![](media/image1.png){width="7.136805555555555in"
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> Sidney N. Kahn, M.D., Ph.D.
>
> President
>
> 23 January 2003

Dockets Management Branch

Food and Drug Administration, HFA-305

5630 Fishers Lane, Room 1061

Rockville, MD 20857

**Re: Docket No. 96D-0041; International Conference on Harmonisation;
Draft Guidance on Addendum to E2C Clinical Safety Data Management:
Periodic Safety Update Reports for Marketed Drugs; Availability (Federal
Register: December 31, 2002; Volume 67, Number 251)**

Dear Sir or Madam:

Pharmacovigilance & Risk Management, Inc. (PvRM) is an independent
corporation providing consulting services to the pharmaceutical industry
and supporting organizations. Dr. Sidney Kahn, its founder and
president, has extensive experience in all aspects of drug safety,
including direct personal involvement in and supervision of personnel
responsible for safety assessment and reporting, including the
preparation of PSURs and other regulatory documents. He also represented
PhRMA on several ICH committees and expert working groups, and is thus
very interested in and well qualified to comment on this ICH step 2
draft Addendum to the ICH E2C harmonised tripartite guideline
recommended for adoption by the ICH Steering Committee on 6 November
1996 and published in the Federal Register on 19 May 1997.

**[Summary of PvRM Comments on Proposal]{.underline}**

The ICH is to be commended for providing updated amplification and
clarification of its previously issued guideline on PSURs based on
feedback from authors and reviewers of these documents. However, there
are some aspects of the draft Addendum that require further
clarification or modification to take account of the evolving regulatory
environment, particularly the imminent introduction of electronic
submission of individual case safety reports (ICSRs), which will render
moot much of the content of the current paper-based PSUR. To facilitate
FDA's review, general introductory comments are presented in standard
text, followed by a columnar presentation of PvRM\'s comments by section
number of the document, with the relevant draft guideline text
identified in bold italics, where appropriate.

# General comments

The aim of the ICH process is to harmonize regulatory processes
associated with the registration of human pharmaceutical products,
thereby avoiding redundant effort by both the pharmaceutical industry
and regulatory authorities and ensuring optimal use of limited resources
in support of global public health protection. To achieve this goal, and
fulfil the spirit of the ICH, it is essential that ICH guidelines, which
are developed jointly by industry and regulatory authorities, be adhered
to by both marketing authorization holders (MAHs) and regulatory
authorities.

Guidelines should be "stand-alone" documents for ease of use. As
currently presented, the guidance needed to comply with ICH standards
for preparation of a PSUR is contained in three separate documents, viz.
the 1996 E2C guideline, this Addendum, and the report of CIOMS Working
Group V (CIOMS-V) referred to in the Addendum, which is not an ICH
document. Therefore, before adoption at step 4, the Addendum, together
with any CIOMS-V text referenced therein, should be incorporated into a
single PSUR guideline.

PSURs are intended to encourage pharmacovigilance activities in support
of public health protection; it is therefore essential that those
activities that address real issues that potentially affect benefit-risk
balance be emphasized and reinforced, especially since the skilled
resources essential for carrying out these activities are highly
constrained, both in pharmaceutical companies and regulatory
authorities. Unfortunately, a minority of regulatory reviewers of PSURs,
while acknowledging in their assessment reports the absence of any
potential impact on benefit-risk balance, have appeared to focus their
concern on medically unimportant issues that nevertheless require
substantial effort on the part of MAHs. Such a misplaced focus diverts
limited MAH resources from more important pharmacovigilance activities
and thus could actually have an overall negative impact on ability to
protect the public health. It therefore needs to be recognized that the
current "one size fits all" approach to PSURs is not necessarily
appropriate. Not every type of medicinal product necessarily requires
the same level of detail, which should be driven by the overall balance
between benefits and risks. For example, the same level of scrutiny may
not be required for topical compared with systemic agents, single-dose
vs. chronic treatment, or products in a well studied drug class with a
long marketing history and extensive safety experience vs. novel
chemical agents with limited clinical use. It is recommended that for
defined categories of products, for which known or potential new risks
are minimal, regulators should accept substantially simplified PSURs, as
described in the CIOMS-V report (Appendix 12, pp. 323-5).

