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14 October 2003

Dockets Management Branch

Food and Drug Administration, HFA-305

5630 Fishers Lane, Room 1061

Rockville, MD 20857

**Re: Docket No. 00N-1484: Safety Reporting Requirements for Human Drug
and Biological Products: Proposed rule (Federal Register, March 14,
2003; Volume 67, Number 50).**

Dear Sir or Madam:

Pharmacovigilance & Risk Management, Inc. (PvRM) is an independent
corporation providing consulting services to the pharmaceutical industry
and supporting organizations. Dr. Sidney Kahn, its founder and
president, has had extensive industry experience in all aspects of
pharmaceutical safety assessment, clinical and regulatory reporting, and
risk management. He represented PhRMA on several ICH committees and
expert working groups, including the M1 WG that developed MedDRA, and is
a current participant in CIOMS. He is thus very interested in and well
qualified to comment on this Proposed Rule.

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

FDA is to be commended for its ongoing regulatory reforms aimed at US
implementation of international standards developed under the auspices
of the ICH. Many of the changes in the proposed rule, e.g. the
harmonization of periodic aggregate reports for newer molecular entities
and the implementation of MedDRA, are in direct concordance with ICH
pharmacovigilance guidelines, CIOMS recommendations, and regulations in
other ICH jurisdictions, and are consistent with the spirit expressed in
the Rationale of eliminating "unnecessary reporting burdens on industry
so that companies can focus on the safety profiles of their products..."
PvRM fully supports these proposals. However, the Proposed Rule also
contains many additional provisions that are not derived from ICH or
CIOMS, have not been subject to critical external discussion, and whose
value is uncertain at best. Examples include:

-   the requirement for active query follow-up by company health
    professionals of large numbers of reports

-   the creation of new categories of report such as "always expedited",
    30-day, and 45-day

-   relatively vague concepts such as "potential medication errors".

Taken together with other provisions such as the change in causality
definition, these proposals will result in a very marked increase in the
number of 15-day expedited reports, as well as of intermediate
categories of reports (e.g. 30 day, 45 day) of dubious utility that have
no counterpart in ICH. Far from decreasing the reporting burden on
industry, these proposals will substantially increase it, with no
counterbalancing benefit of improved pharmacovigilance, and so are
likely to have exactly the opposite of the desired effect of allowing
companies to focus on the [important]{.underline} safety aspects of
their products. In its Q&A on the proposed rule published on 14 August
2003, FDA reiterated its goal of creating "a risk-based approach for
safety reporting so industry can focus its efforts on serious suspected
adverse drug reactions that have more potential public health impact
than do the non-serious SADRs. Currently ...companies often spend
inordinate amounts of resources following up on certain reports that
really add little to our knowledge about the safe use of the product."
Many of the provisions of the Proposed Rule appear to be in direct
contradiction of this stated goal, and if implemented will actually
result in far [more]{.underline} resources being devoted to "reports
that add little to our knowledge about safe use", particularly large
numbers of serious, expected AEs, which under the new rule will have to
be considered SADRs. If FDA has information suggesting that these new
non-ICH provisions are necessary for global public health protection,
PvRM recommends that FDA propose the changes to its ICH partners with
appropriate supporting arguments for their global necessity, but in the
interim should either remove them, or at a minimum modify them to
substantially reduce their anticipated negative impact on good
pharmacovigilance practice.

Finally, while FDA does explain in its introduction that the Proposed
Rule does not address electronic submission of ICSRs, the Rule itself
should specify that it is aimed at paper-based submissions and that
alternative approaches may be considered for electronic submissions,
until addressed in future regulations.

