Guidance for Industry
  
 
E2E Pharmacovigilance 
 
Planning  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
 
Food and Drug Administration 
 
Center for Drug Evaluation and Research (CDER) 
 
Center for Biologics Evaluation and Research (CBER) 
 
 
April 2005
  
ICH 
 
 
 
   
Guidance for Industry
  
 
E2E Pharmacovigilance 

Planning  
  
  
 
 
 
Additional copies are available from: 
 
 
Office of Training and Communication 
 
Division of Drug Information, HFD-240
  
Center for Drug Evaluation and Research 
 
Food and Drug Administration  

5600 Fishers Lane 
 
Rockville, MD 20857 
 
(Tel) 301-827-4573
 
 http://www.fda.gov/cder/guidance/index.htm  

 
Office of Communication, Training and  

Manufacturers Assistance, HFM-40  

Center for Biologics Evaluation and Research
 
 Food and Drug Administration 
 
1401 Rockville Pike, Rockville, MD 20852-1448  

http://www.fda.gov/cber/guidelines.htm. 
 
 (Tel) Voice Information System at 800-835-4709 or 301-827-1800 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
 
Food and Drug Administration 
 
Center for Drug Evaluation and Research (CDER) 
 
Center for Biologics Evaluation and Research (CBER) 
 
 
 
April 2005
  
ICH 
 
 
  Contains Nonbinding Recommendations  
TABLE OF CONTENTS 
 
 
 
 
I.   INTRODUCTION (1, 1.1) ................................................................................................... 1
  
A.   Background (1.2) ..................................................................................................................2
  
B.   Scope of the Guidance (1.3)...................................................................................................2
  
II.   SAFETY SPECIFICATION (2) ...................................................................................... 3 
 
A.   Elements of the Specification (2.1) ........................................................................................4
  
1.  Nonclinical (2.1.1)..................................................................................................................4
  
2.  Clinical (2.1.2).......................................................................................................................4
  
B.   Summary (2.2) ......................................................................................................................6
  
III.   PHARMACOVIGILANCE PLAN (3)............................................................................ 6 
 
A.   Structure of the Pharmacovigilance Plan (3.1)......................................................................7
  
1.  Summary of Ongoing Safety Issues (3.1.1)................................................................................7
  
2.  Routine Pharmacovigilance Practices (3.1.2)...........................................................................7
  
3.  Action Plan for Safety Issues (3.1.3).........................................................................................8
  
4.  Summary of Actions To Be Completed, Including Milestones (3.1.4) ..........................................8
  
B.   Pharmacovigilance Methods (3.2) .........................................................................................8
  
IV.   REFERENCES (4) .......................................................................................................... 10 
 
ANNEX  PHARMACOVIGILANCE METHODS.............................................................. 11
  
  Contains Nonbinding Recommendations  
 
1
 
Guidance for Industry  
 
E2E Pharmacovigilance Planning 
 
 
 
 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
I.   INTRODUCTION (1, 1.1) 2  
 
This guidance is intended to aid in planning pharmacovigilance activities, especially in 
preparation for the early postmarketing period of a new drug (in this guidance, the term drug  
denotes chemical entities,  biotechnology-derived products, and vaccines).  The main focus of 
this guidance is on a safety specification and pharmacovigilance plan that might be submitted at 
the time of license application. The guidance can be used by sponsors to develop a stand-alone 
document for regions that prefer this approach or to provide guidance on incorporation  of 
elements of the safety specification and pharmacovigilance plan into the Common Technical 
Document (CTD).  
 
The guidance describes a method for summarizing the important identified risks of a drug, 
important potential risks, and important missing information, including the potentially at-risk 
populations and situations where the product is likely to be used that have not been studied 
preapproval. It proposes a structure for a pharmacovigilance plan and sets out principles of good 
practice for the design and conduct of observational studies. It does not describe other methods 
to reduce risks from drugs, such as risk communication. The guidance takes into consideration 
ongoing work in the three regions and beyond on these issues.  
 
                                                 
1  This guidance was developed within the Expert Working Group (Efficacy) of the International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 
subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been 
endorsed by the ICH Steering Committee at Step 4 of the ICH process, November 2004.  At Step 4 of the process, 
the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United 
States.  
2  Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee 
at Step 4 of the ICH process, November 2004.  
 
  1
  Contains Nonbinding Recommendations  
 
This guidance does not cover the entire scope of pharmacovigilance.  It uses the World Health 
Organization (WHO) definition of the term pharmacovigilance as the science and activities 
relating to the detection, assessment, understanding and prevention of adverse effects or any 
other drug related problems. This definition encompasses the use of pharmacoepidemiological 
studies.  
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
A.   Background (1.2)  
 
The decision to approve a drug is based on its having a satisfactory balance of benefits and risks  
within the conditions specified in the product labeling. This decision is based on the information 
available at the time of approval. The knowledge related to the safety profile of the product can  
change over time through expanded use in terms of patient characteristics and the number of 
patients exposed. In particular, during the early postmarketing period, the product might be used 
in settings different from clinical trials and a much larger population might be exposed in a 
relatively short timeframe.  
 
