7 replies to this topic

[fkrepubligion]

I have been using atralin to get rid of sunspots and hyperpigmentation caused from dermititis and the fungi picked up while living in the UK for 2 years that caused the worst outbreak in my life since puberty. I have been using the drug every night and am still totally clear with the exception of two small brown marks(clogged pores?) that have appeared around my beards hair follicules. Atralins website was shut down because of false marketing claims and manipulated data...I'm not expecting an IB at this point and I've had everyone from my dentist to coworkers ask how I keep everything so "perfect" and a few are also now on this drug too. I am wondering what this Coria/DOW Chemicals drug is actually doing in the long term even when the active ingredient is removed, especially after being forced to remove their entire marketing claims and is being "re-evaluated" by the FDA. Can other Atralin users that are over the age of 25+ tell me if its actually doing anything when ive had no IB and only shedding of skin that looks almost like lint, small flakes the size of a dot all over the face that is not noticible by anyone except when my glasses rub up against the ridge of my nose. I will admit this is the first topical drug for cosmetic purposes I have used that doesnt burn my face off at all and have had no side-effects except a slight itch/general discomfort towards the end of the day. I have never used a topical that actually smoothes the skin like this, brings back an even skin tone even when its triggered by an allergy or sulfates, and just generally makes it look like porcelin and not even a single spot...I dare say on the level of friends that have taken accutane and now want to hop onto this drug. The only thing that caused a huge flare up initially(just a red mess on both sides of my face "under" my skin that had small spots pop up and never really come to a head) was doxy that subsided after 3-4 months about 1 1/2 years ago to treat the infection and nystatin to get rid of the fungi. Anyway, here is the release from the feds.

DEPARTMENT OF HEALTH & HUMAN SERVICES - Public Health Service
Food and Drug Administration Silver Spring, MD 20993
Charity Abelardo
Acting Director, Regulatory Affairs
Dow Pharmaceutical Sciences, Inc.
1330 Redwood Way
Petaluma, CA 94954-1169