**[Specific comments]{.underline}**

+-----------------------------------+-----------------------------------+
| **Proposed Rule**                 | **PvRM Comment**                  |
+-----------------------------------+-----------------------------------+
| *[P 12409]{.underline}*           | The use of internationally        |
|                                   | harmonized procedures is in the   |
| An addendum to the ICH E2C        | best interests of                 |
| guidance has been prepared by ICH | pharmacovigilance. However, as    |
| based on experience gained over   | ICH guidances often change before |
| the past 5 years in preparation   | finalization, FDA should not      |
| of PSUR reports by companies and  | mandate any activities specified  |
| review of them by regulators (the | in ICH guidelines that have not   |
| ICH V1 draft guidance) (67 FR     | yet reached step 4. It could be   |
| 79939; December 31, 2002). FDA is | helpful if FDA were to            |
| interested in harmonizing, to the | incorporate the ICH V1 guidance   |
| extent possible, its              | by reference, so that new         |
| postmarketing periodic safety     | regulations will not be required  |
| reporting regulations with the    | after it is finalized,            |
| recommendations in the ICH V1     |                                   |
| draft guidance. In this regard,   |                                   |
| FDA is interested in comment from |                                   |
| the public on whether the agency  |                                   |
| should implement these            |                                   |
| recommendations (*e.g.*, permit   |                                   |
| use of summary bridging reports,  |                                   |
| include an executive summary in   |                                   |
| PSURs, permit use of different    |                                   |
| versions of reference safety      |                                   |
| information within a reporting    |                                   |
| interval or use of the version in |                                   |
| effect at the end of the          |                                   |
| reporting interval).              |                                   |
+-----------------------------------+-----------------------------------+
| *[p. 12410, Section               | The majority of ICSRs will soon   |
| I.]{.underline}*                  | be submitted to FDA               |
|                                   | electronically in accordance with |
| In the Federal Register of        | the ICH E2B guideline. However,   |
| November 5, 1998 (63 FR 59746),   | the proposed rule explicitly      |
| FDA published an advance notice   | addresses only ICSR submissions   |
| of proposed rulemaking announcing | on paper (forms 3500A, CIOMS-I,   |
| that it is considering a proposal | VAERS, line listings, etc.). Some |
| to require persons subject to the | requirements of the proposed rule |
| postmarketing safety reporting    | and assessments of the impact of  |
| regulations to submit             | implementation of MedDRA are      |
| postmarketing expedited           | inconsistent with electronic      |
| individual case safety reports    | submission or may be rendered     |
| and individual case safety        | moot by its implementation. For   |
| reports contained in              | example, the E2B(M) specification |
| postmarketing periodic safety     | calls for international reporting |
| reports to the agency             | of the "verbatim" event           |
| electronically using a            | description together with the     |
| standardized medical terminology, | corresponding MedDRA LLT and PT   |
| standardized data elements, and   | and identification of the version |
| electronic transmission standards | of MedDRA employed. In addition,  |
| recommended by the ICH. Under the | the proposed rule requires MedDRA |
| auspices of ICH, standard medical | only for SADRs, while E2B         |
| terminology for regulatory        | requires its use not only to      |
| purposes, MedDRA, the medical     | represent adverse events but also |
| dictionary for regulatory         | in every other field that         |
| activities (ICH M1), has been     | requires a controlled medical     |
| developed (63 FR 59746 at 59748). | terminology, including medical    |
| On November 24, 1998, an          | history, treatment indication,    |
| international maintenance and     | cause of death, etc.              |
| support services organization     |                                   |
| (MSSO) was established to         | FDA should therefore specify      |
| maintain and update MedDRA in     | that, at least as regards the use |
| response to medical/ scientific   | of MedDRA, the proposed rule      |
| advances and regulatory changes   | applies only to that minority of  |
| and to serve as the licensing     | ICSRs that it will receive on     |
| agent for distribution of MedDRA. | paper, and that specific          |
| This proposed rule on safety      | considerations concerning the     |
| reporting would require that      | application and impact of MedDRA  |
| postmarketing individual case     | on electronic submission of ICSRs |
| safety reports be coded using     | will be addressed in other rules  |
| MedDRA prior to submission to the | and/or guidances.                 |
| 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.            |                                   |
+-----------------------------------+-----------------------------------+
| *[pp. 12412-3, Section            | PvRM strongly supports the        |
| II.B.I]{.underline}*              | concept of using the              |
|                                   | ICH-developed MedDRA terminology  |
| Another international             | for safety reporting during all   |
| harmonization effort is           | phases of product development and |
| standardization of medical        | marketing worldwide, and commends |
| terminology used for regulatory   | FDA for adopting this             |
| purposes. As noted previously,    | international standard for safety |
| ICH has developed MedDRA for this | reporting on marketed products.   |
| purpose. Currently, companies use | The long term advantages to       |
| various medical terminologies for | companies and regulators of       |
| safety reporting purposes (e.g.,  | standardized use of MedDRA should |
| WHO's Adverse Reaction            | far outweigh both its             |
| Terminology (WHOART), Coding      | considerable initial              |
| Symbols for a Thesaurus of        | implementation burden and its     |
| Adverse Reaction Terms (COSTART), | maintenance costs, which will be  |
| Japan's Adverse Reaction          | higher than those of previously   |
| Terminology (J-ART)). The         | used terminologies. This          |
| established terminologies have    | perception explains the rapid     |
| been criticized for a number of   | voluntary adoption of MedDRA by   |
| reasons, including: Lack of       | many companies for safety         |
| specificity, limited data         | reporting of both marketed and    |
| retrieval options, and an         | investigational products.         |
| inability to effectively handle   | However, many of the difficulties |
| complex combinations of signs and | associated with previous          |
| symptoms (syndromes). In          | terminologies will not be         |
| addition, use of different        | remedied simply by adoption of    |
| terminologies at different stages | MedDRA; rather, the enhanced      |
| in the development and use of     | specificity and complexity of     |
| products complicates data         | MedDRA could actually aggravate   |
| retrieval and analysis of         | those difficulties unless         |
| information and makes it          | consensus can be reached          |
| difficult to effectively          | regarding methods for event       |
| cross-reference data through the  | codification and safety signal    |
| lifetime of a product.            | identification and                |
| Internationally, communication is | characterization. It is critical  |
| impaired between regulatory       | that MedDRA's implementation and  |
| authorities because of the delays | use be logical and consistent,    |
| and distortions caused by the     | since its benefits could be       |
| translation of data from one      | substantially vitiated by         |
| terminology to another.           | inconsistent implementation       |
|                                   | and/or usage. Although            |
| Use of different terminologies    | codification can never be fully   |
| also has significant consequences | standardized, attempts should be  |
| for pharmaceutical firms.         | made to develop the broadest      |
| Companies operating in more than  | possible consensus on optimal     |
| one jurisdiction have had to      | approaches to codifying SADRs for |
| adjust to subsidiaries or         | safety signal detection. In       |
| clinical research organizations   | recognition of this requirement,  |
| that use different terminologies  | FDA should include a reference to |
| because of variations in data     | the document "MedDRA Term         |
| submission requirements. The      | Selection; Points to Consider"    |
| difficulty of analyzing data      | developed by the ICH to encourage |
| comprehensively may be compounded | rational and reasonably uniform   |
| by use of incompatible            | codification.                     |
| terminologies and could lead to   |                                   |
| delays in recognizing potential   | PvRM has the following comments   |
| public health problems.           | on the impact of MedDRA on safety |
|                                   | reporting to manufacturers by     |
| For these reasons, it is critical | health care providers (HCPs) and  |
| that a single medical terminology | on optimal use of MedDRA terms:   |
| be used internationally for       |                                   |
| coding postmarketing safety       | -   HCPs will continue to use     |
| reports. FDA is proposing to use  |     natural medical language,     |
| MedDRA for this purpose (see      |     rather than dictionaries or   |
| section III.F.2 of this           |     standardized terminologies,   |
| document). MedDRA is the best     |     for communicating with        |
| choice because it was developed   |     manufacturers aboout SADRs.   |
| with input from regulatory        |     The proposed rule should      |
| authorities and industry and the  |     therefore have no impact on   |
| problems associated with the      |     clinicians or other providers |
| other terminologies were taken    |     of healthcare services.       |
| into consideration during         |                                   |
| development of MedDRA. Some       | -   Not only are there no         |
| companies have begun to           |     clinical definitions          |
| voluntarily submit their          |     associated with any MedDRA    |
| postmarketing safety reports to   |     terms, but in many instances  |
| FDA coded using MedDRA.           |     there are not even accepted   |
|                                   |     definitions of clinically     |
| Even though FDA is proposing to   |     important entities. Current   |
| use MedDRA as the standard        |     practice is thus to codify    |
| medical terminology for reporting |     data in strict adherence to   |
| purposes under this rule, the     |     the reporter's verbatim term, |
| agency recognizes that            |     although there are common     |
| alternative standard              |     situations in which this      |
| classification systems for        |     approach does not produce an  |
| clinical information exist in the |     optimally medically           |
| United States and supports the    |     meaningful output, including: |
| national health data              |                                   |
| standardization initiatives       |     -   Reporter                  |
| underway in the United States     |         miscategorization, e.g.   |
| under the Health Insurance        |         reporting "abnormal LFTs" |
| Portability and Accountability    |         to describe a patient     |
| Act.                              |         with jaundice or "acute   |
|                                   |         liver failure" without    |
| Although this proposed rule does  |         encephalopathy,           |
| not impose reporting requirements |         coagulopathy, or          |
| on health care providers, the     |         jaundice.                 |
| agency recognizes that            |                                   |
| clinicians, medical centers,      |     -   Inconsistent event        |
| hospitals and others may report   |         classification; e.g. an   |
| safety information to             |         identical constellation   |
| pharmaceutical companies. These   |         of clinical signs and     |
| third parties may employ clinical |         laboratory results may be |
| terminology standards that differ |         variously categorized by  |
| from those proposed here.         |         different reporters as    |
| Therefore, the agency invites     |         hepatitis, abnormal liver |
| comment on the unintended         |         function, elevated        |
| potential impact of this proposed |         aminotransferases and     |
| rule on those parties not subject |         jaundice, liver necrosis, |
| to FDA's safety reporting         |         etc. Codifying such       |
| requirements. The agency also     |         information strictly in   |
| invites comment on the potential  |         accordance with the       |
| strategies and approaches for     |         reporter's term results   |
| facilitating seamless             |         in fragmentation of       |
| cross-standard communications,    |         essentially similar       |
| such as mapping between           |         information with          |
| alternative terminologies and     |         consequent loss of        |
| MedDRA.                           |         clinical utility.         |
|                                   |         Harmonized definitions of |
|                                   |         terms, ideally agreed     |
|                                   |         internationally, should   |
|                                   |         be developed, as          |
|                                   |         suggested elsewhere by    |
|                                   |         FDA, to ensure the        |
|                                   |         maximum possible accuracy |
|                                   |         and consistency in the    |
|                                   |         classification of adverse |
|                                   |         events and cases.         |
|                                   |                                   |
|                                   | -   Possible solutions for these  |
|                                   |     data quality problems         |
|                                   |     include:                      |
|                                   |                                   |
|                                   |     -   Permitting manufacturers  |
|                                   |         to codify such cases for  |
|                                   |         analysis using available  |
|                                   |         event definitions (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    |
|                                   |         reporter-misclassified or |
|                                   |         vague terms that are not  |
|                                   |         clinically useful.        |
|                                   |                                   |
|                                   | -   It does not seem feasible     |
|                                   |     under current circumstances   |
