopt other appropriate2003.[29] The report defines the term ‘risk management’ as ‘identi-measures to safeguard patient safety, especially during the first 6fication and implementation of strategies to reduce risk to individ-months after the launch of a new drug. Companies are required touals and populations’. The risk management plan is composed ofdevelop a pharmacovigilance plan before product launch and tothree elements, namely: pharmacovigilance specification, pharma-submit the plan to the MHLW. Safety data collected from thecovigilance plan, and a risk minimization toolkit. The pharma-surveillance are to be submitted within 2 months after the end ofcovigilance specification identifies risks of a drug from the preap-the pharmacovigilance activity. The purpose is to collect ADRproval studies, which could facilitate the construction of thedata and identify potential safety issues as early as possible.pharmacovigilance plan and the risk minimization toolkit. TheCompanies are asked to take necessary action to promote thepharmacovigilance plan, which is submitted prior to granting aproper use of drugs based on these early ADR reports obtainedmarketing authorization, focuses on characterizing the safety pro-

file including demonstrating safety and identifying risks in the from the medical professionals.


240 Wu et al.

Elements of pharmacovigilance specification• Identified preclinical safety concerns• Any missing preclinical data• ADRs in clinical trials• Potential ADRs requiring further evaluation• Populations not studied in preapproval phase• Documented interactions• Potential for unidentified interactions• Disease epidemiology• Class effects

Pharmacovigilance plan• For products with an extensive preapproval safety database: the plan may simply be spontaneous reporting systems and periodic safety update reportsfor postapproval safety monitoring• For products with risks of concern: the plan might detail additional data collection including protocol outlinesfor postapproval safety studies or registry

Risk minimization toolkit• Labeling, including population, indication, warnings, contraindications• Communication to healthcare professionalsand the public, including letter, advertisementsand educational programs• Distribution control, including prescription,dispensing, registries and consent• Treatment protocols and guidelines

Risk management plan

Fig. 2. European risk management strategy (contents adopted from the 2003 European Union Report on Developing Risk Management Strategy).[29] ADRs= adverse drug reactions.

In summary, the application of risk management to the early 4.1 Medication Errors

postmarketing period is rapidly evolving, and it has become one ofthe most important topics in pharmacovigilance. In general, risk Medication errors are frequent causes of adverse drugmanagement requires a comprehensive approach to effectively events.[33] They could occur at any point in the medication admin-minimize a drug’s risk and to assess positive drug benefit-risk istration process including ordering, dispensing, and administeringbalance throughout a product’s life cycle. Currently, many ideas medications. The US FDA recognizes the impact of medicationand proposals are being generated by both the regulators and errors, and imposes that all cases of medication errors should beindustry alike. Many of these ideas call for sweeping changes in reported to the agency expeditiously.[60] The agency also requiresthe current practice of pharmacovigilance and the establishment of that drug labels should have bar codes to ensure that the propera more streamlined, multidisciplinary, evidence-based, science- drug is being dispensed using code-scanning machines.[77]

driven, and patient-focused system to manage drug safety issues. In addition, the agency recommends that pharmaceutical com-This would certainly revolutionize the way postmarketing drug panies do not use similar-sounding or ‘look-alike’ drug names. Insafety surveillance is being conducted. Risk management plans the proposed rules released in 2003, the agency stated that compa-will likely become one of the standard requirements for new drug nies should ‘prioritize the errors according to the expected out-approvals in the future. comes and minimize the potential for an error through corrective

action, including renaming, relabeling and repackaging’.[60] Theagency is asking the industry to conduct risk assessment on a4. Miscellaneousproduct’s name, labeling, and packaging to minimize medicationerrors.[28] The risk assessment should identify potential and actualBesides the three areas of development discussed in sections 1,causes of each error.2 and 3, there are two other areas in which there have been recent

changes that are worth mentioning. These are medication errors Besides measures such as expedited reporting of medical errorand pharmacogenomics. cases, bar codes, and repackaging, the industry is being asked to



develop strategies to minimize medication errors. For instance, the who might require a lower dose for the intended effect, couldagency is asking the industry to solicit comments about a product’s minimize toxicity.labeling from healthcare providers, patients, and consumers In reviewing new drug submissions to the agency, the US FDAthrough questionnaires, interviews, and computer models.[28] The found that the most common metabolic pathway studied wasagency noted that further rules and guidance might be developed cytochrome P450 (CYP) 2D6 (72.9%), followed by CYP3A4/5,in the future if cases of medication errors could not be properly and CYP2C19 (14.3% each).[83] The CYP2D6 gene is on chromo-managed through the above means.[28] some 22 and it produces a drug-metabolizing enzyme. Thus, poor

