Chapter 5. Conclusions

The following discussion is organized around our findings, characterizing the state of the acne literature, stating overarching conclusions from the evidence synthesis, providing answers

to our primary and secondary questions as the evidence allows, describing limitations of the

conclusions, and pointing to future research.

Characteristics of the Acne Clinical Research Literature

The literature regarding the treatment of acne vulgaris is characterized by a wide range of

treatments, outcomes, study designs, and methods of assessment. These characteristics render

synthesis of evidence difficult. We chose to focus on evidence presented in controlled clinical

trials as the most efficient and defensible method for identifying which treatments are superior to

others.

The 274 trials included in our review do not build toward an evidence-based consensus on

the most effective process of treatment for acne vulgaris. Of the 250 treatment comparisons, 14

(5.6 percent) provided Level A evidence, 102 (41 percent) provided Level B evidence, and 134

(54 percent) provided Level C evidence (see Table 15). The trials provide a relatively

disconnected series of comparisons among over 140 individual treatments. These trials provided

limited information about subjects, focused on short-term outcomes, and rarely presented

evidence related to the longer-term outcomes that are of greatest interest to patients: scarring,

psychological morbidity, and the costs of treatment. Of trials included, 74 percent reported data

on the age of the subjects, 13 percent reported phase of care at study entry, 8 percent reported

race, and none reported on sexual maturity rating. We identified 25 assessment schemes for acne

severity and 505 distinctly named outcomes. Less than 1 percent of trials addressed psychological

effects. None reported outcomes related to costs of treatment. Four trials stratified results by

gender and only three trials stratified results based on acne type or severity. No trials stratified

their results with respect to degree or type of prior therapy. Such stratification is especially

needed in trials where baseline acne severity ranged from mild to severe. Relating these trials to

one another and drawing generalizable conclusions is impossible.

In our report, we present the evidence as we encountered it in our reading of the literature. To

enhance comparability across studies, we have attempted to classify subjects studied in terms of

acne severity and have grouped outcomes at consistent time points where possible. We have

grouped individual treatments by treatment class.

Overarching Conclusions

Of the 14 comparisons with Level A evidence, half refer to trials where mild or moderate

acne was studied; only one refers to patients with moderate to severe acne; and the remainder, to

studies where acne severity could not be ascertained. The majority of these are efficacy results –

comparison to vehicle or placebo, rather than to some standard of care.

The results are sparse, and, in some cases, surprising. There are no cleanser or keratolytic

products in the list of Level A evidence comparisons. Of the topical anti-bacterials, clindamycin

and erythromycin demonstrate evidence of superiority in mild/moderate acne over vehicle. The

evidence alone suggests that topical tetracycline is no better than vehicle. The treatment mainstay

benzoyl peroxide has both anti-bacterial and keratolytic activity, and the evidence indicates

effectiveness with respect to vehicle, although the severity context is not explicit. The evidence

suggests that the three topical retinoids, tretinoin, adapalene, and motretinide are equally

effective. Of the oral anti-bacterials, the evidence is clear only for tetracycline.  Surprisingly, oral

isotretinoin does not appear on this list, although it is generally perceived by clinicians, including

the reviewers of this report, as the most potent acne treatment. This absence, and others, may

result from limitations of our review, including bias introduced through the exclusion of non-

English language reports of trials. In the case of isotretinoin, this absence is also a function of

limiting the review to controlled trials as such trials are difficult to design for isotretinoin

because of the side effect pattern seen. Of the anti-androgens, the birth-control pill

norgestimate/ethinyl estradiol was demonstrated more effective than placebo. No comparison of

the “miscellaneous” class is represented in this group of comparisons with Level A evidence.

There were 102 comparisons of Level B evidence. In these comparisons, expert opinion is

especially necessary to evaluate the implications for clinical care. In the case of the 134

comparisons of Level C evidence, our results suggest that further research is required to evaluate

the place of those treatments in clinical care. 