Once a product is marketed, new information will be generated, which  can have an impact on the 
benefits or risks of the product; evaluation of this information should be a continuing process, in 
consultation with  regulatory authorities. Detailed evaluation of the information generated 
through pharmacovigilance activities is important for all products to ensure their safe use. The 
benefit-risk balance can be improved by reducing risks to patients through effective  
pharmacovigilance that can enable information feedback to the users of medicines in a timely 
manner.  
 
Industry and regulators have identified the need for better and earlier planning of 
pharmacovigilance activities before a product is approved or a license is granted. This ICH 
guidance has been developed to encourage harmonization and consistency and  prevent 
duplication of effort and could be of benefit to public health programs throughout the world as 
they consider new drugs in their countries.  
 
 
B.   Scope of the Guidance (1.3)  
 
The guidance could be  most useful for new chemical entities,  biotechnology-derived products, 
and vaccines, as well as  for significant changes in established products (e.g., new dosage form, 
new route of administration, or new manufacturing process for a biotechnology-derived product) 
and for established products that are to be introduced to new populations or in significant new 
indications or where a new major safety concern has arisen.  
 
  2
  Contains Nonbinding Recommendations  
 
The purpose of this guidance is to propose a structure for a pharmacovigilance plan and  a safety 
specification that summarizes the identified and potential risks of the product to be addressed in 
the plan. The guidance is divided into the following sections:  
   Safety specification  
   Pharmacovigilance plan  
   Annex  Pharmacovigilance Methods  
 
It is recommended that company pharmacovigilance experts get involved early in product 
development.  Planning and dialogue with regulators should  also start long before license 
application. A safety specification and pharmacovigilance plan can  also be developed for 
products already on the market (e.g., new indication or major new safety concern).  The plan 
could be used as the basis for discussion of pharmacovigilance activities with regulators in the 
different ICH regions and beyond.  
 
For products with important identified risks, important potential risks or important missing 
information, the pharmacovigilance plan should include additional  actions designed to address 
these concerns.  For products for which no special concerns have arisen, routine 
pharmacovigilance as described in section III.A.2 (3.1.2) of this guidance  should be sufficient for 
postapproval safety monitoring, without the need for additional actions (e.g.,  safety studies).    
 
During the course of implementing the various components of the plan, any important emerging 
benefit or risk information should be discussed and used to revise the plan.  
 
The following principles underpin this guidance:  
   Planning of pharmacovigilance activities throughout the product life-cycle  
   Science-based approach to risk docume ntation  
   Effective collaboration between regulators and industry  
   Applicability of the pharmacovigilance plan across the three ICH regions  
 
 
II.   SAFETY SPECIFICATION (2)  
 
The safety specification should be a summary of the important identified risks of a drug, 
important potential risks, and important  missing information.  It should also address the 
populations potentially at-risk (where the product is likely to be used), and outstanding safety 
questions that warrant further investigation to refine understanding of the benefit-risk profile  
during the postapproval period.  This safety specification is intended to help industry and 
regulators identify any need for specific data collection and also to facilitate the construction of 
the pharmacovigilance plan.   The safety specification can be built initially during the 
premarketing phase and, at the time approval is sought, it should reflect the status of issues that 
were being followed during development.   
 
The Common Technical Document (CTD), especially the Overview of Safety (2.5.5), Benefits 
and Risks Conclusions (2.5.6), and the Summary of Clinical Safety (2.7.4) sections, includes  
information relating to the safety of the product and should be the basis of the safety issues 
identified in the safety specification.  Sponsors should support the safety specification with 
  3
  Contains Nonbinding Recommendations  
 
references to specific pages of the CTD or other relevant documents.  The safety specification  
can be a stand-alone document, usually in conjunction with the pharmacovigilance plan, but 
elements can also be incorporated into the CTD. The length of the document will generally 
depend on the product and its development program. Appendices can be added if it is considered 
important to provide a more detailed explanation of important risks or analyses.    
 
A.   Elements of the Safety Specification (2.1)  
 
It is recommended  that sponsors  follow the structure of elements provided below when 
compiling the safety specification. The elements of the safety specification that are included are 
only a guide.  The safety specification can include additional elements, depending on the nature 
of the product and its development program. Conversely, for products already on the market with 
emerging new safety concerns, only a subset of the elements might be relevant.  
 
The focus of the safety specification should be on the identified risks, important potential risks,  
and important missing information.  The following elements should be considered for inclusion.  
 
1.   Nonclinical (2.1.1)  
 
Within the Specification, this section should present nonclinical safety findings that have not 
been adequately addressed by clinical data, for example:  
 	  Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity, 

nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity, etc.)
  
 	  General pharmacology (cardiovascular, including QT interval prolongation; nervous 
system; etc.)  
 	  Drug interactions  
 	  Other toxicity-related information or data  
 
If the product is intended for use in special populations,  consideration should be given to whether  
specific nonclinical data needs exist.  
 
