# Comments from the MedDRA Maintenance and Support Services Organization 

# on the Proposed Rule: Safety Reporting Requirements 

# for Human Drug and Biologic Products (the "Tome") 

# Federal Register Vol. 68, No. 58, 14 March 2003

Note: The comments expressed in this document reflect the opinions of
the MedDRA Maintenance and Support Services Organization (MSSO) and are
not necessarily those of the MedDRA Management Board.

### I. Specific comments on the proposed rule by section/page 

+-----+----+------------------+----------------------+---------------+
| #   | #  | ##               | ## Comment           | ## R          |
| # S | #  | Language of Rule |                      | ecommendation |
| ect | Pa |                  |                      |               |
| ion | ge |                  |                      |               |
+=====+====+==================+======================+===============+
| I   | 1  | Figure 1 --      | Does this            | Please insert |
|     | 24 | "Postmarketing   | requirement to use   | language to   |
|     | 08 | safety reports   | MedDRA relate        | address these |
|     |    | be coded using   | [s                   | questions and |
|     |    | MedDRA (ICH M1)" | trictly]{.underline} | to clarify    |
|     |    |                  | to safety reports    | FDA's         |
|     |    |                  | for marketed         | position.     |
|     |    |                  | products? In other   |               |
|     |    |                  | areas of the rule,   |               |
|     |    |                  | there appear to be   |               |
|     |    |                  | references to use    |               |
|     |    |                  | for expedited safety |               |
|     |    |                  | reports for          |               |
|     |    |                  | non-marketed         |               |
|     |    |                  | products in          |               |
|     |    |                  | development. Does    |               |
|     |    |                  | the requirement for  |               |
|     |    |                  | the use of MedDRA    |               |
|     |    |                  | apply also to these  |               |
|     |    |                  | reports?             |               |
+-----+----+------------------+----------------------+---------------+
| I   | 1  | In the **Federal | The majority of      | FDA should    |
|     | 24 | Register** of    | ICSRs will soon be   | therefore     |
|     | 10 | November 5, 1998 | submitted to FDA     | specify that, |
|     |    | (63 FR 59746),   | electronically in    | at least as   |
|     |    | FDA published an | accordance with the  | regards the   |
|     |    | advance notice   | ICH E2B guideline.   | use of        |
|     |    | of proposed      | However, the         | MedDRA, the   |
|     |    | rulemaking       | proposed rule        | proposed rule |
|     |    | announcing that  | explicitly addresses | applies only  |
|     |    | it is            | only ICSR            | to that       |
|     |    | considering a    | submissions on paper | minority of   |
|     |    | proposal to      | (forms 3500A,        | ICSRs that it |
|     |    | require persons  | CIOMS-I, VAERS, line | will receive  |
|     |    | subject to the   | listings, etc.).     | on paper, and |
|     |    | postmarketing    | Some requirements of | that specific |
|     |    | safety reporting | the proposed rule    | c             |
|     |    | regulations to   | and assessments of   | onsiderations |
|     |    | submit           | the impact of        | concerning    |
|     |    | postmarketing    | implementation of    | the           |
|     |    | expedited        | MedDRA are           | application   |
|     |    | individual case  | inconsistent with    | and impact of |
|     |    | safety reports   | electronic           | MedDRA on     |
|     |    | and individual   | submission or may be | electronic    |
|     |    | case safety      | rendered moot by its | submission of |
|     |    | reports          | implementation. For  | ICSRs will be |
|     |    | contained in     | example, the E2B(M)  | addressed in  |
|     |    | postmarketing    | specification calls  | other rules   |
|     |    | periodic safety  | for international    | and/or        |
|     |    | reports to the   | reporting of the     | guidances.    |
|     |    | agency           | "verbatim" event     |               |
|     |    | electronically   | description together |               |
|     |    | using a          | with the             |               |
|     |    | standardized     | corresponding MedDRA |               |
|     |    | medical          | LLT and PT and       |               |
|     |    | terminology,     | identification of    |               |
|     |    | standardized     | the version of       |               |
|     |    | data elements,   | MedDRA employed. In  |               |
|     |    | and electronic   | addition, the        |               |
|     |    | transmission     | proposed rule        |               |
|     |    | standards        | requires MedDRA only |               |
|     |    | recommended by   | for SADRs, while E2B |               |
|     |    | the ICH. Under   | requires its use not |               |
|     |    | the auspices of  | only to represent    |               |
|     |    | ICH, standard    | adverse events but   |               |
|     |    | medical          | also in every other  |               |
|     |    | terminology for  | field that requires  |               |
|     |    | regulatory       | a controlled medical |               |
|     |    | purposes,        | terminology,         |               |
|     |    | MedDRA, the      | including medical    |               |
|     |    | medical          | history, treatment   |               |
|     |    | dictionary for   | indication, cause of |               |
|     |    | regulatory       | death, etc.          |               |
|     |    | activities (ICH  |                      |               |
|     |    | M1), has been    |                      |               |
|     |    | developed (63 FR |                      |               |
|     |    | 59746 at 59748). |                      |               |
|     |    | On November 24,  |                      |               |
|     |    | 1998, an         |                      |               |
|     |    | international    |                      |               |
|     |    | maintenance and  |                      |               |
|     |    | support services |                      |               |
|     |    | organization     |                      |               |
|     |    | (MSSO) was       |                      |               |
|     |    | established to   |                      |               |
|     |    | maintain and     |                      |               |
|     |    | update MedDRA in |                      |               |
|     |    | response to      |                      |               |
|     |    | me               |                      |               |
|     |    | dical/scientific |                      |               |
|     |    | advances and     |                      |               |
|     |    | regulatory       |                      |               |
|     |    | changes and to   |                      |               |
|     |    | serve as the     |                      |               |
|     |    | licensing agent  |                      |               |
|     |    | for distribution |                      |               |
|     |    | of MedDRA. This  |                      |               |
|     |    | proposed rule on |                      |               |
|     |    | safety reporting |                      |               |
|     |    | would require    |                      |               |
|     |    | that             |                      |               |
|     |    | postmarketing    |                      |               |
|     |    | individual case  |                      |               |
|     |    | safety reports   |                      |               |
|     |    | be coded using   |                      |               |
|     |    | MedDRA prior to  |                      |               |
|     |    | submission to    |                      |               |
|     |    | the agency. In a |                      |               |
|     |    | separate         |                      |               |
|     |    | rulemaking, FDA  |                      |               |
|     |    | plans to propose |                      |               |
|     |    | that             |                      |               |
|     |    | postmarketing    |                      |               |
|     |    | individual case  |                      |               |
|     |    | safety reports   |                      |               |
|     |    | be submitted to  |                      |               |
|     |    | the agency       |                      |               |
|     |    | electronically   |                      |               |
|     |    | using            |                      |               |
|     |    | standardized     |                      |               |
|     |    | data elements    |                      |               |
|     |    | and electronic   |                      |               |
|     |    | transmission     |                      |               |
|     |    | standards. The   |                      |               |
|     |    | proposed         |                      |               |
|     |    | amendments for   |                      |               |
|     |    | electronic       |                      |               |
|     |    | submissions are  |                      |               |
|     |    | beyond the scope |                      |               |
|     |    | of this proposed |                      |               |
|     |    | rule.            |                      |               |
+-----+----+------------------+----------------------+---------------+
| II. | 1  | Another          | MSSO strongly        | FDA should    |
| B.1 | 24 | international    | supports the concept | include a     |
|     | 12 | harmonization    | of using the         | reference to  |
|     |  - | effort is        | ICH-developed MedDRA | the document  |
|     | 3  | standardization  | terminology for      | "MedDRA Term  |
|     |    | of medical       | safety reporting     | Selection;    |
|     |    | terminology used | during all phases of | Points to     |
|     |    | for regulatory   | product development  | Consider"     |
|     |    | purposes. As     | and marketing        | developed by  |
|     |    | noted            | worldwide, and       | the ICH to    |
|     |    | previously, ICH  | commends FDA for     | support       |
|     |    | has developed    | adopting this        | rational      |
|     |    | MedDRA for this  | international        | codification  |
|     |    | purpose.         | standard for safety  | practices.    |
|     |    | Currently,       | reporting on         |               |
|     |    | companies use    | marketed products.   |               |
|     |    | various medical  | The long term        |               |
|     |    | terminologies    | advantages to        |               |
|     |    | for safety       | companies and        |               |
|     |    | reporting        | regulators of        |               |
|     |    | purposes         | standardized use of  |               |
|     |    | (*e.g.*, WHO's   | MedDRA should far    |               |
|     |    | Adverse Reaction | outweigh both its    |               |
|     |    | Terminology      | initial              |               |
|     |    | (WHOART), Coding | implementation       |               |
|     |    | Symbols for a    | burden and its       |               |
|     |    | Thesaurus of     | maintenance costs,   |               |
|     |    | Adverse Reaction | which will be higher |               |
|     |    | Terms (COSTART), | than those of        |               |
|     |    | Japan's Adverse  | previously used      |               |
|     |    | Reaction         | terminologies. This  |               |
|     |    | Terminology      | perception accounts  |               |
|     |    | (J-ART)). The    | for the rapid        |               |
|     |    | established      | voluntary adoption   |               |
|     |    | terminologies    | of MedDRA by many    |               |
|     |    | have been        | companies for safety |               |
|     |    | criticized for a | reporting of both    |               |
|     |    | number of        | marketed and         |               |
|     |    | reasons,         | investigational      |               |
|     |    | including: Lack  | products, and even   |               |
|     |    | of specificity,  | for certain recent   |               |
|     |    | limited data     | NDA submissions.     |               |
|     |    | retrieval        | However, many of the |               |
|     |    | options, and an  | difficulties         |               |
|     |    | inability to     | resulting from the   |               |
|     |    | effectively      | use of previous      |               |
|     |    | handle complex   | terminologies will   |               |
|     |    | combinations of  | not be remedied      |               |
|     |    | signs and        | simply by adoption   |               |
|     |    | symptoms         | of MedDRA. It is     |               |
|     |    | (syndromes). In  | critical that        |               |
|     |    | addition, use of | MedDRA's             |               |
|     |    | different        | implementation and   |               |
|     |    | terminologies at | use be logical and   |               |
|     |    | different stages | consistent, since    |               |
|     |    | in the           | its benefits could   |               |
|     |    | development and  | be substantially     |               |
|     |    | use of products  | vitiated by          |               |
|     |    | complicates data | inconsistent         |               |
|     |    | retrieval and    | implementation       |               |
|     |    | analysis of      | and/or usage.        |               |
|     |    | information and  | Although             |               |
|     |    | makes it         | codification can     |               |
|     |    | difficult to     | never be fully       |               |
|     |    | effectively      | standardized,        |               |
|     |    | cross-reference  | attempts should be   |               |
|     |    | data through the | made to develop the  |               |
|     |    | lifetime of a    | broadest possible    |               |
|     |    | product.         | consensus on optimal |               |
|     |    | Internationally, | approaches to        |               |
|     |    | communication is | codifying SADRs for  |               |
|     |    | impaired between | safety signal        |               |
|     |    | regulatory       | detection. In        |               |
|     |    | authorities      | recognition of this  |               |
|     |    | because of the   | requirement, FDA     |               |
|     |    | delays and       | should include a     |               |
|     |    | distortions      | reference to the     |               |
|     |    | caused by the    | document "MedDRA     |               |
|     |    | translation of   | Term Selection;      |               |
|     |    | data from one    | Points to Consider"  |               |
|     |    | terminology to   | developed by the ICH |               |
|     |    | another.         | to support rational  |               |
|     |    |                  | codification         |               |
|     |    | Use of different | practices.           |               |
|     |    | terminologies    |                      |               |
