> European Federation of Pharmaceutical Industries and Associations
> (EFPIA) Comments on
>
> 21 CFR Parts 310, 312, 314, 320 600, 601, and 606.
>
> \[Docket No. 2000N-1484\]
>
> Safety Reporting Requirements for Human Drug and Biological Products;
> Proposed Rule (The FDA Tome)

**Introduction**

EFPIA represents the pharmaceutical industry operating in Europe. Its
mission is to promote pharmaceutical research and development in Europe.
Founded in 1978, its members consist of 18 national pharmaceutical
industry associations and 43 pharmaceutical companies involved in eth
research, development and manufacturing of medicines for human use. Our
membership also includes national industry associations in the acceding
countries.

The comments submitted in this document have been written by EFPIA
Pharmacovigilance Ad Hoc Group (PhV AHG).

The PhV AHG welcomes the opportunity to provide comments on the FDA\'s
Proposed Rule \"Safety Reporting Requirements for Human Drug and
Biological Products\" which was released for consultation in March 2003.

The PhV AHG completely supports the Agency\'s intention of promoting
worldwide consistency and quality in the collection of safety
information and submission of safety reports, as well as the stated
objective to harmonise the content of the proposed rule with other
international pharmacovigilance initiatives such as CIOMS and ICH. In
particular, EFPIA welcomes the proposal that MedDRA is used in support
of safety reporting to the FDA -- this recognises that MedDRA has been
developed for this purpose, with significant investment in its
development by industry and regulatory parties. Furthermore, it provides
reassurance that the FDA do not intend using an alternative terminology
for this purpose, something that would entail a significant waste or
resource and effort by both industry and FDA in conversion to yet
another terminology.

In practice, however, the Proposed Rule introduces a number of FDA
specific requirements, which will be contrary to the stated intent of
international harmonisation and common understanding of basic
definitions. In addition certain proposals either:

-   fail to take into account local medical culture and regulation in
    the global environment in which industry operates, or

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-   will potentially deter healthcare professionals from spontaneous
    reporting (particularly in the light of heightened awareness of data
    privacy) or

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-   Impose a level of administrative, non-value-added activity that will
    detract industry safety resources from the key surveillance and
    quality tasks that ultimately translate into promoting patient
    safety.

As there will have been extensive comments received by the FDA from the
US perspective, we have limited our comments to those which are
particularly relevant to Europe, and which highlight the PhV AHGs key
areas of concern:

**1. Definition of a Suspected Adverse Drug Reaction (SADR)**

SADR (Suspected Adverse Drug Reaction) - defined as a noxious and
unintended response to any dose of a drug product for which a
relationship between the product and the response to the product cannot
be ruled out. The FDA gives the following example: \"In some cases an
adverse event may most probably have occurred as a result of the
patient\'s underlying disease and not as a result of the drug, but since
it cannot usually be said with certainty that the product did not cause
the adverse event, it should be considered an SADR.\"

Whilst accepting that the FDAs proposed definition of adverse drug
reaction is directly based on ICH E2A\`s "pre-approval clinical
experience" definition , it has, nevertheless, been taken out of context
of the subsequent recommendation in Section III A1 (Standards for
Expedited Reporting ) which clearly states that "reasonable causal
relationship is meant to convey that there are facts or arguments to
suggest a causal relationship"

The FDA has indicated that the term 'reasonable possibility' is
"potentially confusing\" but, placed in parenthesis to the ICH E2A
clarification given above, we consider the concept to be a well
established and understood principle -- also supported by CIOMS and the
recently finalised European Clinical Trial Directive guidelines. We
would also refer to the ICH E2D guidelines, which reached step 2 in
Brussels in July 2003 and which also, cross-refer to the E2A definition
of adverse reaction. This would indicate an international concensus
supporting the definition of ADR in its entirety

As presented, the proposed rule indicates that an adverse event should
be considered an adverse reaction unless the relationship \"cannot be
ruled out\". This is not an acceptable adoption of the most common
understanding of what constitutes a suspected adverse reaction, as
presented in the ICH E2A guideline and other international guidances.
This is a critical issue. If the rule requires that a causal
relationship exists simply because \"the relationship cannot be ruled
out\", then the consequence would be that any adverse event occurring
after drug administration should then be regarded as a suspected adverse
reaction, given that a temporal relationship inevitably means that the
role of the investigational product in the causation of an adverse event
cannot be totally excluded. In practice, this would mean that almost all
adverse events would then be regarded as suspected adverse reactions,
thereby completely negating any value in the distinction drawn between
an adverse event and an adverse reaction.

