Guidance for Industry 
Distributing Scientific and Medical 
Publications on Risk Information for 
Approved Prescription Drugs and 
Biological ProductsRecommended 
Practices 
 
 
DRAFT GUIDANCE 
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 75 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document contact (CDER) Lauren Wedlake at 301-796-2500, 
(CBER) Office of Communication, Outreach and Development, at 800-835-4709 or 240-402-
7800, or (CVM) Dorothy McAdams at (240) 453-6802. 
 
 
 
 
 
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) 
Center for Veterinary Medicine (CVM) 
 
June 2014 
Procedural 
   
Guidance for Industry 
Distributing Scientific and Medical 
Publications on Risk Information for 
Approved Prescription Drugs and 
Biological ProductsRecommended 
Practices 
 
 
Additional copies are available from: 
 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Silver Spring, MD 20993  
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov 
 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., WO71, Room 3128 
Silver Spring, MD 20993 
Phone: 800-835-4709 or 240-402-7800 
ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
and/or 
Communications Staff (CVM) 
Center for Veterinary Medicine 
Food and Drug Administration 
7519 Standish Place, HFV-12 
Rockville, MD 20855 
Phone: 240-276-9300 
AskCVM@fda.hhs.gov 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm 
 
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) 
Center for Veterinary Medicine (CVM) 
 
 June 2014 
Procedural 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................................ 2 
III.  OVERVIEW OF FDA RISK ASSESSMENTPRE- AND POSTMARKET ........... 3 
A.  Premarket Risk Assessment .......................................................................................................... 3 
B.  Postmarket Risk Assessment ........................................................................................................ 5 
IV.  CRITERIA FOR DETERMINING WHETHER NEW RISK INFORMATION IS 
APPROPRIATE FOR DISTRIBUTION TO HEALTH CARE PROFESSIONALS 
AND HEALTH CARE ENTITIES.................................................................................. 6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1
1  Guidance for Industry  
2  Distributing Scientific and Medical Publications on Risk 
3  Information for Approved Prescription Drugs and Biological 
4  ProductsRecommended Practices 
5   
6   
7  This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 
8  thinking on this topic.  It does not create or confer any rights for or on any person and does not operate to 
9  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
10  the applicable statutes and regulations.  If you want to discuss an alternative approach, contact the FDA 
11  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
12  the appropriate number listed on the title page of this guidance.  
13   
14   
15  I.  INTRODUCTION 
16   
17  This draft guidance describes the Food and Drug Administrations (FDAs or Agencys) current 
18  thinking on recommended practices for drug manufacturers (firms) and their representatives to 
19  follow if they choose to distribute to health care professionals2 or health care entities3 scientific 
20  or medical journal articles that discuss new risk information for approved prescription drugs4,5,6 
21  marketed in the United States.  The recommendations in this draft guidance are intended to 
22  address issues specific to the distribution of new information about risks associated with a drug 
23  that further characterizes risks identified in the approved labeling.   
24   
25  The recommendations in this draft guidance are intended to apply to distribution of new risk 
26  information (as that term is further explained in section II of this document) for drugs intended 
27  for human and animal use. Throughout this draft guidance, the Agency provides references to 
28  regulations and guidances specific to drugs intended for human use.  Unless otherwise indicated, 
29  the Agency generally takes a similar approach when addressing the issues raised in this draft 
30  guidance as they pertain to animal drugs. 
31   
32  FDAs guidance documents, including this draft guidance, do not establish legally enforceable 
33  responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
                                                 