# Comments on specific draft guidance proposals

+--------------------------------+-------------------------------------+
| **Draft Consensus Guideline**  | **PvRM Comment**                    |
+================================+=====================================+
| Introduction; para. 2          | The final sentence of this          |
|                                | paragraph can be interpreted as     |
| The PSUR should represent a    | requiring inclusion of either (a)   |
| practical and achievable       | "major signal detection/evaluation" |
| mechanism to summarize         | or (b) "updates on major signal     |
| interval safety data,          | detection/evaluation". Neither the  |
| especially covering short      | format nor the preparation time of  |
| periods (e.g., 6 months or one | the PSUR are appropriate for *de    |
| year) in order to conduct an   | novo* signal analysis, as           |
| ***overall*** safety           | recognized in the final paragraph   |
| evaluation. It serves as a     | of section 1.1; therefore, this     |
| stimulus for Marketing         | section should clarify that the     |
| Authorization Holders (MAHs)   | latter meaning is intended. The     |
| to conduct systematic analyses | following format change will        |
| of safety data on a regular    | improve the clarity:                |
| basis. ***In addition to       |                                     |
| covering usual safety issues   | "In addition to covering usual      |
| the PSUR also includes updates | safety issues, the PSUR also        |
| on urgent safety issues, major | includes updates on (a) urgent      |
| signal detection/evaluation,   | safety issues, (b) major signal     |
| and changes in efficacy which  | detection/evaluation, and (c)       |
| have been or will be addressed | changes in efficacy which have been |
| in other documents.***         | or will be addressed in other       |
|                                | documents."                         |
|                                |                                     |
|                                | It is not clear what is meant by    |
|                                | the term "usual safety issues". As  |
|                                | the usual content of a PSUR is      |
|                                | described in the E2C guideline and  |
|                                | this addendum, I recommend deletion |
|                                | of the uninformative clause "In     |
|                                | addition to covering usual safety   |
|                                | issues".                            |
|                                |                                     |
|                                | The term "changes in efficacy"      |
|                                | requires clarification. It          |
|                                | presumably does not mean            |
|                                | [any]{.underline} change in product |
|                                | usage, e.g. a new indication. Since |
|                                | the purpose of safety reporting is  |
|                                | primarily to review the risk        |
|                                | aspects of an established           |
|                                | benefit-risk profile, the guideline |
|                                | should reflect that only unexpected |
|                                | lack or reduction of efficacy is    |
|                                | relevant.                           |
+--------------------------------+-------------------------------------+
| Section 1.4.1                  | Current guidelines reflect an       |
|                                | implicit assumption that every PSUR |
| It is strongly recommended     | will cover a single drug product or |
| that ***information on all     | fixed product combination, and do   |
| indications, dosage forms and  | not address appropriate methods for |
| regimens for the active        | assessing safety or dealing with    |
| substance be included in a     | overall safety concerns in the      |
| single PSUR, with a single     | increasingly common clinical        |
| data lock point common for all | situation where agents are not used |
| aspects of product use.***     | as monotherapy but only as          |
| There is a great advantage to  | components of multiple drug         |
| having a consistent,           | regimens, e.g. for hepatitis C,     |
| broad-based examination of the | HIV, or cancer. This assumption     |
| safety information for the     | creates significant difficulty for  |
| active substance(s) in a       | appropriate analysis of safety data |
| single document. When          | in PSURs. A separate PSUR for each  |
| relevant, data relating to a   | component of such regimens is at    |
| particular indication, dosage  | best of limited value, especially   |
| form, or dosing regimen should | when the same MAH is responsible    |
| be presented in separate       | for reporting on multiple agents,   |
| sections within the body of    | each with its own safety data       |
| the PSUR and any safety issues | sheet, in a regimen. There are both |
| addressed accordingly without  | important database issues (e.g. a   |
| preparing a separate PSUR.     | given case may be classified as     |
|                                | initial in the PSUR for one         |