|                                   |     to create extensive mappings  |
|                                   |     between MedDRA and other      |
|                                   |     terminologies, nor is it      |
|                                   |     obvious if and when such      |
|                                   |     mappings would be valuable or |
|                                   |     who would bear the            |
|                                   |     substantial cost. If such a   |
|                                   |     commitment of resources were  |
|                                   |     to be considered, it would    |
|                                   |     probably be more useful to    |
|                                   |     apply them to the extensive   |
|                                   |     restructuring of the MedDRA   |
|                                   |     PT and LLT levels previously  |
|                                   |     suggested by EFPIA.           |
+-----------------------------------+-----------------------------------+
| *[p. 12413, II.B.2. Quality of    | FDA's stated aim of adopting a    |
| Postmarketing Safety              | risk-based approach focusing on   |
| Reports]{.underline}*             | the most significant safety       |
|                                   | information is logical. However,  |
| In light of the recommendations   | many of the proposals in the Rule |
| of ICH and CIOMS, FDA has         | appear not to support this        |
| reviewed its postmarketing safety | laudable aim, and will increase,  |
| reporting regulations for human   | rather than reduce, the amount of |
| drugs and licensed biological     | effort expended on activities of  |
| products and identified           | dubious value. This section       |
| additional changes that the       | contains proposals that would     |
| agency believes would further     | substantially increase the        |
| enhance surveillance of marketed  | workload of industry safety       |
| products. Many of the             | departments with no corresponding |
| postmarketing safety reports that | benefit in enhanced quality of    |
| FDA receives are complete and of  | reports of important events.      |
| very high quality. Others are     | There are also areas of conflict  |
| incomplete, of mediocre or poor   | with, or unanticipated            |
| quality or both, making it        | consequences of, other            |
| difficult to ascertain the        | legislation and regulations.      |
| significance of these reports. In | First, HIPAA has placed many      |
| the latter cases, FDA is          | stringent constraints on health   |
| unnecessarily spending            | professionals and has made many   |
| considerable amounts of time      | physicians unwilling to disclose  |
| trying to collect additional      | any information regarding their   |
| information for the reports.      | patients. FDA's requirement for   |
|                                   | aggressive follow-up attempts by  |
| To address this problem, FDA is   | company personnel will be         |
| proposing amendments to its       | perceived by many health          |
| postmarketing safety reporting    | professionals (HPs) as tantamount |
| requirements. For most of these   | to "harassment" and has the       |
| amendments, a risk-based approach | potential to discourage HPs from  |
| is being proposed (*i.e.*,        | reporting adverse events at all.  |
| greater emphasis and effort would | This is particularly true for     |
| be required for reports of        | those reports, which represent    |
| serious adverse drug experiences  | the majority received by          |
| while less information would be   | pharmaceutical companies, in      |
| required for nonserious adverse   | which the reporter's contact is   |
| drug experiences (adverse drug    | initiated to request information  |
| experiences proposed to be called | to help clarify a patient's       |
| SADRs in this proposed rule; see  | diagnosis or management, rather   |
| section III.A.1 of this           | than to report a SADR. PvRM       |
| document)). For example, FDA is   | recommends that FDA should        |
| proposing that complete           | differentiate between these two   |
| information be submitted for      | categories of reported AEs, as    |
| reports of serious SADRs (see     | the reporter's index of suspicion |
| section III.C.5 of this           | is usually substantially          |
| document). If complete            | different. Although FDA's         |
| information is not available, in  | proposals for enhancing data      |
| some cases, a followup report     | quality are logical in theory,    |
| would be required (*e.g.*, for    | they do not coincide with the     |
| serious, unexpected SADRs) (see   | reality of the post-market        |
| section III.D.6 of this           | reporting situation, and if       |
| document). On the other hand, for | implemented will almost certainly |
| SADRs that are determined to be   | create enormous amounts of work   |
| nonserious, not as much           | for highly qualified personnel    |
| information would need to be      | without achieving the desired     |
| acquired (see section III.C.5 of  | end.                              |
| this document).                   |                                   |
|                                   | Second, FDA's proposals for       |
| Another amendment would require   | changes in the safety content of  |
| direct contact with the initial   | labeling will result in many AEs, |
| reporter of an SADR by a health   | including serious AEs, becoming   |
| care professional at the company  | unlabeled, even further           |
| for collection of certain         | increasing the follow-up burden   |
| postmarketing safety information  | with no benefit whatever to the   |
| (*e.g.*, collection of followup   | public health. (*See also PvRM    |
| information for a serious SADR)   | comment on Docket No. 02N-0528,   |
| (see section III.A.6 of this      | Concept Paper - Risk Assessment   |
| document). Currently, some        | of Observational Data, Lines      |
| companies use this approach for   | 84-88*). Busy HPs are very        |
| collecting information, whereas   | unlikely to be willing to take    |
| others send the initial reporter  | precious time from caring for     |
| a letter. The latter case is a    | patients to discuss common        |
| passive approach which, in FDA's  | expected clinical outcomes with   |
| experience, results in limited    | company personnel.                |
| acquisition of new information.   |                                   |
| In most cases, the initial        | FDA should clarify what is meant  |
| reporter simply does not respond  | by "licensed physician". PvRM     |
| to the letter. Instead, using an  | agrees that well-qualified        |
| active approach, as proposed by   | physicians with pharmacovigilance |
| FDA, companies would more likely  | experience should be responsible  |
| obtain the additional information | for medical review of individual  |
| needed for an SADR. Thus, use of  | and aggregate safety reports.     |
| this approach should result in    | However, possession of a US       |
| submission of higher quality      | license is not a meaningful       |
| reports to FDA for review.        | criterion for appropriate         |
|                                   | expertise in this area, and there |
| Another amendment would require   | are large numbers of              |
| that a licensed physician at the  | highly-qualified, experienced,    |
| company be responsible for the    | and competent pharmacovigilance   |
| content of postmarketing safety   | physicians in US companies who do |
| reports submitted to FDA (see     | not have US licensure. FDA should |
| sections III.E.1.h, III.E.2.k.xi, | specify that review requires a    |
| and II.F.4 of this document). As  | qualified physician with          |
| in the previous examples, some    | appropriate clinical and          |
| companies currently use licensed  | pharmacovigilance expertise,      |
| physicians for this purpose,      | which is far more relevant than   |
| whereas others have their         | licensure in any specific         |
| postmarketing safety reports      | jurisdiction.                     |
| prepared and submitted by         |                                   |
| clerical personnel with no health |                                   |
| care training. The medical        |                                   |
| significance of postmarketing     |                                   |
| safety reports warrants review by |                                   |
| a licensed physician. The agency  |                                   |
| believes that licensed physicians |                                   |
| would ensure submission of high   |                                   |
| quality reports to FDA that       |                                   |
| articulately conveys all          |                                   |
| clinically relevant information   |                                   |
| associated with an SADR.          |                                   |
+-----------------------------------+-----------------------------------+
| *[pp 12413-4, Section             | There are different types of      |
| II.B.3.a]{.underline}*            | medication errors, only some of   |
|                                   | which may also be associated with |
| ...FDA believes that ... safety   | clinical adverse events. While    |
| reporting systems do not          | MedDRA was specifically designed  |
| adequately address the nature and | to codify the latter, it has very |
| extent of problems caused by      | limited specificity for capturing |
| medication errors. In most cases, | medication errors. Version 6.0    |
| safety reports associated with a  | contains only the following terms |
| medication error are not          | for codifying medication errors:  |
| identified in the report as being |                                   |
| associated with an error.         | HLT Maladministration and         |
| Instead, the report only          | accidental exposure               |
| highlights the effect of the      |                                   |
| medication error (e.g., patient   | PTs: Accidental exposure          |
| experienced a seizure). This      |                                   |
| information is not sufficient for | Medication error                  |
| FDA to identify medication errors |                                   |
| that could be avoided in the      | Poor quality drug administered    |
| future. For cases that involve a  |                                   |
| medication error, the safety      | Underdose                         |
| report needs to be identified as  |                                   |
| a suspected medication error so   | HLT Overdoses                     |
| that the report can be            |                                   |
| appropriately analyzed and        | PTs: Accidental overdose          |
| addressed. FDA concludes that an  |                                   |
| explicit requirement for          | Multiple drug overdose            |
| reporting medication errors by    |                                   |
| companies subject to the agency's | Non-accidental overdose           |
| postmarketing safety reporting    |                                   |
| regulations is needed to          | Overdose NOS                      |
| adequately assess and respond to  |                                   |
| the problem.                      | The non-specific term "medication |
|                                   | error" appears not to be useful   |
| FDA is therefore proposing to     | for FDA's stated purposes,        |
| require that these companies      | especially if the number of       |
| submit to the agency              | reports of actual or potential    |
| expeditiously all domestic        | errors increases following        |
| reports of actual and potential   | implementation of this rule.      |
| medication errors (see section    | Based on its experience, FDA      |
| III.D.5 of this document). FDA    | should consider whether           |
| would review information about    | additional specific medication    |
| suspected medication errors to    | error terms, e.g. erroneous       |
| determine an appropriate risk     | prescription, medication name     |
| management plan ...               | confusion, dose calculation       |
|                                   | error, patient misidentification, |
|                                   | etc. might enhance codification   |
|                                   | specificity and case retrieval.   |
|                                   | In addition, MedDRA does not      |
|                                   | permit distinction between actual |
|                                   | and potential errors, which are   |
|                                   | clearly of different              |
|                                   | significance; this topic requires |
|                                   | additional discussion and         |
|                                   | clarification before any specific |
|                                   | reporting method is mandated.     |
+-----------------------------------+-----------------------------------+
| *[p. 12414, Section               | The expanded ICH E2A definition   |
| II.B.3.b.]{.underline}*           | of seriousness adopted by FDA in  |
|                                   | 1997 resulted in an approximate   |
| FDA is also proposing to require  | doubling in the annual number of  |
| that companies subject to the     | expedited reports, but it is not  |
| agency's postmarketing safety     | clear whether this increase has   |
| reporting regulations submit to   | resulted in earlier recognition   |
| FDA in an expedited report SADRs  | of any important SADRs. This new  |
| that are unexpected and for which | proposal will be interpreted      |
| a determination of serious or     | conservatively by companies, and  |
| nonserious cannot be made (i.e.,  | taken together with the ambiguity |
| SADR with unknown outcome) (see   | of the existing seriousness       |
| section III.D.3 of this           | criterion "medically              |
| document). This information is    | significant", will certainly      |
| currently submitted to FDA, but,  | result in a further increase in   |
| in most cases, not in an          | the number of expedited reports,  |
| expedited manner. A company that  | with no obvious benefit for       |
| receives a report of an adverse   | effective pharmacovigilance.      |
| drug experience is able, in most  |                                   |
| cases, to determine if it is      |                                   |
| serious or nonserious (i.e.,      |                                   |
| whether it meets the regulatory   |                                   |
| definition of serious), but in    |                                   |
| some cases, this may not be       |                                   |
| possible.                         |                                   |
+-----------------------------------+-----------------------------------+
| *[p. 12414, II.B.3.c. Always      | PvRM considers that this          |
| expedited reports.]{.underline}*  | proposal, which is not part of    |
|                                   | any ICH guideline, would create   |
| FDA is also proposing that        | yet another untested and          |
| companies subject to the agency's | burdensome process with unknown   |
| postmarketing safety reporting    | effectiveness for identifying new |
| regulations always submit to FDA  | risks and hazards of medicinal    |
| in an expedited report certain    | products. Existing regulations    |
| SADRs, which may jeopardize the   | already require all of the        |
| patient or subject and/or require | specified AEs to be expedited     |
| medical or surgical intervention  | reports to FDA if they meet       |