1 This draft guidance has been prepared by the Center for Drug Evaluation and Research (CDER) in cooperation 
with the Center for Biologics Evaluation and Research (CBER) and the Center for Veterinary Medicine (CVM) at 
the Food and Drug Administration.  
2 For purposes of this draft guidance, health care professionals include those providing care to either human or 
animal patients.   
3 As used in this draft guidance, health care entities include hospitals, professional medical organizations, drug 
formulary committees, pharmacy benefit managers, health insurance issuers, group health plans, and Federal or 
State governmental agencies involved in the provision of health care or health insurance.  For purposes of the draft 
guidance, health care entities also include any such similar organizations involved in animal health care. 
4 As used in this draft guidance, the term drug includes drugs approved for use in humans or animals and drugs 
regulated as biological products licensed under section 351 of the Public Health Service Act (42 U.S.C. 262(a)).    
5 For animal drugs, this draft guidance also applies to over-the-counter and Veterinary Feed Directive drugs. 
6 This guidance does not apply to products regulated as medical devices. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
35  cited.  The use of the word should in Agency guidances means that something is suggested or 
36  recommended, but not required. 
37   
38  II. BACKGROUND 
39   
40  In February 2014, FDA issued a draft guidance titled Distributing Scientific and Medical 
41  Publications on Unapproved New UsesRecommended Practices (Draft Revised Reprints 
42  Guidance).7  That draft guidance revised an earlier guidance from 2009 to clarify the Agencys 
43  position on manufacturer dissemination of scientific or medical publications that include 
44  information on unapproved new uses of the manufacturers products. The Draft Revised Reprints 
45  Guidance was issued to enable the public to provide comments.  Stakeholders have raised 
46  questions regarding the Agencys position on manufacturer dissemination of new scientific or 
47  medical information about safety information contained in the labeling for approved drugs.  
48  Because this concerns dissemination of new risk information related to approved uses of a drug, 
49  this issue is distinct from the dissemination of information on unapproved new uses of approved 
50  drugs.   
51   
52  In response to those questions, the Agency is issuing this draft guidance to clarify and solicit 
53  public comments on the Agencys position on manufacturer dissemination of new risk 
54  information regarding lawfully marketed drugs for approved uses to health care professionals or 
55  health care entities.  FDA recognizes that the safety profile of a drug evolves throughout its 
56  lifecycle as the extent of exposure to the product increases and that it can be helpful for health 
57  care practitioners to receive significant new risk information about an approved product in a 
58  timely manner.  FDA anticipates that the earliest distribution of new risk information will 
59  generally involve distribution of recently published studies, as opposed to textbooks or clinical 
60  practice guidelines. Accordingly, FDA is providing guidance for firms that choose to distribute 
61  new risk information in the form of a reprint or digital copy of a published study. 
62   
63  FDA believes that recommendations specific to the distribution of new risk information about 
64  approved prescription drugs and biological products are needed for two reasons.  First, in general 
65  there are differences in the purpose, nature, and reliability of the evidence used to determine the 
66  effectiveness of a drug (e.g., to support a new intended use) and the evidence that is the basis for 
67  the products risk assessment (see section III.A).  Therefore, FDA believes guidance is needed to 
68  address the spectrum of data sources that could be appropriate for distribution to provide new 
69  risk information. Second, new risk information may contradict or otherwise deviate from the risk 
70  information in the approved labeling, which may cause confusion or otherwise contribute to 
71  patient harm.  If the new information is unreliable or presented without the appropriate context, it 
72  could influence prescribing decisions or patient monitoring in a way that could harm patients.  
73  For example, postmarket data concerning an adverse reaction identified in the approved labeling 
74  may suggest that the adverse reaction is less severe or occurs at lower frequency than indicated 
75  in the approved labeling, or may call into question the basis for concluding that there is a causal 
76  relationship between the reaction and the drug.  That information could, for example, lead to use 
                                                 
7 See the 2014 draft guidance for industry entitled Distributing Scientific and Medical Publications on Unapproved 
UsesRecommended Practices.  Although this draft guidance addresses only human products, the general principles 
are the same for animal drugs. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
77  of the drug in a patient for whom the approved labeling indicates an increased risk for the 
78  adverse reaction.   Therefore, FDA is proposing recommendations for study or analysis and 
79  distribution criteria to help ensure that new risk information that rebuts, mitigates, or refines risk 
80  information in approved labeling meets appropriate standards for reliability and is presented with 
81  appropriate disclosure of its limitations. 
82   
83  For purposes of this draft guidance, the term new risk information refers to information that 
84  becomes available after a drug is marketed that rebuts or mitigates information about a risk 
85  already identified in the approved labeling8 or otherwise refines risk information in the approved 
86  labeling in a way that does not indicate greater seriousness of the risk.  New risk information 
87  could, for example, include data indicating that the severity or rate of occurrence of an event is 
88  lower than described in the approved labeling or call into question a causal relationship between 
89  a drug and an event in the approved labeling.  New risk information could also supplement risk 
90  information in approved labeling derived from a general population with information about risks 
91  in subpopulations of interest (e.g., data that show that the risk of an event in patients with hepatic 
92  disease is similar to the risk in a general population).9  
93   
94  New risk information does not include, and this guidance is not intended to apply to, information 
95  about a newly identified risk (not previously included in the approved labeling) or new 
96  information that indicates that a risk already identified in approved labeling is more serious than 
97  is reflected in that labeling. 
98   
99  Nothing in this draft guidance is intended to change a firms existing obligations under the 
100  Federal Food, Drug, and Cosmetic Act (FD&C Act), the Public Health Service Act (PHS Act) 
101  and implementing regulations to update its approved labeling, to accurately reflect what is 
102  known about the safety profile of the drug, to ensure that the labeling is not false or misleading, 
103  or for other reasons.10   
104   
105  III. OVERVIEW OF FDA RISK ASSESSMENTPRE- AND POSTMARKET  
106   
107  A.  Premarket Risk Assessment  
108   
                                                 