|                                | component, but as follow-up for     |
|                                | another), and clinical/regulatory   |
|                                | concerns, e.g. assessment of event  |
|                                | causality and/or listedness for one |
|                                | component of the regimen vs.        |
|                                | another, which may be (a)           |
|                                | impossible and (b) clinically       |
|                                | irrelevant. In addition, PSURS      |
|                                | prepared for more than one regimen  |
|                                | component by the same MAH           |
|                                | frequently cover overlapping        |
|                                | periods and so contain many of the  |
|                                | same cases and benefit-risk         |
|                                | conclusions. As such, they          |
|                                | represent redundant and unnecessary |
|                                | effort, both in their preparation   |
|                                | by MAHs and their review by         |
|                                | regulatory authorities. Discussion  |
|                                | of benefit-risk or label changes    |
|                                | for only one component of the       |
|                                | regimen, as current practice        |
|                                | requires, is often not possible     |
|                                | and/or is clinically irrelevant,    |
|                                | and therefore does not adequately   |
|                                | meet the goal of public health      |
|                                | protection.                         |
|                                |                                     |
|                                | Consideration should therefore be   |
|                                | given to providing guidance on the  |
|                                | optimal assessment and              |
|                                | communication of benefit-risk       |
|                                | profile for products that are       |
|                                | approved as individual agents but   |
|                                | are administered only as components |
|                                | of therapeutic regimens, not as     |
|                                | monotherapy.                        |
|                                |                                     |
|                                | The following potential approach to |
|                                | this problem is suggested:          |
|                                |                                     |
|                                | 1\. When the same MAH markets more  |
|                                | than one of the components of the   |
|                                | regimen, regulatory authorities     |
|                                | should accept a single PSUR         |
|                                | covering those components with a    |
|                                | periodicity based on the IBD of the |
|                                | earliest component, instead of      |
|                                | multiple, asynchronous, overlapping |
|                                | and redundant reports containing    |
|                                | many of the same cases.             |
|                                |                                     |
|                                | 2\. Only those AEs that are not     |
|                                | listed in the CCSI for              |
|                                | [any]{.underline} of the products   |
|                                | in the combined PSUR should be      |
|                                | considered unlisted for the regimen |
|                                | as a whole. This will limit the     |
|                                | amount of redundant analysis and    |
|                                | discussion and permit better focus  |
|                                | on any actual safety issues         |
|                                | associated with clinical use of the |
|                                | regimen.                            |
+--------------------------------+-------------------------------------+
| Section 1.4.4.1, para. 1       | The stated purpose of the ICH is    |
|                                | **"**to achieve greater             |
| For drugs that are on the      | harmonisation in the interpretation |
| market in many countries, the  | and application of technical        |
| MAH might wish to synchronize  | guidelines and requirements for     |
| local or national birthdates   | product registration in order to    |
| with the IBD. ***Although such | reduce or obviate the need to       |
| a process can be difficult     | duplicate the testing carried out   |
| (e.g., it might require        | during the research and development |
| multiple applications for a    | of new medicines. The objective of  |
| variation), such a step might  | such harmonisation is a more        |
| be feasible and can be         | economical use of                   |
| discussed with the Regulatory  | ...resources,...whilst maintaining  |
| Authorities.***                | safeguards on quality, safety and   |