| to treat the patient or subject   | criteria for seriousness,         |
| (e.g., ventricular fibrillation,  | expectedness, and (for clinical   |
| liver necrosis, transmission of   | trials) causality. There are      |
| an infectious agent by an         | obvious difficulties with         |
| approved product) (see section    | uncritical application of this    |
| III.D.4 of this document).        | proposal, e.g. requiring          |
| Currently, all of these adverse   | always-expedited reports of       |
| drug experiences are submitted to | seizures for epileptic patients   |
| the agency for review, but only   | treated with anticonvulsants,     |
| some of them are submitted in an  | anaphylaxis with penicillin,      |
| expedited safety report (i.e., if | cephalosporins, and many          |
| the adverse drug experience is    | biologics, or acute respiratory   |
| serious and unexpected). FDA is   | failure with opiate overdoses,    |
| proposing that all of them be     | which are neither unexpected nor  |
| submitted expeditiously whether   | indicative of any new risk. Even  |
| the SADR is unexpected or         | in the rare situation where a     |
| expected and whether or not the   | safety issue paradoxically mimics |
| SADR leads to a serious outcome.  | the treatment indication, such as |
| This is because of the medical    | the proarrhythmic effects of      |
| gravity of these SADRs. For       | certain antiarrhythmic agents,    |
| example, even though the labeling | contrary to FDA's suggestion that |
| for a product indicates that      | it requires to review each        |
| ventricular fibrillation may be   | individual spontaneous report of  |
| associated with use of the        | the event, single cases cannot be |
| product and thus not subject to   | used to assess and evaluate such  |
| expedited reporting to FDA (i.e., | issues, which are quantitative    |
| SADR is expected), the agency     | rather than qualitative, and can  |
| needs to review each new report   | only be adequately addressed in   |
| of ventricular fibrillation for   | the aggregate. FDA has recognized |
| this product as quickly as        | the futility of attempting to     |
| possible to ascertain if there is | quantitate risk from spontaneous  |
| a qualitative or quantitative     | reports of serious expected       |
| change in the nature of the SADR. | events, stating in its Final Rule |
| Information from these reports    | (Federal Register: June 25, 1997) |
| could result in either new        | that "expedited increased         |
| studies being undertaken to       | frequency reports have not        |
| evaluate the SADR or appropriate  | contributed to the timely         |
| regulatory action by FDA (e.g.,   | identification of safety problems |
| labeling change, distribution of  | requiring regulatory action and   |
| Dear Health Care Professional     | are no longer necessary for FDA   |
| letter, restriction on            | surveillance of postmarketing     |
| distribution of product,          | adverse experiences." The current |
| withdrawal of product from the    | proposal appears to be a modified |
| market).                          | readoption of this known          |
|                                   | ineffective strategy.             |
|                                   |                                   |
|                                   | Finally, as discussed previously, |
|                                   | reporter terminology is often     |
|                                   | inappropriate; many reports of    |
|                                   | "liver necrosis" are nothing but  |
|                                   | minor asymptomatic elevations in  |
|                                   | aminotransferases. Requiring      |
|                                   | events to be considered serious   |
|                                   | simply because of the reporter's  |
|                                   | term, which is often inaccurate,  |
|                                   | rather than the actual clinical   |
|                                   | condition being described, is not |
|                                   | helpful.                          |
|                                   |                                   |
|                                   | For all these reasons, PvRM       |
|                                   | strongly recommends that all      |
|                                   | serious expected events continue  |
|                                   | to be analyzed and reported       |
|                                   | periodically, as specified in the |
|                                   | ICH E2C guideline.                |
+-----------------------------------+-----------------------------------+
| *[p. 12417, III.A.1. Suspected    | As FDA indicates, this change in  |
| Adverse Drug Reaction             | definition, derived from the ICH  |
| (SADR)]{.underline}*              | E2A guideline, will primarily     |
|                                   | affect clinical trial safety      |
| FDA's existing premarketing       | reporting. However, there is no   |
| safety reporting regulations in § | evidence to date that current US  |
| 312.32(a) define ''associated     | regulations for clinical trial    |
| with the use of the drug'' to     | safety reporting are inadequate   |
| mean: ''There is a reasonable     | to protect the health and         |
| possibility that the experience   | well-being of study subjects.     |
| may have been caused by the       |                                   |
| drug.'' ...                       | It is almost NEVER possible to    |
|                                   | "rule out", i.e. definitively     |
| Proposed §§ 310.305(a),           | exclude, a possible causal        |
| 312.32(a), 314.80(a), and         | association, unless (a) the study |
| 600.80(a) would also replace the  | subject was not exposed to the    |
| definitions for ''associated with | investigational agent or (b) the  |
| the use of the drug,'' ''adverse  | event was documented as           |
| drug experience'' and ''adverse   | pre-existing and did not change   |
| experience'' with the following   | during the trial, in which case   |
| definition for ''SADR'': A        | it would not be considered an AE, |
| noxious and unintended response   | i.e. a "treatment-emergent"       |
| to any dose of a drug             | event.                            |
| (''biological'' for proposed §    |                                   |
| 600.80(a)) product for which      | The consequences of adopting this |
| there is a reasonable possibility | approach would be:                |
| that the product caused the       |                                   |
| response. In this definition, the | -   every clinical trial SAE      |
| phrase ''a reasonable             |     would require expedited       |
| possibility'' means that the      |     reporting if it occurred      |
| relationship cannot be ruled out. |     during, or at any time        |
|                                   |     following, exposure to the    |
|                                   |     investigational agent, since  |
|                                   |     a causal relationship "cannot |
|                                   |     be ruled out"                 |
|                                   |                                   |
|                                   | -   every clinical trial SAE      |
|                                   |     would require treatment       |
|                                   |     unblinding to determine the   |
|                                   |     treatment assignment, so that |
|                                   |     a causal association could be |
|                                   |     "ruled out" if, and only if,  |
|                                   |     the subject was not exposed   |
|                                   |     to the investigational agent  |
|                                   |                                   |
|                                   | -   every clinical trial SAE in   |
|                                   |     which the subject was exposed |
|                                   |     to the investigational agent  |
|                                   |     would have to be expedited to |
|                                   |     FDA, and also to              |
|                                   |     investigators and IRBs, who   |
|                                   |     already labor under a huge    |
|                                   |     excess of clinically          |
|                                   |     meaningless and               |
|                                   |     uninterpretable IND 15-day    |
|                                   |     reports                       |
|                                   |                                   |
|                                   | -   expedited reporting would     |
|                                   |     create a totally distorted    |
|                                   |     view of the investigational   |
|                                   |     agent's safety profile by     |
|                                   |     FDA, investigators, and IRBs, |
|                                   |     since only events occurring   |
|                                   |     in subjects exposed to it,    |
|                                   |     but not to comparator         |
|                                   |     agent(s), would be reported   |
|                                   |                                   |
|                                   | -   any worsening of the study    |
|                                   |     indication (e.g.              |
|                                   |     hospitalization for           |
|                                   |     hyperglycemia in a diabetes   |
|                                   |     study, or cancer progression  |
|                                   |     in an oncology trial) would   |
|                                   |     have to be considered a       |
|                                   |     serious unexpected SADR,      |
|                                   |     requiring handling as above,  |
|                                   |     unless specifically agreed    |
|                                   |     otherwise with FDA.           |
|                                   |                                   |
|                                   | This proposal could only be       |
|                                   | meaningfully implemented for      |
|                                   | clinical trials in relatively     |
|                                   | minor illnesses. As presented, it |
|                                   | would essentially halt            |
|                                   | pharmaceutical trials in the US   |
|                                   | for many serious diseases         |
|                                   | (cancer, Parkinson's,             |
|                                   | Alzheimer's, diabetes, heart      |
|                                   | failure, severe infections,       |
|                                   | AIDS), as treatment blinding      |
|                                   | could not be maintained unless    |
|                                   | FDA were to grant wholesale       |
|                                   | exceptions to minimize            |
|                                   | "over-reporting". This would both |
|                                   | create an additional regulatory   |
|                                   | burden and also defeat the        |
|                                   | proposed purpose. Since there is  |
|                                   | no reason to believe that the     |
|                                   | current clinical trial safety     |
|                                   | system is not working adequately, |
|                                   | PvRM recommends that FDA revisit  |
|                                   | this concept and attempt to       |
|                                   | revise ICH E2A to reflect a more  |
|                                   | clinically appropriate definition |
|                                   | and eschew a burdensome           |
|                                   | regulation of dubious necessity.  |
|                                   |                                   |
|                                   | An alternative is to consider the |
|                                   | recent EU Clinical Trials         |
|                                   | Directive, assess its             |
|                                   | effectiveness in Europe, and      |
|                                   | potentially adopt a similar       |
|                                   | approach. This would have         |
|                                   | advantages for both FDA and       |
|                                   | sponsors of harmonization with    |
|                                   | another major regulatory          |
|                                   | jurisdiction "to eliminate        |
|                                   | unnecessary reporting burdens on  |
|                                   | industry so that companies can    |
|                                   | focus on the safety profiles of   |
|                                   | their products and not on the     |
|                                   | different reporting requirements  |
|                                   | of different regions."            |
+-----------------------------------+-----------------------------------+
| *[p. 12421, Section III.A.7.      | PvRM supports FDA's assessment of |
| Spontaneous Report]{.underline}*  | the lack of clinical utility of   |
|                                   | class action suits, but suggests  |
| The proposed rule would consider  | that this provision should cover  |
| SADR information compiled in      | [all]{.underline} lawsuits        |
| support of class action lawsuits  | against companies for alleged     |
| to be neither spontaneous nor     | adverse drug effects. Not only    |
| ''study'' information. FDA        | are these neither spontaneous nor |
| believes that the vast majority   | clinical study reports, they are  |
| of SADR information from class    | deliberately designed to be       |
| action lawsuits is duplicative    | prejudicial to the defendant      |
| (*i.e.*, the same SADR            | company, and thus often allege    |
| information is reported by        | multiple harms to maximize        |
| multiple individuals). In many    | potential damage claims. Many     |
| cases, information in addition to | cases are vague, medically        |
| the minimum data set is not       | unsubstantiated, and when         |
| available for these SADR reports  | defended often result in a        |
| and followup is unlikely to       | judgement for the defendant.      |
| result in acquisition of new      | There are also situations in      |
| information. For these reasons,   | which the alleged harm is an      |
| the agency is proposing to        | expected consequence of the drug, |
| require in TPSRs, PSURs and IPSRs | e.g. suits alleging addiction to  |
| summary information for SADRs     | prescription narcotic analgesics, |
| from class action lawsuits...     | or other events described in US   |
|                                   | labeling, which lawyers often use |
|                                   | to identify potential litigation  |
|                                   | targets. In the absence of more   |
|                                   | reliable sources of information,  |
|                                   | e.g. spontaneous reports, no      |
|                                   | medically important information   |
|                                   | relevant to the safety of the     |
|                                   | product is identifiable from      |