Use of FDA's definition would result in almost every serious unexpected
adverse event including \"incidental events\" being reported to FDA,
worldwide authorities and investigators as an expedited Safety Report,
since a relationship could rarely be totally ruled out. The example
given by FDA in the proposal (an event most probably related to the
patient's underlying disease, but for which a relationship with the
investigational drug cannot absolutely be eliminated) underscores this
point.

One impact of this interpretation will be a significant increase
(estimated as approximately tenfold) in the number of IND Safety Reports
submitted to FDA and to investigators and IRBs particularly for long
term post-marketing studies that can extend over several years. This
increase will make the detection of true safety signals more difficult
due to the increased \"noise\". Investigators and IRBs have complained
about the current abundance of uninformative IND Safety Reports, and the
proposed change will increase their administrative burden without adding
any true value.

A potentially more significant impact of the revised definition of
"reasonable possibility" relates to the need to unblind all serious
unexpected adverse events, potentially compromising the integrity of
clinical trials that have a large number of serious adverse events. The
Agency suggests that protocols could be written to exclude certain
disease-related events that are study endpoints or in high
morbidity/mortality studies from expedited reporting. However, this is a
rather unwieldy approach when applied to other common serious events
that may not be study endpoints.

**Recommendations**

-   The definitions presented within this proposed rule should, wherever
    possible, match those presented within the ICH E2A guideline, which
    provides definitions for the pre- and post-marketing situations.

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-   It is more appropriate that the rule provides support for the
    concept that there is a reasonable possibility of a causal
    relationship if there are positive reasons for such a judgement
    rather than on the basis of simply being unable to totally exclude a
    drug\'s role.

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-   Since one of the stated objectives of the proposed regulations is to
    harmonise with international initiatives, we would urge the Agency
    to consider the EU Clinical Trial Directive and CIOMS VI proposals
    regarding reports to investigators. These documents recommend
    submission of periodic (e.g., quarterly) line listings to
    investigators during Phase I-III, instead of individual expedited
    reports. These periodic summaries should be accompanied by a summary
    of the evolving safety profile of the investigational product.
    Although the Agency would continue to receive individual reports in
    an expedited fashion, periodic summaries of safety information from
    clinical trials would be more informative for investigators and
    IRBs, and would be easier for them to manage administratively.

**2. Active Follow-up**

Under Sections III.C.5 and III.D.6 the FDA proposes

1.  the requirement of the \'full data set\' together with the need for
    active (non-postal) follow-up by a Health Care Professional (HCP)

2.  to obtain this within 30 days (or to provide reasons and
    documentation showing why the full set could not be obtained).

In the EU environment this could have a detrimental impact on
spontaneous reporting i.e. if the HCP knew that potentially every time
he/she reports there will be a need for extensive follow-up via a direct
dialogue (face to face or telephone) with the company (rather than allow
a practice manager or nurse to do some of the form filling) - then
he/she may not report at all!

This also takes into account the heightened awareness and sensitivities
around data privacy, as well as local medical culture and regulation
which some EU countries e.g. Italy do not permit the Marketing
Authorisation Holder (MAH) to actively obtain follow-up information.
Under the provisions of the Italian Legislative Decree No 95, (Article
4, Comma 6, Requirements for the Local Health Units) - follow-up is on
suspected adverse reaction reports may only be undertaken by the
Pharmacovigilance Responsible Person of the respective Local Health Unit
or a designee or personnel of the Ministry of Health). If the MAH does
not comply with the obligations the organisation will be subject to
extensive fines.

