**Pharmaceutical Safety Assessments, Inc.**

Gerald A. Faich MD, MPH Telephone 610. 664.1088

President Fax 610.664.1148

104 Foxhall Lane Email: <gfaich@yahoo.com>

Narberth PA 19072

**To:** Public Record**, Docket no. 02N-0528**

> FDA Workshop on [Pharmacovigilance and Pharmacoepidemiology, April 11,
> 2003,]{.underline} Washington

**From:** Gerald Faich MD MPH

**Re:** Public Comments

**Date:** April 8, 2003

**Introduction and Disclosure:**

As the former Director of the Office of Epidemiology and Biostatistics
from 1983 to 1990 and as one who has worked with a large number of
sponsors on pre and postmarketing safety issues, I am most interested in
FDA's concept papers on Pharmacovigilance and epidemiology. I commend
FDA for the thoughtful work contained in these papers and largely agree
with their content. My remarks are to respond to FDA's request for
suggestions and concerns. The views I present are mine alone. I hold no
stock nor have any financial interest in any sponsor company, however, I
have provided consultative services to a large number of companies. Also
I am on the Board of Directors for a company specializing in clinical
safety services, Sentrx, Inc.

**Responses to FDA questions (lines 78-117)**

**1. Spontaneous report case quality\
**

Much attention has been given to reporting elements, forms, standardized
coding and regulatory requirements for spontaneous case reports. The key
to further improvement is to focus on the content of reports and the
most important way to improve content is to focus [on the process of
information intake.]{.underline} It is imperative to obtain as much
information as possible on the first encounter with the reporter and to
simultaneously identify missing data. The best way to do this is to use
trained health care professionals at a call center equipped with
computer-assisted interview technology. This technology is not merely
word-processing; instead it uses a structured, branching logic to guide
the intake of information. This approach can aid greatly in
standardizing information as well. For example, the categorization of
the anatomic location of signs and symptoms could be a starting point.
Once its location is the "chest" then appropriate questions related to
pain, shortness or breath and the like can be prompted. There are a
number of specific programs for doing this and FDA should investigate
these and encourage their use.

In terms of use of spontaneous reports, it should be further emphasized
that they are most important for preliminary signaling. In the words of
a draft statement from an International Society of Pharmavigilance
(ISoP) panel, it must be recognized that volume for a drug is affected
by:

-   Volume of use

-   Publicity -- regulatory and manufacturer and lay media

-   Recency of marketing

-   Type and severity of the event

Therefore the reporting rate is not a true measure of the rate or the
risk . The ISoP panel also noted that reporting is a method with a very
high sensitivity and low specificity. An observed event may be due to
the indication for therapy rather than the therapy itself (e.g. suicide
after anti-depressant ); therefore observed report associations should
be viewed as signal detecting, and causal conclusions drawn with caution

**2. Data mining advantages and disadvantages (lines 464-466)**

The FDA and other databases have evolved over time. This introduced a
variety of variables e.g. volume, quality, requirements, waivers which
affected report volume and type. In addition, numerous nonbiologic
influences, for example labeling and publicity, affect reporting,.
Reported adverse events for a drug are greatly affected by the
indication for use of the drug and the patient population exposed. For
these reasons, false signals are inevitable in any data mining activity.
Moreover, data mining is grounded only on the information coded and
entered into the database and this may be incomplete.

Two examples of false signals are emblematic of the false signal
problem. WHO concluded that Claritin was associated with cardiac
arrhythmias in a letter to Lancet. FDA reviewers responded by pointing
out that the reports involved high risk patient with preexisting
arrhythmias and risks resulting in channeling to the drug that was
safest. This illustrates the need to examine all the data available and
not only those data in the electronic database.

The second example is that of Prozac and suicide where confounding by
indication, i.e. the relationship of depression to suicide and publicity
must be taken into account. One suggestion to lessen the problem of
confounding by indication is to primarily use data mining within a
therapeutic class.

**3. Causality Assessments-advantages and disadvantages ? (lines
324-372)\
**

It has long been recognized (see Koch-Weser 1968) that there is no
standard method for causality assessment and that inter and
intra-evaluator reproducibility of causality assessments is low. Given
this and the time and resource consumptive nature of causality
assessments for spontaneous sADR reports, they should be used only when
a signal has arisen. Much of the work in causality assessment goes to
distinguishing between probable and possible caseness, a distinction of
dubious value. [Routine]{.underline} causality assessments of
spontaneous reports were dropped at FDA in 1983 because of its limited
value and because it was a major source of delay in entry and
contributed to backlogging. Hopefully, regression to an inefficient and
low utility activity can be avoided based on prior experience. Of
course, all these considerations are made worse by incomplete data found
in the reports themselves, but even if data were complete the value
would be problematic.

Whenever causality assessments are done, care should be taken to note
these are done as preliminary efforts to assist in interpreting patterns
of reporting and do not represent definite conclusions (secondary
incomplete records, legal implications).

For serious trial reports, where event monitoring is being done,
causality assessment has an appropriate role. It should be noted that
the new proposed safety regulations (March 14 Federal Register, the
"Tome") calls for report submission to FDA when causality cannot be
ruled out. This has the potential of clogging the system and undermining
the value of expedited reporting and should be reconsidered returning to
the "reasonable possibility" standard.

**4. Registries (lines 186-209)**

Several key issues have arisen relative to registries related to sizing
(power), duration, feasibility and data collection. FDA should recognize
that to go from ruling out a risk of 3 or more to 2 or more may add many
thousand of person-years to a study and recognize the feasibility
implications of this. Another real world issue that conditions the
feasibility of registries is the needed duration of follow-up. Drop outs
are a fact of life; in many cases a dropout rate of 20% per year should
be anticipated. Thus, very long follow-up (except via National Death
Index) may not be feasible. From experience it is evident that following
patients for more than 5 years is not generally realistic. Lastly, it is
important to consider obtaining at least preliminary data directly from
patients. This is necessary due to patient and physician mobility. For
example, patients are well able to recall sentinel events (e.g.
hospitalization or biopsy) which then can be appropriately follow-up for
detailed data.

**Other Suggestions-large simple safety trials (LSSTs)**

As recognized in the risk assessment concept paper, LSSTs done in the
periapproval period can be most important to investigating risk and
assuring safety. These should be seen as drawing on pharmacoepidemiology
because of their safety focus and because their design is much akin to
cohort studies (broad inclusion criteria, simple focused data
collection). Most important for more passive observational studies, one
must remember that these traditional studies, even using automated
databases, will be delayed until enough penetration of the drug of
interest into populations has occurred. As noted by the ISoP panel
"Large simple safety trials (LSSTs) and structured cohorts, such as
Prescription Event Monitoring (PEM), started in the peri-approval period
can provide relevant risk information for anticipated ADRs and should be
encouraged ."\
\
**Summary:**

1.  For spontaneous case reports, the means to improve content is to
    standardize and improve intake

2.  Data mining is an interesting tool, but likely will generate many
    false positives and affirmations of what was previously known

3.  Causality assessments should largely be reserved for refining
    important signals

4.  Registry challenges of size, duration and data collection are
    markedly intertwined with feasibility issues

5.  Large safety trials need epidemiologic input

6.  The PE-PV concept paper overall is excellent.