**Executive Summary**

#### NDA 21-177

#### New Formulation Isotretinoin

**Applicant**: HLR Technology Corporation

> (Hoffman-La Roche), Nutley NJ

**Pharmacologic Category**: Retinoid

**Dosage Form**: Soft Gelatin Capsules (7.5 mg, 15 mg, 22.5 mg)

**Route of Administration**: Oral

**Proposed Indication:** Severe recalcitrant nodular acne (with
qualifiers unchanged from currently approved Accutane® labeling)

**Summary Date:** August 9, 2000

**[Introduction]{.underline}**

Accutane "NF" is a new formulation of isotretinoin, a drug substance
that was approved in 1982. The indication remains severe recalcitrant
nodular acne. The Sponsor's stated reason for pursuing this new
formulation is that improved bioavailability will allow once daily
dosing with or without food, as opposed to twice daily with food as per
labeling for the current Accutane® formulation. The Sponsor is aware
that the name "Accutane NF" is unacceptable because "NF" is widely
recognized as "National Formulary". Nonetheless, for the purposes of
this review, the ***new formulation** under review will be referred to
as "**NF**", and the **currently marketed formulation** as "**AC***".

The proposed labeling for NF is based on the "backbone" of tradename AC.
The development program for NF was designed to supplement the data
already available for AC. There are five pharmacokinetic studies in the
application and one multi-center clinical trial. The objective of the
clinical trial was to compare the efficacy and safety of the new
formulation of isotretinoin administered once daily without food versus
currently marketed Accutane®administered twice daily with food. The
pharmacokinetic studies are of pivotal importance to this application.

####### 

####### Biopharmaceutics

####### 

####### Formulation

# The Accutane NF product is a micronized form of the current Accutane soft gelatin capsules currently marketed. The NDA indicates that by reducing the particle size of isotretinoin, bioavailability was significantly enhanced over the current product. Similar examples of the effect of micronization on bioavailability exist for other drugs such as nitrofurantoin and griseofulvin. 

# Pharmacokinetic Comparison of Accutane NF and Accutane

Throughout the NDA the Sponsor states that the current Accutane product
produces plasma levels 240% greater than those seen with Accutane NF.
While true, the doses of drug are *[not]{.underline}* comparable: they
are comparing 70mg of Accutane to 30mg of Accutane NF or 70mg/30mg
\*100% = 233%. The micronizing of isotretinoin simply eliminates the
need for food to enhance the bioavailability of the drug product. The
net result is that if one took 30mg of current Accutane with a high fat
meal, it would look like 30mg of Accutane NF (fed or fasted). See figure
below for comparison.

###### **[Isotretinoin Levels]{.smallcaps}** 

![](media/image1.wmf)

True estimates of the bioavailability of isotretinoin are not possible
without an intravenous dose. However, using this data in a "relative"
comparison between the products, it appears that the NF formulation is
approximately 15% more bioavailable than current Accutane on a mg to mg
basis.

# **Clinical Summary of Trial Design, Procedures, and Analysis Plan**

The clinical trial was a randomized, double-blind, parallel group,
multicenter design. The study design included a screening/baseline
evaluation followed by randomization to receive either AC capsules,
twice daily at a total dose of approximately 1 mg/kg, along with placebo
capsules, or to receive NF, at a once-daily total dose of approximately
0.4 mg/kg, along with placebo capsule(s), for a period of 20 weeks.
Patients in the AC treatment group were dosed as directed in the package
insert, twice daily with food (breakfast and dinner), and received
placebo in late evening at least 2 hours after dinner. In order to
maintain the double-blind status, the patients taking NF received
placebos for two meals (breakfast and dinner) and active drug once per
day in late evening. No dose adjustments were allowed in this trial.

The safety population consisted of all patients who were randomized and
who received at least one dose of medication. This population is
therefore identical to the Intent-To-Treat (ITT) population. The
Standard (STD) population analysis included patients who (a) did not
have any major protocol violations, (b) had complied to the extent of
returning 20% of the allocated study drug, (c) had completed at least 12
weeks of treatment, and (d) had not used Ortho Tri-Cyclen as a method of
contraception. Comments refer to this as the Per Protocol (PP)
population.