**2.(i) Autopsy/Death Certificate/Hospital Discharge Summary**

Under Section III.D.7, the FDA proposes that the MAH must obtain and
translate into English the autopsy report/death certificate/discharge
summaries for all deaths and all hospitalisations.

Again, in the European Union (EU) such documents are not always easily
obtained and there are often local procedures and/or legal requirements
in place impacting their availability to industry (e.g. with regard to
patient consent/data privacy).

Death certificates cannot be obtained in some countries e.g. The
Netherlands. The physician who diagnoses death in a patient completes
the death certificate part A and B . **A** is for the town hall,
required to declare the patient\'s death and has no information on cause
of death only natural/non-natural and is directly sent to them, **B** is
an anonymised document used for national health statistics and therefore
of no utility for case follow-up. For the medical records there are only
the physician\'s notes.

In other countries, particularly in the third world, the poor health
care system standards make it impossible to obtain supporting
documentation such as autopsy reports, even if it were possible to
contact the reporter. Post-mortem examinations may not be done at all in
other countries for religious reasons.

**Recommendations**

The requirement for active query and provision of autopsy reports and
other personal documentation [should be limited to case reports of US
origin.]{.underline}

**3 . PSURs**

The proposed regulation refers to ICH E2C but does not take into account
the recently released addendum that was based on CIOMS V recommendations
and offered practical pragmatic solutions.

The new requirement to submit IPSRs (Interim Periodic Safety Reports) on
year 7.5 and 12.5 presented as abbreviated forms of PSURs is in fact
more demanding than the CIOMS or ICH suggested abbreviated or addendum
reports format (which many companies have already implemented). Also
this may complicate significantly the establishment of a global PSUR
schedule and may require more documents to be written for old products
where in general periodicity is every 5 years or annually but never
every 2.5 years .

The new requirement of semi-annual submission of Individual Case Safety
Reports as 3500 A forms instead of accepting the PSURs listings is a
redundant requirement and seems of no added value. It will create
unnecessary significant extra-work for the industry.

It is unclear what are the expectations of the FDA regarding increased
frequency assessment after it has been previously revoked. The
requirement to assess whether it is believed that the frequency of lack
of efficacy reports is not greater compared to pre-marketing clinical
trial data is inappropriate as we all know that we do not collect all
lack of efficacy reports from the spontaneous reporting area and the
difficulties in obtaining a correct denominator.

FDA requests cumulative data for all SADRs that are serious & unlisted.
This is in many instances impossible due to the large number of cases is
some PSURs. The ICH Addendum to E2C clearly recommends including
cumulative data only for selected cases/issues considered by the company
of medical relevance.

**Recommendations**

-   FDA should follow ICH E2C (S) as closely as possible with
    US-specifics as addenda if required.

-   The requirement for the semi-annual submission of ICSRs should be
    revoked. FDA should leave it to expedited reports and PSURs.

-   The requirement for the Annual Report should be revoked. FDA should
    consider whether specific features of the Annual Report can be part
    of the addenda of the PSURs.

-   The requirement for the IPSR should be revoked and the ICH agreed
    periodicity be adopted.

**4. Definition of Contractor and Exchange of Safety Information**

As it currently stands, the proposed definition of contractor seems to
include licensing partners. Many companies are involved in literally
hundreds of such alliances at a corporate and local level involving
multiple partners and, for legitimate business reasons there is no
\"standard \" licensing agreement so each will have its own unique set
of arrangements (in licensing, out licensing, co promotion in some
countries, co-marketing in other countries, local divestment etc) - the
permutations can be endless. In addition, there will be situations where
licensing partners hold independent marketing authorisations in
different countries and where there are local divestment arrangements
for \"legacy\" products that have been on the market for many years.

Whilst we support the need for prompt safety data exchange in any
licensing agreement, the proposed requirement to exchange all adverse
event reports within 5 calendar days, including those which do not meet
the minimum required data set, with all the contractors stipulated, will
be inordinately complex and burdensome. Neither will it bring true
benefit in terms of promoting patient safety. For alliances with foreign
companies, particularly Japanese partners, the deadline would be almost
impossible to meet due to translation. Equally, it would not be
practical for a European or US based licensor to undertake local
follow-up in, for example, Japan on behalf of the Japanese licensee.