2.   Clinical (2.1.2)  
 
  a.   Limitations of the human safety database  
 
Limitations of the safety database (e.g., related to the size of the study population, study 
inclusion/exclusion criteria) should be considered, and the implications of such limitations with 
respect to predicting the safety of the product in the marketplace should be explicitly discussed.   
Particular reference should be made to populations likely to be exposed during the intended or 
expected use of the product in medical practice.  
 
The worldwide experience should be briefly discussed, including:  
 	  The extent of the worldwide exposure  
 	  Any new or different safety issues identified  
 	  Any regulatory actions related to safety  
 
  4
  Contains Nonbinding Recommendations  
 
b.	   Populations not studied in the preapproval phase  
 
The specification should discuss which populations have not been studied or have only been 
studied to a limited degree in the preapproval phase. The implications of this with respect to 
predicting the safety of the product in the marketplace should be explicitly discussed (CTD 
2.5.5).  Populations to be considered should include (but might not be limited to):  
   Children  
   The elderly  
   Pregnant or lactating women  
   Patients with relevant co-morbidity such as hepatic or renal disorders  
   Patients with disease severity different from that studied in clinical trials  
   Sub-populations carrying known and relevant genetic polymorphism  
   Patients of different racial and/or ethnic origins  
 
c.	   Adverse events (AEs)/adverse drug reactions (ADRs)  
 
This section should list the important identified and potential risks that require further 
characterization or evaluation.  Specific references should be made to guide a reviewer to where 
clinical safety data are presented (e.g.,  relevant sections of the CTD 2.5.5 and 2.7.4).  
Discussion of risk factors and potential mechanisms that apply to identified AEs/ADRs should 
draw on information from any part of the CTD (nonclinical and clinical) and other relevant 
information, such as other drug labels, scientific literature, and postmarketing experience.  
 
Identified risks for further evaluation  
More detailed information should be included on the most important identified  AEs/ADRs, 
which would include those that are serious or frequent and that also might have an impact on the 
balance of benefits and risks of the product. This information should include evidence bearing on 
a causal relationship, severity, seriousness, frequency, reversibility and at-risk groups, if 
available. Risk factors and potential mechanisms should be discussed. These AEs/ADRs should 
usually  call for further evaluation as part of the pharmacovigilance plan (e.g., frequency in 
normal conditions of use, severity, outcome, at-risk groups).  
 
Potential risks for further evaluation  
Important potential risks should be described in this section. The evidence that led to the 
conclusion that there was a potential risk should be presented. It is anticipated that for any 
important potential risk, there should be further evaluation to characterize the association.  
 
d.	   Identified and potential interactions, including food-drug and drug-drug 
interactions  
 
Identified and potential pharmacokinetic and pharmacodynamic interactions should be discussed. 
For each, the evidence supporting the interaction and possible mechanism should be 
summarized, and the potential health risks posed for the different indications and in the different 
populations should be discussed.  
 
  5
  Contains Nonbinding Recommendations  
 
e.   Epidemiology  
 
The epidemiology of the indication(s) should be discussed. This discussion should include 
incidence, prevalence,  mortality and relevant co-morbidity, and should take into account 
whenever possible stratification by age, sex, and racial and/or ethnic origin.   Differences in the 
epidemiology in the different regions should be discussed (because the epidemiology of the 
indication(s) may vary across regions), if this information is available.  
 
In addition, for important adverse events that may require further investigation, it is useful to 
review the incidence rates of these events among patients in whom the drug is indicated (i.e., the 
background incidence rates). For example, if condition X is an important adverse event in 
patients who are treated with drug Y for disease Z, then it is useful to review the incidence of 
condition X in patients with disease Z who are not treated with drug Y; this is the background 
rate of condition X among patients with disease Z.  Information on risk factors for an adverse 
event (condition X) would also be useful to include, if available.  
 
f.   Pharmacological class effects  
 
The safety specification should identify risks believed to be common to the pharmacological  
class.   
 
B.   Summary (2.2)  
 
At the end of the safety specification, a summary should be provided of the:  
  
   Important identified risks  
   Important potential risks  
   Important missing information  
 
Sponsors are encouraged to summarize specific ongoing safety issues on an issue-by-issue basis, 
including both nonclinical and clinical data that are pertinent to the problem.  
 
III.   PHARMACOVIGILANCE PLAN (3)  
 
This section gives guidance on the structure of a pharmacovigilance plan. The 
pharmacovigilance plan  should be based on the safety specification.  The specification and plan 
can be written as two parts of the same document. The plan would normally be developed by the 
sponsor and can be discussed with regulators during product development, prior to approval (i.e., 
when the marketing application is submitted) of a new product, or when a safety concern arises 
postmarketing.   It can be a stand-alone document, but elements could also be incorporated into 
the CTD.  
 
For products for which no special concerns have arisen, routine pharmacovigilance as described 
in section III.A.2 (3.1.2) of this guidance should be sufficient for postapproval safety monitoring, 
without the need for additional actions (e.g.,  safety studies).  However, for products with 
  6
  Contains Nonbinding Recommendations  
 
important identified risks, important potential risks, or important missing information, additional  
actions designed to address these concerns should be considered.  
 
The length of the document will likely depend on the product and its development program. The 
pharmacovigilance plan should be updated as important information on safety becomes available 
and milestones are reached.  
 