|                                | efficacy, and regulatory            |
|                                | obligations to protect public       |
|                                | health." It is difficult to         |
|                                | envision circumstances in which     |
|                                | submission of PSURs based on the    |
|                                | IBD rather than a local birth date  |
|                                | could have any public health        |
|                                | repercussions. Therefore, in the    |
|                                | spirit of harmonization, instead of |
|                                | requiring MAHs to negotiate with    |
|                                | multiple authorities to adopt an    |
|                                | international regulatory standard,  |
|                                | all ICH regulatory authorities      |
|                                | should accept IBD-based PSURs by    |
|                                | default. Any authority that wishes  |
|                                | to receive routine PSURs based on   |
|                                | other periods should be required to |
|                                | request such from the MAH, and      |
|                                | provide a public health based       |
|                                | rationale for their necessity.      |
+--------------------------------+-------------------------------------+
| Section 1.4.4.1, para 3        | The IBD is a fixed date, so the     |
|                                | intent of this paragraph in         |
| It is recognized that the long | relation to paragraph 1 of this     |
| interval between approvals     | section is not clear. Different     |
| could put the drug in a 5 year | approval dates in different regions |
| cycle in one region and a 6    | may affect the frequency of local   |
| month cycle in the other       | reporting, but all PSURs should     |
| region(s). For practical       | still be based on the IBD (see also |
| purposes, ***if a single       | comment on section 1.4.4.1, para.   |
| month, day and year for the    | 1).                                 |
| IBD is not attainable,*** the  |                                     |
| MAH can contact the Regulatory |                                     |
| Authorities to negotiate a     |                                     |
| mutually acceptable birth      |                                     |
| month and day. For example,    |                                     |
| where there are different      |                                     |
| approval dates, it can be      |                                     |
| useful for reports to be       |                                     |
| submitted on the same month    |                                     |
| and day (e.g. every January 18 |                                     |
| and July 18), whether every 6  |                                     |
| months, yearly or every 5th    |                                     |
| year.                          |                                     |
+--------------------------------+-------------------------------------+
| Section 1.4.4.3, para. 2       | As stated previously in the comment |
|                                | on section 1.4.4.1, para. 1,        |
| An Addendum Report is an       | Regulatory Authorities should       |
| update to the most recently    | adhere to the spirit of             |
| completed PSUR ***when a       | harmonization by accepting PSURs    |
| Regulatory Authority requires  | based on the IBD, and should not    |
| a routine safety update        | routinely require Addendum Reports, |
| outside the usual IBD          | e.g. due to asynchrony between      |
| reporting cycle.*** It should  | local and international birth       |
| be used when more than 3       | dates, or for detailed analysis of  |
| months for a 6-month report,   | medically trivial signs or symptoms |
| and more than 6 months for an  | that will be included in the next   |
| annual or longer-interval      | regularly-scheduled PSUR. There are |
| report, have elapsed since the | established regulatory mechanisms   |
| data lock point of the most    | for dealing with critical safety    |
| recent PSUR. It might also be  | issues that are too urgent for      |
| appropriate to provide an      | scheduled periodic reporting. Thus, |
| addendum to the summary        | without clear definition of the     |
| bridging report.               | circumstances in which Addendum     |
|                                | reports are appropriate and the     |
|                                | purposes for which they will be     |
|                                | used, they are liable to become     |
|                                | nothing more than a bureaucratic    |
|                                | exercise, consuming scarce          |
|                                | resources for no valid public       |
|                                | health reason. If an MAH is still   |
|                                | preparing regular IBD-based 6-month |
|                                | PSURs, there appears to be no       |
|                                | rationale for requesting addendum   |
|                                | reports that provide no more than a |
|                                | "preview", without meaningful       |
