This event was reported to Collagen Corporation on 9/14/90, the period
between the 8/29/90 meeting and the 12/6/90 FDA letter. This event has
since been reported as an MDR on 4/26/91 (MDR #228557). However, it
should be noted that since this event was reported to Collagen
Corporation before FDA's 12/6/90 letter, the scar reportability criteria
had not yet been definitively established.
This event was reported as an MDR on 3/19/91 (MDR_ #224867), and was on the list of MDRs given to the Inspectors during their inspection.
ADVERSE CONDITION NOT IN LABELING:
89-01098. 90-03077. 90-03215
These events were all described using the term "granuloma". This is a
histologic term used to describe hypersensitivity reactions, and is used
especially often outside of the U.S. (where all of these reports
originated). Therefore, since these three events all involved temporary
reactions which are described in the product labeling, no MDR reports
were required.
"Some_MDR_reports sent to FDA list an incorrect "Date MFG. Alerted" of complaint. For example Complains 90-02399 (M205007) received by FDA on 7/19/90 reports that manufacturer was alerted of revisional surgery for scar on 7/16/90 but the complaint file records include a copy of a letter dated 6/4/90 on Collagen Corp. letterhead that shows that Collagen was already aware at that time of the surgery."
This was an oversight by Collagen Corporation and has been brought to the MDR staff's attention in a corrective letter dated 4/25/91.
"Adverse reaction reports involving MDR_reportable events which the firm has filed with the FDA were not always reported within the required 5-day_time_limit."
The majority of our MDR reports are submitted according to the time frames specified in the MDR regulation. When reports are submitted late, it is either because a reportable event which was not reported is discovered through an internal audit, a complaint is received in writing from an international source without sufficient detail to clarify the event, the records were not available to conduct necessary follow-up to determine reportability because they were subject to review as part of an FDA inspection, or a variety of other
administrative reasons. We believe that our reporting timeliness is well
within industry averages, and further believe that the FDA must
understand the difficulty imposed by the 5 calendar day time frame,
since extending the 5 day time frame is one of the changes to the MDR
regulation being considered.
"A downgrading of or inaccurately reporting of the severity of adverse
reaction reports received by the firm sometimes leading to lack of MDR
reporting when an MDR should have been reported, was found in
several files we reviewed. For example complaint No. 91-03631 shows
that the treating physician had to incise the treatment sites with a
scalpel and he states he is concerned about the bruising caused by the
treatment and he had fears about possible scarring. This complaint was
recorded in the files as a "25" (beading) only. No MDR was filed."
During the inspectional exit interview, it was noted by the inspectors
that this observation was the most serious observation on the Form 483.
As a result, we asked the inspectors to supply all examples of
"downgrading" that they found so that we could have the opportunity to
address this serious charge. Ten additional complaint file numbers were
provided to us as examples over the phone on 4/23/91. These additional
ten files are addressed below.
The reporting physician described the event as "beading", and stated
that he was concerned about potential scarring caused by the
procedure to remove the beading, not by the beading itself. The record
says that the patient, not the physician. is concerned about the
bruising. In any event, beading and bruising are both temporary and
described in the product's labeling. In addition, a report of "fears about
possible scarring" regardless of whether it is due to the procedure or
the beading, does not constitute a report of a scar. Even if this was a
report of a scar and not a fear of a scar, the required 6 month waiting
period for scars has not yet elapsed. Therefore, we believe this event
was appropriately coded as "25" (beading) and that no MDR report was
required.
Both of these events have been reported to the FDA as MDRs for scars in the category "permanent damage to body structure" (MDR # M211531 for 90-3144, no MDR number for 89-1169 since part of retrospective report submitted 3/6/91). This is the appropriate coding of these events, as agreed upon with the FDA.
Our internal computer coding for these two events did not indicate "24"
(scar). In the case of 90-3144, the lack of the code "24" was an oversight:
although, as noted above, an MDR for a scar was filed. Complaint 89-
1169 was part of the files reviewed in the two-year retrospective review,
and as explained to the inspectors during the inspection, the computer
codes for these records have not yet been updated. Due to time
constraints, Collagen Corporation placed higher priority on submitting
the required MDR reports to the agency in the established time frame,
than on updating our computer files to be consistent with the MDR
reports; however, the worksheets used for the retrospective review
contain a record of the code changes as a result of the review. It was,
and is. Collagen Corporation's intention to update these codes. (The two-
year retrospective review was completed on time and submitted to the
agency on 3/6/91; the current inspection began on 3/25/91.)
La reviewing this complaint file, we were unable to determine why this
file was cited as "downgrading". On 1/30/90, the following symptoms
were reported: inflammation, tenderness, blanching, bruising,
weeping, scab. This event was coded as "22" (necrosis). On 7/26/90, the
physician called to question if he could inject Zyderm Implant at the site
of the previous "necrosis" (his word). On 2/1/91, a report of "some
scarring, probably a little pink" was received. On 2/8/91, the code was
changed to "22, 24" (necrosis, scar), and an MDR was filed as part of the
retrospective MDR reports on 3/6/91. This file was also contained on the
list of MDRs given to the inspectors during the inspection.