A.   Structure of the Pharmacovigilance Plan (3.1)  
 
Outlined below is a suggested structure for the pharmacovigilance plan. The structure can be 
varied depending on the product in question and the issues identified in the safety specification.  
 
1.   Summary of Ongoing Safety Issues (3.1.1)  
 
At the beginning of the pharmacovigilance plan, a summary should be provided of the:  
 
 	  Important identified risks  
 	  Important potential risks  
 	  Important missing information  
 
This is important if the pharmacovigilance plan is a separate document from the safety 
specification.  
 
2.   Routine Pharmacovigilance Practices (3.1.2)  
 
Routine pharmacovigilance should be conducted for all medicinal products, regardless of 
whether or not additional actions are appropriate as part of a pharmacovigilance plan. This 
routine pharmacovigilance should include the following:  
 
 	  Systems and processes that ensure that information about all suspected adverse 
reactions that are reported to the personnel of the company are collected and collated in 
an accessible manner  
 
 	  The preparation of reports for regulatory authorities:  
	  E  xpedited adverse drug reaction (ADR) reports  
	 Periodic safety update reports (PSURs)  
 
 	  Continuous monitoring of the safety profile of approved products including signal 
detection, issue evaluation, updating of labeling, and liaison with regulatory authorities  
 
 	  Other requirements, as defined by local regulations  
 
In some ICH regions, there might be a regulatory requirement to present within the 
pharmacovigilance plan an overview of the companys organization and practices for conducting 
pharmacovigilance.  In the absence of such a requirement, a statement that the companys routine 
  7
  Contains Nonbinding Recommendations  
 
pharmacovigilance practices include the elements outlined in the bulleted list above should be 
sufficient.  
 
3.   Action Plan for Safety Issues (3.1.3)  
 
The plan for each important safety issue should be presented and justified according to the 
following structure:  
 
 	  Safety issue  
 	  Objective of proposed action(s)  
 	  Action(s) proposed  
 	  Rationale for proposed action(s)  
 	  Monitoring by the sponsor for safety issue and proposed action(s)  
 	  Milestones for evaluation  and reporting  
 
Any protocols for specific studies can be provided in the CTD section 5.3.5.4 Other Clinical 
Study Reports or other sections as appropriate (e.g., Module 4 if the study is a nonclinical study).  
 
4.   Summary of Actions To Be Completed, Including Milestones (3.1.4)  
 
An overall pharmacovigilance plan for the product bringing together the actions for all individual 
safety  issues should be presented. Whereas section 3.1.3 suggests presenting an action plan by 
ongoing safety issue, for this section the pharmacovigilance plan for the product should be 
organized in terms of the actions to be undertaken and their milestones.  The reason for this is 
that one proposed action (e.g., a prospective safety cohort study) could address  more than one of 
the identified issues.  
 
It is recommended that milestones for completion of studies and other evaluations, and for 
submission of safety results, be included in the pharmacovigilance plan.  In developing these 
milestones, one should consider when:  
 
 	  Exposure to the product will have reached a level sufficient to allow potential 
identification/characterization of the AEs/ADRs of concern or resolution of a particular 
concern, and/or  
 	  The results of ongoing or proposed safety studies are expected to be available.  
 
These milestones might be aligned with regulatory milestones (e.g., PSURs, annual reassessment 
and license renewals) and used to revise the pharmacovigilance plan.   
 
B.   Pharmacovigilance Methods (3.2)  
 
The best method to address a specific situation can vary, depending on the product, the 
indication, the population being treated and the issue to be addressed. The method chosen can 
also depend on whether an identified risk, potential risk, or missing information is the issue and 
whether signal detection, evaluation, or safety demonstration is the main objective of further 
study.  When choosing a method to address a safety concern, sponsors should employ the most 
  8
  Contains Nonbinding Recommendations  
 
appropriate design.  The Annex provides a summary of the key methods used in 
pharmacovigilance.  This is provided to aid sponsors considering possible methods to address 
specific issues identified by the safety specification.  This list is not all-inclusive, and sponsors  
should use the most up-to-date methods that are relevant and applicable.   
 
Design and Conduct of Observational Studies (3.2.1)  
 
Carefully designed and conducted pharmacoepidemiological studies, specifically observational 
(noninterventional, nonexperimental) studies, are  important tools in pharmacovigilance.  In 
observational studies, the investigator observes and evaluates results of ongoing medical care 
without 'controlling' the therapy beyond normal medical practice.1  
 
Before the observational study that is part of a pharmacovigilance plan commences, a protocol 
should be finalized.  Experts from relevant disciplines (e.g., pharmacovigilance experts, 
pharmacoepidemiologists and biostatisticians) should be consulted.    It is recommended that the 
protocol be discussed with the regulatory authorities before the study starts.   It is also suggested 
that the circumstances in which a study should be terminated early be discussed with regulatory 
authorities and documented in advance.   A study report after completion, and interim reports if 
appropriate, should be submi tted to the authorities according to the milestones within the 
pharmacovigilance plan.  
 