The primary efficacy variable was the change from baseline to Week 20 in
the total number of nodular lesions. These were counted at baseline and
at the completion of treatment. At the final visit (Week 20), the lesion
count was performed after the global assessment was done. The minimum
duration of treatment required for evaluation for efficacy was 12 weeks.
A supportive analysis on the proportion of patients who achieved at
least a 90% reduction of baseline total nodular lesion count was also
done. Secondary efficacy variables were the change from baseline to Week
20 in the number of non-nodular inflammatory lesions (papules and
pustules), and global response at the end of the treatment (Week 20).
Summary statistics were provided for need for retreatment and change of
total nodular lesion count from baseline at Week 20 for women using
Ortho Tri-Cyclen® as contraception.

Safety endpoints were adverse events, prospectively defined as any
adverse change from the patient's baseline (pre-treatment) condition,
including intercurrent illness, which occurred during the course of the
clinical study after treatment had started, whether considered related
to treatment or not. Adverse medical conditions present at baseline that
became worse following exposure to study drug were also to be reported
as adverse events. Abnormal laboratory test values were also recorded.

The labeling for marketed Accutane served as the safety guide for
investigators. Because the trial was designed and implemented prior to
the March 1998 labeling change regarding psychiatric adverse events,
mood was specifically monitored. The purpose was protection of study
subjects; the trial was *not* intended or designed to study the
association of isotretinoin and psychiatric symptoms.

The mood evaluation questions were:

1\. When you were on Accutane (since your last visit) have you felt
depressed, sad or blue much of the time?

2\. When you were on Accutane(since your last visit) have you often felt
helpless about the future?

3\. When you were on Accutane(since your last visit) have you had little
interest or pleasure in doing things?

4\. When you were on Accutane(since your last visit) have you had
trouble sleeping many nights?

Patients who answered "yes" to two or more of these questions while
undergoing treatment were asked to complete a Beck Depression Inventory
(BDI-II). The Sponsor proposed that If the score was 30, the patient
would be permitted to continue in the study; if the score was 31, the
patient would be discontinued from the study drug. However, the Division
advised the Sponsor not to use the BDI as the criterion for
discontinuation, but to leave the decision to the investigators'
clinical judgment. As will be summarized below under Results,
implementation of this protocol procedure appears to have been
problematic. This inconsistency in implementation significantly affects
interpretation of the safety results in this comparison trial.

# 

# 

# **Study Results**

### 

### Population

A total of 657 patients were screened for enrollment at 17 centers: 302
were randomized to receive NF and 300 were randomized to receive AC. Two
randomized patients chose not to participate and returned all
medication, therefore the ITT population consisted of 600 patients, 300
in each arm. Eighty-seven percent of patients in the NF group and 85% in
the AC group completed the study. Each center enrolled from 7 to 76
evaluable patients. Treatment groups were comparable with respect to
age, sex, race, weight and height (dosing was weight adjusted). A total
of 244 females were enrolled. About 80% of patients in each treatment
group were Caucasian with the remainder distributed among Black,
Oriental, Hispanic and Other racial categories.

[Efficacy]{.underline}

According to our biostatistical analysis, NF was marginally less
effective than AC as measured by the proportion of patients who had at
least 90% reduction in nodules after a 20-week course of therapy (the
95% confidence interval does not quite cover zero and the upper
endpoints of the intervals are close to zero). Therapeutic equivalence
is, however, supported by equivalent global assessments and relapse
rates *in the overall population* (no greater need for retreatment in
the NF arm). Furthermore, the need for retreatment [^1] in the NF arm
was consistent with published figures for marketed Accutane®, about 20%.

The published literature suggests that pediatric-aged patients may have
higher acne relapse rates after isotretinoin treatment than older
patients. Retreatment requirements are particularly important for
pediatric-age patients because they may still be growing and
isotretinoin affects the musculoskeletal system. There were 92 patients
per arm aged 12-17. While the percentage reduction in total nodules did
not show any statistically significant difference between AC and NF in
this pediatric population, 77% of subjects in the AC arm had at least
90% reduction in nodular lesions vs. 64% in the NF arm. In addition,
about 26% in the NF arm required re-treatment, while about 14% required
re-treatment in the AC arm.