|                                   | these cases, which should         |
|                                   | therefore be handled differently  |
|                                   | from both study and spontaneous   |
|                                   | reports.                          |
|                                   |                                   |
|                                   | One additional aspect of legal    |
|                                   | cases should be clarified. During |
|                                   | the legal discovery process, many |
|                                   | hundreds, thousands, or even      |
|                                   | millions of pages of medical      |
|                                   | records and related documentation |
|                                   | are provided to the defending     |
|                                   | company. These records, which     |
|                                   | frequently cover long periods of  |
|                                   | therapy in relatively ill         |
|                                   | patients, often contain           |
|                                   | documentation of multiple         |
|                                   | clinical occurrences that occur   |
|                                   | either during or after exposure   |
|                                   | to the accused product. In        |
|                                   | general, these occurrences are    |
|                                   | not related or relevant to the    |
|                                   | alleged harm, or have ever been   |
|                                   | identified by the recorder as a   |
|                                   | SADR for the product. FDA should  |
|                                   | clarify that such incidentally    |
|                                   | found events, for which the       |
|                                   | recorder has not indicated either |
|                                   | an *a priori* or *post hoc*       |
|                                   | suspicion of causality with the   |
|                                   | product, should not be captured   |
|                                   | as adverse events, to avoid       |
|                                   | massive "over-coding" and         |
|                                   | "over-reporting" of extraneous    |
|                                   | and irrelevant information. This  |
|                                   | is particularly important in      |
|                                   | light of the revised definition   |
|                                   | of causality, in which any        |
|                                   | clinical event temporally         |
|                                   | associated with a drug will have  |
|                                   | to be considered drug-related     |
|                                   | because a relationship "cannot be |
|                                   | ruled out."                       |
|                                   |                                   |
|                                   | These cases should be codifed to  |
|                                   | reflect the alleged harm (e.g.    |
|                                   | "drug addiction") only, and no    |
|                                   | additional events whatever should |
|                                   | be extracted from medical records |
|                                   | unless specifically identified by |
|                                   | the recorder as SADRs for the     |
|                                   | company's product(s).             |
|                                   | Furthermore, whatever the harm    |
|                                   | alleged, such cases should not be |
|                                   | subject to expedited reporting    |
|                                   | unless a health professional      |
|                                   | [directly involved in the care of |
|                                   | the patient]{.underline} (as      |
|                                   | opposed to an external expert     |
|                                   | witness) specifically identifies  |
|                                   | an unexpected event as serious    |
|                                   | and attributable to the drug      |
|                                   | concerned.                        |
+-----------------------------------+-----------------------------------+
| *[p. 12430, Section               | The wide variety of reports for   |
| III.C.5]{.underline}*             | which active query is required    |
|                                   | will, as stated earlier, create a |
| Proposed §§ 310.305(c)(1)(iv),    | very large burden for health      |
| 314.80(c)(1)(iv), and             | professionals both in companies   |
| 600.80(c)(1)(iv) state that, for  | and in clinical practice, with    |
| reports of serious SADRs, always  | relatively little benefit to the  |
| expedited reports, and medication | public health. It is impractical  |
| error reports, manufacturers and  | for FDA to "**require**           |
| applicants would be required to   | *(emphasis added)* submission of  |
| submit a full data set for the    | complete information for reports  |
| report (see section III.D.4 of    | of serious SADRs, always          |
| this document for discussion of   | expedited reports, and medication |
| always expedited reports and      | error reports", since companies   |
| section III.D.5 of this document  | are very often unable to obtain   |
| for discussion of medication      | the necessary follow-up despite   |
| error reports). If a full data    | repeated attempts. In the         |
| set is not available for the      | majority of cases, where the      |
| report, the manufacturer or       | event in question is well         |
| applicant would be required to    | understood and adequately         |
| use active query to obtain this   | reflected in the product's label, |
| information. If a full data set   | this degree of follow-up is       |
| is not available, after active    | entirely unnecessary. These very  |
| query, the manufacturer or        | onerous and burdensome activities |
| applicant would provide the       | should be reserved for serious,   |
| following information:            | unexpected SADRs, which are the   |
|                                   | most likely to be of real         |
| -   All safety information,       | significance for the public       |
|     received or otherwise         | health, and not for all the types |
|     obtained, for the report;     | of reports suggested. Here again, |
|                                   | the effect of FDA's proposed      |
| -   The reason(s) for their       | changes to labeling, which will   |
|     inability to acquire a full   | result in many more SAEs being    |
|     data set; and                 | unlabeled, must be taken into     |
|                                   | consideration.                    |
| -   Documentation of their        |                                   |
|     efforts to obtain a full data | The proposed rule does not        |
|     set (*i.e.*, description of   | specify any reporting format for  |
|     unsuccessful steps taken to   | documenting the required          |
|     obtain this information).     | follow-up activities. There are   |
|                                   | no fields on form 3500A or in the |
| In some cases, the agency has     | ICH E2B specification for         |
| received incomplete safety        | recording this information, and   |
| reports for serious SADRs, making | capturing it in narrative text in |
| interpretation of their           | the absence of a codification     |
| significance difficult. This      | scheme does not support database  |
| proposed amendment would require  | searching to identify relevant    |
| submission of complete            | cases. The pharmacovigilance      |
| information for reports of        | value of this information to FDA  |
| serious SADRs, always expedited   | is not clear, and the exercise    |
| reports, and medication error     | itself seems to be another        |
| reports, which would facilitate   | regulatory burden with no direct  |
| their expeditious review.         | or indirect public health         |
|                                   | benefit.                          |
+-----------------------------------+-----------------------------------+
| *[p. 12431, III.C.7. Lack of      | PvRM supports FDA's approach,     |
| Efficacy Reports]{.underline}*    | consistent with its stated goal   |
|                                   | of avoiding unnecessary and       |
| ...FDA would not require          | burdensome activities to allow    |
| submission of individual case     | companies to focus on real        |
| safety reports for reports of a   | product safety issues, of         |
| lack of efficacy. Instead,        | requiring expedited reporting of  |
| applicants would be required to   | the types of clinically important |
| submit to FDA expedited reports   | information described here.       |
| of information sufficient to      | However, the basis on which a     |
| consider a product administration | "greater than predicted"          |
| change, based upon appropriate    | frequency of lack of efficacy     |
| medical judgement, for any        | could be assessed is entirely     |
| significant unanticipated safety  | unclear, since even controlled    |
| finding or data in the aggregate  | clinical trials often give        |
| from a study that suggests a      | substantially differing efficacy  |
| significant human risk. For       | results. Such information can     |
| example, applicants would be      | almost never be derived from      |
| required to submit information    | spontaneous reports, with the     |
| concerning reports of a lack of   | possible exception of reports of  |
| efficacy with a drug or           | microbial resistance to an        |
| biological product used in        | antibiotic taken in the correct   |
| treating a lifethreatening or     | dose and duration for a           |
| serious disease \... In addition, | culture-confirmed susceptible     |
| applicants would be required to   | organism; this type of            |
| include in postmarketing periodic | information is tracked elsewhere  |
| safety reports (*i.e.*, TPSRs,    | in the public health system and   |
| PSURs, IPSRs) an assessment of    | should not be considered "safety" |
| whether it is believed that the   | information in and of itself. In  |
| frequency of lack of efficacy     | short, it is impossible in        |
| reports is greater than would be  | practice to comply with this      |
| predicted by the premarketing     | proposed periodic assessment, and |
| clinical trials for the drug or   | PvRM recommends very strongly     |
| biological product \... This      | that this provision be deleted    |
| assessment would be provided for  | from the Final Rule.              |
| reports of a lack of efficacy     |                                   |
| whether a serious SADR,           |                                   |
| nonserious SADR, or no SADR       |                                   |
| occurs. Applicants that submit    |                                   |
| PSURs and IPSRs to FDA would also |                                   |
| include in these reports a        |                                   |
| discussion of medically relevant  |                                   |
| lack of efficacy reports (*e.g.*, |                                   |
| might represent a significant     |                                   |
| hazard to the treated population) |                                   |
| for a product(s) used to treat    |                                   |
| serious or life-threatening       |                                   |
| diseases.                         |                                   |
+-----------------------------------+-----------------------------------+
| *p. 12432, III.D.3. Unexpected    | This provision will create        |
| SADRs With Unknown Outcome*       | another reporting timeframe that  |
|                                   | is outside ICH standards, and     |
| FDA expects that, in most cases,  | also raises the specter of        |
| manufacturers and applicants will | "second-guessing" of companies by |
| be able to determine the outcome  | regulators. If it is maintained   |
| for an SADR (whether the SADR is  | in the Final Rule, most companies |
| serious or nonserious). However,  | will take a conservative approach |
| in those few cases where a        | to such reports, categorize them  |
| determination may not be          | as "medically significant", and   |
| possible, FDA would require       | report them within 15 days,       |
| submission of unexpected SADRs    | rather than the proposed 45. As   |
| with unknown outcome in an        | many of these cases will not have |
| expedited manner (proposed §§     | subsequent information provided,  |
| 310.305(c)(2)(iii),               | the net effect will be to add     |
| 314.80(c)(2)(iii), and            | more cases with poor data quality |
| 600.80(c)(2)(iii)). Expedited     | to the AERS database, This        |
| safety reports for unexpected     | provision should be deleted from  |
| SADRs with unknown outcome would  | the Final Rule, as it is          |
| be submitted to FDA within 45     | inconsistent with international   |
| calendar days after initial       | standards and will add nothing to |
| receipt by the manufacturer or    | good pharmacovigilance practice.  |
| applicant of the minimum data set |                                   |
| for the unexpected SADR. FDA is   |                                   |
| proposing this action to expedite |                                   |
| review of potentially serious     |                                   |
| SADRs.                            |                                   |
+-----------------------------------+-----------------------------------+
| *[p. 12432, Section II.D.4.       | Given FDA's previously stated     |
| Always Expedited                  | position that a causal            |
| Reports]{.underline}*             | association is possible unless it |
|                                   | can be explicitly ruled out, the  |
| The agency is proposing that a    | impact of this provision will be  |
| confirmed or suspected            | to make any reported infection in |
| transmission of an infectious     | a patient treated with any        |
| agent by a marketed drug or       | product immediately reportable to |
| biological product would be the   | FDA. Despite the illustrative     |
| subject of an always expedited    | examples given, the impossibility |
| report.                           | of proving a negative and the     |
|                                   | conservative approach of most     |
|                                   | companies will result in          |
|                                   | expedited reporting of all        |
|                                   | reported infections, regardless   |
|                                   | of product. Even if FDA were to   |
|                                   | specify that this provision       |
|                                   | applies only to parenteral        |
|                                   | products, as appears to be the    |
|                                   | intent, every IV line infection   |
|                                   | will require expedited reporting, |
|                                   | since it will not be possible to  |
|                                   | rule out the possibility that the |
|                                   | parenteral solution itself, or    |
|                                   | any of the medications            |
|                                   | administered through it, was the  |