RE: NDA # 022070
AtralinTM (tretinoin) Gel, 0.05%
MA #70/89

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration
(FDA) has reviewed Dow Pharmaceutical Sciences, Inc.’s (Dow) direct-to-consumer website
and a professional detail aid (COR-137719-0610) submitted by Dow under cover of Form
FDA 2253 for its drug product, AtralinTM (tretinoin) Gel, 0.05% (Atralin Gel).1 The website
and detail aid are false or misleading because they make unsubstantiated claims, including
unsubstantiated superiority claims, overstate the efficacy of Atralin Gel, and omit material
facts and important risk information associated with the use of the product. Therefore, these
pieces misbrand Atralin Gel in violation of the Federal Food, Drug, and Cosmetic Act (FD&C
Act), 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1(e)(5)(i),(iii); (e)(6)(i), (ii), (vii), (x);
(e)(7)(i).
Background
Below is the indication and summary of the most serious and most common risks associated
with the use of Atralin Gel.2
According to its FDA-approved product labeling (PI), Atralin Gel is indicated for topical
treatment of acne vulgaris.
Atralin Gel is associated with the following warnings and precautions: skin irritation, ultraviolet
light and environmental exposure, and use in patients with fish allergies. The most common
adverse reactions associated with Atralin Gel include dry skin, peeling/scaling/flaking skin,
skin burning sensation, and erythema.
1 Atralin Gel website at http://www.atralingel.com/ (last accessed October 18, 2011).
2 This information is for background purposes only and does not necessarily represent the risk information that should be included in the
promotional pieces cited in this letter.
Reference ID: 3097677
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Dow Pharmaceutical Sciences, Inc.
NDA # 022070/MA #70/89 Unsubstantiated Superiority/Unsubstantiated Claims
Promotional materials are misleading if they contain a drug comparison that represents or
suggests that a drug is safer or more effective than another drug, when this has not been
demonstrated by substantial evidence or substantial clinical experience.
The detail aid includes the following claims and presentations:
• “Advance to the head of the class”
• “Optimized tretinoin . . . .”
• “At” in the tradename circled and appearing to look like “A+”
• “Uniquely formulated for targeted delivery” along with claims of the purported benefits
of Atralin Gel’s micronized formulation
• “A smart combination for improved tolerability” along with claims of the purported
benefits of ingredients in Atralin Gel’s vehicle and an “A+” graphic
• “Superior delivery” along with a graph of in vitro data showing Atralin Gel with the
greatest mean cumulative level of tretinoin to the dermis at 24 hours compared to
Retin-A Micro® 0.1% gel and Retin-A Micro® 0.04% gel.”[3] A footnote to the graph
states, “In vitro data; clinical significance is unknown. Differences between products
were not statistically significant.”
These claims and presentations misleadingly suggest that Atralin’s formulation and its
purported greater delivery to the dermis result in superior safety and efficacy compared to
other tretinoin products. However, FDA is not aware of any substantial evidence from clinical
trials demonstrating that Atralin Gel 0.05% is more effective than another tretinoin product,
such as Retin-A Micro 0.1% or 0.04% gel. FDA is also not aware of substantial evidence
from adequate and well-controlled clinical trials of Atralin Gel versus another tretinoin product
of similar strength demonstrating that Atralin Gel is more tolerable. Although Atralin Gel
0.05% was associated with fewer adverse events in one clinical trial than Retin-A Micro 0.1%
gel, the strength of the Retin-A Micro was twice the strength of Atralin Gel in this trial.
Additionally, the trial failed to show that Atralin Gel’s efficacy was superior or non-inferior to
Retin-A Micro 0.1%, thus limiting the clinical relevance of the difference in adverse events.
Furthermore, we are unaware of evidence demonstrating that Atralin Gel has
pharmacological activity in the dermis, and there are no data to support that in vitro
percutaneous absorption data, as presented in the graph of comparative dermis levels at 24
hours, predict or correlate with comparative clinical efficacy. Moreover, in vitro percutaneous
absorption testing is conducted using healthy cadaver skin, animal skin, or a suitable
membrane. For topically administered drugs, disease state might affect drug penetration and
bioavailability. Due to the physiological difference between healthy and diseased skin, the in
vitro percutaneous absorption method is not adequate for assessing comparative in vivo
levels clinically at the dermis for different formulations. We note that the small footnote to the
presentation indicates that the clinical significance of the in vitro data is unknown and
differences between products were not statistically significant. However, this does not correct
the misleading impression.
3 Data on file, CORIA Laboratories.
Reference ID: 3097677
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Dow Pharmaceutical Sciences, Inc.
NDA # 022070/MA #70/89 The website makes the following claims (emphasis in original):
• “ATRALIN™ (tretinoin) Gel 0.05% is a prescription acne medication that is formulated