Table 15 categorizes the levels of evidence for the primary comparisons by treatment class

and Table 16 lists the 14 comparisons for which there was Level A evidence.

Answers to Specific Questions

Primary Questions

1.  What Treatments Are Effective in the Management of Acne?

The variable study quality, as well as the non-comparability of studies due to lack of

standardization, prevented us from performing quantitative meta-analyses to answer this

question, which was our initial intent. In particular, we cannot make general statements about

classes of treatment.

Many trials documented decreases in lesion counts with respect to baseline. However,

because improvements from baseline were documented in both the active and placebo arms of

many trials, we deemed treatment was “effective” only if it was deemed so in comparison to

another treatment. 

These conclusions are all based on severity or lesion-count based outcomes. As noted in

Chapter 4, only two trials reported on psychological outcomes, beyond globally assessed patient

preference.

There were few trials involving procedural, or nonmedical, treatment and the level of

evidence for these trials was rated at Level C. No trials addressed diet.

2.  What is the Responsiveness of Acne to First-line, Second-line, and Referral Treatments?

Although clinicians and practice guidelines often discuss management of acne using this

approach, the literature is not organized to answer this question. Investigators were not

systematic in evaluating subjects’ prior therapy. There is no basis from controlled trials to judge

the efficacy of any treatment in relation to the sequence of therapy. 

3.  What Are the Side Effects of Treatment?

The variability in the literature affects our ability to make firm statements about adverse

effects. There were 88 comparisons concerning adverse effects provided in the controlled trials.

Of these, five provided enough evidence to be rated as Level A; they are shown in Table 17. The

evidence suggests that topical clindamycin and erythromycin have a similar rate of side effect

severity that leads to patients dropping out. The evidence further suggests that, of the retinoids,

tretinoin and topical isotretinoin both cause a higher rate of local reactions than vehicle and that

motretinide leads to more local reactions than does tretinoin, and that tretinoin leads to more

local reactions than does azelaic acid.

Readers are directed to package inserts and post-marketing data that provide further

information concerning possible adverse effects. This is especially important for the teratogenic

oral isotretinoin. Because appropriate exclusions were made, the teratogenicity of isotretinoin

was not documented in the controlled trials reviewed.

Secondary Questions

Because of the volume of literature available, this review focused on controlled clinical trials,

rather than observational, laboratory, or other designs. Answers to our secondary questions

require such designs (e.g., epidemiological observational studies for the residuum of untreated

acne). Because of our focus, this report cannot be definitive on such issues as the true

teratogenicity risk of isotretinoin, or the risk of depression in patients treated with oral retinoids. 

What Baseline Characteristics Raise the Likelihood of Acne?

None of the controlled trials related evidence on risk factors for the development of acne. 

What Care Do Patients Provide for Themselves at Home?

We reviewed trials specifically for locus of care but found none where “home” was the focus

of care.  It may be that this type of question is best addressed by other study designs that were not

included in this evidence review.

How Effective Is Initial Home Care?

None of the reviewed trials provided information addressing this question.

What Is the Presentation of Acne to Physicians?

The term “presentation” suggests ways of describing acne and its natural history. These are

acne duration, lesion type and count, severity, and prior therapy. Only 40 trials (14 percent)

provided data on acne duration in describing their study sample at baseline. Most studies provided some information about lesion type, count, or severity. However, because these were

controlled trials, where patients volunteered or were recruited in unstated ways, we do not know

if the acne experienced by these subjects present the experience of all patients, and we therefore

cannot say how these findings generalize. In some cases, the acne may be recent, in which case

high spontaneous remission (“placebo”) rates may be seen, while in others, it may be only

subjects with refractory acne that are referred and recruited. A few trials included information on

what treatments had been received prior to enrollment. No study quantified this information, and

none stratified their results based on prior treatment. There are no standard ways of documenting

“refractory” acne.

Also implicit in this question is the issue of how acne presents to dermatologists as opposed

to primary care providers. Only 29 studies had patients seen in primary care offices or health

clinics; so our data cannot provide a generalizable description of the patients seen in primary

care. 