|                                   | source of the "transmission". FDA |
|                                   | should reconsider this proposal,  |
|                                   | and either remove it as redundant |
|                                   | to the "medically significant"    |
|                                   | seriousness reporting criterion,  |
|                                   | or else strictly define the       |
|                                   | circumstances in which it would   |
|                                   | be applicable.                    |
+-----------------------------------+-----------------------------------+
| *[pp 12444-5, Section             | As previously stated, the         |
| III.F.2.]{.underline}*            | proposed rule does not consider   |
|                                   | the imminent implementation of    |
| ICH has developed an              | electronic submission of ICSRs    |
| international medical             | via E2B and M2. The effect of     |
| terminology, MedDRA (the medical  | MedDRA updates on follow-up paper |
| dictionary for regulatory         | reports should be considered. For |
| activities), to support the       | example, if a MedDRA PT used to   |
| computerization and transmission  | codify an event becomes           |
| of information related to many    | non-current, would a follow-up    |
| aspects of the regulation of      | report containing a new concept   |
| medical products (ICH M1). Use of | but providing no additional       |
| a single medical terminology      | information concerning the        |
| internationally would facilitate  | previously reported concept be    |
| global communication of safety    | expected to show the previously   |
| information for human drug and    | reported but non-current PT, or   |
| biological products (see section  | the current PT which has replaced |
| II.B.1 of this document).         | it, despite the absence of any    |
|                                   | new information? FDA should offer |
| Proposed §§ 310.305(d)(2),        | guidance to industry to avoid     |
| 314.80(c)(4)(ii), and             | unnecessary recodification while  |
| 600.80(c)(4)(ii) would require    | maintaining appropriate           |
| that each SADR in an individual   | specificity and dictionary        |
| case safety report be coded on    | currency for retrieval purposes.  |
| the FDA Form 3500A, CIOMS I Form, |                                   |
| or VAERS Form using the           | See also comments on p 12454,     |
| appropriate ''preferred term'' in | Section V.D. regarding the use of |
| the latest version of MedDRA in   | the term "latest version of       |
| use at the time the manufacturer  | MedDRA" and pp 12413-4, Section   |
| or applicant becomes aware of the | II.B.3.a. regarding the           |
| individual case safety report.    | codification of medication        |
| FDA is proposing to require use   | errors.                           |
| of MedDRA to be consistent with   |                                   |
| ICH M1.                           | FDA is correct in believing that  |
|                                   | MedDRA wil be enthusiastically    |
| Proposed §§ 310.305(d)(2),        | adopted by the majority of        |
| 314.80(c)(4)(ii), and             | pharmaceutical companies. As      |
| 600.80(c)(4)(ii) would also       | previously pointed out, many      |
| require that each individual case | companies have already            |
| safety report of a medication     | implemented MedDRA voluntarily    |
| error be coded both as a          | for both marketed and             |
| medication error and, if          | investigational products. Given   |
| applicable, with the preferred    | the general recognition of        |
| term for any SADRs associated     | MedDRA's overall benefits and     |
| with the medication error. The    | value, the circumstances in which |
| proposal clarifies how actual and | use of MedDRA might cause         |
| potential medication errors would | economic hardship should be       |
| be coded.                         | better defined. Any entity that   |
|                                   | maintains a safety database may   |
| FDA believes that use of MedDRA,  | reasonably be expected to use     |
| a standardized medical            | MedDRA in its reports to FDA.     |
| terminology, will be welcomed by  | Only organizations that have no   |
| most of industry. However, for    | safety reporting responsibilities |
| some manufacturers and            | under this proposed rule, or that |
| applicants, use of MedDRA may     | have a reporting requirement but  |
| result in a significant economic  | insufficient numbers of reports   |
| hardship. Applicants may request, | to require a safety database of   |
| under §§ 314.90 or 600.90, that   | any type, should be exempt from   |
| FDA waive the requirement that    | using MedDRA. However, FDA should |
| each SADR in an individual case   | provide guidance on the           |
| safety report be coded using      | appropriate method of reporting   |
| MedDRA. If FDA finds that this    | in these circumstances; it is     |
| requirement is economically       | suggested that such applicants    |
| burdensome for a small company,   | should submit their reports as    |
| the agency intends to grant the   | narrative text only, so that FDA  |
| company a waiver. A large company | can assign the appropriate MedDRA |
| may also be granted a waiver if,  | terms, rather than assigning      |
| for instance, it only markets a   | terms from another,               |
| single product that generates a   | non-harmonized terminology.       |
| few safety reports a year. FDA    |                                   |
| intends to grant all reasonable   |                                   |
| waiver requests. This             |                                   |
| determination will be made on a   |                                   |
| case-by-case basis.               |                                   |
+-----------------------------------+-----------------------------------+
| *[p 12451, Section                | The replacement of multiple       |
| V.C]{.underline}*                 | dictionaries by MedDRA does       |
|                                   | create the potential for enhanced |
| This rule would ...require the    | retrieval and analysis of safety  |
| use of MedDRA, a medical          | data. However, the use of MedDRA  |
| dictionary developed by the ICH,  | cannot *per se* improve the       |
| in coding SADR terms. MedDRA will | **quality** of safety analyses,   |
| provide a uniform, consistent and | which depends on multiple other   |
| specific presentation of medical  | steps and processes throughout    |
| terms. By eliminating the use of  | the collection, entry, and        |
| multiple dictionaries, MedDRA     | analysis of safety data. Methods  |
| would facilitate the retrieval,   | and procedures for improving the  |
| presentation, and summarization   | accuracy and completeness of      |
| of SADR data and enhance the      | clinical information relevant to  |
| global communication and          | SADRs are recommended elsewhere   |
| acceptance of safety information  | in the proposed rule, but there   |
| and reports. The use of a single  | is no mention of the need for     |
| dictionary will substantially     | uniform application of accepted   |
| upgrade the quality of safety     | standards to create clinically    |
| analysis by incorporating         | meaningful codified data from     |
| uniformity of terms. MedDRA will  | individual case reports (see also |
| aid in more expeditious and       | comment on pp. 12412-3, Section   |
| broader international drug use    | II.B.I). FDA should thus include, |
| comparisons within a class, and   | either in the final rule itself   |
| prescribing and use decisions.    | or in a supporting guidance, a    |
| Providing more complete           | reference to the ICH MedDRA Term  |
| information and more timely       | Selection: Points to Consider     |
| safety assessments would enhance  | document, which provides helpful  |
| the ability of the manufacturers  | advice on developing reasonably   |
| to more quickly identify,         | uniform approaches to safety data |
| monitor, and communicate the      | codification. Without             |
| potential risks and benefits of   | (relatively) uniform codification |
| marketed drugs and biologics.     | practices among the many users of |
|                                   | MedDRA worldwide, together with   |
| *[p 12452, Section                | agreed definitions and criteria   |
| V.C.2]{.underline}*               | for categorizing medically        |
|                                   | important terms and methods to    |
| ...Standardizing the terms and    | mitigate the confounding effects  |
| improving the quality of the      | of reporter miscategorization as  |
| roughly 250,000 safety reports    | discussed above, the goal of      |
| submitted annually to FDA would   | comparing the safety profiles of  |
| lead to better and more timely    | similar products using data       |
| safety assessments and to         | codified by multiple reporting    |
| improved communication of risk    | entities will be extremely        |
| information. The widespread use   | difficult to achieve. The         |
| and acceptance of standardized    | challenge of achieving an         |
| SADR information by regulators    | acceptable level of uniformity    |
| would ultimately enhance drug     | will become even more acute once  |
| comparisons within a class and    | the majority of SADRs are entered |
| drug prescribing and use          | into AERS by direct electronic    |
| decisions.                        | transmission from multiple        |
|                                   | companies.                        |
+-----------------------------------+-----------------------------------+
| *[p 12454, Section                | The concept of "latest version of |
| V.D.]{.underline}*                | MedDRA" requires definition.      |
|                                   | There is a lag period between the |
| Each SADR in a postmarketing      | release of a new version of       |
| individual case safety report for | MedDRA by the MSSO and its        |
| human drugs and biologics must be | implementation by users. Current  |
| coded using the appropriate       | "best practice" for MedDRA        |
| ''preferred term'' in the latest  | version updating is that \"A new  |
| version of MedDRA.                | release version of MedDRA should  |
|                                   | become the reporting version on   |
|                                   | the first Monday following the    |
|                                   | second month after it is          |
|                                   | released." SADR reports submitted |
|                                   | during the period between the     |
|                                   | MSSO release date and the         |
|                                   | implementation date will not in   |
|                                   | fact be codified in the "latest"  |
|                                   | version. To avoid ambiguity or    |
|                                   | confusion, e.g. by an FDA         |
|                                   | investigator conducting an audit, |
|                                   | FDA should define "latest         |
|                                   | version" in terms of the date the |
|                                   | version is implemented in the     |
|                                   | relevant database(s), rather than |
|                                   | the MSSO release date, This is    |
|                                   | also essential for electronic     |
|                                   | submissions. (See also comment on |
|                                   | update reports (pp 12444-5,       |
|                                   | Section III.F.2.)                 |
+-----------------------------------+-----------------------------------+
| *[p 12455, V.D.1.b]{.underline}*  | There should be little additional |
|                                   | burden solely as a result of      |
| ...the proposed rule requires     | using MedDRA for the activities   |
| that every individual case safety | referenced in sections            |
| report submitted to the agency be | V.D.i.b.i - V.D.i.b.vii, although |
| assigned an appropriate MedDRA    | there may be a change in the type |
| code. Although individual case    | of personnel needed (see comment  |
| safety reports are currently      | on p 12461-2, Section V.E.3.b.)   |
| submitted for most SADRs,         |                                   |
| depending on the type of SADR,    | FDA's use of the phrase "MedDRA   |
| the proposed rule may impose an   | code" is misleading. Every MedDRA |
| additional burden on health       | text term, from SOC to LLT, has a |
| professional personnel if active  | corresponding 8-digit numeric     |
| query is not already used         | code, which is used for database, |
| routinely by a manufacturer or    | translation, and other IT         |
| applicant. Regulatory affairs     | purposes; it appears that FDA     |
| personnel working with the health | means that every ICSR should be   |
| professional may spend additional | assigned (an) appropriate MedDRA  |
| time assigning the MedDRA code    | term(s).                          |
| and documenting the active query. |                                   |
| The agency seeks comment on the   |                                   |
| reasonableness of the estimates   |                                   |
| of the time burden and the type   |                                   |
| of employee anticipated to        |                                   |
| fulfill the new requirements      |                                   |
| detailed in the following         |                                   |
| paragraphs.                       |                                   |
+-----------------------------------+-----------------------------------+
| *[pp 12459-60, Section            | This section, derived from the    |
| V.D.2.]{.underline}*              | ERG report dated 5 January 2001,  |
|                                   | contains several implicit or      |
| FDA contracted with ERG to        | explicit assumptions of unproven  |
| estimate the industry cost of     | validity, viz.                    |
| using MedDRA terms to code        |                                   |
| individual case safety reports... | 1.  The total amount of work, and |
|                                   |     therefore the cost,           |
| Limitations on ERG cost           |     associated with MedDRA        |
| estimation include the            |     implementation and            |
| complexities associated with      |     maintenance is directly       |
| firms' abilities to separate      |     proportional to the size and  |
| incremental costs from factors    |     complexity of the             |
| that substantially influence      |     organization                  |
| expenditures, such as integrating |                                   |
| operations of one or more newly   | 2.  Most small firms (e.g. blood  |
| merged corporations, isolating    |     facilities) will not have     |
| U.S. corporate policies and       |     databases requiring           |
| operations from global corporate  |     conversion                    |
| policies and operations, and      |                                   |
| reaching consensus on the extent  | 3.  Many small firms will use     |
| and timing of the conversion of   |     external agencies, e.g. CROs, |
| historical SADRs and data.        |     to handle their regulatory    |
|                                   |     reporting obligations         |
| *[V.D.2.a. One-time               |                                   |
| costs]{.underline}*               | 4.  Autoencoding software is      |
|                                   |     required only for legacy data |