with a combination of moisturizing ingredients that you won’t find in any other
prescription acne treatment.” [ATRALINTM Gel homepage]
• “But unlike other acne medications, ATRALIN™ Gel is the only tretinoin formulation
that features a unique combination of ingredients that are known to moisturize and
hydrate skin.*” [Why ATRALINTM Gel is Right for You webpage]
• “ATRALIN™ Gel is formulated with a smart combination of ingredients that are known
to hydrate and moisturize skin.*” [ATRALINTM Gel for Teens webpage]
• “As we age, our skin loses moisture [4] and may be drier and more sensitive. You may
benefit from an acne treatment like ATRALIN™ (tretinoin) Gel 0.05% because it’s the
only tretinoin that offers a unique combination of ingredients that are known to
moisturize and hydrate skin.*” [ATRALINTM Gel for Adults webpage]
• “ATRALIN™ Gel contains a combination of ingredients that are known to moisturize
and hydrate skin* -making it more ideal for adult skin.” [ATRALINTM Gel for Adults
webpage]
*The contribution to efficacy of individual components has not been evaluated.
Similarly, the detail aid claims:
• “A smart combination for improved tolerability
• Sodium hyaluronate†
− Plays a role in moisturizing the stratum corneum due to its unique waterbinding
properties[5]
• Soluble collagen†‡
− Increases moisture content of the skin[6]
• Glycerin†
− Enhances the water-binding capacity of the stratum corneum[7]
†The contribution of individual components to efficacy has not been evaluated.
‡Soluble collagen comprises methylparaben, propylparaben, ethylparaben, butylparaben,
isobutylparaben, phenoxyethanol, fish collagen, and water.”
These claims misleadingly suggest that Atralin Gel is clinically superior to other tretinoin
formulations because the individual ingredients of Atralin Gel’s vehicle are purported to
provide specific clinical benefits, such as moisturizing and hydrating skin, when this has not
been demonstrated by substantial evidence or substantial clinical experience. Generally,
superiority claims must be supported by adequate and well-controlled head-to-head clinical
trials comparing appropriate doses and dose regimens of your drug and the comparator drug.
None of the references cited in the detail aid discuss adequate and well-controlled clinical
4 National Institute on Aging. Skin care and aging. www.niapublications.org. Accessed October 1, 2007.
5 Weindl G, Schaller M, Schafer-Korting M, Korting HC. Hyaluronic acid in the treatment and prevention of skin diseases; molecular, biological, pharmaceutical and clinical aspects. Skin Pharmacol Physiol. 2004;17(5):207-213.
6 Morganti P. Skin hydration. In: Magdassi S, Touitou E, eds. New Cosmetic Delivery Systems. New York, NY. Marcel Dekker, Inc;
1999:71-98.
7 Kraft JN, Lynde CW. Moisturizers: what they are and a practical approach to product selection. Skin Therapy Lett. 2005;10(5):1-8.
Reference ID: 3097677
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Dow Pharmaceutical Sciences, Inc.
NDA # 022070/MA #70/89 trials with Atralin Gel versus other tretinoin products in which clinical benefits of the individual
vehicle ingredients, including improved tolerability or efficacy, were demonstrated. In fact,
the references do not discuss Atralin Gel at all. In addition, the Description section of the PI
states, “the contribution to efficacy of individual components of the vehicle has not been
evaluated.” We note that this information is presented in the website and detail aid in
association with the claims; however, this does not mitigate the misleading impression.
Furthermore, according to the Adverse Reactions section of the PI, 16% of patients
experienced dry skin with Atralin Gel treatment and the Warnings and Precautions section of
the PI states, “Mild to moderate skin dryness may also be experienced; if so, use of an
appropriate moisturizer during the day may be helpful.”
Overstatement of Efficacy
Promotional materials are misleading if they represent or suggest that a drug is better or
more effective than has been demonstrated by substantial evidence or substantial clinical
experience.
The Why ATRALINTM Gel is Right for You webpage claims, “In fact, many dermatologists
prescribe a tretinoin because it works so well—even on tough acne. . . ” (underlined
emphasis added). This claim misleadingly suggests that the drug has been specifically
studied for the treatment of “tough” or severe acne in clinical trials, when this is not the case.
According to the Clinical Studies section of the PI, the safety and efficacy of Atralin Gel was
only studied in patients with mild to moderate acne vulgaris. Therefore, claims that suggest
that Atralin Gel has specifically demonstrated efficacy in treating severe acne are not
supported by substantial evidence.
The detail aid misleadingly overstates the efficacy of Atralin Gel by selectively presenting
more favorable lesion reduction data from the registration trials, while failing to include less
favorable Global Severity Score Success data, which measures overall acne severity and
was also a primary endpoint in the trials. Specifically, the detail aid claims that Atralin Gel
provides “Efficacy that makes a powerful impact.” This claim is followed by graphs showing a
36% versus 20% reduction in inflammatory lesions and a 41% versus 21% reduction in noninflammatory