In reviewing this complaint file, we were unable to determine why this file was cited as "downgrading". The patient states that she noticed no difference in the areas that were injected. This event was coded as "43" (loss of correction). We believe that this event was appropriately coded and that no MDR was required.
This complaint involved a report from a physician in Greece who wrote
to us regarding a patient with "marks" and "points" shortly after
treatment with Zyplast and Zyderm Implants, respectively. The
physician also sent pictures of this patient. Given the short duration
between treatment and reaction, and the pictures which clearly
depicted a hypersensitivity reaction, the event was coded as *34"
(hypersensitivity). We are assuming the inspectors cited this complaint
because of the use of the term "marks" by the physician, which they
interpreted to be scars. However, the reporting physician is Greek, and
from reading his letter it is clear that he does not have an extensive
command of the English language. Therefore, we relied on the pictures,
which were quite clear, to categorize this event. We believe that this event was appropriately coded and that no MDR was required.
In a letter from a physician in Australia to a physician in California,
the Australian physician describes an adverse event involving
persistent local swelling, fluctuating lumpiness, and intermittent
redness and itching, which the physician called "some form of a local
allergic reaction." In addition, photographs were provided, which have
since been returned to the physician at his request, which depicted a
local hypersensitivity reaction. This event was coded as "34"
(hypersensitivity). We are assuming that the inspectors cited this case
as "downgrading" because it was not coded as "51" (abscess). We
explained to the inspectors during the inspection that an abscess is a
severe form of a hypersensitivity reaction, which is expressed as A
fluctuant mass. We believe that the inspectors interpreted the
"fluctuating lumpiness" described in the physician's letter to be a
"fluctuant mass", distinguishing it as an abscess. The two are medically
quite different, and fluctuating lumpiness is not indicative of an
abscess. Therefore, we believe this event was appropriately coded
and that no MDR was required.
With this complaint, the reporting physician described symptoms
indicative of a hypersensitivity reaction and signed a case report form
indicating only these symptoms, but the patient described the reaction
as a "scar". Since the physician is the more appropriate judge of
whether the patient's symptoms are a hypersensitivity reaction or a
scar, we coded this event according to the health care professional's
judgment, "34" (hypersensitivity). This is consistent with the agency's
letter dated 12/6/90 which states: "If a health care professional reports
the existence of a scar six months after the injection, then you will have
information that reasonably suggests that your product caused or
contributed to a serious injury" (emphasis added). It is understandable
that a patient would call a cosmetically undesirable event such as a
persistent hypersensitivity reaction, a "scar". We believe this event was
appropriately coded and did not require an MDR report.
In cases where we are unable to contact the patient's physician for a
medical evaluation of the symptoms, we use the patient's determination
that a scar is present and file an MDR report accordingly.
Page 10
483 Response
90-03216
This complaint involved a patient (M.S.) who we became aware of in a
letter to Collagen Corporation, dated 10/28/93, from a different patient
(D.S.). Attached to this 10/28/90 letter was a letter to the San Jose
Mercury News, dated 10/11/90, from patient M.S. who states in the letter
that both patients have "permanent scarring". However, when we
contacted patient M.S. in response to the letter, she did not mention
permanent scarring, but rather lumpiness, erythema, and blister-like
hard lesions, which we believed to be a lay person's description of a
hypersensitivity reaction. In addition, as reported with other
hypersensitivity responses, this patient reported an association of these
symptoms with her menstrual cycle and consumption of alcohol.
Consequently, this event was coded as "34" (hypersensitivity). We
believe this event was appropriately coded and that no MDR was
required.
The report of this complaint came from the treating physician who
described erythema at the injection sites for a 1 month period.
Therefore, this event was coded as "34" (hypersensitivity). Subsequent
information from the treating physician was that the patient's reaction
was continuing at 3 months from injection and that the patient reported
she saw another physician who told her she had hypertrophic scarring
and should have a biopsy. This event was not then upgraded to a "34, 24"
(hypersensitivity, scar) because 1) the information about the scar was
third-hand, 2) the information was relayed through a lay person, and 3)
the physician who reported the event to us did not state that a scar had
occurred. Even in the patient's subsequent letter to the reporting
physician she does not say she has scars, but rather describes "marks",
"stripes", "lines", and states that she "looked like" she had scars, which
can be true of the erythema and induration seen with a
hypersensitivity reaction. Therefore, we believe this event was
appropriately coded and that no MDR was required.
Although this complaint involved the use of the term "scar", the time
period between treatment and reaction was less than 1 month. Since the
time course of this event was consistent with that of the onset of a
hypersensitivity reaction and was unusually short for the development
of a scar, we interpreted this event to be a report of the induration and
erythema typical of a hypersensitivity reaction. and the event was
coded as "34" (hypersensitivity). The red, swollen, indurated
appearance of an acute hypersensitivity reaction to bovine collagen
can appear very similar to that of an immature scar even to the trained
eye of a health care professional, if she is unfamiliar with
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