|     |    | also has         | MSSO has the         |               |
|     |    | significant      | following comments   |               |
|     |    | consequences for | on the impact of     |               |
|     |    | pharmaceutical   | MedDRA on safety     |               |
|     |    | firms. Companies | reporting to         |               |
|     |    | operating in     | manufacturers by     |               |
|     |    | more than one    | health care          |               |
|     |    | jurisdiction     | providers (HCPs) and |               |
|     |    | have had to      | on optimal use of    |               |
|     |    | adjust to        | MedDRA terms:        |               |
|     |    | subsidiaries or  |                      |               |
|     |    | clinical         | -   In general, HCPs |               |
|     |    | research         |     will continue to |               |
|     |    | organizations    |     use natural      |               |
|     |    | that use         |     medical          |               |
|     |    | different        |     language, rather |               |
|     |    | terminologies    |     than             |               |
|     |    | because of       |     dictionaries or  |               |
|     |    | variations in    |     standardized     |               |
|     |    | data submission  |     terminologies,   |               |
|     |    | requirements.    |     for              |               |
|     |    | The difficulty   |     communicating    |               |
|     |    | of analyzing     |     with             |               |
|     |    | data             |     manufacturers    |               |
|     |    | comprehensively  |     about SADRs. The |               |
|     |    | may be           |     proposed rule    |               |
|     |    | compounded by    |     should therefore |               |
|     |    | use of           |     have no impact   |               |
|     |    | incompatible     |     on clinicians or |               |
|     |    | terminologies    |     other providers  |               |
|     |    | and could lead   |     of healthcare    |               |
|     |    | to delays in     |     services.        |               |
|     |    | recognizing      |                      |               |
|     |    | potential public | -   Current practice |               |
|     |    | health problems. |     is to codify     |               |
|     |    |                  |     data in strict   |               |
|     |    | For these        |     adherence to the |               |
|     |    | reasons, it is   |     reporter's       |               |
|     |    | critical that a  |     verbatim term,   |               |
|     |    | single medical   |     although there   |               |
|     |    | terminology be   |     are relatively   |               |
|     |    | used             |     common           |               |
|     |    | internationally  |     situations in    |               |
|     |    | for coding       |     which this       |               |
|     |    | postmarketing    |     approach does    |               |
|     |    | safety reports.  |     not result in an |               |
|     |    | FDA is proposing |     optimally        |               |
|     |    | to use MedDRA    |     medically        |               |
|     |    | for this purpose |     meaningful       |               |
|     |    | (see section     |     output,          |               |
|     |    | III.F.2 of this  |     including:       |               |
|     |    | document).       |                      |               |
|     |    | MedDRA is the    |     -   Reporter     |               |
|     |    | best choice      |                      |               |
|     |    | because it was   |   miscategorization, |               |
|     |    | developed with   |         e.g.         |               |
|     |    | input from       |         reporting    |               |
|     |    | regulatory       |         "abnormal    |               |
|     |    | authorities and  |         LFTs" to     |               |
|     |    | industry and the |         describe a   |               |
|     |    | problems         |         patient with |               |
|     |    | associated with  |         jaundice or  |               |
|     |    | the other        |         "acute liver |               |
|     |    | terminologies    |         failure"     |               |
|     |    | were taken into  |         without      |               |
|     |    | consideration    |                      |               |
|     |    | during           |      encephalopathy, |               |
|     |    | development of   |                      |               |
|     |    | MedDRA. Some     |        coagulopathy, |               |
|     |    | companies have   |         or jaundice. |               |
|     |    | begun to         |                      |               |
|     |    | voluntarily      |     -   Inconsistent |               |
|     |    | submit their     |         event        |               |
|     |    | postmarketing    |                      |               |
|     |    | safety reports   |      classification; |               |
|     |    | to FDA coded     |         e.g. an      |               |
|     |    | using MedDRA.    |         identical    |               |
|     |    |                  |                      |               |
|     |    | Even though FDA  |        constellation |               |
|     |    | is proposing to  |         of clinical  |               |
|     |    | use MedDRA as    |         signs and    |               |
|     |    | the standard     |         laboratory   |               |
|     |    | medical          |         results may  |               |
|     |    | terminology for  |         be variously |               |
|     |    | reporting        |         categorized  |               |
|     |    | purposes under   |         by different |               |
|     |    | this rule, the   |         reporters as |               |
|     |    | agency           |         hepatitis,   |               |
|     |    | recognizes that  |         abnormal     |               |
|     |    | alternative      |         liver        |               |
|     |    | standard         |         function,    |               |
|     |    | classification   |         elevated     |               |
|     |    | systems for      |                      |               |
|     |    | clinical         |    aminotransferases |               |
|     |    | information      |         and          |               |
|     |    | exist in the     |         jaundice,    |               |
|     |    | United States    |         liver        |               |
|     |    | and supports the |         necrosis,    |               |
|     |    | national health  |         etc.         |               |
|     |    | data             |         Codifying    |               |
|     |    | standardization  |         such         |               |
|     |    | initiatives      |         information  |               |
|     |    | underway in the  |         strictly in  |               |
|     |    | United States    |         accordance   |               |
|     |    | under the Health |         with the     |               |
|     |    | Insurance        |         reporter's   |               |
|     |    | Portability and  |         term results |               |
|     |    | Accountability   |         in           |               |
|     |    | Act.             |                      |               |
|     |    |                  |        fragmentation |               |
|     |    | Although this    |         of           |               |
|     |    | proposed rule    |         essentially  |               |
|     |    | does not impose  |         similar      |               |
|     |    | reporting        |         information  |               |
|     |    | requirements on  |         with         |               |
|     |    | health care      |         consequent   |               |
|     |    | providers, the   |         loss of      |               |
|     |    | agency           |         clinical     |               |
|     |    | recognizes that  |         utility.     |               |
|     |    | clinicians,      |         Harmonized   |               |
|     |    | medical centers, |         definitions  |               |
|     |    | hospitals and    |         of terms,    |               |
|     |    | others may       |         ideally      |               |
|     |    | report safety    |         agreed       |               |
|     |    | information to   |                      |               |
|     |    | pharmaceutical   |     internationally, |               |
|     |    | companies. These |         should be    |               |
|     |    | third parties    |         developed,   |               |
|     |    | may employ       |         as suggested |               |
|     |    | clinical         |         elsewhere by |               |
|     |    | terminology      |         FDA, to      |               |
|     |    | standards that   |         ensure the   |               |
|     |    | differ from      |         maximum      |               |
|     |    | those proposed   |         possible     |               |
|     |    | here. Therefore, |         accuracy and |               |
|     |    | the agency       |         consistency  |               |
|     |    | invites comment  |         in the       |               |
|     |    | on the           |                      |               |
|     |    | unintended       |       classification |               |
|     |    | potential impact |         of adverse   |               |
|     |    | of this proposed |         events and   |               |
|     |    | rule on those    |         cases.       |               |
|     |    | parties not      |                      |               |
|     |    | subject to FDA's | -   Possible         |               |
|     |    | safety reporting |     solutions for    |               |
|     |    | requirements.    |     these data       |               |
|     |    | The agency also  |     quality issues   |               |
|     |    | invites comment  |     include:         |               |
|     |    | on the potential |                      |               |
|     |    | strategies and   |     -   Permitting   |               |
|     |    | approaches for   |                      |               |
|     |    | facilitating     |        manufacturers |               |
|     |    | seamless         |         to codify    |               |
|     |    | cross-standard   |         such cases   |               |
|     |    | communications,  |         for analysis |               |
|     |    | such as mapping  |         using        |               |
|     |    | between          |         available    |               |
|     |    | alternative      |         event        |               |
|     |    | terminologies    |         definitions  |               |
|     |    | and MedDRA.      |         (cf. ICH E2B |               |
|     |    |                  |         field        |               |
|     |    |                  |         B.5.3 -      |               |
|     |    |                  |         Sender\'s    |               |
|     |    |                  |                      |               |
|     |    |                  |   diagnosis/syndrome |               |
|     |    |                  |         and/or       |               |
|     |    |                  |                      |               |
|     |    |                  |     reclassification |               |
|     |    |                  |         of           |               |
|     |    |                  |                      |               |
|     |    |                  |     reaction/event), |               |
|     |    |                  |         while also   |               |
|     |    |                  |         capturing    |               |
|     |    |                  |         and          |               |
|     |    |                  |         displaying   |               |
|     |    |                  |         the          |               |
|     |    |                  |         reporter's   |               |
|     |    |                  |         verbatim     |               |
|     |    |                  |         term.        |               |
|     |    |                  |                      |               |
|     |    |                  |     -   Applying an  |               |
|     |    |                  |         appropriate  |               |
|     |    |                  |         diagnostic   |               |
|     |    |                  |         term, even   |               |
|     |    |                  |         if not       |               |
|     |    |                  |         specifically |               |
|     |    |                  |         reported,    |               |
|     |    |                  |         when         |               |
|     |    |                  |         reported     |               |
|     |    |                  |         signs,       |               |
|     |    |                  |         symptoms,    |               |
|     |    |                  |         and/or       |               |
|     |    |                  |         treatment    |               |
|     |    |                  |         strongly     |               |
|     |    |                  |         suggest that |               |
|     |    |                  |         diagnosis    |               |
|     |    |                  |         (e.g.        |               |
|     |    |                  |         myocardial   |               |
|     |    |                  |         infarction   |               |
|     |    |                  |         when chest   |               |
|     |    |                  |         pain,        |               |
|     |    |                  |         elevated CK, |               |
|     |    |                  |         abnormal     |               |
|     |    |                  |         ECG, and     |               |
|     |    |                  |         thrombolytic |               |
|     |    |                  |         treatment    |               |
|     |    |                  |         are          |               |
|     |    |                  |         reported).   |               |
|     |    |                  |                      |               |
|     |    |                  |     -   Basing       |               |
|     |    |                  |         safety       |               |
|     |    |                  |         analyses on  |               |
|     |    |                  |         the          |               |
|     |    |                  |                      |               |
|     |    |                  |       manufacturer's |               |
|     |    |                  |         diagnosis    |               |
|     |    |                  |         terms, which |               |
|     |    |                  |         are defined  |               |
|     |    |                  |         and          |               |
|     |    |                  |         consistent,  |               |
|     |    |                  |         to avoid     |               |
|     |    |                  |         erroneous    |               |
|     |    |                  |         inclusion of |               |
|     |    |                  |         re           |               |
|     |    |                  | porter-misclassified |               |
|     |    |                  |         or vague     |               |
|     |    |                  |         terms that   |               |
|     |    |                  |         are not      |               |
|     |    |                  |         clinically   |               |
|     |    |                  |         useful.      |               |