The implications of imposing this deadline in co-marketing agreements
(ie where two or more companies hold independent marketing
authorisations in different countries) are significant:

1.  The partners would be expected to translate and exchange incomplete
    information in a time frame that is significantly shorter than
    expected for expedited reporting in the countries where they hold
    the marketing authorisation.

2.  There would be the need to implement 2 processes for handling case
    reports - one for the co-marketing agreements and one for handling
    internally generated (non-alliance) reports.

3.  The 5 day time frame would force companies to exchange raw data vs a
    completed CIOMS / MedWatch form so, at any given time, the partners
    would hold potentially different information on their respective
    databases, including different narratives and possibly coding. As
    such, different authorities around the world would receive different
    versions of the same report, which is clearly a highly undesirable
    situation. If completed forms are exchanged this facilitates more
    rapid processing of the case, utilising the same AE terms and
    narratives.

4.  Each case would inevitably require multiple iterations and follow-up
    reports as more information will inevitable come in after such a
    short exchange period. This is highly inefficient and hardly
    conducive to the \"quality\" reports that agencies wish to receive.

**Recommendations**

-   Given the complex nature of licensing agreements and the need to
    promote quality and efficiency and at the same time ensure that
    sponsors and marketing authorisation holders meet their regulatory
    obligations, we would urge the FDA to adopt a more flexible approach
    in its definition of contractor and the time frames stipulated for
    safety data exchange.

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-   We would also recommend that whatever provisions are ultimately
    finalised in the Rule, they only apply to prospective agreements in
    order to avoid the re-negotiation of hundreds of agreements already
    in existence.

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-   It seems reasonable to include paid vendors (e.g. CROs ) or
    co-promotion partners

> (ie in agreements where Company A is co-promoting a product on behalf
> of Company B as the marketing authorisation holder) in the definition
> of contractor. We would, however, recommend the exclusion of
> co-marketing partner companies who hold independent authorisations in
> different countries for a given product or, at least, propose a
> different arrangement for safety data exchange.

-   The analogous situation in co-development agreements would relate to
    sponsorship of a given study ie where company B is conducting a
    study in Country X and company A is the partner and sponsor of the
    study, the term contractor would apply but would exclude situations
    in which companies A and B are conducting studies in different
    countries with separate sponsorship status.

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-   Companies should also be allowed the flexibility of allowing
    licensees to undertake local follow-up where appropriate and
    particularly in countries where local medical culture and language
    are important considerations.

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-   In the interests of promoting quality and efficiency only cases
    meeting valid case criteria should be exchanged with the
    understanding that every attempt should be made to obtain the
    information

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-   In the \"redefined\" contractor situations given above, it seems
    reasonable to exchange serious adverse event information in the 5
    calendar days indicated to ensure that the marketing
    authorisation/sponsor can meet expedited reporting requirements. We
    would also recommend a longer time frame for non-serious spontaneous
    case reports eg monthly, as these are not expeditable.

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-   In co-marketing and independent sponsorship situations, we recommend
    that the reporting clock start when the marketing authorisation
    holder/sponsor of each respective company receives the minimum
    information and wherever possible, the time frame for regulatory
    submission should be no longer than 15 days from first receipt by
    the second company. This allows the case to be processed through the
    first company's case management process according to internal
    procedures and exchanged with the partner no later than 15 calendar
    days by way of a completed CIOMS/MedWatch form allowing the second
    company to quickly enter the same information on their own database,
    eliminating the potential for discrepancies and allowing more rapid
    and efficient handling and submission to the authorities as
    appropriate. Once electronic data exchange becomes established
    receipt and submission by the second company will become virtually
    simultaneous.

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-   A shorter time frame could be made for fatal/life threatening
    reports to accommodate the 7-calendar day submission time frame in
    clinical trials/co-development situations.