|                                | analysis, of cases that will appear |
|                                | in the next PSUR, as described in   |
|                                | Section 1.4.4.3, para. 3. Addendum  |
|                                | reports should therefore be         |
|                                | reserved for products with a long   |
|                                | (1 or 5 year) routine reporting     |
|                                | periodicity to address issues with  |
|                                | the potential for an adverse public |
|                                | health impact, such as the          |
|                                | identification of a new safety      |
|                                | signal (e.g. a clinically important |
|                                | drug interaction).                  |
+--------------------------------+-------------------------------------+
| Section 1.4.4.3, para. 3       | As indicated in the preceding       |
|                                | comment, the medical utility of     |
| The Addendum Report should     | Addendum Reports is unclear. The    |
| summarize the safety data      | absence of an in-depth analysis of  |
| received between the data lock | included cases implies that         |
| point of the most recent PSUR  | Addendum Reports are not meant to   |
| and the Regulatory Authority's | communicate important safety        |
| requested cut-off date. ***It  | issues; their purpose thus seems    |
| is not intended that the       | primarily bureaucratic, contrary to |
| addendum report provide an     | the purpose of ICH.                 |
| in-depth analysis of the       |                                     |
| additional cases,*** as these  | The proposed minimal report format  |
| should be included in the next | should thus be the default for an   |
| regularly scheduled PSUR.      | Addendum Report, unless it is being |
| Depending on circumstances and | used to address a significant new   |
| the volume of additional data  | issue as described in the preceding |
| since the last scheduled       | comment. Although not addressed in  |
| report, ***an Addendum Report  | the current proposed guideline, a   |
| can follow the ICH E2C format  | similar minimal format should also  |
| or a simplified                | be applied to PSURs for products    |
| presentation.***               | with a long marketing history and a |
|                                | well-established safety profile,    |
|                                | for which a full PSUR, even if all  |
|                                | the requisite data were available,  |
|                                | would rarely be routinely           |
|                                | necessary.                          |
+--------------------------------+-------------------------------------+
| Section 1.4.4.5, bullet 3      | It is to be hoped that reviewers    |
|                                | will limit requests for additional  |
| Regulatory Authority reviewers | analyses in the next scheduled PSUR |
| intend to attempt to send any  | to issues with a real potential     |
| comments on the PSUR to the    | adverse effect on the public        |
| MAH ...before the next data    | health. One reviewer, after         |
| lock point ***if any           | concluding that PSUR data did not   |
| additional analyses or issues  | indicate any alteration in          |
| of content are identified that | benefit-risk balance, nevertheless  |
| should be included in the next | requested the MAH to perform        |
| PSUR***                        | comprehensive analyses of 23        |
|                                | (twenty-three) AEs, almost all of   |
|                                | which were non-serious, many were   |
|                                | subjective symptoms occurring with  |
|                                | comparable frequency in active and  |
|                                | placebo-treated subjects in         |
|                                | clinical trials, and one of which   |
|                                | was the non-life threatening        |
|                                | treatment indication itself. None   |
|                                | of these extensive additional       |
|                                | analyses identified any change in   |
|                                | the established benefit-risk        |
|                                | profile or resulted in any          |
|                                | medically important label changes.  |
|                                | However, the response to this       |
|                                | request was extremely resource      |
|                                | intensive, potentially compromising |
|                                | the MAH's ability to deal           |
|                                | effectively with other issues.      |
+--------------------------------+-------------------------------------+
| Section 1.4.5, para. 1-5       | The recommendation to use the CCSI  |
|                                | in effect at the beginning of the   |
| For 6 month and 1 year         | period as the reference for short   |
| reports, the version of the    | period PSURs, as proposed in the    |
| Company Core Safety            | November 1996 E2C guideline, has no |
| Information (CCSI) in effect   | obvious rationale. If the MAH has   |