Relapse is also of particular concern for women of childbearing
potential, since retreatment increases the chance of fetal exposure.
Although the sample size is too small to allow conclusions (19 and 21
patients per arm), the proportion of

women using [OrthoTri-Cyclen®]{.underline} who had at least 90%
reduction in nodular lesions was 57% in the NF arm, as compared to 84%
in the AC arm. This trend was also observed for total inflammatory
lesions: 74% of women using AC vs. 33% using NF achieved at least 90%
reduction.

While the overall trial supports the therapeutic equivalence of AC and
NF, these subset results suggest that AC may have been slightly more
efficacious than NF [at the dosage tested]{.underline}. The Sponsor
stated that isotretinoin exposure from the administration of 0.4
mg/kg/day NF under fed or fasted conditions was calculated to fall
within the lower end of the range of the expected drug exposure from the
administration of recommended doses of AC with food. The current
recommended dosage range for ACfor the treatment of severe recalcitrant
nodular acne is 0.5 to 2.0 mg/kg/day given with food in two divided
doses. The dosage of AC used in the clinical trial in this application
was 1 mg/kg with food. According to the Sponsor, it is likely that
patients who received AC in the therapeutic study had approximately 240%
higher exposure to isotretinoin than the subjects who received NF. Since
therapeutic equivalence was demonstrated in the adequately powered total
trial population, it would appear that the *currently recommended dosing
range for Accutane*® *may be too high*. This is of considerable clinical
importance because many of the side effects of isotretinoin are
dose-dependent. Even those that would appear to be "non-serious" (e.g.
mucocutaneous effects, transient moderate hypertriglyceridemia) can lead
to treatment discontinuation for patients who might otherwise greatly
benefit by completing a course. Available dose-ranging studies for
Accutane® do not definitively establish that even the lower end of the
currently labeled dosage is the *minimum* effective dose.

## Safety

The total safety population for NF is 583 subjects, 300 of whom
participated in the clinical equivalence study. The remainder
participated in the PK studies.

Sixteen patients from each treatment group withdrew because of adverse
events. Eight patients in each group "refused treatment". The lost to
follow-up population during the 20 week treatment phase was 3.7% and
6.7% patients, respectively, in the NF and AC groups. At the Week 36
assessment for acne relapse, 68 of the 516 patients who completed the
study in the ITT population were lost to follow-up.

While the proportion of patients with early termination was equivalent
between arms, the reasons for discontinuation were not. Seven of the 16
for NF involved the nervous system, including 5 with psychiatric
symptoms. For AC, 6 of 16 involved elevated triglycerides, 3 for
headache, and none for psychiatric events. It should also be noted that
8 additional patients in each arm terminated early for refusal to take
medication. The reason for their refusal is unknown. The number of
discontinuations for psychiatric symptoms is probably a poor comparative
measure of safety due to problems with the criteria for discontinuation.
However, there is no readily apparent reason why such problems would be
unbalanced between arms. This issue will receive further discussion
below.

In the NF group, a total of 1362 adverse events were reported involving
296 of 300 patients. In the AC group, 1450 adverse events were submitted
involving 293 of 300 patients. Over 95% of all patients experienced
adverse events that were considered as probably related to the study
drug. Approximately 15% of all adverse events were coded as unrelated to
study drug. The majority of adverse events (about 90%) were mild or
moderate in intensity. Of the 1362 adverse events reported by patients
in the NF group, 10.7% were *severe*; in the AC group, the corresponding
number was 11.6%. Thirty-four percent of subjects in the NF group
experienced *severe* adverse events compared with 35% of patients in the
AC group. The Sponsor has stated that the adverse event profile of NF in
this trial did not reveal any events not previously observed in the
safety database for marketed Accutane®.