lesions from baseline at week 12 for Atralin Gel and vehicle, respectively, in a
combined analysis of the registration trials. However, the presentation fails to report that
success based on the Global Severity Score was achieved by 21% and 23% of patients using
Atralin Gel versus 12% and 14% using vehicle in study 1 and study 2, respectively. 8 In the
absence of providing the Global Severity Score success data with this presentation, the detail
aid overstates the efficacy of the product.
Omission and Minimization of Risk Information
Promotional materials are misleading if they fail to reveal material facts with respect to
consequences that may result from the use of the drug as recommended or suggested by the
materials.
8 Success is defined as a score of 0 (clear) or 1 (very mild) for study 1 and a score of 0 or 1 with at least 2 grades reduction from baseline for
study 2.
Reference ID: 3097677
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Dow Pharmaceutical Sciences, Inc.
NDA # 022070/MA #70/89 The website makes the following claims:
• “ATRALIN™ Gel offers a low potential for irritation. Chances are you’ll stick with your
treatment if there’s less risk of irritation, which will help you get the best results.” [Why
ATRALINTM Gel is Right for You webpage]
• “ATRALIN™ Gel has a low potential for irritation.[9] This may help make your treatment
more tolerable as your acne is getting better.” [ATRALINTM Gel for Teens webpage]
• “ATRALIN™ Gel has low potential for irritation.[10] This may help you look better as
your acne is getting better.” [ATRALINTM Gel for Adults webpage]
• “The most common adverse reactions were mild to moderate irritation of the skin and
occurred during the first few weeks of treatment with ATRALIN™ Gel.” [ATRALINTM
Gel homepage, Why ATRALINTM Gel is Right for You, ATRALINTM Gel for Teens,
ATRALINTM Gel for Adults webpages, and detail aid ]
These specific pages within the website misleadingly minimize the risks of Atralin Gel by
implying that patients are likely to “stick” with their treatment because there is a “low
potential of skin irritation” associated with use of the drug, when this is not the case.
Furthermore, these webpages with the claims noted above, as well as the detail aid, also
omit material facts about the possible duration and/or severity of skin-related adverse
reactions and the potential need for discontinuation of the drug and therefore,
misleadingly suggest that Atralin Gel is safer than has been demonstrated by substantial
evidence or substantial clinical experience. These claims are particularly concerning
since the Warnings and Precautions section of the PI states that, "The skin of certain
individuals may become dry, red, or exfoliated while using Atralin Gel. If the degree of
irritation warrants, patients should be directed to temporarily reduce the amount or
frequency of application of the medication, discontinue use temporarily, or discontinue use
all together. . . .Tretinoin has been reported to cause severe irritation on eczematous or
sunburned skin. . . ." In addition, according to the Adverse Reactions section of the PI,
the most common adverse reactions (incidence > 5%) were dry skin (16% vs. 2%),
peeling/scaling/flaking skin (12% vs. 1%), skin burning sensation (8% vs. 2%), and
erythema (7% vs. <1%) in the Atralin Gel and vehicle groups, respectively. The Adverse
Reactions section of the PI also indicates that in some subjects the skin-related adverse
reactions persisted throughout the treatment period. Moreover, characterizing these
events as “mild to moderate irritation of the skin” fails to adequately communicate the
specific types of skin irritation associated with Atralin Gel, as described above.
Finally, the website and detail aid also completely omit the following important Warning and
Precaution regarding fish allergies: Atralin Gel contains soluble fish proteins and should be used with caution in
patients with known sensitivity or allergy to fish. Patients who develop pruritus or
urticaria should contact their health care provider.
9 Data on file, CORIA Laboratories, Ltd.
10 Data on file, CORIA Laboratories, Ltd.
Reference ID: 3097677
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Dow Pharmaceutical Sciences, Inc.
NDA # 022070/MA #70/89 Unsubstantiated Claims
The detail aid includes the following claims for Atralin Gel:
• “Uniquely formulated for targeted delivery”
• “Micronized tretinoin facilitates efficient delivery to the follicle*”
• “85% of tretinoin particles in Atralin Gel are <10 microns
− Follicular openings on the forehead can be as small as 11 microns[11]
• “Lipophilic tretinoin dissolves in sebum within the follicle
− Micronized tretinoin particles in Atralin Gel are small enough to easily enter
the follicular opening
− Fewer tretinoin particles may remain on the skin surface”
“*The clinical significance of micronization is unknown.”
These claims are accompanied by a schematic of Atralin Gel entering a follicle. The claims
and schematic misleadingly suggest that Atralin Gel’s micronized formulation confers a
beneficial effect on product safety and/or efficacy by enabling the majority of tretinoin
particles to enter follicles, when this has not been demonstrated by substantial evidence or
substantial clinical experience. Furthermore, the cited reference does not provide any