| *[V.D.2.a.i. Planning and         |     conversion                    |
| coordination.]{.underline}*       |                                   |
|                                   | 5.  Standard operating procedures |
| Companies will need to allocate   |     (SOPs) for small firms are    |
| time to plan and coordinate the   |     much less complex and require |
| conversion of MedDRA across their |     less revision than those for  |
| affected operations. Planning     |     large firms                   |
| costs are affected by the extent  |                                   |
| of decentralization of coding and | 6.  Database complexity and       |
| pharmacovigilance work within the |     validation are proportional   |
| corporate structure. Managers for |     to company size               |
| drug and biologics firms are      |                                   |
| expected to spend from 240 hours  | 7.  Drugs and biologics firms of  |
| for very small firms to 1,400     |     comparable size and           |
| hours for very large firms        |     complexity will have          |
| (greater than 750 or 500          |     different burdens of effort   |
| employees respectively for drug   |                                   |
| and biologics firms) for planning | 8.  Blood facilities, newly       |
| and coordination. Costs per       |     required to report many more  |
| company ranged from \$10,800 to   |     events than previously, will  |
| \$64,500 for drug and biologics   |     experience little impact and  |
| firms. In contrast to drug and    |     will be able to use a very    |
| biologics firms, blood facilities |     limited subset of MedDRA      |
| have a limited range of products, |     terms for categorization of   |
| do not need to convert legacy     |     serious events following      |
| data, and typically operate only  |     transfusion.                  |
| in the United States. Therefore,  |                                   |
| ERG judged that compliance costs  | PvRM believes that the above      |
| for blood facilities would be 4   | assumptions are seriously flawed  |
| to 5 percent of equivalent-sized  | for the following reasons:        |
| drug and biologics firms.         |                                   |
| Estimated costs per firm range    | -   The figures in the ERG report |
| from \$450 to \$2,260 for very    |     derive from estimates         |
| small and very large firms,       |     collected during 1999, when   |
| respectively.                     |     almost no companies had       |
|                                   |     implemented MedDRA; actual    |
| *[V.D.2.a.ii. Development of      |     experience is now available   |
| information technology support    |     and should either be          |
| structure.]{.underline}*          |     incorporated into the cost    |
|                                   |     assumptions or, at a minimum, |
| Companies reported that           |     used to validate them         |
| information technology (IT)       |                                   |
| personnel will need to modify     | -   The annual MedDRA             |
| existing database systems to:     |     subscription fee is the only  |
|                                   |     cost component explicitly     |
| Accommodate adding a new medical  |     linked to company size        |
| dictionary,                       |                                   |
|                                   | -   The scaling of estimated      |
| Allow for MedDRA's complex        |     costs of different            |
| hierarchical structure and wider  |     MedDRA-related activities by  |
| field widths,                     |     company size is unfounded.    |
|                                   |     For example, the price of an  |
| Reconcile the comparability of    |     autoencoder is unrelated to   |
| existing dictionaries with MedDRA |     company size, so that the     |
| (in the short term),              |     suggested autoencoder         |
|                                   |     cost:size ratio of 4:1 for    |
| Integrate a Web browser, and      |     pharmaceutical and 4.5:1 for  |
|                                   |     biologics firms has no        |
| Install or modify an autoencoder  |     apparent basis, Conversely,   |
| system.                           |     economies of scale in larger  |
|                                   |     organizations make the cost   |
| IT personnel are estimated to     |     per employee of MedDRA        |
| need from 720 hours for very      |     training substantially lower  |
| small firms to 1,920 hours for    |     for large than for small      |
| very large firms to develop and   |     companies. There is also no   |
| validate computer data systems    |     reason to believe that        |
| that will accommodate MedDRA.     |     biologics firms will have     |
| Costs are estimated to range from |     lower costs than traditional  |
| \$25,850 to \$68,900 for drug and |     pharmaceutical companies of   |
| biologics firms. No costs were    |     comparable size (cf. the      |
| forecast for blood facilities.    |     illustration in Table 3-1 of  |
|                                   |     the ERG report of personnel   |
| *[V.D.2.a.iii. Purchase or        |     training costs of \$133,241   |
| development of an                 |     for a 625-person              |
| autoencoder.]{.underline}*        |     pharmaceutical company vs.    |
|                                   |     \$63,910 for a 625-person     |
| Companies reported that they      |     biologics company). Rather,   |
| currently use an existing         |     it is far more likely that    |
| database such as COSTART or       |     MedDRA implementation costs   |
| WHOART and supplement these       |     will depend on the type of    |
| dictionaries with their own       |     database and product mix the  |
| medical vocabulary. Autoencoders  |     company has, which need not   |
| assist with the automated         |     correlate with the molecular  |
| conversion of existing medical    |     nature of its products, its   |
| terms to MedDRA. Companies may    |     total number of employees. or |
| purchase autoencoders, adapt      |     its revenue. Small companies  |
| existing in-house versions, or    |     are also much less likely     |
| use outside contractors.          |     than large ones to have the   |
| Converting existing terms to      |     requisite in-house capability |
| MedDRA is estimated to cost from  |     for implementing and          |
| \$20,000 to \$100,000 for drug    |     maintaining MedDRA and will   |
| and biologics firms. Costs are    |     therefore need external       |
| not applicable to blood           |     support, incurring additional |
| facilities.                       |     cash (as opposed to overhead) |
|                                   |     operating costs.              |
| *[V.D.2.a.iv. Conversion of       |                                   |
| legacy safety data.]{.underline}* | -   The assumptions regarding     |
|                                   |     blood facilities are          |
| Some companies reported that they |     unevaluable. FDA currently    |
| would convert virtually all of    |     requires reporting only of    |
| their legacy data into MedDRA     |     fatal transfusion reactions,  |
| terms even though it is not       |     and thus receives very few    |
| required by this proposed rule.   |     reports. Estimates are        |
| Some companies maintain that this |     lacking of the number, and,   |
| conversion includes information   |     more important, the nature of |
| from clinical trials.             |     reports that will be received |
| Nonetheless, some companies may   |     from blood facilities under   |
| not convert their legacy drug     |     the proposed rule. However,   |
| safety data into MedDRA or may    |     the number is likely to       |
| convert only some of their        |     increase substantially, as is |
| products, based on criteria       |     the variety of clinical       |
| associated with experience and    |     events reported; thus, it     |
| history of the drug. ERG          |     will probably be necessary    |
| estimated that 75 percent of      |     for at least the larger       |
| companies would incur conversion  |     facilities to implement       |
| costs to allow for the range of   |     MedDRA in their databases.    |
| company responses. The number of  |                                   |
| terms that are converted          | -   There is a stated presumption |
| automatically (with autoencoders) |     that blood facilities may     |
| or manually will affect           |     require only a subset of      |
| conversion costs. Estimated costs |     MedDRA terms for their SADR   |
| per company for converting        |     reporting. It is accepted     |
| existing legacy data range from   |     that the majority of MedDRA   |
| about \$16,500 (for converting    |     terms will not be applicable  |
| 15,000 terms) for very small      |     to blood product reactions;   |
| firms to \$275,000 (for           |     however, to a greater or      |
| converting roughly 250,000 terms) |     lesser degree, this is        |
| for very large drug firms. Costs  |     equally true for every        |
| for biologics firms of            |     medicinal product, each of    |
| corresponding size range from     |     which requires only a small   |
| \$3,300 (for 3,000 terms) to      |     minority of the terms         |
| \$55,000 (for about 50,000        |     available in MedDRA to        |
| terms). Costs are not applicable  |     capture and describe its      |
| to blood facilities.              |     entire safety profile. Thus,  |
|                                   |     it is not possible to         |
| *[V.D.2.a.v. Training of          |     identify prospectively which  |
| personnel.]{.underline}*          |     terms may or may not be       |
|                                   |     needed. Furthermore, any      |
| Companies reported that staff     |     attempt to create             |
| most likely to receive MedDRA     |     application-specific subsets  |
| training include medical coders,  |     of MedDRA terms will          |
| biostatisticians, and             |     invalidate the multi-axiality |
| pharmacovigilance, IT, and        |     which is one of the most      |
| regulatory affairs personnel. In  |     important attributes of       |
| addition to formal training,      |     MedDRA,.                      |
| medical data coders will require  |                                   |
| several months of experience      | > MedDRA v 6.0 contains the       |
| before they become proficient     | > following terms related to      |
| with coding in MedDRA. Training   | > transfusion reactions:          |
| costs are dependent on the number | >                                 |
| of employees that must be trained | > HLT Transfusion related         |
| in MedDRA and the level of        | > complications                   |
| training needed for their         | >                                 |
| relevant duties. Training costs   | > PTs: Hepatitis post transfusion |
| were estimated to range from      | >                                 |
| \$9,300 to \$330,300 for very     | > Refractoriness to platelet      |
| small to very large drug          | > transfusion                     |
| manufacturers and from \$9,300 to | >                                 |
| \$90,600 for biologics firms of   | > Transfusion reaction            |
| corresponding size. ERG estimated | >                                 |
| training costs from \$1,300 to    | > Transfusion with incompatible   |
| \$4,300 for very small to very    | > blood                           |
| large blood facilities.           | >                                 |
|                                   | > Transfusion-related acute lung  |
| *[V.D.2.a.vi. Revision of         | > injury                          |
| standard operating procedures     | >                                 |
| (SOPs).]{.underline}*             | > It is clear that these terms    |
|                                   | > alone cannot adequately         |
| Companies will revise a           | > represent all the clinical      |
| substantial group of SOPs in      | > events that may be associated   |
| implementing MedDRA. Affected     | > with blood product transfusion, |
| procedures include                | > which include many general      |
| dictionary/coding, IT, and drug   | > systemic symptoms and signs as  |
| safety/ pharmacovigilance. Drug   | > well as actual or potential     |
| and biologics firms are expected  | > transmission of a variety of    |
| to need from 130 to 1,300 hours   | > infectious agents. The examples |
| for very small to very large      | > given in the proposed rule      |
| firms to revise their SOPs for    | > illustrate this well, viz.      |
| MedDRA, with costs ranging from   | >                                 |
| \$5,900 to \$59,200. ERG          | > *"...FDA received reports from  |
| allocated 8 to 50 hours for       | > a blood establishment of        |
| developing or revising SOPs for   | > allergic adverse reactions ...  |
| blood facilities. Per firm costs  | > The symptoms included bilateral |
| for SOPs are estimated to range   | > conjunctival edema, severe      |
| from \$370 to \$2,260 for very    | > headaches, eye pain, nausea     |
| small to very large blood         | > sometimes associated with       |
| facilities.                       | > vomiting and joint pain.*       |
|                                   | >                                 |
|                                   | > *... a blood collection center  |
|                                   | > ...had numerous donors with     |
|                                   | > vasovagal reactions that        |
|                                   | > required treatment by emergency |
|                                   | > medical personnel."*            |
|                                   | >                                 |
|                                   | > Thus, unless FDA can specify *a |
|                                   | > priori* what clinical events,   |
|                                   | > and their corresponding MedDRA  |
|                                   | > PTs, it will consider to be     |
|                                   | > transfusion-related, facilities |
|                                   | > reporting all                   |
|                                   | > transfusion-related SADRs will  |
|                                   | > have to implement MedDRA in its |
|                                   | > entirety. Even if such subsets  |
|                                   | > of appropriate MedDRA terms     |
|                                   | > could be developed, the         |
|                                   | > practical difficulty of         |
|                                   | > maintaining their currency and  |
|                                   | > uniformity with each MedDRA     |
|                                   | > update remains.                 |
|                                   |                                   |
|                                   | -   There is an erroneous         |
|                                   |     assumption that autoencoders  |
|                                   |     are required only for legacy  |
|                                   |     data conversion. MedDRA is so |
|                                   |     large, rich, and complex that |
|                                   |     its use for any purpose       |
|                                   |     whatsoever requires           |
|                                   |     computerized application      |
|                                   |     tools. SADR codification      |
|                                   |     needs may be met by text      |
|                                   |     manipulation algorithms,      |
|                                   |     synonym lists, etc., which    |