+-----+----+------------------+----------------------+---------------+
| I   | 1  | "These summary   | By inference from    | Insert        |
| II. | 24 | tabulations \[of | the rest of the      | wording to    |
| E.2 | 40 | individual case  | proposed rule, the   | clarify FDA's |
|     |    | safety reports   | SADR term level      | position on   |
|     |    | in the PSUR\]    | represented in these | summary       |
|     |    | would be made up | tabulations would be | tables,       |
|     |    | of lists by body | the PT. However, if  | including use |
|     |    | system or        | "rolling up" the     | of other      |
|     |    | standard organ   | counts of            | hierarchical  |
|     |    | system           | occurrences to the   | terms (HLGT   |
|     |    | classification   | HLT or even HLGT     | and HLT) and  |
|     |    | scheme (*e.g.*,  | level provides a     | use of        |
|     |    | cardiovascular,  | better grouping of   | primary SOC   |
|     |    | central nervous  | concepts that may    | allocation    |
|     |    | system,          | highlight a          | and secondary |
|     |    | endocrine,       | potential safety     | SOC analyses  |
|     |    | renal) of all    | signal, what is the  |               |
|     |    | SADR terms and   | FDA's position about |               |
|     |    | counts of        | a company providing  |               |
|     |    | occurrences."    | supplemental         |               |
|     |    |                  | tabulations          |               |
|     |    |                  | organized in this    |               |
|     |    |                  | fashion? Also,       |               |
|     |    |                  | industry needs to    |               |
|     |    |                  | hear from the FDA    |               |
|     |    |                  | that these summary   |               |
|     |    |                  | tabulations will be  |               |
|     |    |                  | displayed using the  |               |
|     |    |                  | [                    |               |
|     |    |                  | primary]{.underline} |               |
|     |    |                  | SOC allocation for   |               |
|     |    |                  | individual PTs as    |               |
|     |    |                  | provided in the      |               |
|     |    |                  | standard MedDRA      |               |
|     |    |                  | terminology (*i.e.*, |               |
|     |    |                  | not a primary SOC    |               |
|     |    |                  | allocation defined   |               |
|     |    |                  | by the company). To  |               |
|     |    |                  | that end, FDA should |               |
|     |    |                  | clarify when a       |               |
|     |    |                  | secondary SOC        |               |
|     |    |                  | analysis may be an   |               |
|     |    |                  | appropriate          |               |
|     |    |                  | alternative way to   |               |
|     |    |                  | present data.        |               |
+-----+----+------------------+----------------------+---------------+
| I   | 1  | ICH has          | As previously stated | Wording to    |
| II. | 24 | developed an     | (comment on p.       | address the   |
| F.2 | 44 | international    | 12410, Section I),   | effect of     |
|     |  - | medical          | the proposed rule    | MedDRA        |
|     | 5  | terminology,     | does not consider    | updates on    |
|     |    | MedDRA (the      | the imminent         | follow-up     |
|     |    | medical          | implementation of    | paper reports |
|     |    | dictionary for   | electronic           | should be     |
|     |    | regulatory       | submission of ICSRs  | considered.   |
|     |    | activities), to  | via E2B and M2. The  |               |
|     |    | support the      | effect of MedDRA     | FDA should    |
|     |    | computerization  | updates on follow-up | offer         |
|     |    | and transmission | paper reports should | guidance to   |
|     |    | of information   | be considered. For   | industry to   |
|     |    | related to many  | example, if a MedDRA | avoid         |
|     |    | aspects of the   | PT used to codify an | unnecessary   |
|     |    | regulation of    | event is demoted to  | r             |
|     |    | medical products | a LLT, would a       | ecodification |
|     |    | (ICH M1). Use of | follow-up report     | while         |
|     |    | a single medical | containing a new     | maintaining   |
|     |    | terminology      | concept but          | appropriate   |
|     |    | internationally  | providing no         | specificity   |
|     |    | would facilitate | additional           | and           |
|     |    | global           | information          | dictionary    |
|     |    | communication of | concerning the       | currency for  |
|     |    | safety           | previously reported  | retrieval     |
|     |    | information for  | concept be expected  | purposes.     |
|     |    | human drug and   | to show the          |               |
|     |    | biological       | previously reported  | Remove        |
|     |    | products (see    | but unavailable PT,  | references to |
|     |    | section II.B.1   | or a new PT which    | any specific  |
|     |    | of this          | has replaced it,     | entity (e.g., |
|     |    | document).       | despite the absence  | TRW) in the   |
|     |    |                  | of any new           | role of the   |
|     |    | Proposed §§      | information? FDA     | maintenance   |
|     |    | 310.305(d)(2),   | should offer         | organization  |
|     |    | 3                | guidance to industry | and instead   |
|     |    | 14.80(c)(4)(ii), | to avoid unnecessary | include a     |
|     |    | and              | recodification while | reference to  |
|     |    | 600.80(c)(4)(ii) | maintaining          | where such    |
|     |    | would require    | appropriate          | information   |
|     |    | that each SADR   | specificity and      | can be        |
|     |    | in an individual | dictionary currency  | ascertained   |
|     |    | case safety      | for retrieval        | on the FDA's  |
|     |    | report be coded  | purposes.            | website.      |
|     |    | on the FDA Form  |                      |               |
|     |    | 3500A, CIOMS I   | See comment on p     | FDA should    |
|     |    | Form, or VAERS   | 12454, Section V.D.  | provide       |
|     |    | Form using the   | regarding the use of | guidance on   |
|     |    | appropriate      | the term "latest     | the           |
|     |    | ''preferred      | version of MedDRA."  | appropriate   |
|     |    | term'' in the    |                      | method of     |
|     |    | latest version   | See comment on pp    | reporting in  |
|     |    | of MedDRA in use | 12413-4, Section     | those         |
|     |    | at the time the  | II.B.3.a. regarding  | circumstances |
|     |    | manufacturer or  | the codification of  | where a       |
|     |    | applicant        | medication errors.   | company has   |
|     |    | becomes aware of |                      | no database   |
|     |    | the individual   | The final rule       | or has a very |
|     |    | case safety      | should not mention   | small number  |
|     |    | report. FDA is   | any specific         | of reports.   |
|     |    | proposing to     | information          | Perhaps the   |
|     |    | require use of   | regarding the entity | FDA should    |
|     |    | MedDRA to be     | responsible for the  | consider the  |
|     |    | consistent with  | functions of the     | approach      |
|     |    | ICH M1.          | MSSO. Competitive    | taken in the  |
|     |    |                  | bidding for the      | EMEA's        |
|     |    | Proposed §§      | MedDRA maintenance   | E             |
|     |    | 310.305(d)(2),   | contract is part of  | udraVigilance |
|     |    | 3                | the ICH maintenance  | system.       |
|     |    | 14.80(c)(4)(ii), | strategy for MedDRA, |               |
|     |    | and              | allowing the MedDRA  |               |
|     |    | 600.80(c)(4)(ii) | Management Board to  |               |
|     |    | would also       | replace any service  |               |
|     |    | require that     | provider that does   |               |
|     |    | each individual  | not adequately       |               |
|     |    | case safety      | support its users.   |               |
|     |    | report of a      | However, even if the |               |
|     |    | medication error | MSSO contract were   |               |
|     |    | be coded both as | to remain with the   |               |
|     |    | a medication     | same service         |               |
|     |    | error and, if    | provider             |               |
|     |    | applicable, with | indefinitely,        |               |
|     |    | the preferred    | business changes may |               |
|     |    | term for any     | still render the     |               |
|     |    | SADRs associated | information          |               |
|     |    | with the         | obsolete, as shown   |               |
|     |    | medication       | by the MSSO          |               |
|     |    | error. The       | corporate sponsor's  |               |
|     |    | proposal         | recent name change   |               |
|     |    | clarifies how    | following a merger.  |               |
|     |    | actual and       | It would be more     |               |
|     |    | potential        | appropriate to       |               |
|     |    | medication       | include in the final |               |
|     |    | errors would be  | rule a reference to  |               |
|     |    | coded.           | the FDA web site     |               |
|     |    |                  | where a current link |               |
|     |    | MedDRA must be   | to the MSSO can be   |               |
|     |    | licensed for a   | found.               |               |
|     |    | fee from an      |                      |               |
|     |    | international    | FDA is correct in    |               |
|     |    | MSSO. TRW was    | believing that       |               |
|     |    | selected as the  | MedDRA is being      |               |
|     |    | MSSO by ICH and  | enthusiastically     |               |
|     |    | the              | adopted by the       |               |
|     |    | International    | majority of          |               |
|     |    | Federation of    | pharmaceutical       |               |
|     |    | Pharmaceutical   | companies. As        |               |
|     |    | Manufacturers    | previously pointed   |               |
|     |    | Associations     | out, many companies  |               |
|     |    | (IFPMA) through  | have already         |               |
|     |    | a contract       | implemented MedDRA   |               |
|     |    | process that     | voluntarily for both |               |
|     |    | involved bids    | marketed and         |               |
|     |    | from companies   | investigational      |               |
|     |    | globally. FDA    | products. Given the  |               |
|     |    | was involved in  | general recognition  |               |
|     |    | this process.    | of MedDRA's overall  |               |
|     |    | The costs that   | benefits and value,  |               |
|     |    | would be imposed | the circumstances in |               |
|     |    | on industry to   | which use of MedDRA  |               |
|     |    | license MedDRA   | might cause economic |               |
|     |    | was a            | hardship should be   |               |
|     |    | consideration in | better defined. Any  |               |
|     |    | the selection of | entity that          |               |
|     |    | the MSSO.        | maintains a safety   |               |
|     |    |                  | database may         |               |
|     |    | Companies may    | reasonably be        |               |
|     |    | license the      | expected to use      |               |
|     |    | latest version   | MedDRA in its        |               |
|     |    | of MedDRA 5.1 by | reports to FDA. Only |               |
|     |    | contacting TRW   | organizations that   |               |
|     |    | in Reston, VA,   | have no safety       |               |
|     |    | toll free number | reporting            |               |
|     |    | 877--258--8280   | responsibilities     |               |
|     |    | (703--345--7799  | under this proposed  |               |
|     |    | in Washington,   | rule, or that have a |               |
|     |    | DC area), FAX    | reporting            |               |
|     |    | 703--345-- 7755, | requirement but      |               |
|     |    | e-mail           | insufficient numbers |               |
|     |    | subscrib         | of reports to        |               |
|     |    | @meddramsso.com, | require a safety     |               |
|     |    | Internet at      | database of any      |               |
|     |    | www              | type, should be      |               |
|     |    | .meddramsso.com. | exempt from using    |               |
|     |    | Updated versions | MedDRA. However, FDA |               |
|     |    | of MedDRA will   | should provide       |               |
|     |    | be provided to   | guidance on the      |               |
|     |    | subscribers as   | appropriate method   |               |
|     |    | part of the      | of reporting in      |               |
|     |    | annual licensing | these circumstances. |               |
|     |    | fee.             |                      |               |
|     |    |                  | The MSSO has a pilot |               |
|     |    | MedDRA is a      | program in place     |               |
|     |    | hierarchical     | with the EMEA to     |               |
|     |    | system composed  | provide access to    |               |
|     |    | of various       | MedDRA within the    |               |
|     |    | levels of        | EMEA's               |               |
|     |    | terminology      | EudraVigilance       |               |
|     |    | (i.e., system    | system. The EMEA     |               |
|     |    | organ class,     | developed the tool   |               |
|     |    | high level group | so that all reports, |               |
|     |    | term, high level | regardless of their  |               |
|     |    | term, preferred  | financial status,    |               |
|     |    | term, lower      | could provide ICSR   |               |
|     |    | level term). The | reports to the EMEA. |               |
|     |    | agency is        | If a company is      |               |
|     |    | proposing to     | truly a small or     |               |
|     |    | require use of   | micro sized          |               |
|     |    | the preferred    | enterprise and they  |               |
|     |    | term for         | have a small number  |               |
|     |    | reporting to FDA | of reports per year, |               |
|     |    | because each     | there is no charge   |               |
|     |    | preferred term   | for the use of       |               |
|     |    | represents a     | MedDRA. This allows  |               |
|     |    | unique medical   | for all data,        |               |
|     |    | concept accepted | regardless of the    |               |
|     |    | internationally, | source, to be        |               |
|     |    | which will aid   | reported in MedDRA   |               |
|     |    | in the           | at a minimal cost to |               |
|     |    | transmission and | the company.         |               |
|     |    | translation of   |                      |               |
|     |    | reports from     | Please note that     |               |