## 

## Mucocutaneous Adverse Events

Cheilitis occurred in over 90% of patients in both NF and AC treatment
groups. Epistaxis and nasal dryness together with dry and irritated eyes
were reported by approximately one third of the patients in both groups.
The mucocutaneous adverse event profile is important because it is a
frequent cause for treatment discontinuation, which can have serious
consequences (disfiguring scarring) for patients with severe cystic
acne. The trial indicates that the mucocutaneous safety profile for NF
is comparable to AC at the dosages tested.

## 

## Headache

Headache was reported for 16% of patients in the NF arm compared with
13.3% of AC patients, and headache duration at all levels of intensity
was longer in the NF group (2-5 days). Both cases characterized as
"migraine" in the trial occurred in the NF arm, as did the one suspected
case of pseudotumor cerebri. However, the 3 discontinuations in the
trial for headache occurred in the AC arm.

## Psychiatric Adverse Events

As reported in the NDA, there were 11 psychiatric adverse events in the
NF arm, and only 1 in the AC arm. Although none were deemed "serious" by
investigators, this disproportion is statistically significant and would
be cause for concern if verified. It appears, however, that the
psychiatric adverse event numbers refer *only* to subjects who
complained of symptoms verbally, regardless of their answers to the
screening questionnaire or the Beck's Depression Inventory (BDI-II). The
final study report submitted in the NDA states that patients were
"required to answer four specific questions to determine whether or not
they had experienced any significant depression or insomnia since the
last visit that affected their work or ability to perform normal daily
activities". It is unclear why neuropsychiatric symptoms gathered in
this manner that were severe enough to interfere with the conduct of
normal activities did not qualify as an adverse event. Furthermore, it
does not seem reasonable to exclude patients' events because they did
not verbally report psychiatric symptoms when they had just finished
filling out a questionnaire about them. Indeed, there were several
subjects in this trial who answered "yes" to the self-injurious behavior
question on the BDI-II, who answered "yes" to all four screening
questions, and/or had BDI-II scores only one point below that considered
"severe" who had *no* psychiatric adverse event recorded.

The issue of case ascertainment will not be expanded because the trial
was *not* designed to evaluate the psychiatric effects of isotretinoin.
When all of the cases with a possible psychiatric adverse event are
included, the numbers are approximately equal in the two arms (9 or 10
cases with AC and 11 cases with NF). The disproportion in *reporting* of
adverse events between the arms, however, is not explained.

The inconsistencies in follow-up of positive survey responses, recording
of psychiatric events, and implementation of discontinuation rules
preclude reliable estimates of the incidence of psychiatric adverse
events in the trial. In addition, bias against reporting of mood changes
was likely a factor in this trial. Unlike a trial for a new drug of
unknown effectiveness, it is likely that most patients were very aware
of the expected benefit. Answering "yes" to bad mood and feelings at any
time on-study would logically be viewed as a liability by a patient who
wanted to complete treatment. Likewise, investigator bias may have also
contributed to under-reporting by affecting the risk-benefit analysis
for continuing the study drug, since all subjects in the trial were
receiving isotretinoin and expected to derive significant benefit.

The baseline BDI-II scores in the trial were low (the mean at baseline
was 3.5 4.6, which is significantly lower than the mean reference score
reported in the NDA for college students, 12.56). In addition to low
baseline scores, there was no correlation between follow-up scores and
acne resolution in the trial. These observations are consistent with
published studies on acne as a risk factor for depression[^2].

Twelve cases in the trial with "spontaneously" reported psychiatric
adverse events and 5 additional cases with increases on BDI-II were
reviewed for the Sponsor by two consultants: Douglas Jacobs, MD,
Associate Clinical Professor of Psychiatry, Harvard Medical School, and
Robert Nelson[^3], PhD, pharmacoepidemiology consultant. Since the trial
was neither intended nor designed to study the issue, the consultants'
reports will not be reviewed in this Summary. The association of
isotretinoin with psychiatric adverse events is on the agenda for panel
discussion in the context of currently marketed Accutane®.