|                                   |     are essential requirements    |
|                                   |     for consistent and accurate   |
|                                   |     codification by different     |
|                                   |     personnel over time and       |
|                                   |     across products and           |
|                                   |     locations. Therefore, any     |
|                                   |     entity that plans to codify   |
|                                   |     data using MedDRA will        |
|                                   |     require some type of          |
|                                   |     autoencoding system, at a     |
|                                   |     cost unrelated to company     |
|                                   |     size.                         |
|                                   |                                   |
|                                   | -   The basis of the ERG estimate |
|                                   |     that only 75% of companies    |
|                                   |     would need to convert legacy  |
|                                   |     data to MedDRA is unclear. It |
|                                   |     is generally not feasible to  |
|                                   |     maintain multiple             |
|                                   |     terminologies in a single     |
|                                   |     safety database. Codifying    |
|                                   |     newer data in MedDRA while    |
|                                   |     leaving historic data in      |
|                                   |     different terminology(ies)    |
|                                   |     would seriously hamper        |
|                                   |     effective pharmacovigilance   |
|                                   |     and create substantial        |
|                                   |     difficulties for periodic     |
|                                   |     aggregate reporting and       |
|                                   |     responses to regulatory       |
|                                   |     agency queries. Therefore,    |
|                                   |     all companies with reporting  |
|                                   |     obligations for marketed      |
|                                   |     products will have no option  |
|                                   |     but to convert 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  |
|                                   |     yet exist. Although clinical  |
|                                   |     analysis requires appropriate |
|                                   |     software tools, their proper  |
|                                   |     use 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      |
|                                   |     personnel retraining 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.     |
+-----------------------------------+-----------------------------------+
| *[p 12460, Section V.D.2.b.ii     | The cost impact of the current    |
| MedDRA versions and quarterly     | semi-annual updates of MedDRA is  |
| updates.]{.underline}*            | not adequately characterized. As  |
|                                   | previously pointed out, by far    |
| Currently the MSSO intends to     | the most significant impact of    |
| provide quarterly updates as well | MedDRA updates, especially major  |
| as periodic new versions of       | version changes involving         |
| MedDRA. Companies did not have a  | alterations to the structure of   |
| sufficient history with           | the hierarchy, is on retrieval    |
| incorporating MedDRA changes to   | and analysis. While in large      |
| estimate the costs of updates.    | companies there is usually no     |
| Cost components would include     | direct monetary cost associated   |
| senior level reviews of each      | with this type of training, it    |
| update, communicating the changes | does have a very significant      |
| to affected personnel, and IT     | unquantifiable cost in time and   |
| support to upload and reconcile   | effort by many highly skilled and |
| new versions. Costs are estimated | highly paid employees (physicians |
| to range from \$5,700 to \$43,000 | and other well-qualified health   |
| for drug and biologics firms. No  | professionals, including doctoral |
| costs were assigned to blood      | level scientists, nurses, and     |
| facilities.                       | pharmacists). However, for        |
|                                   | smaller companies, which do not   |
|                                   | have extensive internal           |
|                                   | resources, and potentially        |
|                                   | require external assistance, the  |
|                                   | financial impact may be very      |
|                                   | disproportionate.                 |
+-----------------------------------+-----------------------------------+
| *[p 12461-2, Section              | PvRM disagrees with the assertion |
| V.E.3.b.]{.underline}*            | that "No additional professional  |
|                                   | skills would be necessary" for    |
| Implementing MedDRA would impose  | "...coding and analysis of SADRs" |
| additional significant one-time   | as a result of the implementation |
| and recurring costs on drug and   | of MedDRA. The limited            |
| biological product manufacturers. | specificity of previous           |
| Costs would vary among individual | terminologies, typically          |
| firms depending on circumstances, | containing fewer than 2000 terms, |
| including the number of products  | often provided no more than one   |
| manufactured, the frequency of    | matching dictionary term for any  |
| SADRs, and the extent of legacy   | given reporter term, and thus     |
| data converted. Table 20 displays | allowed sufficiently accurate     |
| ERG's estimates per firm of       | data codification by personnel    |
| revenues, annualized compliance   | with relatively limited clinical  |
| costs and costs as a percent of   | knowledge. By contrast, the       |
| revenues. Costs for small         | extremely high specificity of     |
| entities are 0.15 percent and     | MedDRA frequently results in the  |
| 0.28 percent of revenues for drug | identification of multiple        |
| and biological product            | related but distinct dictionary   |
| manufacturers, respectively.      | terms reflecting clinical nuances |
| Similarly, average compliance     | of the reported event, and so     |
| costs for small entities are 0.01 | requires greater clinical         |
| percent and 0.03 percent of       | knowledge by the codifier.        |
| revenue for SICs 8062 and 8099,   | Autoencoding is helpful when the  |
| respectively.                     | reported term is an exact match   |
|                                   | for a MedDRA LLT or a term in the |
| The reporting, coding, and        | company's synonym list; however,  |
| analysis of SADRs are standard    | not every exact match is          |
| procedures that manufacturers     | necessarily appropriate (e.g. a   |
| routinely conduct under current   | reported term describing an       |
| regulations. No additional        | adverse event that matches an LLT |
| professional skills would be      | in the Social Circumstances SOC). |
| necessary to comply with this     | In addition, when a reported term |
| rule. However, current safety     | does not have an exact match,     |
| reviewers, analysts, and IT       | identification of all potentially |
| personnel would need training to  | appropriate terms and selection   |
| implement MedDRA.                 | of the most appropriate requires  |
|                                   | understanding both of the         |
|                                   | reported medical concept and of   |
|                                   | the concepts reflected in the     |
|                                   | MedDRA terms. Thus, codification  |
|                                   | personnel using MedDRA need       |
|                                   | substantially greater clinical    |
|                                   | skills than those that were       |
|                                   | adequate for codification using   |
|                                   | e.g. COSTART.                     |
|                                   |                                   |
|                                   | For the same reason, SADR         |
|                                   | analysis using relatively         |
|                                   | non-specific terminologies may be |
|                                   | performed with limited physician  |
|                                   | oversight by other health care    |
|                                   | professionals, such as nurses and |
|                                   | pharmacists. However, the much    |
|                                   | greater clinical depth and nuance |
|                                   | of MedDRA means that most, if not |
|                                   | all, database searches and        |
|                                   | analyses either need to be        |
|                                   | created or, at a minimum,         |
|                                   | reviewed by a knowledgeable       |
|                                   | physician to ensure their         |
|                                   | accuracy and completeness.        |
+-----------------------------------+-----------------------------------+
| *[p 12462, Section                | These two sections appear to be   |
| V.E.4.b.]{.underline}*            | mutually contradictory. On the    |
|                                   | one hand, FDA is requiring that   |
| The agency considered but         | MedDRA be used in ICSRs for       |
| rejected the alternative of not   | medicinal products to ensure      |
| requiring the use of MedDRA terms | uniformity of safety reporting,   |
| in individual case safety         | while on the other, it appears    |
| reports. MedDRA is an integral    | not to require any such           |
| part of the postmarket safety     | uniformity in the increased       |
| reporting system that was         | number of reports considered      |
| developed jointly with            | necessary to protect the safety   |
| international stakeholders.       | of the blood supply. FDA should   |
| Requiring MedDRA terms in safety  | either provide the rationale for  |
| reports will enhance the analysis | this apparent discrepancy in its  |
| of drug safety information.       | approach to safety reporting for  |
| Moreover, MedDRA is a medical     | the protection of the public      |
| dictionary designed to translate  | health, or else require that      |
| terms in multiple languages, thus | blood facilities use MedDRA to    |
| aiding in more expeditious and    | report serious transfusion        |
| broader international drug use    | reactions, as suggested           |
| comparisons and analysis. Not     | previously (see comment on        |
| requiring MedDRA would compromise | section V.D.2.).                  |
| the agency objective of improving |                                   |
| drug safety reporting and         |                                   |
| analysis. In addition, continued  |                                   |
| use of multiple medical           |                                   |
| dictionaries to code SADRs will   |                                   |
| perpetuate the major problems     |                                   |
| with comparing safety data        |                                   |
| globally that currently exist.    |                                   |
|                                   |                                   |
| *[p 12462, Section                |                                   |
| V.E.4.d.]{.underline}*            |                                   |
|                                   |                                   |
| The agency considered but         |                                   |
| rejected the alternative of not   |                                   |
| requiring blood establishments to |                                   |
| submit reports for all serious    |                                   |
| SADRs associated with blood       |                                   |
| collection and transfusion, in    |                                   |
| addition to the current           |                                   |
| requirement to submit reports of  |                                   |
| fatalities. Because these         |                                   |
| establishments are currently      |                                   |
| required to conduct               |                                   |
| investigations and prepare and    |                                   |
| maintain reports of serious       |                                   |
| SADRs, this proposal would impose |                                   |
| minimal costs. However, only some |                                   |
| serious SADRs must be reported in |                                   |
| a timely manner. The agency       |                                   |
| believes it is critical that we   |                                   |
| receive all such reports. This    |                                   |
| would improve the agency's        |                                   |
| ability to take appropriate       |                                   |
| action to protect the blood       |                                   |
| supply more consistently, to      |                                   |
| enhance donor safety and to       |                                   |
| ensure the safety, purity and     |                                   |
| potency of blood and blood        |                                   |
| components for administration to  |                                   |
| patients.                         |                                   |
+-----------------------------------+-----------------------------------+
| *[p 12462, Section                | The annual subscription cost of   |
| V.E.4.f.]{.underline}*            | MedDRA for the smallest firms     |
|                                   | subject to the proposed rule      |
| The agency recognizes that        | cannot be considered onerous      |
| requiring individual case safety  | compared with the cost of         |
| reports to be coded using MedDRA  | maintaining an in-house database, |
| will likely impose significant    | of licensing other                |
| costs on some small firms (see    | subscription-based terminologies, |
| section III.F.2 of this           | such as WHO-ART, or even of the   |
| document). One alternative would  | smallest clinical trial. As       |
| be to consider the option of      | previously suggested (comment on  |
| allowing companies to request a   | pp 12444-5, Section III.F.2.),    |
| waiver from MedDRA coding, based  | the only commercial entities for  |
| on economic hardship. The agency  | which waivers of MedDRA use       |
| is seeking comment on ways to     | should be considered are those    |
| reduce economic hardships of      | that do not have any safety       |
| implementing MedDRA while         | reporting responsibilities under  |
| maintaining adequate procedures   | this proposed rule or that have   |
| to monitor and assess the safety  | insufficient numbers of reports   |
| of products.                      | to require an in-house safety     |
|                                   | database of any type.             |
+-----------------------------------+-----------------------------------+

Pharmacovigilance & Risk Management, Inc. appreciates the opportunity to
provide comments on the proposed rule.

Respectfully submitted,

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