|     |    | various parts of | there may be a       |               |
|     |    | the world. The   | slight misstatement  |               |
|     |    | preferred term   | in the proposed      |               |
|     |    | provides         | rule. Preferred      |               |
|     |    | medically        | Terms (PTs) do       |               |
|     |    | validated        | **not** represent    |               |
|     |    | representations  | colloquial concepts; |               |
|     |    | of colloquial    | such concepts are    |               |
|     |    | terms, which     | found at the Lowest  |               |
|     |    | will result in   | Level Term (LLT)     |               |
|     |    | fewer            | level.               |               |
|     |    | mi               |                      |               |
|     |    | srepresentations |                      |               |
|     |    | and              |                      |               |
|     |    | m                |                      |               |
|     |    | isunderstandings |                      |               |
|     |    | of colloquial    |                      |               |
|     |    | reports from     |                      |               |
|     |    | various parts of |                      |               |
|     |    | the world. The   |                      |               |
|     |    | preferred term   |                      |               |
|     |    | also provides    |                      |               |
|     |    | medically        |                      |               |
|     |    | validated        |                      |               |
|     |    | representations  |                      |               |
|     |    | of non-current   |                      |               |
|     |    | terms in other   |                      |               |
|     |    | previously       |                      |               |
|     |    | widely used      |                      |               |
|     |    | coding           |                      |               |
|     |    | terminologies    |                      |               |
|     |    | such as COSTART  |                      |               |
|     |    | and WHOART.      |                      |               |
|     |    |                  |                      |               |
|     |    | FDA believes     |                      |               |
|     |    | that use of      |                      |               |
|     |    | MedDRA, a        |                      |               |
|     |    | standardized     |                      |               |
|     |    | medical          |                      |               |
|     |    | terminology,     |                      |               |
|     |    | will be welcomed |                      |               |
|     |    | by most of       |                      |               |
|     |    | industry.        |                      |               |
|     |    | However, for     |                      |               |
|     |    | some             |                      |               |
|     |    | manufacturers    |                      |               |
|     |    | and applicants,  |                      |               |
|     |    | use of MedDRA    |                      |               |
|     |    | may result in a  |                      |               |
|     |    | significant      |                      |               |
|     |    | economic         |                      |               |
|     |    | hardship.        |                      |               |
|     |    | Applicants may   |                      |               |
|     |    | request, under   |                      |               |
|     |    | §§ 314.90 or     |                      |               |
|     |    | 600.90, that FDA |                      |               |
|     |    | waive the        |                      |               |
|     |    | requirement that |                      |               |
|     |    | each SADR in an  |                      |               |
|     |    | individual case  |                      |               |
|     |    | safety report be |                      |               |
|     |    | coded using      |                      |               |
|     |    | MedDRA. If FDA   |                      |               |
|     |    | finds that this  |                      |               |
|     |    | requirement is   |                      |               |
|     |    | economically     |                      |               |
|     |    | burdensome for a |                      |               |
|     |    | small company,   |                      |               |
|     |    | the agency       |                      |               |
|     |    | intends to grant |                      |               |
|     |    | the company a    |                      |               |
|     |    | waiver. A large  |                      |               |
|     |    | company may also |                      |               |
|     |    | be granted a     |                      |               |
|     |    | waiver if, for   |                      |               |
|     |    | instance, it     |                      |               |
|     |    | only markets a   |                      |               |
|     |    | single product   |                      |               |
|     |    | that generates a |                      |               |
|     |    | few safety       |                      |               |
|     |    | reports a year.  |                      |               |
|     |    | FDA intends to   |                      |               |
|     |    | grant all        |                      |               |
|     |    | reasonable       |                      |               |
|     |    | waiver requests. |                      |               |
|     |    | This             |                      |               |
|     |    | determination    |                      |               |
|     |    | will be made on  |                      |               |
|     |    | a case-by-case   |                      |               |
|     |    | basis.           |                      |               |
+-----+----+------------------+----------------------+---------------+
| V.C | 1  | This rule would  | The replacement of   | FDA should    |
|     | 24 | ...require the   | multiple             | include,      |
|     | 51 | use of MedDRA, a | dictionaries by      | either in the |
|     |  - | medical          | MedDRA does create   | final rule    |
|     | 2  | dictionary       | the potential for    | itself or in  |
|     |    | developed by the | enhanced retrieval   | a supporting  |
|     |    | ICH, in coding   | and analysis of      | guidance, a   |
|     |    | SADR terms.      | safety data.         | reference to  |
|     |    | MedDRA will      | However, the use of  | the ICH       |
|     |    | provide a        | MedDRA cannot *per   | MedDRA Term   |
|     |    | uniform,         | se* improve the      | Selection:    |
|     |    | consistent and   | quality of safety    | Points to     |
|     |    | specific         | analyses, which      | Consider      |
|     |    | presentation of  | depends on multiple  | document.     |
|     |    | medical terms.   | other steps and      |               |
|     |    | By eliminating   | processes throughout |               |
|     |    | the use of       | the collection,      |               |
|     |    | multiple         | entry, and analysis  |               |
|     |    | dictionaries,    | of safety data.      |               |
|     |    | MedDRA would     | Methods and          |               |
|     |    | facilitate the   | procedures for       |               |
|     |    | retrieval,       | improving the        |               |
|     |    | presentation,    | accuracy and         |               |
|     |    | and              | completeness of      |               |
|     |    | summarization of | clinical information |               |
|     |    | SADR data and    | relevant to SADRs    |               |
|     |    | enhance the      | are recommended      |               |
|     |    | global           | elsewhere in the     |               |
|     |    | communication    | proposed rule, but   |               |
|     |    | and acceptance   | there is no mention  |               |
|     |    | of safety        | of the need for      |               |
|     |    | information and  | uniform application  |               |
|     |    | reports. The use | of accepted          |               |
|     |    | of a single      | standards to create  |               |
|     |    | dictionary will  | clinically           |               |
|     |    | substantially    | meaningful codified  |               |
|     |    | upgrade the      | data from individual |               |
|     |    | quality of       | case reports (see    |               |
|     |    | safety analysis  | also comment on pp.  |               |
|     |    | by incorporating | 12412-3, Section     |               |
|     |    | uniformity of    | II.B.I). FDA should  |               |
|     |    | terms. MedDRA    | thus include, either |               |
|     |    | will aid in more | in the final rule    |               |
|     |    | expeditious and  | itself or in a       |               |
|     |    | broader          | supporting guidance, |               |
|     |    | international    | a reference to the   |               |
|     |    | drug use         | ICH MedDRA Term      |               |
|     |    | comparisons      | Selection: Points to |               |
|     |    | within a class,  | Consider document,   |               |
|     |    | and prescribing  | which provides       |               |
|     |    | and use          | helpful advice on    |               |
|     |    | decisions.       | developing           |               |
|     |    | Providing more   | reasonably uniform   |               |
|     |    | complete         | approaches to safety |               |
|     |    | information and  | data codification.   |               |
|     |    | more timely      | Without (relatively) |               |
|     |    | safety           | uniform codification |               |
|     |    | assessments      | practices among the  |               |
|     |    | would enhance    | many users of MedDRA |               |
|     |    | the ability of   | worldwide, agreed    |               |
|     |    | the              | definitions and      |               |
|     |    | manufacturers to | criteria for         |               |
|     |    | more quickly     | categorizing         |               |
|     |    | identify,        | medically important  |               |
|     |    | monitor, and     | terms, or methods to |               |
|     |    | communicate the  | mitigate the         |               |
|     |    | potential risks  | confounding effects  |               |
|     |    | and benefits of  | of reporter          |               |
|     |    | marketed drugs   | miscategorization,   |               |
|     |    | and biologics.   | the goal of          |               |
|     |    |                  | comparing the safety |               |
|     |    | *[p 12452,       | profiles of similar  |               |
|     |    | Section          | products using data  |               |
|     |    | V.C              | codified by multiple |               |
|     |    | .2]{.underline}* | reporting entities   |               |
|     |    |                  | is not realistically |               |
|     |    | The proposed     | achievable. The      |               |
|     |    | rule would also  | challenge of         |               |
|     |    | require the use  | achieving an         |               |
|     |    | of MedDRA, a     | acceptable level of  |               |
|     |    | single, medical  | uniformity will      |               |
|     |    | terminology      | become even more     |               |
|     |    | developed by ICH | acute once the       |               |
|     |    | that can be used | majority of SADRs    |               |
|     |    | for the coding   | are entered into     |               |
|     |    | of SADR terms.   | AERS by direct       |               |
|     |    | MedDRA is a      | electronic uploading |               |
|     |    | broad-based      | from multiple        |               |
|     |    | dictionary,      | companies.           |               |
|     |    | developed for    |                      |               |
|     |    | international    |                      |               |
|     |    | use, that        |                      |               |
|     |    | combines both    |                      |               |
|     |    | SADR and         |                      |               |
|     |    | morbidity        |                      |               |
|     |    | terminology to   |                      |               |
|     |    | provide a        |                      |               |
|     |    | uniform,         |                      |               |
|     |    | consistent, and  |                      |               |
|     |    | specific         |                      |               |
|     |    | presentation of  |                      |               |
|     |    | medical terms.   |                      |               |
|     |    | By eliminating   |                      |               |
|     |    | the use of       |                      |               |
|     |    | multiple         |                      |               |
|     |    | dictionaries,    |                      |               |
|     |    | MedDRA would     |                      |               |
|     |    | facilitate the   |                      |               |
|     |    | retrieval,       |                      |               |
|     |    | presentation,    |                      |               |
|     |    | and              |                      |               |
|     |    | summarization of |                      |               |
|     |    | SADR data and    |                      |               |
|     |    | enhance the      |                      |               |
|     |    | global           |                      |               |
|     |    | communication    |                      |               |
|     |    | and acceptance   |                      |               |
|     |    | of safety        |                      |               |
|     |    | information and  |                      |               |
|     |    | reports. In      |                      |               |
|     |    | addition, the    |                      |               |
|     |    | use of a single  |                      |               |
|     |    | comprehensive    |                      |               |
|     |    | medical          |                      |               |
|     |    | dictionary by    |                      |               |
|     |    | drug safety      |                      |               |
|     |    | reporters and    |                      |               |
|     |    | reviewers would  |                      |               |
|     |    | substantially    |                      |               |
|     |    | upgrade the      |                      |               |
|     |    | quality of       |                      |               |
|     |    | safety analysis  |                      |               |
|     |    | by incorporating |                      |               |
|     |    | uniformity of    |                      |               |
|     |    | terms.           |                      |               |
|     |    | Standardizing    |                      |               |
|     |    | the terms and    |                      |               |
|     |    | improving the    |                      |               |