Study protocols should, as a minimum, include the study aims and objectives, the methods to be 
used, and the plan for analysis. The final study report should accurately and completely present 
the study objectives, methods, results, and the principal investigators interpretation of the 
findings.  
 
It is recommended that the sponsor follow good epidemiological practice for observational 
studies and also internationally accepted guidelines, such as the guidelines endorsed by the 
International Society for Pharmacoepidemiology.2   In some of the ICH regions, local laws and 
guidelines also apply to the design and conduct of observational studies and should be followed.   
 
The highest possible standards of professional conduct and confidentiality should always be 
maintained, and any relevant national legislation on data protection followed.  
 
  9
  Contains Nonbinding Recommendations  
 
IV.   REFERENCES (4)  
 
1. 	  CIOMS, Current Challenges in Pharmacovigilance: Pragmatic Approaches.  Report of 
CIOMS Working Group V.  Geneva; World Health Organization (WHO), 2001.  
 
2. 	  Guidelines for Good Pharmacoepidemiology Practices (GPP),  International Society for 
Pharmacoepidemiology, http://www.pharmacoepi.org/resources/guidelines_08027.cfm, 
August 2004.  
  10
  Contains Nonbinding Recommendations  
 
ANNEX   PHARMACOVIGILANCE METHODS  
 
1.   Passive Surveillance  
 
   Spontaneous Reports  
 
A spontaneous report is an unsolicited communication by healthcare professionals or consumers 
to a company, regulatory authority or other organization (e.g., WHO, regional centers, poison 
control center) that describes one or more adverse drug reactions in a patient who was given one 
or more medicinal products and that does not derive from a study or any organized data 
collection scheme.1  
 
Spontaneous reports play a major role in the identification of safety signals once a drug is 
marketed. In many instances, a company can be alerted to rare adverse events that were not 
detected in earlier clinical trials or other premarketing studies. Spontaneous reports can also 
provide important information on at-risk groups, risk factors, and clinical features of known 
serious adverse drug reactions. Caution should be exercised in evaluating spontaneous reports, 
especially when comparing drugs. The data accompanying spontaneous reports are often 
incomplete, and the rate at which cases are reported is dependent on many factors including the 
time since launch, pharmacovigilance-related regulatory activity, media attention, and the 
indication for use of the drug.2,  3,  4,  5  
 
Systematic Methods for the Evaluation of Spontaneous Reports  
 
More recently, systematic methods for the detection of safety signals from spontaneous reports 
have been used.  Many of these techniques are still in development and their usefulness for 
identifying safety signals is being evaluated. These methods include the calculation of the 
proportional reporting ratio, as well as the use of Bayesian and other techniques for signal 
detection.6,  7,  8  Data mining techniques have also been used to examine drug-drug interactions.9  
Data mining techniques should always be used in conjunction with, and not in place of, analyses 
of single case reports. Data mining techniques facilitate the evaluation of spontaneous reports by 
using statistical methods to detect potential signals for further evaluation. This tool does not 
quantify the magnitude of risk, and caution should be exercised when comparing drugs. Further, 
when using data mining techniques, consideration should be given to the threshold established 
for detecting signals, since this will have implications for the sensitivity and specificity of the 
method (a high threshold is associated with high specificity and low sensitivity). Confounding 
factors that influence spontaneous adverse event reporting are not removed by data mining. 
Results of data mining should be interpreted with the knowledge of the weaknesses of the 
spontaneous reporting system and, more specifically, the large differences in the ADR reporting 
rate among different drugs and the many potential biases inherent in spontaneous reporting. All 
signals should be evaluated recognizing the possibility of false positives.  In addition, the 
absence of a signal does not mean that a problem does not exist.  
 
  11
  Contains Nonbinding Recommendations  
 
   Case Series  
 
Series of case reports can provide evidence of an association between a drug and an adverse 
event, but they are generally more useful for generating hypotheses than for verifying an 
association between drug exposure and outcome. There are certain distinct adverse events known 
to be associated more frequently with drug therapy, such as anaphylaxis, aplastic anemia, toxic 
epidermal necrolysis and Stevens-Johnson Syndrome.10,  11 Therefore, when events such as these 
are spontaneously reported, sponsors should place more emphasis on these reports for detailed 
and rapid follow-up.  
 
2.   Stimulated Reporting   
 
Several methods have been used to encourage and facilitate reporting by health professionals in 
specific situations (e.g., in-hospital settings) for new products or for limited time periods.12 Such 
methods include on-line reporting of adverse events and systematic stimulation of reporting of 
adverse events based on a predesigned method. Although these methods have been shown to 
improve reporting, they are not devoid of the limitations of passive surveillance, especially 
selective reporting and incomplete information.  
 
During the early postmarketing phase, companies might actively provide health professionals 
with safety information, and at the same time encourage cautious use of new products and the 
submission of spontaneous reports when an adverse event is identified. A plan can be developed 
before the product is launched (e.g., through site visits by company representatives, by direct 
mailings or faxes, etc.). Stimulated adverse event reporting in the early postmarketing phase can 
lead companies to notify healthcare professionals of new therapies and provide safety 
information early in use by the general population (e.g., Early Post-marketing Phase Vigilance, 
EPPV in Japan). This should be regarded as a form of spontaneous event reporting; thus, data 
obtained from stimulated reporting cannot be used to generate accurate incidence rates, but 
reporting rates can be estimated.  
 