## Pregnancy

The approval of Accutane in 1982 was followed by reports of severe
congenital malformations[^4], leading to changes in labeling, advisory
committee hearings (1988-1991), and implementation of the Roche
Pregnancy Prevention Program and registry. Risk management strategies to
address persistent problems with fetal exposures are on the agenda for
panel discussion.

In the NF arm of the trial, one patient became pregnant while taking
isotretinoin. The stated facts of the case do not suggest patient
non-compliance with contraceptive measures. A pregnancy among 244 female
patients in the controlled setting of a trial for a known teratogen is
of great concern. The issue of a possible drug interaction that would
decrease the effectiveness of hormonal contraceptives is not unique to
the new formulation and is on the agenda for panel discussion.

Because available data for isotretinoin are inadequate to rule out an
interaction that might decrease the effectiveness of currently marketed
hormonal contraceptives, the Sponsor and the Agency developed a formal
study plan to address this critically important question for both AC and
NF[^5]. As an interim safety measure, the labeling for Accutane® has
been revised to further emphasize the need for two effective forms of
contraception.

"Sharing" of isotretinoin is of significant public health importance
because the drug can cause serious adverse events, including birth
defects, and the drug is highly efficacious for a common disease of
young people. Of the approximately 600 subjects enrolled in this trial,
one subject was discontinued because her daughter consumed her study
medication. The current labeling and patient brochure for Accutane® warn
against sharing. While the trial event was not "sharing" in the
intentional sense, it underscores the need for robust risk management
strategies to ensure the interests of both the public health and the
patients who need this uniquely efficacious drug.

## Laboratory Abnormalities

Hypertriglyceridemia due to isotretinoin is reportedly reversible and
appears to be only rarely associated with serious acute outcomes (the
long-term effects, if any, are unknown). Of the nine patients who
withdrew prematurely from the study because of elevated triglycerides,
three were in the NF group and six in the AC group. These early
terminations for hypertriglyceridemia would likely have been manageable
by dose adjustment in a practice setting (dose adjustment was not
allowed in the trial). According to the Sponsor's analysis of laboratory
findings, the relative increase in levels was 49% and 88% over baseline
for NF and AC, respectively. Neither triglyceride nor cholesterol values
had returned to baseline by Week 20. According to the Sponsor, all
abnormal liver function tests in both arms returned to baseline by Week
20 except GGT, which was greater in the AC group than in the NF group.
These findings are consistent with lower serum levels of isotretinoin in
the NF arm.

# **Risk-Benefit Analysis**

As stated by the Sponsor, the rationale for evaluating Accutane NF is to
provide a new formulation of isotretinoin that can be administered once
daily and without food. The Sponsor expects this dosing regimen to
enhance convenience and patient compliance, and reduce intra- and
inter-patient variability while at the same time retaining the efficacy
and safety profiles of currently marketed Accutane. This hypothesized
benefit would seem completely dependent on equivalent (or better) safety
and efficacy, since the impact of the convenience factor is likely to be
small (taking medication without food is *more* difficult than with
food, not less).

The maximum dose of Accutane used in this trial was approximately 1
mg/kg/day with food. The new formulation was reportedly "dose-adjusted"
to compensate for increased bioavailability (0.32 to 0.44 mg/kg/day).
However, patients who received Accutane 1.0 mg/kg/day with food in the
therapeutic study likely had approximately 240% higher exposure to
isotretinoin than the subjects who received the new formulation. Thus,
the trial is essentially a 2-arm isotretinoin dose-ranging study. At the
dosage tested, the new formulation is essentially therapeutically
equivalent to Accutane. Viewed within the context of the relative serum
levels of isotretinoin, the results suggest that the *currently
recommended dosing range for Accutane® is too high*[^6]*.*

The safety database for a new drug at the time of approval is almost
always "inconclusive" in the sense that the database is too small to
detect all relevant signals. This NDA has *inconclusive signals*.
Specifically, it can not be definitively determined whether the new
formulation is associated with a higher incidence of psychiatric adverse
events, nor whether the new formulation reduces the effectiveness of
hormonal contraceptives.