|     |    | quality of the   |                      |               |
|     |    | roughly 250,000  |                      |               |
|     |    | safety reports   |                      |               |
|     |    | submitted        |                      |               |
|     |    | annually to FDA  |                      |               |
|     |    | would lead to    |                      |               |
|     |    | better and more  |                      |               |
|     |    | timely safety    |                      |               |
|     |    | assessments and  |                      |               |
|     |    | to improved      |                      |               |
|     |    | communication of |                      |               |
|     |    | risk             |                      |               |
|     |    | information. The |                      |               |
|     |    | widespread use   |                      |               |
|     |    | and acceptance   |                      |               |
|     |    | of standardized  |                      |               |
|     |    | SADR information |                      |               |
|     |    | by regulators    |                      |               |
|     |    | would ultimately |                      |               |
|     |    | enhance drug     |                      |               |
|     |    | comparisons      |                      |               |
|     |    | within a class   |                      |               |
|     |    | and drug         |                      |               |
|     |    | prescribing and  |                      |               |
|     |    | use decisions.   |                      |               |
+-----+----+------------------+----------------------+---------------+
| V   | 1  | Some companies   | The cost saving from |               |
| .C. | 24 | noted that they  | implementing MedDRA  |               |
| 4.d | 53 | would convert    | in clinical trial    |               |
|     |    | medical terms    | databases depends on |               |
|     |    | from clinical    | multiple factors,    |               |
|     |    | trials to MedDRA | including product    |               |
|     |    | whether or not   | spectrum, company    |               |
|     |    | it was required  | size, organizational |               |
|     |    | by FDA. Assuming | structure,           |               |
|     |    | that this        | dictionary           |               |
|     |    | transition will  | management and       |               |
|     |    | gradually apply  | codification         |               |
|     |    | to future        | methods, number of   |               |
|     |    | clinical trials, | partnerships         |               |
|     |    | a single medical | involving data       |               |
|     |    | terminology,     | exchange, etc.       |               |
|     |    | internationally  |                      |               |
|     |    | developed,       |                      |               |
|     |    | accepted, and    |                      |               |
|     |    | applied, would   |                      |               |
|     |    | allow companies  |                      |               |
|     |    | to more easily   |                      |               |
|     |    | transmit,        |                      |               |
|     |    | integrate, and   |                      |               |
|     |    | analyze clinical |                      |               |
|     |    | trial data from  |                      |               |
|     |    | global sites.    |                      |               |
|     |    | Subsequent       |                      |               |
|     |    | reductions in    |                      |               |
|     |    | time and         |                      |               |
|     |    | resources would  |                      |               |
|     |    | contribute to    |                      |               |
|     |    | reduced costs    |                      |               |
|     |    | during drug      |                      |               |
|     |    | development.     |                      |               |
|     |    | Based on input   |                      |               |
|     |    | from industry,   |                      |               |
|     |    | ERG developed a  |                      |               |
|     |    | narrow focus of  |                      |               |
|     |    | savings          |                      |               |
|     |    | associated with  |                      |               |
|     |    | clinical trial   |                      |               |
|     |    | data management  |                      |               |
|     |    | valued at \$7.2  |                      |               |
|     |    | million          |                      |               |
|     |    | annually.        |                      |               |
+-----+----+------------------+----------------------+---------------+
| V.D | 1  | Each SADR in a   | The concept of       | FDA should    |
|     | 24 | postmarketing    | "latest version of   | define        |
|     | 54 | individual case  | MedDRA" requires     | "latest       |
|     |    | safety report    | definition. The      | version" in   |
|     |    | for human drugs  | MedDRA Management    | terms of the  |
|     |    | and biologics    | Board has proposed   | agreed        |
|     |    | must be coded    | that each            | international |
|     |    | using the        | semi-annual version  | i             |
|     |    | appropriate      | update should be     | mplementation |
|     |    | ''preferred      | implemented by all   | date, rather  |
|     |    | term'' in the    | MedDRA users 60 days | than the      |
|     |    | latest version   | after release. If    | release date. |
|     |    | of MedDRA.       | this proposal is     |               |
|     |    |                  | adopted, SADR        |               |
|     |    |                  | reports submitted    |               |
|     |    |                  | during the 60-day    |               |
|     |    |                  | period between the   |               |
|     |    |                  | MSSO release date    |               |
|     |    |                  | and the              |               |
|     |    |                  | international        |               |
|     |    |                  | implementation date  |               |
|     |    |                  | will not in fact be  |               |
|     |    |                  | codified in the      |               |
|     |    |                  | "latest" version. To |               |
|     |    |                  | avoid ambiguity or   |               |
|     |    |                  | confusion, e.g. by   |               |
|     |    |                  | an FDA investigator  |               |
|     |    |                  | conducting a         |               |
|     |    |                  | manufacturer audit,  |               |
|     |    |                  | FDA should define    |               |
|     |    |                  | "latest version" in  |               |
|     |    |                  | terms of the agreed  |               |
|     |    |                  | international        |               |
|     |    |                  | implementation date, |               |
|     |    |                  | rather than the      |               |
|     |    |                  | release date.        |               |
|     |    |                  |                      |               |
|     |    |                  | XSee also comment on |               |
|     |    |                  | update reports (pp   |               |
|     |    |                  | 12444-5, Section     |               |
|     |    |                  | III.F.2.)            |               |
+-----+----+------------------+----------------------+---------------+
| V   | 1  | "...the proposed | FDA's use of the     | The proposed  |
| .D. | 24 | rule requires    | phrase "MedDRA code" | rule should   |
| 1.b | 55 | that every       | is misleading. Every | be clear to   |
|     |    | individual case  | MedDRA text term has | make a        |
|     |    | safety report... | a corresponding      | distinction   |
|     |    | be assigned an   | 8-digit numeric      | between a     |
|     |    | appropriate      | code, which is used  | MedDRA "term" |
|     |    | MedDRA *code*"   | for database and     | and a MedDRA  |
|     |    | \[Italics        | other IT purposes;   | "code".       |
|     |    | added\]          | however, it appears  | MedDRA        |
|     |    |                  | that in this context | "codes" are   |
|     |    | "Regulatory      | FDA means that every | unique,       |
|     |    | affairs          | ICSR should be       | 8-digit       |
|     |    | personnel... may | assigned (an)        | numbers       |
|     |    | spend additional | appropriate MedDRA   | (no           |
|     |    | time assigning   | term(s).             | n-expressive) |
|     |    | the MedDRA       |                      | associated    |
|     |    | *code*... "      |                      | with each     |
|     |    | \[Italics        |                      | MedDRA term.  |
|     |    | added\]          |                      |               |
|     |    |                  |                      |               |
|     |    | "...report must  |                      |               |
|     |    | contain a full   |                      |               |
|     |    | data set,        |                      |               |
|     |    | including MedDRA |                      |               |
|     |    | *codes*... "     |                      |               |
|     |    | \[Italics        |                      |               |
|     |    | added\]          |                      |               |
+-----+----+------------------+----------------------+---------------+
| V   | 1  | FDA contracted   | This section,        |               |
| .D. | 24 | with ERG to      | derived from the ERG |               |
| 2.a | 59 | estimate the     | report dated 5       |               |
|     |  - | industry cost of | January 2001,        |               |
|     | 60 | using MedDRA     | contains several     |               |
|     |    | terms to code    | implicit or explicit |               |
|     |    | individual case  | assumptions of       |               |
|     |    | safety           | unproven validity,   |               |
|     |    | reports...       | viz.                 |               |
|     |    |                  |                      |               |
|     |    | Limitations on   | 1.  The total amount |               |
|     |    | ERG cost         |     of work, and     |               |
|     |    | estimation       |     therefore the    |               |
|     |    | include the      |     cost, associated |               |
|     |    | complexities     |     with MedDRA      |               |
|     |    | associated with  |     implementation   |               |
|     |    | firms' abilities |     and maintenance  |               |
|     |    | to separate      |     is directly      |               |
|     |    | incremental      |     proportional to  |               |
|     |    | costs from       |     the size and     |               |
|     |    | factors that     |     complexity of    |               |
|     |    | substantially    |     the organization |               |
|     |    | influence        |                      |               |
|     |    | expenditures,    | 2.  Most small firms |               |
|     |    | such as          |     (e.g. blood      |               |
|     |    | integrating      |     facilities) will |               |
|     |    | operations of    |     not have         |               |
|     |    | one or more      |     databases        |               |
|     |    | newly merged     |     requiring        |               |
|     |    | corporations,    |     conversion       |               |
|     |    | isolating U.S.   |                      |               |
|     |    | corporate        | 3.  Many small firms |               |
|     |    | policies and     |     will use         |               |
|     |    | operations from  |     external         |               |
|     |    | global corporate |     agencies, e.g.   |               |
|     |    | policies and     |     CROs, to handle  |               |
|     |    | operations, and  |     their regulatory |               |
|     |    | reaching         |     reporting        |               |
|     |    | consensus on the |     obligations      |               |
|     |    | extent and       |                      |               |
|     |    | timing of the    | 4.  Autoencoding     |               |
|     |    | conversion of    |     software is      |               |
|     |    | historical SADRs |     required only    |               |
|     |    | and data.        |     for legacy data  |               |
|     |    |                  |     conversion       |               |
|     |    | V.D.2.a.         |                      |               |
|     |    | One-time costs   | 5.  Standard         |               |
|     |    |                  |     operating        |               |
|     |    | V.D.2.a.i.       |     procedures       |               |
|     |    | Planning and     |     (SOPs) for small |               |
|     |    | coordination.    |     firms are much   |               |
|     |    |                  |     less complex and |               |
|     |    | Companies will   |     require less     |               |
|     |    | need to allocate |     revision than    |               |
|     |    | time to plan and |     those for large  |               |
|     |    | coordinate the   |     firms            |               |
|     |    | conversion of    |                      |               |
|     |    | MedDRA across    | 6.  Database         |               |
|     |    | their affected   |     complexity and   |               |
|     |    | operations.      |     validation are   |               |
|     |    | Planning costs   |     proportional to  |               |
|     |    | are affected by  |     company size     |               |
|     |    | the extent of    |                      |               |
|     |    | decentralization | 7.  Drugs and        |               |
|     |    | of coding and    |     biologics firms  |               |
|     |    | p                |     of comparable    |               |
|     |    | harmacovigilance |     size and         |               |
|     |    | work within the  |     complexity will  |               |
|     |    | corporate        |     have different   |               |
|     |    | structure.       |     burdens of       |               |
|     |    | Managers for     |     effort           |               |
|     |    | drug and         |                      |               |
|     |    | biologics firms  | 8.  Blood            |               |
|     |    | are expected to  |     facilities,      |               |
|     |    | spend from 240   |     newly required   |               |
|     |    | hours for very   |     to report many   |               |
|     |    | small firms to   |     more events than |               |
|     |    | 1,400 hours for  |     previously, will |               |
|     |    | very large firms |     experience       |               |
|     |    | (greater than    |     little impact    |               |
|     |    | 750 or 500       |     and will be able |               |
|     |    | employees        |     to use a very    |               |
|     |    | respectively for |     limited subset   |               |
|     |    | drug and         |     of MedDRA terms  |               |
|     |    | biologics firms) |     for              |               |
|     |    | for planning and |     categorization   |               |