3.   Active Surveillance  
 
Active surveillance, in contrast to passive surveillance, seeks to ascertain completely the number 
of adverse events via a continuous preorganized process. An example of active surveillance is 
the follow-up of patients treated with a particular drug through a risk management program. 
Patients who fill a prescription for this drug may be asked to complete a brief survey form and 
give permission for later contact.13 In general, it is more feasible to get comprehensive data on 
individual adverse event reports through an active surveillance system than through a passive 
reporting system.  
 
   Sentinel Sites  
 
Active surveillance can be achieved by reviewing medical records or interviewing patients 
and/or physicians in a sample of sentinel sites to ensure complete and accurate data on reported 
adverse events from these sites. The selected sites can provide information, such as data from 
specific patient subgroups, that would not be available in a passive spontaneous reporting 
  12
  Contains Nonbinding Recommendations  
 
system. Further, information on the use of a drug, such as abuse, can be targeted at selected 
sentinel sites14. Some of the major weaknesses of sentinel sites are problems with selection bias, 
small numbers of patients, and increased costs. Active surveillance with sentinel sites is most 
efficient for those drugs used mainly in institutional settings such as hospitals, nursing homes, 
hemodialysis centers, etc.  Institutional settings can have a greater frequency of use for certain 
drug products and can provide an infrastructure for dedicated reporting.  In addition, automatic 
detection of abnormal laboratory values from computerized laboratory reports in certain clinical 
settings can provide an efficient active surveillance system. Intensive monitoring of sentinel sites 
can also be helpful in identifying risks among patients taking orphan drugs.  
 
   Drug Event Monitoring  
 
Drug event monitoring is a method of active pharmacovigilance surveillance. In drug event 
monitoring, patients might be identified from electronic prescription data or automated health 
insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or 
patient at prespecified intervals to obtain outcome information. Information on patient 
demographics, indication for treatment, duration of therapy (including start dates), dosage,  
clinical events, and reasons for discontinuation can be included in the questionnaire.12,  15,  16,  17  
Limitations of drug event monitoring can include poor physician and patient response rates and 
the unfocused nature of data collection, which can obscure important signals. In addition, 
maintenance of patient confidentiality might be a concern. On the other hand, more detailed 
information on adverse events from a large number of physicians and/or patients might be 
collected.  
 
   Registries  
 
A registry is a list of patients presenting with the same characteristic(s). This characteristic can 
be a disease (disease registry) or a specific exposure (drug registry). Both types of registries, 
which only differ by the type of patient data of interest, can collect a battery of information using 
standardized questionnaires in a prospective fashion. Disease registries, such as registries for 
blood dyscrasias, severe cutaneous reactions, or congenital malformations can help collect data 
on drug exposure and other factors associated with a clinical condition. A disease registry might 
also be used as a base for a case-control study comparing the drug exposure of cases identified 
from the registry and controls selected from either patients with another condition within the 
registry, or patients outside the registry.   
 
Exposure (drug) registries address populations exposed to drugs of interest (e.g., registry of 
rheumatoid arthritis patients exposed to biological therapies) to determine if a drug has a special 
impact on this group of patients. Some exposure (drug) registries address drug exposures in 
specific populations, such as pregnant women. Patients can be followed over time and included 
in a cohort study to collect data on adverse events using standardized questionnaires. Single 
cohort studies can measure incidence, but, without a comparison group, cannot provide proof of 
association. However, they can be useful for signal amplification, particularly for rare outcomes. 
This type of registry can be very valuable when examining the safety of an orphan drug indicated 
for a specific condition.  
 
  13
  Contains Nonbinding Recommendations  
 
4.   Comparative Observational Studies  
 
Traditional epidemiologic methods are a key component in the evaluation of adverse events. 
There are a number of observational study designs that are useful in validating signals from 
spontaneous reports or case series. Major types of these designs are cross-sectional studies, case-
control studies, and cohort studies (both retrospective and prospective).12,  15   
 
   Cross-sectional Study (Survey)  
 
Data collected on a population of patients at a single point in time (or interval of time) regardless 
of exposure or disease status constitute a cross-sectional study. These types of studies are 
primarily used to gather data for surveys or for ecological analyses. The major drawback of 
cross-sectional studies is that the temporal relationship between exposure and outcome cannot be 
directly addressed. These studies are best used to examine the prevalence of a disease at one time 
point or to examine trends over time, when data for serial time points can be captured. These 
studies can also be used to examine the crude association between exposure and outcome in 
ecologic analyses. Cross-sectional studies are best utilized when exposures do not change over 
time.  
 