| at the beginning of the period | added new safety information to the |
| covered by the report should   | CCSI during the reporting period,   |
| be used as the reference.      | whatever its duration, there would  |
|                                | seem to be no added value in        |
| When producing a longer        | presenting any previous,            |
| duration PSUR, such as a 5     | non-current version. It would be    |
| year report, it is often       | more logical to present the latest  |
| impractical to base the        | version of the CCSI in every PSUR,  |
| analysis of listedness on the  | together with a description of the  |
| CCSI that was in effect at the | changes made and the supporting     |
| beginning of the 5 year        | analyses, regardless of the period  |
| period. There can be           | covered. This would also be         |
| considerable variation in      | consistent with data entry          |
| listedness over 5 years,       | standards in most companies, i.e.   |
| depending on when the          | categorization of listedness of     |
| assessment of listedness is    | events according to the CCSI in     |
| made (i.e. on an ongoing       | effect at the time of case entry.   |
| basis, such as at AE/ADR case  |                                     |
| entry, or when a PSUR is       | The recommendation to use multiple  |
| compiled). The latest CCSI in  | CCSIs for long period PSURs         |
| effect at the end of the       | consisting of multiple short period |
| period can be used. The MAH    | reports is both impractical and of  |
| should ensure that all changes | dubious value. If, as suggested in  |
| to the CCSI made over the      | the previous paragraph, all changes |
| 5-year period are described in | to the CCSI over the entire period  |
| Section 4 of the PSUR (Changes | are described, together with the    |
| to the Reference Safety        | rationale for doing so, there is no |
| Information).                  | obvious public health reason to     |
|                                | adopt different approaches to       |
| If a long duration PSUR is     | unitary vs. multiple-component long |
| prepared using several shorter | period reports. Rather, the         |
| duration PSURs (e.g. a 5-year  | additional work involved will       |
| report using 10 consecutive    | divert limited resources from more  |
| 6-month PSURs), the CCSI in    | useful and rewarding                |
| force at the beginning of each | pharmacovigilance activities.       |
| shorter duration report should |                                     |
| be used. A discussion of the   | I therefore suggest that the        |
| changes that occurred in the   | guideline be revised to allow the   |
| CCSI and its implications over | MAH the option of using either the  |
| the long duration should be    | earliest or latest CCSI as the      |
| included in the summary        | reference document, subject to the  |
| bridging report.               | provision of appropriate            |
|                                | explanations and justifications for |
|                                | the changes made during the         |
|                                | reporting period.                   |
+--------------------------------+-------------------------------------+
| Section 1.4.5, para. 6         | The numerical references to PSUR    |
|                                | sections throughout this Addendum   |
| Whether listedness is assessed | guideline do not correspond to the  |
| at case entry or as a batch    | numbering of the sections in the    |
| process at the time of         | November 1996 E2C guideline. For    |
| preparing the PSUR, there will | clarity and non-ambiguity, this     |
| be an impact on ***Section 6   | Addendum should cross-reference the |
| of the PSUR***.                | relevant section of the 1996        |
|                                | guideline; for example, this        |
|                                | paragraph seems to refer to Section |
|                                | 2.6, Presentation of Individual     |
|                                | Case Histories, in the original E2C |
|                                | guideline.                          |
+--------------------------------+-------------------------------------+
| Section 2.5, para. 1           | Difficulties in assessing safety of |
|                                | individual components of multiple   |
| ***Estimating patient exposure | drug regimens have been discussed   |
| data for marketed drugs often  | in the comment on section 1.4.1     |
| relies on gross approximations | above. It is often impossible to    |
| of in-house or purchased sales | estimate exposure to such combined  |
| data or volume to determine    | regimens, or in the situation,      |
| patient exposure. This is not  | common for cancer chemotherapeutic  |
| always reliable or available   | agents, where dosages are           |
| for all products.*** For       | individualized according to body    |
| example, hospital-based        | weight, surface area, renal         |
| (inpatient exposure)           | function, etc. Calculations of      |
| statistics from the major      | patient exposure in such situations |
| use-monitoring sources are     | are fundamentally meaningless; the  |
| frequently unavailable. It is  | guideline should recognize that     |
| also difficult to obtain       | there are situations where no       |