|     |    | coordination.    |     of serious       |               |
|     |    | Costs per        |     events following |               |
|     |    | company ranged   |     transfusion.     |               |
|     |    | from \$10,800 to |                      |               |
|     |    | \$64,500 for     | MSSO makes the       |               |
|     |    | drug and         | following points:    |               |
|     |    | biologics firms. |                      |               |
|     |    | In contrast to   | -   The figures in   |               |
|     |    | drug and         |     the ERG report   |               |
|     |    | biologics firms, |     derive from      |               |
|     |    | blood facilities |     estimates        |               |
|     |    | have a limited   |     collected during |               |
|     |    | range of         |     1999, when       |               |
|     |    | products, do not |     almost no        |               |
|     |    | need to convert  |     companies had    |               |
|     |    | legacy data, and |     implemented      |               |
|     |    | typically        |     MedDRA; actual   |               |
|     |    | operate only in  |     experience is    |               |
|     |    | the United       |     now available    |               |
|     |    | States.          |     and should       |               |
|     |    | Therefore, ERG   |     either be        |               |
|     |    | judged that      |     incorporated     |               |
|     |    | compliance costs |     into the cost    |               |
|     |    | for blood        |     assumptions or,  |               |
|     |    | facilities would |     at a minimum,    |               |
|     |    | be 4 to 5        |     used to validate |               |
|     |    | percent of       |     or refute them   |               |
|     |    | equivalent-sized |                      |               |
|     |    | drug and         | -   The annual       |               |
|     |    | biologics firms. |     MedDRA           |               |
|     |    | Estimated costs  |     subscription fee |               |
|     |    | per firm range   |     is the only cost |               |
|     |    | from \$450 to    |     component        |               |
|     |    | \$2,260 for very |     explicitly       |               |
|     |    | small and very   |     linked to        |               |
|     |    | large firms,     |     company size     |               |
|     |    | respectively.    |                      |               |
|     |    |                  | -   The scale of     |               |
|     |    | V.D.2.a.ii.      |     estimated costs  |               |
|     |    | Development of   |     of different     |               |
|     |    | information      |     MedDRA-related   |               |
|     |    | technology       |     activities from  |               |
|     |    | support          |     smallest to      |               |
|     |    | structure.       |     largest firms is |               |
|     |    |                  |     unfounded. For   |               |
|     |    | Companies        |     example, the     |               |
|     |    | reported that    |     price of an      |               |
|     |    | information      |     autoencoder is   |               |
|     |    | technology (IT)  |     unrelated to     |               |
|     |    | personnel will   |     company size, so |               |
|     |    | need to modify   |     that the         |               |
|     |    | existing         |     suggested        |               |
|     |    | database systems |     autoencoder      |               |
|     |    | to:              |     cost:size ratio  |               |
|     |    |                  |     of 4:1 for       |               |
|     |    | -   Accommodate  |     pharmaceutical   |               |
|     |    |     adding a new |     and 4.5:1 for    |               |
|     |    |     medical      |     biologicsmay not |               |
|     |    |     dictionary,  |     be accurate,     |               |
|     |    |                  |     Conversely,      |               |
|     |    | -   Allow for    |     economies of     |               |
|     |    |     MedDRA's     |     scale in larger  |               |
|     |    |     complex      |     organizations    |               |
|     |    |     hierarchical |     make the cost    |               |
|     |    |     structure    |     per employee of  |               |
|     |    |     and wider    |     MedDRA training  |               |
|     |    |     field        |     substantially    |               |
|     |    |     widths,      |     lower for large  |               |
|     |    |                  |     than for small   |               |
|     |    | -   Reconcile    |     companies. There |               |
|     |    |     the          |     is also no       |               |
|     |    |                  |     reason to        |               |
|     |    |    comparability |     believe that     |               |
|     |    |     of existing  |     biologics firms  |               |
|     |    |     dictionaries |     will have lower  |               |
|     |    |     with MedDRA  |     costs than       |               |
|     |    |     (in the      |     traditional      |               |
|     |    |     short term), |     pharmaceutical   |               |
|     |    |                  |     companies of     |               |
|     |    | -   Integrate a  |     comparable size  |               |
|     |    |     Web browser, |     (cf. the         |               |
|     |    |     and          |     illustration in  |               |
|     |    |                  |     Table 3-1 of the |               |
|     |    | -   Install or   |     ERG report of    |               |
|     |    |     modify an    |     personnel        |               |
|     |    |     autoencoder  |     training costs   |               |
|     |    |     system.      |     of \$133,241 for |               |
|     |    |                  |     a 625-person     |               |
|     |    | IT personnel are |     pharmaceutical   |               |
|     |    | estimated to     |     company vs.      |               |
|     |    | need from 720    |     \$63,910 for a   |               |
|     |    | hours for very   |     625-person       |               |
|     |    | small firms to   |     biologics        |               |
|     |    | 1,920 hours for  |     company).        |               |
|     |    | very large firms |     Rather, it is    |               |
|     |    | to develop and   |     far more likely  |               |
|     |    | validate         |     that MedDRA      |               |
|     |    | computer data    |     implementation   |               |
|     |    | systems that     |     costs will       |               |
|     |    | will accommodate |     depend on the    |               |
|     |    | MedDRA. Costs    |     type of database |               |
|     |    | are estimated to |     and product mix  |               |
|     |    | range from       |     the company has, |               |
|     |    | \$25,850 to      |     which is not     |               |
|     |    | \$68,900 for     |     necessarily      |               |
|     |    | drug and         |     correlated with  |               |
|     |    | biologics firms. |     the molecular    |               |
|     |    | No costs were    |     nature of its    |               |
|     |    | forecast for     |     products, its    |               |
|     |    | blood            |     total number of  |               |
|     |    | facilities.      |     employees. or    |               |
|     |    |                  |     its revenue.     |               |
|     |    | V.D.2.a.iii.     |     Small companies  |               |
|     |    | Purchase or      |     are also much    |               |
|     |    | development of   |     less likely than |               |
|     |    | an autoencoder.  |     large ones to    |               |
|     |    |                  |     have the         |               |
|     |    | Companies        |     requisite        |               |
|     |    | reported that    |     in-house         |               |
|     |    | they currently   |     capability for   |               |
|     |    | use an existing  |     implementing and |               |
|     |    | database such as |     maintaining      |               |
|     |    | COSTART or       |     MedDRA and will  |               |
|     |    | WHOART and       |     therefore need   |               |
|     |    | supplement these |     external         |               |
|     |    | dictionaries     |     support,         |               |
|     |    | with their own   |     incurring        |               |
|     |    | medical          |     additional cash  |               |
|     |    | vocabulary.      |     (as opposed to   |               |
|     |    | Autoencoders     |     overhead)        |               |
|     |    | assist with the  |     operating costs. |               |
|     |    | automated        |                      |               |
|     |    | conversion of    | -   The assumptions  |               |
|     |    | existing medical |     regarding blood  |               |
|     |    | terms to MedDRA. |     facilities are   |               |
|     |    | Companies may    |     unevaluable. FDA |               |
|     |    | purchase         |     currently        |               |
|     |    | autoencoders,    |     requires         |               |
|     |    | adapt existing   |     reporting only   |               |
|     |    | in-house         |     of fatal         |               |
|     |    | versions, or use |     transfusion      |               |
|     |    | outside          |     reactions, and   |               |
|     |    | contractors.     |     thus receives    |               |
|     |    | Converting       |     very few         |               |
|     |    | existing terms   |     reports.         |               |
|     |    | to MedDRA is     |     Estimates are    |               |
|     |    | estimated to     |     lacking of the   |               |
|     |    | cost from        |     number, and,     |               |
|     |    | \$20,000 to      |     more important,  |               |
|     |    | \$100,000 for    |     the nature of    |               |
|     |    | drug and         |     reports that     |               |
|     |    | biologics firms. |     will be received |               |
|     |    | Costs are not    |     from blood       |               |
|     |    | applicable to    |     facilities under |               |
|     |    | blood            |     the proposed     |               |
|     |    | facilities.      |     rule. However,   |               |
|     |    |                  |     the number is    |               |
|     |    | V.D.2.a.iv.      |     likely to        |               |
|     |    | Conversion of    |     increase         |               |
|     |    | legacy safety    |     substantially,   |               |
|     |    | data.            |     as is the        |               |
|     |    |                  |     variety of       |               |
|     |    | Some companies   |     clinical events  |               |
|     |    | reported that    |     reported; thus,  |               |
|     |    | they would       |     it will probably |               |
|     |    | convert          |     be necessary for |               |
|     |    | virtually all of |     at least the     |               |
|     |    | their legacy     |     larger           |               |
|     |    | data into MedDRA |     facilities to    |               |
|     |    | terms even       |     implement MedDRA |               |
|     |    | though it is not |     in their         |               |
|     |    | required by this |     databases.       |               |
|     |    | proposed rule.   |                      |               |
|     |    | Some companies   | -   There is a       |               |
|     |    | maintain that    |     stated           |               |
|     |    | this conversion  |     presumption that |               |
|     |    | includes         |     blood facilities |               |
|     |    | information from |     may require only |               |
|     |    | clinical trials. |     a subset of      |               |
|     |    | Nonetheless,     |     MedDRA terms for |               |
|     |    | some companies   |     their SADR       |               |
|     |    | may not convert  |     reporting. It is |               |
|     |    | their legacy     |     accepted that    |               |
|     |    | drug safety data |     the majority of  |               |
|     |    | into MedDRA or   |     MedDRA terms     |               |
|     |    | may convert only |     will not be      |               |
|     |    | some of their    |     applicable to    |               |
|     |    | products, based  |     blood product    |               |
|     |    | on criteria      |     reactions;       |               |
|     |    | associated with  |     however, to a    |               |
|     |    | experience and   |     greater or       |               |
|     |    | history of the   |     lesser degree,   |               |
|     |    | drug. ERG        |     this is equally  |               |
|     |    | estimated that   |     true for every   |               |
|     |    | 75 percent of    |     medicinal        |               |
|     |    | companies would  |     product, each of |               |
|     |    | incur conversion |     which requires   |               |
|     |    | costs to allow   |     only a small     |               |
|     |    | for the range of |     minority of the  |               |
|     |    | company          |     terms available  |               |
|     |    | responses. The   |     in MedDRA to     |               |
|     |    | number of terms  |     capture and      |               |
|     |    | that are         |     describe its     |               |
|     |    | converted        |     entire safety    |               |
|     |    | automatically    |     profile. Thus,   |               |
|     |    | (with            |     it is not        |               |
|     |    | autoencoders) or |     possible to      |               |
|     |    | manually will    |     identify         |               |
|     |    | affect           |     prospectively    |               |
|     |    | conversion       |     which terms may  |               |
|     |    | costs. Estimated |     or may not be    |               |
|     |    | costs per        |     needed.          |               |
|     |    | company for      |     Furthermore, any |               |
|     |    | converting       |     attempt to       |               |
|     |    | existing legacy  |     create           |               |
|     |    | data range from  |                      |               |
|     |    | about \$16,500   | application-specific |               |
|     |    | (for converting  |     subsets of       |               |
|     |    | 15,000 terms)    |     MedDRA terms     |               |
|     |    | for very small   |     will invalidate  |               |
|     |    | firms to         |     the              |               |
|     |    | \$275,000 (for   |     multi-axiality   |               |
|     |    | converting       |     which is one of  |               |
|     |    | roughly 250,000  |     the most         |               |
|     |    | terms) for very  |     important        |               |
|     |    | large drug       |     attributes of    |               |
|     |    | firms. Costs for |     MedDRA,.         |               |
|     |    | biologics firms  |                      |               |
|     |    | of corresponding | > MedDRA v 6.0       |               |
|     |    | size range from  | > contains the       |               |