The possibility of an interaction between currently prescribed hormonal
contraceptives has not been adequately studied for either formulation.
This is a very serious deficiency in the safety database for a potent
teratogen widely prescribed for healthy women of reproductive potential.
*If* there is an interaction that decreases the effectiveness of
hormonal contraceptives, the information is critical to improving
compliance with the labeled advice about using two methods
simultaneously. In addition, if there is an interaction, many
prescribers and female patients may choose other acne management
strategies.

*If* there is an interaction between hormonal contraceptives and
isotretinoin, there is no pharmacokinetic basis to suspect that the
lower dose new formulation would be less safe than currently marketed
Accutane®. Interim measures for risk management pending completion of
the formal studies now underway are on the agenda for panel discussion.

The trial data are also inconclusive regarding psychiatric adverse
events, suggesting the possibility that the lower dose new formulation
is less safe than Accutane. Although the *reported* incidence in the
trial was significantly higher in the lower dose new formulation arm,
the disproportion appears to be more apparent than real if all cases
with symptoms from any source in the database are included. In addition,
the incidence reported by the Sponsor in the new formulation arm does
not exceed the range suggested in the published literature for
psychiatric adverse events with currently marketed Accutane. This
supports the notion that the results reflect *under*-accounting in the
Accutane arm, instead of increased incidence in the lower dose new
formulation arm. The disproportion in *reporting* is, however,
unexplained. Disproportion in discontinuations for psychiatric adverse
events is also unexplained because problems with protocol interpretation
should have been balanced. However, all four discontinuations for
psychiatric adverse events were confined to 2 of 17 sites.

A chance finding for the disproportion is consistent with the lower
serum levels of isotretinoin in the new formulation arm, assuming there
is no greater central nervous system accumulation of the new formulation
relative to Accutane. It is also consistent with the finding that the
more common adverse events were not significantly increased in the lower
dose new formulation arm (although the one patient with possible
pseudotumor cerebri was in this arm, and headache duration was longer).
It is, however, an *assumption* that the incidence of psychiatric events
should track with the incidence of well-established dose-related
effects, such as hypertriglyceridemia or mucocutaneous drying. The
dose-threshold, in any, for isotretinoin-associated psychiatric events
is unknown.

Causality between psychiatric disease and isotretinoin use has not been
established. If there is no causal relationship, then a lower dose new
formulation cannot be less safe than Accutane in this regard. The
uncertainty about the new formulation might be resolved if an adequately
powered, well-designed trial showed no evidence for causality. If the
data *did* support a causal relationship, there would be doubts about
the relative safety of the two formulations based on the observations in
the NDA 21-177 trial. However, if the lower dose new formulation is
safer than Accutane in other *significant* respects, it is unlikely that
a small increase in risk of reversible psychiatric symptoms would
override the advantages of the new formulation.

Since it would seem that the safety of isotretinoin treatment might be
improved by simply lowering the recommended dosage of current Accutane®
given with food, is there reason to replace Accutane with the new
formulation if there is *any* possibility that the new formulation is
less safe[^7]?

The food effect is so large with Accutane®, that even adequate
dose-ranging would not eliminate "over-dosage" and 'under-dosage" due to
the realities of compliance with food instructions. The clinical
significance of over-dosage has already been addressed. Under-dosing,
which would likely result if patients took a minimum effective dose of
current Accutane *without* food, has significant public health
importance because many years of experience support the observation that
cumulative dosage is positively correlated with "cure" rates.
Re-treatment with Accutane exposes patients to many more weeks of
potentially serious adverse effects, increases the risk of fetal
exposure, and delays resolution of nodulocystic lesions that can lead to
permanent disfiguring scars.

We believe that the relative food independence of the new formulation is
an important advantage over the currently marketed formulation because
of reduced pharmacokinetic variability, independent of "convenience".
There does not appear, however, to be any apparent public health
advantage to marketing both formulations.