evidence that tretinoin, whether micronized or non-micronized, enters hair follicles. In fact,
according to the PI, the exact mode of action of tretinoin is unknown. The cited reference
discusses hair follicle density and size in different regions of the body, but contains no data
with tretinoin addressing penetration into follicles or the effect of particle size on follicular drug
absorption. Additionally, the reference provides information on hair follicle orifice size in
healthy skin. There is no information on hair follicle orifice size in diseased skin, specifically
skin with acne vulgaris. The disclaimer that, “The clinical significance of micronization is unknown” is not sufficient to correct the misleading impression created by the claims and
schematic.
The website makes the following claim (emphasis in original):
• “In a clinical study, the number of people who said they were dissatisfied by their self-appearance due to their facial acne was reduced by half after using
ATRALIN™ Gel for 12 weeks.” [12] 􀁧
􀁧Combining the top three categories of a patient survey, Extremely, Very Much, and Quite a Bit, the
numbers dropped from 29% to 14%.”
[ATRALINTM Gel for Teens webpage]
This claim suggests that patients will experience an improvement in satisfaction with their
self-appearance after using Atralin Gel, when this is not supported by substantial evidence or
substantial clinical experience. Specifically, the webpage references data on file in support of
11 Otberg N, Richter H, Schaefer H, et al. Variations of hair follicle size and distribution in different body sites. J Invest Dermatol.
2004;122(1):14-19.
12 Data on file, CORIA Laboratories, Ltd.
Reference ID: 3097677
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Dow Pharmaceutical Sciences, Inc.
NDA # 022070/MA #70/89 this claim, which includes a summary of Acne-QoL Questionnaire responses (at baseline and
Week 12) from the clinical study report. From this questionnaire, only the responses to one
question were referenced as support for the above claim. These data do not support this
claim because the Acne-QoL instrument analysis failed to demonstrate any statistically
significant differences between treatment groups from Baseline to Week 12 in the overall
composite scores or in the Self Perception, Role-social, and Acne Symptom domains.
Furthermore, it is misleading to make claims based on individual components of an overall
composite score when the study was not adequately designed to evaluate these individual
components. Therefore, suggesting any treatment benefit for Atralin Gel based on the Acne-
QoL instrument or any of its individual components is misleading.
Conclusion and Requested Action
For the reasons discussed above, the website and detail aid misbrand Atralin Gel in violation
of the FD&C Act, 21 U.S.C. 352(a) & (n); 321(n). See 21 CFR 202.1 (e)(5)(i),(iii); (e)(6)(i), (ii),
(vii), (x); (e)(7)(i).
OPDP requests that Dow immediately cease the dissemination of violative promotional
materials for Atralin Gel such as those described above. Please submit a written response to
this letter on or before March 20, 2012 stating whether you intend to comply with this request,
listing all promotional materials (with the 2253 submission date) for Atralin Gel that contain
violations such as those described above, and explaining your plan for discontinuing use of
such violative materials.
Please direct your response to the undersigned at the Food and Drug Administration,
Center for Drug Evaluation and Research, Office of Prescription Drug Promotion,
Division of Professional Promotion/Division of Direct-to-Consumer Promotion, 5901-B
Ammendale Road, Beltsville, Maryland 20705-1266 or by facsimile at (301) 847-8444.
Please note that the Division of Drug Marketing, Advertising, and Communications (DDMAC)
has been reorganized and elevated to the Office of Prescription Drug Promotion (OPDP).
OPDP consists of the Immediate Office, the Division of Professional Promotion (DPP) and
the Division of Direct-to-Consumer Promotion (DDTCP). To ensure timely delivery of your
submissions, please use the full address above and include a prominent directional notation
(e.g., a sticker) to indicate that the submission is intended for OPDP. In addition, OPDP
recently migrated to a different tracking system. Therefore, OPDP letters will now refer to MA
numbers instead of MACMIS numbers. Please refer to the MA #70/89 in addition to the NDA
number in all future correspondence relating to this particular matter. OPDP reminds you that
only written communications are considered official.
Reference ID: 3097677
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Dow Pharmaceutical Sciences, Inc.
NDA # 022070/MA #70/89 The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Atralin Gel comply with each
applicable requirement of the FD&C Act and FDA implementing regulations.
Sincerely,
{See appended electronic signature page}
Lynn Panholzer, PharmD &
Sheetal Patel, PharmD
Regulatory Review Officers
Office of Prescription Drug Promotion
Reference ID: 3097677
---------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
---------------------------------------------------------------------------------------------------------
/s/
----------------------------------------------------
SHEETAL PATEL
03/06/2012
LYNN M PANHOLZER
03/06/2012
Reference ID: 3097677