8 As used in this draft guidance, approved labeling refers to the labeling reviewed and approved under section 351 
of the Public Health Service Act, or section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or a 
conditional approval under section 571 of such act.  See 21 CFR 201.56, 201.57, 201.100, and 201.105. 
9 The term new risk information for purposes of this draft guidance should not be confused with the term new 
safety information, as defined in section 505-1(b)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for 
purposes of FDA determinations about (among other things) the exercise of its authority under section 505(o)(4) of 
the FD&C Act to require and, if necessary, order labeling changes if it becomes aware of new safety information it 
believes should be included in the labeling of a drug.  Although in some cases, the same information may constitute 
new risk information as used in this draft guidance and new safety information as defined in section 505-1(b)(3) of 
the FD&C Act, this draft guidance is not intended to address new safety information nor the implementation of 
section 505(o)(4).  For information regarding section 505(o)(4), see the 2013 guidance for industry entitled Safety 
Labeling ChangesImplementation of Section 505(o)(4) of the FD&C Act.   
10 See, e.g., 21 CFR 201.56(a)(2) ([approved] labeling must be updated when new information becomes available 
that causes the labeling to become inaccurate, false, or misleading), 21 CFR 314.70 and 601.12 (concerning 
supplements and other changes to an approved application, including labeling), and 21 CFR 514.8(c) (concerning 
supplements and other changes to an approved application for a new animal drug, including labeling).   
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
109  As reflected in the statutory new drug and new animal drug approval standards in sections 505 
110  and 512 of the FD&C Act and the standard for licensure under section 351 of the PHS Act, the 
111  evidence that is the basis for the risk assessment of a drug differs from the evidence that is the 
112  basis for an effectiveness determination.  The effectiveness determination is generally intended 
113  to evaluate a drugs positive effect based on adequate and well-controlled trials designed to 
114  evaluate a specific efficacy variable (or a discrete number of efficacy variables) for the purpose 
115  of distinguishing the effect of the drug from other influences.11  In contrast, FDAs premarket 
116  risk assessment is intended to identify and characterize the nature, frequency, and severity of the 
117  usually broad spectrum of adverse events and other risks associated with the use of a product 
118  based on a range of data sources.  For human drugs, the supporting data are generally not derived 
119  from studies designed to test a specific safety hypothesis.  The assessment is based largely on 
120  observations of adverse events from studies intended to assess effectiveness and includes all 
121  patients exposed to the investigational drug during its development.  For animal drugs, there are 
122  generally data from safety studies in the target animal, in addition to observations of adverse 
123  events from studies intended to assess effectiveness.12  For both human and animal drugs, 
124  relevant data are weighted and integrated, based on the nature and reliability of the data sources, 
125  into a coherent assessment of what adverse reactions are reasonably associated with the use of a 
126  product and, to the extent possible, their frequency and severity.13       
127   
128  Risk information is presented in various sections of the approved labeling.  The ADVERSE 
129  REACTIONS section is the repository for all adverse reactions associated with a drug.  
130  Depending on the seriousness or other important clinical implications of an adverse reaction, it 
131  may also be discussed in greater detail in other labeling sections, in particular the WARNINGS 
132  AND PRECAUTIONS, CONTRAINDICATIONS, and BOXED WARNING sections.14  For 
133  example, the ADVERSE REACTIONS section of approved human drug labeling is explicitly 
134  required to describe the overall adverse reaction profile of the drug based on the entire safety 
135  database.15  The threshold for inclusion of an adverse event16 in approved human drug labeling 
136  is a determination that there is some basis to believe there is a causal relationship between the 
137  drug and the occurrence of the adverse event.17  Whether there is some basis to believe there is 
138  a causal relationship is a matter of judgment based on factors such as: (1) the frequency of 
139  reporting of the event, (2) whether the adverse event rate for a drug exceeds the placebo rate, (3) 
140  the extent of dose-response, (4) the extent to which the adverse event is consistent with the 
141  pharmacology of the drug, (5) the timing of the event relative to the time of drug exposure, (6) 
                                                 
