![](media/image1.jpeg){width="2.1875in" height="1.1770833333333333in"}

Number range CHAPTEROctober 13, 2003

Dockets Management Branch

(HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Dear Sir or Madam:

The AIDS Treatment Activist Coalition (ATAC) is a national coalition of
AIDS activists, many living with HIV/AIDS, working together to end the
AIDS epidemic by advancing research on HIV/AIDS, its opportunistic
infections and co-infection like hepatitis C virus, as well as
broadening access to treatment. ATAC's Drug Development Committee (DDC)
works with government, industry and academia to provide a community
perspective to the development of new HIV drugs and the utilization of
HIV therapies. We are writing to provide comments to the proposed
amendments to 21 CFR Parts 310, 312, 314, 320, 600, 601, and 606.

We wish to express our dismay at a number of the changes proposed by the
agency. Initially, we oppose the agency revoking the pediatric rule
issued in December 2, 1998 (63 FR 66632), whereby sponsors are required
to report specific information regarding pediatric populations. We
believe it unconscionable for the agency to turn its back on this
helpless population. Pediatric research, which has historically lagged
far behind research in other populations, will undoubtedly make even
less progress in the future if this requirement is revoked.

We are adamantly opposed to changing the term "adverse drug experience"
as defined in Sections 310.305(b), 314.80(a) and 600.80(a) of FDA's
existing post-marketing safety regulations with proposed Section
312.32(a), which would replace the term "associated with the use of the
drug" with the term "suspected adverse drug reaction" (SADR); and rename
"adverse experience" as "suspected adverse experience" in Section
600.80(a) and throughout the proposed regulations. To make our comments
concise, but very much to the point, we can just imagine industry's
marketing spin on the term "suspected". In this age of marketing frenzy
on the part of industry from magazines to TV, etc., can you imagine the
field day public relations departments will have with the patient
community? We submit that "suspect" should only be used when describing
industry's use of the proposed new term.

We are also extremely concerned with the new definition of "SADRs" in
proposed Sections 310.305(a), 312.32(a), 314.80(a), and 600.80(a). The
proposed definition for an SADR is "\... there is a reasonable
possibility that the product caused the response. In this definition,
the phrase "a reasonable possibility" means that the relationship cannot
be ruled out." The Federal Register notes that "the relationship cannot
be ruled out" will be the controlling language for cases to be reported
to the agency. We contend that if the relationship cannot be ruled out,
it is clearly not "suspected." Further, the concept that "the
relationship cannot be ruled out" is a much more strict standard for
reporting adverse events than the more loosely defined current standard
of "a reasonable possibility that the experience may have been caused by
the drug" found in Section 313.32(a) of existing FDA pre-marketing
reporting regulations. We believe that although "a reasonable
possibility" may be potentially confusing, it greatly avoids the risk of
under-reporting important safety events. The "reasonableness" standard
has been employed in every facet of our nation's common law system since
legal decisions were recorded in England and adopted by the United
States in 1776.

From the perspective of a consumer, we firmly believe that changing the
current definition as proposed will greatly enhance the safety risk to
patients. Thus, we are opposed to the proposed changes and believe that
in no event should the "reasonable possibility" standard be changed to
include, "the relationship cannot be ruled out". For all the foregoing
reasons, we are even more opposed to the definition only being "the
relationship cannot be ruled out," omitting the "reasonable possibility"
language completely. We believe that this alternative is even more
dangerous to patient safety.

The proposed section on IND safety reports found in Section 314.80 does
not seem to address adverse events that may be caused by one or more
experimental agents. Differentiating between drugs to ascertain which
drug in a multi-drug regimen is the probable cause of the adverse
experience does not seem to be considered. We believe that this is a
fatal flaw in this day of multi-drug experiments. We also wonder whether
the new definition which mandates that the causal "relationship cannot
be ruled out" will serve to completely preclude reporting such adverse
events.

We fail to see how the proposed grading system of one (1) through four
(4) will be applied to serious, non-serious, expected, and non-expected
drug reactions in the New Drug Applications rules found in Section
314.80 and throughout the proposed regulations. We believe that it is
imperative that the agency provide more guidance in this regard in
ensure patient safety. Additionally, a patient report is not adequately
described in this section and throughout. Patient reports are also
treated as less than reliable. We fail to see the rationale for this
apparent determination.

We are also vehemently opposed to the changes to the reporting
requirement intervals proposed in Sections 314.80(c)(3)(i), (ii) and
(iv) and 600.80(c)(3)(i) , (ii) and (iv).

Current agency reporting intervals require the submission of
post-marketing periodic safety reports at quarterly intervals for three
(3) years from the date of approval of the application in the United
States. Thereafter, said reports are required annually. FDA is proposing
revisions that would greatly reduce these reporting intervals. In cases
where a marketed drug or biologic product has been approved on or after
January 1, 1998, the agency is now proposing that reporting intervals
should occur only semiannually; i.e., two (2) times per year for two (2)
years after approval in the United States, annually for the next three
(3) years, and every five (5) years thereafter.

Experience clearly shows that most adverse drug reactions are identified
within the first few years of approval. Thus, we firmly believe if these
relaxed regulations are promulgated as currently proposed by FDA,
patient safety will be severely compromised by the very agency that is
charged with protecting consumer safety in this regard.

In the current and proposed regulations set forth in Section 314.80(i)
and(f) respectively, sponsors are required to maintain safety records
for only ten (10) years. We believe that safety records should be
maintained by sponsors for as long as a drug is marketed; and, that said
sections should be amended accordingly.

Data from non-manufacturer initiated studies does not seem to be
contemplated in the proposed regulations. Independent studies have been
an important source of defining and confirming adverse events. How will
safety reporting and requirements be regulated in these studies?

Moreover, race and age as adverse event factors do not seem to be
contemplated. Gender seems to be unevenly recognized as a contributing
factor, required in some reports, but not in others.

On the other hand, we applaud the agency for the new regulations that we
believe will enhance patient safety and modernize its regulations. We
are particularly pleased with a number of other proposed regulations,
exemplified by the following:

The agency's acceptance of the concept of and its attempt to foster
worldwide standardization of medical terminology, as well as regulatory
definitions, reporting forms, documents and reporting requirements where
patient safety is not compromised by the proposed regulation as
previously indicated above.

Ensuring that adverse drug reactions will be reported to FDA if either
the sponsor "OR" the investigator believes it is an adverse drug event.

Ensuring that safety information from both the sponsor's domestic and
foreign study sites will be reported to the agency.

Ensuring documentation of worldwide exposure to a drug.

Ensuring that discordant data will also be reported to the agency
regularly. .

Ensuring that physician supervision will be present in a number of
important instances.

Codifying the definitions and requirements regarding electronic
communications.

Codifying "Guidance Documents" and deletion of redundant and variant
sections.

We sincerely hope that these proposed regulations, especially the new
term for and definition of an adverse drug experience and the new
reporting requirement intervals will not be promulgated by the agency
without the patient community having an opportunity to personally
discuss these proposals with relevant agency personnel.

Please respond to Lynda Dee at 111 North Charles Street, Suite 500,
Baltimore, MD 21201.

Thank you for the opportunity to comment.

Very truly yours,

Lynda Dee, Co-Chair

ATAC DDC

cc: Health and Human Services Secretary Tommy Thompson

FDA Commissioner Mark McClellan

ATAC DDC