FDA - "Combining the top three categories of a patient survey, Extremely, Very Much, and Quite a Bit, the
numbers dropped from 29% to 14%.”, almost the same as the vehicle used without the active drug....

[lb111923]

this is so interesting! i used atralin for about a year with some improvement, but definitely not total improvement...so i've recently switched to retin-a .04. i used atralin in conjunction with aczone and duac and never noticed any negative side effects in terms of peeling/burning/etc...in fact, it may have actually made me more oily but i just assumed it wasn't strong enough for my stubborn clogged pores...will def ask my derm about this!

[Fred Q]

I used this stuff post accutane and it sucked.

[May853]

Interesting. I started switching from diacneal to atralin almost a year ago, I think, and I am over 25 (31). I haven't had the great results that you have, although I have had essentially no irritation. I had an IB from the diacneal and was very slow to switch over the atralin, so I think that may have prevented an additional IB. I know my acne is hormonal b/c of location, etc, and it would have been nice to have results like you. I didn't read all that, I skimmed it, but what I did skim seems like there are issues with semantics as opposed to real risk ( I guess the fish allergy could qualify)? Unless I missed that part, LOL. I remember a substantial packet when I pick up my rx for this stuff. I figure any tretinoin is potentially risky and can cause irritation.

[fkrepubligion]

The problem with Atralin is that the FDA reviewed the claims made by Coria/DOW Chems and claim that their entire marketing and study data was maniupulated and false, with the atralin gel actually showing no higher of a success rate than when used with the vessel alone. It drops to the same clearance level as when the tretinoin is removed and just the vessel(vehicle) was used in the patients that were pretty much given the placebo. The response from the company? Remove all marketing material from derms offices and shut down the website leaving only the prescribing information available.

[Flyer17]

I used Atralin for about three months and saw no results. In fact, I think it made my skin as bad as it's ever been. I didn't have any irritation when I applied the product, but beyond that I don't think it did anything to help my complexion or fight acne.

[sasch12]

Flyer17, on 25 May 2012 - 01:15 PM, said:

I used Atralin for about three months and saw no results. In fact, I think it made my skin as bad as it's ever been. I didn't have any irritation when I applied the product, but beyond that I don't think it did anything to help my complexion or fight acne.

Kinda second your opinion. The only consistent improvement was my forehead. My chin/mouth acne has gotten progressively worse and painful and i have begin to develop cyst on my jaw. What will the next step be for you?

[Flyer17]

sasch12, on 26 May 2012 - 07:00 AM, said:

Kinda second your opinion. The only consistent improvement was my forehead. My chin/mouth acne has gotten progressively worse and painful and i have begin to develop cyst on my jaw. What will the next step be for you?

I used Atralin from late August '11 to early January '12. I stopped using it in early January '12 and I've been on Doxycycline since then. I'm pretty pleased with the results, but I know I can't stay it on forever.