| accurate data for drugs for    | meaningful estimate of exposure can |
| which there is use of generic  | be derived, and should permit MAHs, |
| versions. For nonprescription  | with appropriate explanation, to    |
| drugs, use is often on an      | omit exposure calculations in such  |
| as-required basis, and         | situations.                         |
| individual packages are        |                                     |
| frequently used by multiple    |                                     |
| family members of different    |                                     |
| ages and weights.              |                                     |
+--------------------------------+-------------------------------------+
| Section 2.5, para. 2           | The 60 day interval between data    |
|                                | lock and report submission very     |
| When the exposure data are     | rarely permits the MAH to obtain    |
| based on information from a    | marketing data that are congruent   |
| period that does not fully     | with the reporting period,          |
| cover the period of the PSUR,  | especially for 6-month PSURs, where |
| the MAH can make               | actual data are typically available |
| extrapolations using the       | only for the first half of the      |
| available data. When this is   | period. Therefore, extrapolation    |
| done it should be clearly      | from prior exposure data is the     |
| indicated what data were used  | norm in PSUR preparation. However,  |
| and why it is valid to         | the examples of situations in which |
| extrapolate for the PSUR       | extrapolation is considered valid   |
| period in question (e.g.,      | are unrealistic, since the stated   |
| stable sales over a long       | purpose of PSURs is to present      |
| period of time, seasonality of | safety updates primarily for        |
| use of the product, etc.).     | relatively new products, which      |
|                                | typically experience relatively     |
|                                | rapid increases in patient exposure |
|                                | over relatively short periods.      |
|                                | Furthermore, estimates of exposure  |
|                                | are at best highly imprecise, when  |
|                                | they can be calculated at all (see  |
|                                | also comment on Section 2.5, para.  |
|                                | 1); thus, the relatively minor      |
|                                | "error" introduced by extrapolation |
|                                | is merely one among many sources of |
|                                | significant inaccuracy. Exposure    |
|                                | estimates can be regarded only as   |
|                                | very rough approximations, with     |
|                                | limited validity, and thus should   |
|                                | receive minimal attention.          |
+--------------------------------+-------------------------------------+
| Section 2.5, para. 4           | The intent and meaning of this      |
|                                | paragraph are unclear. The CIOMS-V  |
| In a summary bridging report   | document states (p.155) that        |
| every effort should be made to | exposure data should be "an         |
| avoid patient exposure data    | estimate of the total number of     |
| and calculations that overlap  | patients exposed in the time period |
| time periods.                  | covered by the bridging             |
|                                | report...particularly...if          |
|                                | different methods of calculation    |
|                                | have been applied from one PSUR     |
|                                | period to another. The method used  |
|                                | for the bridging report should be   |
|                                | clearly stated."                    |
+--------------------------------+-------------------------------------+
| Section 2.6                    | Overall, this document reflects a   |
|                                | continued assumption that MAHs will |
| There is no specific guidance  | continue to submit individual case  |
| in E2C on the presentation of  | safety reports (ICSRs) to           |
| individual case report         | regulatory authorities on paper.    |
| narratives. ***It is sometimes | However, the ICH has developed      |
| impractical to present all     | standards for electronic submission |
| individual case safety reports | of ICSRs which are about to be      |
| for the reporting period       | implemented by regulatory           |
| and/or for specific issues in  | authorities in the ICH regions.     |
| this section.*** A brief       | This issue will become moot when    |
| description of the criteria    | regulatory authorities already have |
| used to select cases for       | all reportable cases (both          |
| presentation should be given.  | expedited and routine) in their own |
|                                | databases, and the only added value |
| This section should contain a  | will be derived from aggregate      |
| description and analysis of    | clinical analysis of important      |
| selected cases containing new  | cases suggesting new safety signals |
| or relevant safety information | or issues. The guideline should     |