   Case-control Study  
 
In a case-control study, cases of disease (or events) are identified. Controls, or patients without 
the disease or event of interest, are then selected from the source population that gave rise to the 
cases. The controls should be selected in such a way that the prevalence of exposure among the 
controls represents the prevalence of exposure in the source population. The exposure status of 
the two groups is then compared using the odds ratio, which is an estimate of the relative risk of 
disease in the two groups. Patients can be identified from an existing database or using data 
collected specifically for the purpose of the study of interest. If safety information is sought for 
special populations, the cases and controls can be stratified according to the population of 
interest (the elderly, children, pregnant women, etc.). For rare adverse events, existing large 
population-based databases are a useful and efficient means of providing needed drug exposure 
and medical outcome data in a relatively short period of time. Case-control studies are 
particularly useful when the goal is to investigate whether there is an association between a drug 
(or drugs) and one specific rare adverse event, as well as to identify risk factors for adverse 
events. Risk factors can include conditions such as renal and hepatic dysfunction, that might 
modify the relationship between the drug exposure and the adverse event. Under specific 
conditions, a case-control study can provide the absolute incidence rate of the event. If all cases 
of interest (or a well-defined fraction of cases) in the catchment area are captured and the 
fraction of controls from the source population is known, an incidence rate can be calculated.  
 
   Cohort Study  
 
In a cohort study, a population-at-risk for the disease (or event) is followed over time for the 
occurrence of the disease (or event). Information on exposure status is known throughout the 
follow-up period for each patient. A patient might be exposed to a drug at one time during 
follow-up, but nonexposed at another time point. Since the population exposure during follow-up 
  14
  Contains Nonbinding Recommendations  
 
is known, incidence rates can be calculated. In many cohort studies involving drug exposure, 
comparison cohorts of interest are selected on the basis of drug use and followed over time. 
Cohort studies are useful when there is a need to know the incidence rates of adverse events in 
addition to the relative risks of adverse events. Multiple adverse events can also be investigated 
using the same data source in a cohort study. However, it can be difficult to recruit sufficient 
numbers of patients who are exposed to a drug of interest (such as an orphan drug) or to study 
very rare outcomes.  Like case-control studies, the identification of patients for cohort studies 
can come from large automated databases or from data collected specifically for the study at 
hand. In addition, cohort studies can be used to examine safety issues in special populations (the 
elderly, children, patients with co-morbid conditions, pregnant women) through over-sampling 
of these patients or by stratifying the cohort if sufficient numbers of patients exist.  
 
There are several automated databases available for pharmacoepidemiologic studies.12,  15,  18   They 
include databases that contain automated medical records or automated accounting/billing 
systems. Databases that are created from accounting/billing systems might be linked to pharmacy 
claims and medical claims databases. These datasets might include millions of patients. Since 
they are created for administrative or billing purposes, they might not have the detailed and 
accurate information needed for some research, such as validated diagnostic information or 
laboratory data. Although medical records can be used to ascertain and validate test results and 
medical diagnoses, one should be cognizant of the privacy and confidentiality regulations that 
apply to patient medical records.  
 
5.   Targeted Clinical Investigations  
 
When significant risks are identified from preapproval clinical trials, further clinical studies 
might be called for to evaluate the mechanism of action for the adverse reaction. In some 
instances, pharmacodynamic and pharmacokinetic studies might be conducted to determine 
whether a particular dosing instruction can put patients at an increased risk of adverse events. 
Genetic testing can also provide clues about which group of patients might be at an increased 
risk of adverse reactions. Furthermore, based on the pharmacological properties and the expected 
use of the drug in general practice, conducting specific studies to investigate potential drug-drug 
interactions and food-drug interactions might be called for.  These studies can include population 
pharmacokinetic studies and drug  concentration monitoring in patients and normal volunteers.  
 
Sometimes, potential risks or unforeseen benefits in special populations might be identified from 
preapproval clinical trials, but cannot be fully quantified due to small sample sizes or the 
exclusion of subpopulations of patients from these clinical studies. These populations might 
include the elderly, children, or patients with renal or hepatic disorder. Children, the elderly, and 
patients with co-morbid conditions might metabolize drugs differently than patients typically 
enrolled in clinical trials. Further clinical trials might be used to determine and to quantify the 
magnitude of the risk (or benefit) in such populations.  
 
To elucidate the benefit-risk profile of a drug outside of the formal/traditional clinical trial 
setting and/or to fully quantify the risk of a critical but relatively rare adverse event, a large 
simplified trial might be conducted. Patients enrolled in a large simplified trial are usually 
randomized to avoid selection bias. In this type of trial, though, the event of interest will be 
  15
  Contains Nonbinding Recommendations  
 
focused to ensure a convenient and practical study.  One limitation of this method is that the 
outcome measure might be too simplified and this might have an impact on the quality and 
ultimate usefulness of the trial.  Large, simplified trials are also resource-intensive.  
 
6.   Descriptive Studies  
 
Descriptive studies are an important component of pharmacovigilance, although not for the 
detection or verification of adverse events associated with drug exposures. These studies are 
primarily used to obtain the background rate of outcome events and/or establish the prevalence 
of the use of drugs in specified populations.  
 