11 21 CFR 314.126; 21 CFR 514.117 
12 Target animals are the specific animals (e.g., species, class, etc.) for which the drug is intended for use.  This draft 
guidance pertains only to risk information relevant to target animal safety.  The Agency conducts a separate review 
with respect to the human food safety of drugs given to food animals which takes different factors into account.   
13 See the 2005 guidance for industry entitled Premarketing Risk Assessment for a more detailed discussion of 
premarket assessment of safety to support drug approval.     
14 See, e.g., the 2011 guidance for industry entitled Warnings and Precautions, Contraindications, and Boxed 
Warnings Sections of Labeling for Human Drug and Biological ProductsContent and Format. 
15 21 CFR 201.57(c)(7) 
16 The term adverse event refers to the universe of untoward medical occurrences observed in conjunction with 
exposure to a drug, whether or not considered drug-related (see 21 CFR 312.32(a)).  Adverse reactions are a subset 
of adverse events for which there is evidence to conclude there is some basis to believe there is a causal relationship 
between the drug and the adverse event (see 21 CFR 201.57(c)(7)).   
17 21 CFR 201.57(c)(7) 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
142  the existence of dechallenge and rechallenge experience, and (7) whether the adverse event is 
143  known to be caused by related drugs.18   
144   
145  As these factors suggest, the strength of the evidence of a causal relationship between a drug and 
146  an adverse event (and, where applicable, the assessment of rate of occurrence) may vary across 
147  different drugs and diseases, and across different adverse reactions for the same drug, based on 
148  the types of data sources available in the premarket safety database, the size of the premarket 
149  population exposed to the drug, the pharmacology of the drug, and the nature of the event.  
150  Placebo-controlled and dose-response studies, if available, will generally be more informative 
151  than active-control and single-arm studies, and a larger premarket population will generally be 
152  more informative than a smaller one.  Also, certain types of events are more strongly suggestive 
153  of a causal relationship than others.  For example, a single occurrence, or a small number of 
154  occurrences, of a hypersensitivity reaction to a drug in which the patient was rechallenged with 
155  the drug and reacted, or an event that very rarely occurs spontaneously in a population not 
156  exposed to a drug (e.g., agranulocytosis, Stevens-Johnson Syndrome), can provide strong 
157  evidence of a causal relationship.  However, a limited number of occurrences of a serious event 
158  that would be expected to occur in the study population independent of exposure to a drug (e.g., 
159  cardiovascular events in an elderly study population) provide more ambiguous evidence of a 
160  causal relationship.  Therefore, a premarket risk assessment, although a thorough and rigorous 
161  assessment of the available safety data from the entire population exposed to a drug prior to 
162  marketing, may be limited in its ability to fully characterize a drugs safety profile by the nature 
163  of the supporting data and the size of the population exposed.   
164   
165  B.  Postmarket Risk Assessment 
166   
167  Because of the inherent limitations of the premarket risk assessment, postmarketing 
168  pharmacovigilance activitiesboth active (new controlled and epidemiologic studies) and 
169  passive (spontaneous reports)may be critically important to developing and refining the safety 
170  profile of a drug.  For example, new adverse reactions may be identified through postmarket 
171  reports of adverse events, particularly rare serious events that occur at a frequency too low to 
172  have been identified and characterized premarketing.  Also, new data and information may be 
173  developed to further characterize previously identified adverse events.  The types of data that can 
174  contribute to further developing the safety profile of a drug after marketing include data from 
175  controlled trials intended to evaluate a specific safety endpoint, controlled and uncontrolled trials 
176  evaluating efficacy (e.g., new uses), pooled analyses of new and existing risk information from 
177  controlled trials, epidemiologic studies evaluating a particular safety endpoint or safety 
178  generally, registries, and analyses of postmarketing reports of adverse events obtained through 
179  active (e.g., Sentinel) or passive surveillance processes.  In some cases, additional new studies
180  controlled trials or epidemiologic studiesmay be postmarketing requirements or commitments 
181  made at the time of approval or thereafter (e.g., a cardiovascular outcome study is often required 
182  for a new drug to treat type 2 diabetes).19           
                                                 