| and grouped by medically       | take account of these imminent      |
| relevant headings/System Organ | international regulatory            |
| Classes (SOCs).                | developments, to avoid being        |
|                                | obsolete by the time it reaches     |
|                                | step 5.                             |
+--------------------------------+-------------------------------------+
| Section 2.6.2, bullet 2        | The recommendation to "handle" all  |
|                                | AEs from solicited reports          |
| -   Solicited reports, if not  | similarly to reports from clinical  |
|     medically confirmed,       | trials requires clarification. From |
|     should be treated as       | a procedural viewpoint, most MAHs   |
|     consumer reports, and thus | have separate clinical study and    |
|     not reported in the PSUR   | safety databases, and typically do  |
|     unless specifically        | not enter non-serious AEs from      |
|     requested by the           | clinical studies into the safety    |
|     authorities (same as for   | database. Further, AEs from         |
|     spontaneous consumer       | clinical trials are reported by     |
|     reports)                   | health professionals, while almost  |
|                                | all solicited reports will be       |
| -   Solicited reports should   | received direct from consumers, and |
|     be processed separately    | will very rarely be medically       |
|     and categorized in the     | confirmed. The implication of this  |
|     data base as solicited     | statement is that a serious         |
|     reports. The reports       | unexpected AE that the reporting    |
|     should also be identified  | consumer attributes to the          |
|     as solicited cases in any  | medication will qualify for         |
|     reports or tabulations     | expedited reporting. A more logical |
|     that are prepared.         | approach is presented in the        |
|                                | CIOMS-V report, p. 61, which        |
| ***All AEs from solicited      | clarifies that a consumer's         |
| reports should be handled in   | assessment of causality is not the  |
| the same way as similar        | same as that provided by a health   |
| reports from clinical          | professional, and that in this      |
| trials.***                     | situation the MAH is responsible    |
|                                | for determining causality.          |
+--------------------------------+-------------------------------------+
| Section 2.6.3                  | None of the existing ICH or CIOMS   |
|                                | documents provides any guidance for |
| "Comments" field               | MAHs on what constitutes "special   |
|                                | information that helps to clarify   |
| E2C indicates that ***[the     | individual cases". Guidance on a    |
| "Comments" field should be     | consistent approach to the          |
| used only for special          | appropriate contents of this field  |
| information that helps to      | would be extremely helpful to both  |
| clarify individual             | creators and reviewers of ICSRs and |
| cases.]{.underline}*** That    | PSURs.                              |
| field should not be routinely  |                                     |
| used to convey causality       |                                     |
| assessment conclusions and     |                                     |
| other non-essential            |                                     |
| information.                   |                                     |
+--------------------------------+-------------------------------------+
| Section 2.9                    | The value of this recommendation is |
|                                | uncertain. The overwhelming         |
| Overall Safety Evaluation      | majority of products and reports    |
|                                | are unlikely to contain clinically  |
| Discussion and analysis for    | important new information in more   |
| the Overall Safety Evaluation  | than a small minority of SOCs.      |
| should be organized by SOC     | Taken in conjunction with the text  |
| rather than by listedness or   | of the 1996 E2C guideline, this     |
| seriousness; the latter        | wording could be interpreted as     |
| properties should, of course,  | suggesting that the discussion      |
| still be covered under each    | should cover every SOC, which would |
| SOC. Although related terms    | be neither necessary nor            |
| might be found in different    | appropriate. The wording of this    |
| SOCs, they should be reviewed  | paragraph should be modified to     |
| together for clinical          | reflect the same concepts as        |
| relevance.                     | section 2.9 of the 1996 guideline,  |
|                                | i.e. that discussion and analysis   |
|                                | should be confined to those SOCs    |
|                                | that contain new clinically         |
|                                | important information.              |
+--------------------------------+-------------------------------------+

Pharmacovigilance & Risk Management, Inc. appreciates the opportunity to
comment on the proposed guideline.

Respectfully submitted,

![](media/image2.jpeg){width="2.6666666666666665in"
height="0.8666666666666667in"}

Sidney N Kahn, M.D., Ph. D.

President