Similar activities have also occurred in Europe. For example, metabolizers of drugs that depend on the CYP2D6 pathway couldthe UK regulatory authority has made a number of recommenda- potentially experience a higher rate of adverse events.tions for the redesign of packaging and product labels to reduce The US FDA is considering that future drug labeling shouldserious medication errors by 40% by 2005.[78] The MHRA recom- include pharmacogenetic information.[83] For instance, future la-mends using computer technology and expert review to avoid bels might be required to include information on the phenotype of‘look-alike’ and ‘sound-alike’ drug names. In addition, the agency poor metabolizers, the chromosome allele where the mutation isbelieves that creation of a “number plate”, which would contain located, enzyme activity, or allele frequency.the name of the drug, strength, and route of administration is the There are some examples of pharmacogenetic information in-best way to reduce medication errors. The dosage and warnings cluded in a drug label. For instance, the label of the new drugwould also be placed on the dispensing label. aprepitant (Emend®1) includes a statement indicating that it is a

Overall, while medication errors are not directly related to the moderate CYP3A4 inhibitor and should be used with caution inintrinsic toxicity of a drug itself, they constitute an important drug patients receiving concomitant drugs that are primarily metabo-safety issue resulting from human errors. Regulators are currently lized through that pathway, e.g. docetaxel, paclitaxel, etc.[84] Thetaking actions to address this issue and the industry is encouraged label of another drug, ‘atomoxetine’ (Strattera®), contains infor-to work with the regulators to help minimize these problems. mation on the effect of atomoxetine in poor metabolizers of the

CYP2D6 pathway and cautions physicians on concomitant use4.2 Pharmacogenomics and Pharmacogenetics with other CYP2D6 inhibitors such as fluoxetine, paroxetine, and

quinidine.[83]An important future trend to further improve patient safety is

Overall, pharmacogenomic information will be a useful tool inthe application of pharmacogenomics/pharmacogenetics in drugthe future to customize drug therapy as well as to serve as atherapy. As a result of the Human Genome Project, new develop-potential screening tool to alert prescribers of potential ADRs.ments in the identification of genetic information will allow theHowever, both regulatory agencies and industry currently haveindividualization of drug therapy in the future.[79-81] Individualiz-limited knowledge on this topic and more research and experienceing therapy in patients with varying abilities to metabolize drugsare needed to apply pharmacogenomics to drug safety manage-has many potential benefits, including reducing ADRs.[79-81] Al-ment. The utility and impact of pharmacogenomics in postmarket-though the primary impact of pharmacogenomics/pharmacogene-ing drug safety surveillance are likely to be promising, therefore,tics is on drug therapy, pharmacovigilance could also employ themore development activities are expected in the near future.new knowledge and technology to minimize drug risks and to

promote patient safety.5. Conclusions and Future Trends

Recently, the US FDA announced that it will issue three gui-dance documents on pharmacogenomics by the end of 2004.[82] In summary, postmarketing drug safety surveillance is rapidlyThe documents will include the following issues: (i) co-develop- evolving, and regulatory authorities worldwide are undertaking ament of a drug and a diagnostic test; (ii) specifying when number of new initiatives. The most important initiative is thepharmacogenomics data will have a ‘regulatory impact’; and (iii) application of the concept of risk management programs. Regula-general standards and techniques for pharmacogenomics. The tory authorities are currently developing guidance to the industryagency is focusing on applying pharmacogenomic principles to and healthcare providers through various concept papers andidentify the broad variation in drug responses due to individual workshops. In addition, global harmonization of safety reportingdifferences. For example, identifying poor metabolizers of a drug, has been taking place by regulatory agencies worldwide for some

1 The use of tradenames is for product identification purposes only and does not imply endorsement.


242 Wu et al.

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