8/21AC

[^1]: The Week 36 assessment was by telephone and 68 subjects were not
    contacted. In addition, the sponsor reported that 8 patients
    received additional isotretinoin beyond the Week-20 assessment at
    the "discretion" of investigators in a "minor protocol violation".
    Six were in the NF arm (the protocol stated that retreatment with
    isotretinoin was not allowed after the 20 week treatment period and
    prior to the 36 week assessment for recurrence). These 8 cases were
    identified by the Sponsor because of case report form notations
    about the added medication. It is not known if all investigators who
    prescribed isotretinoin in the week 20-36 interval entered
    information that would have alerted the Sponsor. *It is also unknown
    how many patients received other acne treatments, such as
    antibiotics, after completion of the 20-week course*.

[^2]: While the literature suffers from significant methodological
    limitations, the studies tend to confirm an intuitive perception
    that significant acne is associated with some degree of
    *psychological distress,* but do *not* demonstrate that severe
    nodular acne *causes* depression; in fact, a prospective study
    supported the opposite conclusion. Rubinow et al. (J Am Acad
    Dermatol 1987, 17:25-32) reported that severe recalcitrant nodular
    acne patients had evidence of "moderate psychological distress"
    prior to Accutane® treatment, but no excess *psychiatric* morbidity,
    including depression, in comparison with normative prevalence
    figures. Prospectively defined analysis showed a statistically
    significant lessening in *anxiety* after treatment with Accutane®,
    but [not]{.underline} in depression. Niemeier et al. (Dermatology
    1998,196:108-15) investigated depression and social anxiety in acne
    vulgaris patients in the course of evaluating a chronic skin
    disorders questionnaire. Comparison was made between the 50 acne
    patients and a control group of 33 persons without skin disorders
    (the two groups were *not* matched for age or gender). The two
    groups did not differ significantly on the Beck Depression Inventory
    (mean score non-depressed for both), but the acne patient group did
    show significant differences on other scales seen as indicative of
    psychosocial distress (e.g., social anxiety and avoidance) compared
    to the control group.

[^3]: Dr. Nelson led the "Accutane Monitoring Group" in the Epidemiology
    Division during prior employment at FDA.

[^4]: Accutane causes abnormal development of craniofacial bones, eyes,
    ears, thymus, heart, and brain. Congenital malformations range from
    severe physical and developmental defects to significant
    neurodevelopmental dysfunction in long-term survivors of in-utero
    exposure who appeared to be without major congenital malformation at
    birth. It is also associated with spontaneous abortion.

[^5]: [Biopharmaceutics Overview: Oral
    Contraceptive-Accutane]{.underline}

    Because of the known teratogentic potential of isotretinoin at the
    time of the original approval of Accutane, Roche conducted a
    pharmacokinetic drug interaction trial between Accutane and
    Ortho-Novum 1/35. At the time of the original approval the results
    of this study were used to support the generalized recommendation
    that hormonal contraceptives did not interact with isotretinion and
    vice versa. The accuracy of this conclusion is now open to question
    as the hormonal contraceptive marketplace has changed greatly in the
    last 15 years. With the development of "low dose", "tri-cyclic", and
    implantable contraceptive options, we believe that the level of
    assurance provided by the original in vivo biostudy has been
    superceded by market options.

    In light of this, a program to re-evaluate the contraceptive
    efficacy of these agents using current methods has been developed.
    Since it is not feasible to test all hormonal contraceptives in
    clinical trials, a program of in vitro metabolism studies combined
    with selective in vivo studies has been developed to cover the
    current options available in the marketplace. A description of this
    program and its development will be presented at the advisory
    committee meeting.

[^6]: The currently recommended dosage range for Accutane®is 0.5 mg/kg
    to 2.0 mg/kg/day with food.

[^7]: The term "less safe" encompasses both the adverse event profile
    already discussed, and the potential switch-over problems delineated
    in the NDA:

    > Inappropriate dosing of Accutaneand Accutane NF
    >
    > Concurrent administration of Accutaneand Accutane NF
    >
    > Confusion about capsule strengths on the prescription
    >
    > Uncertainty about bioavailability and actual drug exposure
    >
    > Misunderstanding about once daily administration without food for
    > Accutane NF
    >
    > and twice daily with food for Accutane

    Potential for inappropriate substitution at the pharmacy