|     |    | \$3,300 (for     | > following terms    |               |
|     |    | 3,000 terms) to  | > related to         |               |
|     |    | \$55,000 (for    | > transfusion        |               |
|     |    | about 50,000     | > reactions:         |               |
|     |    | terms). Costs    | >                    |               |
|     |    | are not          | > HLT Transfusion    |               |
|     |    | applicable to    | > related            |               |
|     |    | blood            | > complications      |               |
|     |    | facilities.      | >                    |               |
|     |    |                  | > PTs: Hepatitis     |               |
|     |    | V.D.2.a.v.       | > post transfusion   |               |
|     |    | Training of      | >                    |               |
|     |    | personnel.       | > Refractoriness to  |               |
|     |    |                  | > platelet           |               |
|     |    | Companies        | > transfusion        |               |
|     |    | reported that    | >                    |               |
|     |    | staff most       | > Transfusion        |               |
|     |    | likely to        | > reaction           |               |
|     |    | receive MedDRA   | >                    |               |
|     |    | training include | > Transfusion with   |               |
|     |    | medical coders,  | > incompatible blood |               |
|     |    | b                | >                    |               |
|     |    | iostatisticians, | >                    |               |
|     |    | and              |  Transfusion-related |               |
|     |    | ph               | > acute lung injury  |               |
|     |    | armacovigilance, | >                    |               |
|     |    | IT, and          | > It is clear that   |               |
|     |    | regulatory       | > these terms alone  |               |
|     |    | affairs          | > cannot adequately  |               |
|     |    | personnel. In    | > represent all the  |               |
|     |    | addition to      | > clinical events    |               |
|     |    | formal training, | > that may be        |               |
|     |    | medical data     | > associated with    |               |
|     |    | coders will      | > blood product      |               |
|     |    | require several  | > transfusion, which |               |
|     |    | months of        | > include many       |               |
|     |    | experience       | > general systemic   |               |
|     |    | before they      | > symptoms and signs |               |
|     |    | become           | > as well as actual  |               |
|     |    | proficient with  | > or potential       |               |
|     |    | coding in        | > transmission of a  |               |
|     |    | MedDRA. Training | > variety of         |               |
|     |    | costs are        | > infectious agents. |               |
|     |    | dependent on the | > The examples given |               |
|     |    | number of        | > in the proposed    |               |
|     |    | employees that   | > rule illustrate    |               |
|     |    | must be trained  | > this well, viz.    |               |
|     |    | in MedDRA and    | >                    |               |
|     |    | the level of     | > *"...FDA received  |               |
|     |    | training needed  | > reports from a     |               |
|     |    | for their        | > blood              |               |
|     |    | relevant duties. | > establishment of   |               |
|     |    | Training costs   | > allergic adverse   |               |
|     |    | were estimated   | > reactions ... The  |               |
|     |    | to range from    | > symptoms included  |               |
|     |    | \$9,300 to       | > bilateral          |               |
|     |    | \$330,300 for    | > conjunctival       |               |
|     |    | very small to    | > edema, severe      |               |
|     |    | very large drug  | > headaches, eye     |               |
|     |    | manufacturers    | > pain, nausea       |               |
|     |    | and from \$9,300 | > sometimes          |               |
|     |    | to \$90,600 for  | > associated with    |               |
|     |    | biologics firms  | > vomiting and joint |               |
|     |    | of corresponding | > pain.*             |               |
|     |    | size. ERG        | >                    |               |
|     |    | estimated        | > *... a blood       |               |
|     |    | training costs   | > collection center  |               |
|     |    | from \$1,300 to  | > ...had numerous    |               |
|     |    | \$4,300 for very | > donors with        |               |
|     |    | small to very    | > vasovagal          |               |
|     |    | large blood      | > reactions that     |               |
|     |    | facilities.      | > required treatment |               |
|     |    |                  | > by emergency       |               |
|     |    | V.D.2.a.vi.      | > medical            |               |
|     |    | Revision of      | > personnel."*       |               |
|     |    | standard         | >                    |               |
|     |    | operating        | > Thus, unless FDA   |               |
|     |    | procedures       | > can specify *a     |               |
|     |    | (SOPs).          | > priori* what       |               |
|     |    |                  | > clinical events,   |               |
|     |    | Companies will   | > and their          |               |
|     |    | revise a         | > corresponding      |               |
|     |    | substantial      | > MedDRA PTs, it     |               |
|     |    | group of SOPs in | > considers to be    |               |
|     |    | implementing     | >                    |               |
|     |    | MedDRA. Affected | transfusion-related, |               |
|     |    | procedures       | > reporting of all   |               |
|     |    | include          | >                    |               |
|     |    | di               |  transfusion-related |               |
|     |    | ctionary/coding, | > SADRs will require |               |
|     |    | IT, and drug     | > the implementation |               |
|     |    | safety/          | > of MedDRA in its   |               |
|     |    | ph               | > entirety. Even if  |               |
|     |    | armacovigilance. | > such a list of PTs |               |
|     |    | Drug and         | > could be           |               |
|     |    | biologics firms  | > developed, the     |               |
|     |    | are expected to  | >                    |               |
|     |    | need from 130 to | previously-described |               |
|     |    | 1,300 hours for  | > drawbacks of       |               |
|     |    | very small to    | > MedDRA term        |               |
|     |    | very large firms | > subsets, and the   |               |
|     |    | to revise their  | > practical          |               |
|     |    | SOPs for MedDRA, | > difficulty of      |               |
|     |    | with costs       | > maintaining their  |               |
|     |    | ranging from     | > currency after     |               |
|     |    | \$5,900 to       | > each MedDRA        |               |
|     |    | \$59,200. ERG    | > update, remain.    |               |
|     |    | allocated 8 to   |                      |               |
|     |    | 50 hours for     | -   Autoencoders are |               |
|     |    | developing or    |     useful for not   |               |
|     |    | revising SOPs    |     only legacy data |               |
|     |    | for blood        |     conversion but   |               |
|     |    | facilities. Per  |     also for         |               |
|     |    | firm costs for   |     production       |               |
|     |    | SOPs are         |     MedDRA coding.   |               |
|     |    | estimated to     |                      |               |
|     |    | range from \$370 | -   The basis of the |               |
|     |    | to \$2,260 for   |     ERG estimate     |               |
|     |    | very small to    |     that only 75% of |               |
|     |    | very large blood |     companies would  |               |
|     |    | facilities.      |     need to convert  |               |
|     |    |                  |     legacy data to   |               |
|     |    |                  |     MedDRA is        |               |
|     |    |                  |     unclear. It is   |               |
|     |    |                  |     generally not    |               |
|     |    |                  |     feasible to      |               |
|     |    |                  |     maintain         |               |
|     |    |                  |     multiple         |               |
|     |    |                  |     terminologies in |               |
|     |    |                  |     a single safety  |               |
|     |    |                  |     database, while  |               |
|     |    |                  |     codifying newer  |               |
|     |    |                  |     data in MedDRA   |               |
|     |    |                  |     while leaving    |               |
|     |    |                  |     historic data    |               |
|     |    |                  |     in (a) different |               |
|     |    |                  |     terminology(ies) |               |
|     |    |                  |     would seriously  |               |
|     |    |                  |     hamper effective |               |
|     |    |                  |                      |               |
|     |    |                  |    pharmacovigilance |               |
|     |    |                  |     and create       |               |
|     |    |                  |     substantial      |               |
|     |    |                  |     difficulties for |               |
|     |    |                  |     periodic         |               |
|     |    |                  |     aggregate        |               |
|     |    |                  |     reporting.       |               |
|     |    |                  |     Therefore, all   |               |
|     |    |                  |     companies with   |               |
|     |    |                  |     reporting        |               |
|     |    |                  |     obligations for  |               |
|     |    |                  |     marketed         |               |
|     |    |                  |     products will    |               |
|     |    |                  |     have no option   |               |
|     |    |                  |     but to convert   |               |
|     |    |                  |     their legacy     |               |
|     |    |                  |     data into        |               |
|     |    |                  |     MedDRA.          |               |
|     |    |                  |                      |               |
|     |    |                  | -   ERG omitted the  |               |
|     |    |                  |     single most      |               |
|     |    |                  |     important and    |               |
|     |    |                  |     costly aspect of |               |
|     |    |                  |     personnel        |               |
|     |    |                  |     training from    |               |
|     |    |                  |     its analysis,    |               |
|     |    |                  |     viz. training    |               |
|     |    |                  |     safety           |               |
|     |    |                  |     professionals in |               |
|     |    |                  |     appropriate data |               |
|     |    |                  |     retrieval        |               |
|     |    |                  |     strategies for   |               |
|     |    |                  |     signal           |               |
|     |    |                  |     detection.       |               |
|     |    |                  |     Autoencoders can |               |
|     |    |                  |     help consistent  |               |
|     |    |                  |     and accurate     |               |
|     |    |                  |     codification     |               |
|     |    |                  |     considerably,    |               |
|     |    |                  |     but comparable   |               |
|     |    |                  |     tools for the    |               |
|     |    |                  |     much more        |               |
|     |    |                  |     complex and      |               |
|     |    |                  |     subjective task  |               |
|     |    |                  |     of clinically    |               |
|     |    |                  |     appropriate      |               |
|     |    |                  |     retrieval do not |               |
|     |    |                  |     exist. Although  |               |
|     |    |                  |     clinical         |               |
|     |    |                  |     analysis         |               |
|     |    |                  |     requires         |               |
|     |    |                  |     appropriate      |               |
|     |    |                  |     software tools,  |               |
|     |    |                  |     their proper     |               |
|     |    |                  |     application also |               |
|     |    |                  |     requires         |               |
|     |    |                  |     extensive        |               |
|     |    |                  |     knowledge of     |               |
|     |    |                  |     clinical         |               |
|     |    |                  |     medicine and of  |               |
|     |    |                  |     the structure    |               |
|     |    |                  |     and content of   |               |
|     |    |                  |     MedDRA .         |               |
|     |    |                  |     Consequently, a  |               |
|     |    |                  |     very high level  |               |
|     |    |                  |     of expertise is  |               |
|     |    |                  |     a prerequisite   |               |
|     |    |                  |     for both         |               |
|     |    |                  |     trainers and     |               |
|     |    |                  |     trainees. In     |               |
|     |    |                  |     addition, each   |               |
|     |    |                  |     MedDRA update    |               |
|     |    |                  |     requires         |               |
|     |    |                  |     re-evaluation of |               |
|     |    |                  |     established      |               |
|     |    |                  |     search           |               |
|     |    |                  |     strategies,      |               |
|     |    |                  |     taking into      |               |
|     |    |                  |     account both     |               |
|     |    |                  |     newly added      |               |
|     |    |                  |     terms and        |               |
|     |    |                  |     inactivation of  |               |
|     |    |                  |     prior terms,     |               |
|     |    |                  |     followed by      |               |
|     |    |                  |     repeated         |               |
|     |    |                  |     training to      |               |
|     |    |                  |     ensure complete  |               |
|     |    |                  |     and accurate     |               |
|     |    |                  |     case retrieval.  |               |
|     |    |                  |     The extent and   |               |