18 See the 2006 guidance for industry entitled Adverse Reactions Section of Labeling for Human Prescription Drug 
and Biological ProductsContent and Format for a more detailed discussion of how to identify adverse reactions 
for inclusion in approved labeling. 
19 See the 2005 guidance for industry entitled Good Pharmacovigilance Practices and Pharmacoepidemiologic 
Assessment for a more detailed discussion of postmarketing safety assessment.  
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
183   
184  IV. CRITERIA FOR DETERMINING WHETHER NEW RISK INFORMATION IS 
185  APPROPRIATE FOR DISTRIBUTION TO HEALTH CARE PROFESSIONALS 
186  AND HEALTH CARE ENTITIES 
187   
188  FDA recognizes that the safety profile of a drug evolves throughout its lifecycle as the extent of 
189  exposure to the product increases and that it can be helpful for health care practitioners to receive 
190  significant new risk information about an approved product in a timely manner.  Firms may 
191  distribute to healthcare entities and healthcare professionals new risk information under 
192  appropriate circumstances, even if such data are not consistent with the risk information 
193  currently in approved labeling.  Before distributing new risk information that suggests that an 
194  adverse reaction or other risk currently in approved labeling is not causally related to a drug or is 
195  less consequential than is reflected in the labeling, or that otherwise refines the characterization 
196  of an adverse reaction identified in approved labeling, firms should carefully consider the 
197  reliability and persuasiveness of the data.  As discussed in section III.A, there are cases in which 
198  even one occurrence of an adverse event can provide strong evidence that the drug caused the 
199  event.  In contrast, where existing evidence provides some basis to believe that there is a causal 
200  relationship between an event and a drug,20 the evidence offered to overcome that prior showing 
201  should generally be from a study or analysis in a population large enough to detect a meaningful 
202  difference in the rate of occurrence of an event in patients who are exposed to the drug versus 
203  those who are not.   
204   
205  FDA does not intend to object to the distribution of new risk information that rebuts, mitigates, 
206  or refines risk information in the approved labeling, and is distributed by a firm in the form of a 
207  reprint or digital copy of a published study, if the study or analysis and the manner of distribution 
208  meet the principles set out below.  Distribution of information that is not consistent with this 
209  guidance may render the labeling of a drug false or misleading under section 502(a) of the 
210  FD&C Act. 
211   
212  DATA SOURCE 
213   
214    The study or analysis should meet accepted design and other methodologic standards for 
215  the type of study or analysis (e.g., provides a clear description of the hypothesis tested, 
216  acknowledges and accounts for potential bias and multiplicity) and should be sufficiently 
217  well-designed and informative to merit consideration in assessing the implications of a 
218  risk.    
219   
220    To rebut a prior determination (reflected in the approved labeling) that there is some basis 
221  to believe there is causal relationship between the drug and the occurrence of an adverse 
222  event, or to otherwise mitigate a described risk, the study or analysis should also be at 
223  least as persuasive as the data sources that underlie the existing risk assessment of 
224  causality, severity, and/or incidence of the adverse reaction as reflected in approved 
225  labeling (e.g., data from a new controlled trial designed to estimate the relative risk of the 
226  event, a pharmacoepidemiologic study that is capable of reliably estimating the relative 
                                                 
20 See 21 CFR 201.57(c)(7). 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
227  risk, or a rigorous meta-analysis of all relevant data from new and existing controlled 
228  trials).     
229   
230    The conclusions of the study or analysis should give appropriate weight and 
231  consideration to, and should be a fair characterization of, all relevant information in the 
232  safety database, including contrary or otherwise inconsistent findings.  As discussed 
233  above, there is a broad spectrum of potential data sources that can contribute in some way 
234  to characterization of a products safety; new risk information should be considered in 
235  light of all relevant existing information and integrated with that data to the extent 
236  possible. 
237   
238    The study or analysis should be published in an independent, peer-reviewed journal.   
239   
240  DISTRIBUTION 
241   
242    The reprint or digital copy should be accompanied by a cover sheet that clearly and 
243  prominently discloses: 
244   
245    The study design, critical findings, and significant methodologic or other 
o
246  limitations of the study or analysis that may limit the persuasiveness or scope of 
247  findings that rebut, mitigate, or refine risk information in the approved labeling. 
248  Limitations should be discussed in relation to the specific circumstances of the 
249  study and its conclusions about a risk.21 
250   
251    That the information is not consistent with certain risk information in the 
o
252  approved labeling (should specifically identify the inconsistent information). 
253   
254    That FDA has not reviewed the data. 
o
255   
256    Any financial interests or affiliations between the study author(s) and the firm. 
o
257   
258    The reprint or digital copy should be accompanied by the approved labeling for the 
259  product. 
260   
261    The reprint or digital copy, when distributed, should be separate from any promotional 
262  material. 
263   
264    Any statements made by a representative of the firm to a recipient concerning the reprint 
265  should be consistent with its content and the information in the disclosure cover sheet. 
                                                 
21 Randomized, controlled trials designed to assess relative risk of occurrence of an adverse reaction would generally 
provide the most persuasive information, although they can have quality and interpretation problems.  Other types of 
data sources that could be relied on to rebut, mitigate, or refine risk information, such as pharmacoepidemiologic 
studies or meta-analyses, will generally warrant more extensive discussions of their limitations.   
  7