   Natural History of Disease  
 
The science of epidemiology originally focused on the natural history of disease, including the 
characteristics of diseased patients and the distribution of disease in selected populations, as well 
as estimating the incidence and prevalence of potential outcomes of interest. These outcomes of 
interest now include a description of disease treatment patterns and adverse events. Studies that 
examine specific aspects of adverse events, such as the background incidence rate of or risk 
factors for the adverse event of interest, can be used to assist in putting spontaneous reports into 
perspective.15  For example, an epidemiologic study can be conducted using a disease registry to 
understand the frequency at which the event of interest might occur in specific subgroups, such 
as patients with concomitant illnesses.  
 
   Drug Utilization Study  
 
Drug utilization studies (DUS) describe how a drug is marketed, prescribed, and used in a 
population, and how these factors influence outcomes, including clinical, social, and economic 
outcomes.12  These studies provide data on specific populations, such as the elderly, children, or 
patients with hepatic or renal dysfunction, often stratified by age, gender, concomitant 
medication, and other characteristics.  DUS can be used to determine if a product is being used in 
these populations.  From these studies denominator data can be developed for use in determining 
rates of adverse drug reactions.  DUS have been used to describe the effect of regulatory actions 
and media attention on the use of drugs, as well as to develop estimates of the economic burden 
of the cost of drugs. DUS can be used to examine the relationship between recommended and 
actual clinical practice.  These studies can help to determine whether a drug has the potential for 
drug abuse by examining whether patients are taking escalating dose regimens or whether there 
is evidence of inappropriate repeat prescribing. Important limitations of these studies can include 
a lack of clinical outcome data or information of the indication for use of a product.  
  16
  Contains Nonbinding Recommendations  
 
 
REFERENCES  
 
1.	   ICH Guidance E2D; Post-approval Safety Data Management: Definitions and Standards for 
Expedited Reporting, 3.1.1 Spontaneous Reports.  
 
2.	   Pinkston V, Swain EJ, Management of adverse drug reactions and adverse event data 
through collection, storage, and retrieval. In Stephens MDB, Talbot JCC, and Routledge PA, 
eds. Detection of New Adverse Drug Reactions. 4th ed. 1998;  MacMillan Reference Ltd, 
London. p 282.  
 
3.	   Faich GA, U.S. adverse drug reaction surveillance 1989  1994. Pharmacoepidemiology 
Drug Safety 1996; 393-398.  
 
4.	   Goldman SA, Limitations and strengths of spontaneous reports data. Clinical Therapeutics 
1998; 20 (Suppl C):C40-C44.  
 
5.	   Hartmann K, Doser AK, Kuhn M, Postmarketing safety information: How useful are 
spontaneous reports. Pharmacoepidemiology and Drug Safety 1999;  8:S65-S71.  
 
6. 	  Responding to Signals Waller PC and Arlett PA, in Pharmacovigilance, Editor Mann RD, 
John Wiley and Sons Ltd 2002.  
 
7. 	  DuMouchel W, Bayesian data mining in large frequency tables, with an application to the 
FDA Spontaneous Reporting system. Am Stat 1999;  53:177-190.  
 
8. 	  Bate A, Lindquist M, Edwards IR, A Bayesian neural network method for adverse drug 
reaction signal generation. Eur J Clin Pharmacology 1998;  54:315-321.  
 
9. 	  Van Puijenbroek E, Egberts ACG, Heerdink ER, Leufkens HGM, Detecting drug-drug 
interactions using a database for spontaneous adverse drug reactions: An example with 
diuretics and non-steroidal anti-inflammatory drugs. Eur J Clin Pharmacol 2000;  56:733
738.  
 
10.  Venning GR, Identification of adverse reactions to new drugs. III: Alerting processes and 
early warning systems. BMJ 1983;  286:458-460.  
 
11.  Edwards IR, The management of adverse drug reactions: From diagnosis to signal. Therapie 
2001;  56:727-733.  
 
12.  In Strom BL (ed.). Pharmacoepidemiology, 3rd ed. 2002; John Wiley and Sons, Ltd, New 
York, NY.  
 
13.  Mitchell AA,  V	 an Bennekom CM, Louik C, A pregnancy-prevention program in women of 
childbearing age receiving isotretinoin. N Engl J Med (1995 Jul 13); 333(2):101-6.  
 
  17
  Contains Nonbinding Recommendations  
 
14.  Task Force on Risk Management. Report to the FDA Commissioner. Managing the risks 
from medical product use: Creating a risk management framework. Part 3. How does FDA 
conduct postmarketing surveillance and risk assessment. May 1999.  
 
15.  In Mann RD and Andrews EB (eds.) Pharmacovigilance 2002, John Wiley and Sons, Ltd, 
West Sussex, England.  
 
16.  Coulter DM, The New Zealand intensive medicines monitoring programme in pro-active 
safety surveillance. Pharmacoepidemiology and Drug Safety 2000;  9:273-280.  
 
17.  Mackay FJ, Post-marketing studies. The work of the Drug Safety Research Unit. Drug 
Safety 1998;19:  343-353.  
 
18.  Garcia Rodriguez LA, Perez Gutthann S, Use of the UK General Practice Research Database 
for Pharmacoepidemiology. Br. J Clin Pharmacol 1998;  45:419-425.  
 
  
  18