|     |    |                  |     complexity of    |               |
|     |    |                  |     re-evaluation    |               |
|     |    |                  |     will vary with   |               |
|     |    |                  |     the magnitude of |               |
|     |    |                  |     the changes to   |               |
|     |    |                  |     MedDRA, e.g. at  |               |
|     |    |                  |     the PT level     |               |
|     |    |                  |     only vs.         |               |
|     |    |                  |     structural       |               |
|     |    |                  |     changes to the   |               |
|     |    |                  |     hierarchy.       |               |
|     |    |                  |                      |               |
|     |    |                  | It is unclear why    |               |
|     |    |                  | ERG estimated such a |               |
|     |    |                  | wide range of time   |               |
|     |    |                  | and cost to develop  |               |
|     |    |                  | and/or revise SOPs.  |               |
|     |    |                  | Apart from review    |               |
|     |    |                  | and approval, which  |               |
|     |    |                  | tend to be somewhat  |               |
|     |    |                  | more cumbersome in   |               |
|     |    |                  | larger               |               |
|     |    |                  | organizations, there |               |
|     |    |                  | is not a great deal  |               |
|     |    |                  | of difference in the |               |
|     |    |                  | amount of work or    |               |
|     |    |                  | the number and skill |               |
|     |    |                  | of personnel         |               |
|     |    |                  | responsible for      |               |
|     |    |                  | drafting SOPs,       |               |
|     |    |                  | whatever the size of |               |
|     |    |                  | the company.         |               |
+-----+----+------------------+----------------------+---------------+
| V.D | 1  | Companies must   | Concerning the       | Delete        |
| .2. | 24 | pay subscription | statement "*ERG      | references to |
| b.i | 60 | costs on an      | judged that blood    | quarterly     |
|     |    | annual basis to  | facilities would     | releases of   |
|     |    | the MedDRA MSSO. | incur only modest    | MedDRA        |
|     |    | Core             | annual costs         | versions as   |
|     |    | subscription     | associated with      | this is no    |
|     |    | costs vary with  | MedDRA subscription  | longer the    |
|     |    | the size of the  | and updates because  | case.         |
|     |    | company and with | of the limited range |               |
|     |    | the level of     | of terminology       |               |
|     |    | services.        | describing medical   |               |
|     |    | Estimates of     | outcomes*", this     |               |
|     |    | costs range from | statement implies    |               |
|     |    | \$5,000 to       | that the costs of    |               |
|     |    | \$40,000 for     | using MedDRA are     |               |
|     |    | drug and         | dependent of how     |               |
|     |    | biologics firms. | much of the          |               |
|     |    | ERG judged that  | terminology is used  |               |
|     |    | blood facilities | by the subscriber;   |               |
|     |    | would incur only | this is only partly  |               |
|     |    | modest annual    | true. The baseline   |               |
|     |    | costs associated | subscription cost is |               |
|     |    | with MedDRA      | not based on number  |               |
|     |    | subscription and | of terms used; this  |               |
|     |    | updates because  | is a fixed annual    |               |
|     |    | of the limited   | cost. The amount of  |               |
|     |    | range of         | resources to update  |               |
|     |    | terminology      | from one version to  |               |
|     |    | describing       | another is           |               |
|     |    | medical          | essentially the only |               |
|     |    | outcomes. **ERG  | non-fixed cost       |               |
|     |    | assumed that     | directly related to  |               |
|     |    | blood facilities | use of the           |               |
|     |    | would either     | terminology. In      |               |
|     |    | work through     | other words, the     |               |
|     |    | industry         | fewer the number of  |               |
|     |    | associations to  | terms used, the      |               |
|     |    | negotiate lower  | fewer the number of  |               |
|     |    | per firm         | re-codings, etc.     |               |
|     |    | subscription     | with any new version |               |
|     |    | costs or,        | release.             |               |
|     |    | alternatively,   |                      |               |
|     |    | contract with    | The assumption by    |               |
|     |    | contract         | ERG that companies   |               |
|     |    | research         | could contract with  |               |
|     |    | organizations to | contract research    |               |
|     |    | obtain the       | organizations (CROs) |               |
|     |    | necessary MedDRA | to obtain the        |               |
|     |    | codes.**         | necessary MedDRA     |               |
|     |    |                  | (without being       |               |
|     |    | V.D.2.b.ii.      | MedDRA subscribers)  |               |
|     |    | MedDRA versions  | is a violation of    |               |
|     |    | and quarterly    | the MedDRA license.  |               |
|     |    | updates.         | The MSSO has a pilot |               |
|     |    | Currently the    | program in place     |               |
|     |    | MSSO intends to  | with the EMEA to     |               |
|     |    | provide          | provide access to    |               |
|     |    | quarterly        | MedDRA within the    |               |
|     |    | updates as well  | EMEA's               |               |
|     |    | as periodic new  | EudraVigilance       |               |
|     |    | versions of      | system. The EMEA     |               |
|     |    | MedDRA.          | developed the tool   |               |
|     |    | Companies did    | so that all reports, |               |
|     |    | not have a       | regardless of their  |               |
|     |    | sufficient       | financial status,    |               |
|     |    | history with     | could provide ICSR   |               |
|     |    | incorporating    | reports to the EMEA. |               |
|     |    | MedDRA changes   | If a company is      |               |
|     |    | to estimate the  | truly a small or     |               |
|     |    | costs of         | micro sized          |               |
|     |    | updates. Cost    | enterprise and they  |               |
|     |    | components would | have a small number  |               |
|     |    | include senior   | of reports per year, |               |
|     |    | level reviews of | there is no charge   |               |
|     |    | each update,     | for the use of       |               |
|     |    | communicating    | MedDRA. This allows  |               |
|     |    | the changes to   | for all data,        |               |
|     |    | affected         | regardless of the    |               |
|     |    | personnel, and   | source, to be        |               |
|     |    | IT support to    | reported in MedDRA   |               |
|     |    | upload and       | at a minimal cost to |               |
|     |    | reconcile new    | the company.         |               |
|     |    | versions. Costs  |                      |               |
|     |    | are estimated to | MedDRA versions are  |               |
|     |    | range from       | no longer released   |               |
|     |    | \$5,700 to       | on a quarterly       |               |
|     |    | \$43,000 for     | basis; as of         |               |
|     |    | drug and         | mid-2003, they are   |               |
|     |    | biologics firms. | released twice       |               |
|     |    | No costs were    | yearly. There is a   |               |
|     |    | assigned to      | possibility that     |               |
|     |    | blood            | this may be reduced  |               |
|     |    | facilities.      | to an annual release |               |
|     |    |                  | in the future.       |               |
|     |    | V.D.2.b.iii.     |                      |               |
|     |    | Maintenance of   |                      |               |
|     |    | existing         |                      |               |
|     |    | dictionaries.    |                      |               |
|     |    | Companies        |                      |               |
|     |    | reported that    |                      |               |
|     |    | they may need to |                      |               |
|     |    | maintain their   |                      |               |
|     |    | existing         |                      |               |
|     |    | dictionaries for |                      |               |
|     |    | an indeterminate |                      |               |
|     |    | time. Conditions |                      |               |
|     |    | that could       |                      |               |
|     |    | influence        |                      |               |
|     |    | whether and for  |                      |               |
|     |    | how long a       |                      |               |
|     |    | company would    |                      |               |
|     |    | need to maintain |                      |               |
|     |    | its existing     |                      |               |
|     |    | dictionaries     |                      |               |
|     |    | are: (1) The     |                      |               |
|     |    | company uses     |                      |               |
|     |    | different        |                      |               |
|     |    | dictionaries for |                      |               |
|     |    | its              |                      |               |
|     |    | postmarketing    |                      |               |
|     |    | safety and       |                      |               |
|     |    | clinical study   |                      |               |
|     |    | data bases; (2)  |                      |               |
|     |    | the company has  |                      |               |
|     |    | products in      |                      |               |
|     |    | late-stage       |                      |               |
|     |    | clinical trials; |                      |               |
|     |    | and (3) the      |                      |               |
|     |    | company has      |                      |               |
|     |    | marketed         |                      |               |
|     |    | products near    |                      |               |
|     |    | the end of their |                      |               |
|     |    | useful life. ERG |                      |               |
|     |    | estimates the    |                      |               |
|     |    | maintenance      |                      |               |
|     |    | costs for        |                      |               |
|     |    | existing         |                      |               |
|     |    | dictionaries are |                      |               |
|     |    | expected to      |                      |               |
|     |    | range from       |                      |               |
|     |    | \$4,300 to       |                      |               |
|     |    | \$136,400        |                      |               |
|     |    | annually for     |                      |               |
|     |    | drug             |                      |               |
|     |    | manufacturers    |                      |               |
|     |    | and from \$4,300 |                      |               |
|     |    | to \$43,400      |                      |               |
|     |    | annually for     |                      |               |
|     |    | biologics        |                      |               |
|     |    | manufacturers.   |                      |               |
|     |    | No costs were    |                      |               |
|     |    | assigned to      |                      |               |
|     |    | blood            |                      |               |
|     |    | facilities.      |                      |               |
+-----+----+------------------+----------------------+---------------+
| V   | 1  | The agency       | The MSSO has a pilot | FDA should    |
| .E. | 24 | recognizes that  | program in place     | provide       |
| 4.f | 62 | requiring        | with the EMEA to     | guidance on   |
|     |    | individual case  | provide access to    | the           |
|     |    | safety reports   | MedDRA within the    | appropriate   |
|     |    | to be coded      | EMEA's               | method of     |
|     |    | using MedDRA     | EudraVigilance       | reporting in  |
|     |    | will likely      | system. The EMEA     | those         |
|     |    | impose           | developed the tool   | circumstances |
|     |    | significant      | so that all reports, | where a       |
|     |    | costs on some    | regardless of their  | company has   |
|     |    | small firms (see | financial status,    | no database   |
|     |    | section III.F.2  | could provide ICSR   | or has a very |
|     |    | of this          | reports to the EMEA. | small number  |
|     |    | document). One   | If a company is      | of reports.   |
|     |    | alternative      | truly a small or     | Perhaps the   |
|     |    | would be to      | micro sized          | FDA should    |
|     |    | consider the     | enterprise and they  | consider the  |
|     |    | option of        | have a small number  | approach      |
|     |    | allowing         | of reports per year, | taken in the  |
|     |    | companies to     | there is no charge   | EMEA's        |
|     |    | request a waiver | for the use of       | E             |
|     |    | from MedDRA      | MedDRA. This allows  | udraVigilance |
|     |    | coding, based on | for all data,        | system.       |
|     |    | economic         | regardless of the    |               |
|     |    | hardship. The    | source, to be        |               |
|     |    | agency is        | reported in MedDRA   |               |
|     |    | seeking comment  | at a minimal cost to |               |
|     |    | on ways to       | the company.         |               |
|     |    | reduce economic  |                      |               |
|     |    | hardships of     |                      |               |
|     |    | implementing     |                      |               |
|     |    | MedDRA while     |                      |               |
|     |    | maintaining      |                      |               |
|     |    | adequate         |                      |               |
|     |    | procedures to    |                      |               |
|     |    | monitor and      |                      |               |
|     |    | assess the       |                      |               |
|     |    | safety of        |                      |               |
|     |    | products.        |                      |               |
+-----+----+------------------+----------------------+---------------+