How Compliant Are Patients With Their Treatment?

Measuring compliance is difficult in acne studies. The most commonly used method is to

require the volunteers to bring back the used containers of medication at the time of a study visit. 

However, one never knows if the subjects are emptying the containers at home in order to

demonstrate compliance or otherwise not taking the medication as prescribed and few of the

studies documented even attempting any measure of compliance. Seventy-four trials (27 percent)

provided information to conclude that they monitored compliance prospectively and only 39 of

these provided some documentation of the degree of compliance (36 saying 80 percent

compliance or greater and 3 trials reporting 50-80 percent compliance).

What Is the Residuum of Untreated Acne? Of Treated Acne?

Only 15 studies observed their subjects for more than 6 months: Trial 52,214 Trial 70,36 Trial 86,219 Trial 97,215 Trial 115,212 Trial 123,128 Trial 154,203 Trial 160,242 Trial 173,199 Trial 185230 Trial 191,220 Trial 202,216 Trial 237,198 Trial 241,231 and Trial 278.235 None assessed scarring or long-term morbidity.

What Is the Quality of Life (Psychological Morbidity) in Untreated Acne? In Treated Acne?

As described in Chapter 4, only two trials provided specific evidence. 

What Is the Financial Cost of Therapy?

As described in Chapter 3, no studies provided evidence. 

Limitations

Our conclusions must be qualified because of the great heterogeneity present in the acne literature at all levels: there are a large number of treatments, compared in multiple ways;

although there are a limited number of primary acne outcomes, there are a large number of ways

of defining on what part of the body lesions are counted (over 30 ways); there are a large number

(25) of ways of classifying severity; and there are many ways that these outcomes were expressed

(raw measures, absolute change with respect to baseline, and percent change with respect to

baseline). There is no standard approach to describing side effects. Similarly, there is no

standardization of followup times. Our division into short-term, mid-term, long-term, and post-

therapy, while a result of consensus among our technical experts, is still an arbitrary arrangement.

The practical decision to focus on English language reports of trials meant that potentially

high quality non-English studies were not included in this review. Syntheses on more focused

questions (e.g., a synthesis on isotretinoin alone) should include a search for and inclusion of

non-English language reports of trials.

While some effort was made to use sources that may provide nonpublished reports of trials

(such as the use of the Cochrane Collaboration’s CENTRAL database, which contains hand

searching results as well as ongoing trials, and our own searching of reference lists of key

articles) we must also recognize that this report is open to publication bias—that is, trials with

positive results are more likely to be published, thereby potentially leading to an overestimation

of the true effects of the treatments.  This report summarizes the available evidence as found in

published reports of trials and, as such, may not include all of the relevant evidence.  We might

expect publication bias in the field of acne, since so much of the research is industry-sponsored,

and pharmaceutical companies may be less motivated to publish negative results than researchers

without a commercial interest in the results. Syntheses on more focused questions should include

a more intensive search for nonpublished reports of trials. This may include a hand search of

proceedings of relevant conferences and contacting key researchers in the field to ask if they

know of any completed or ongoing unpublished trials.

Conversely, At the same time, there were some surprises.  sSome treatments currently in use or soon to be

in use had little to no evidence in the literature reviewed. For instance, although tazarotene was

recently approved by the FDA for use in acne, we found no published trials in our search procedure that included asking our technical experts for controlled trials we might have missed.

(One trial on tazarotene has been published since the literature review for this report was

completed.)

Industry plays a major role in acne research. Of the 145 trials (out of 274) that reported funding, 127 were pharmaceutical company funded, and an additional 113 trials mentioned other

forms of support from drug companies, such as provision of medicine. Because these companies

design their research to comply with FDA requests (in the United States), these requests have a

great influence on the nature and scope of the trials on acne. Such requests could encourage

pharmaceutical companies to support trials that not only establish the efficacy versus safety of

their product but also provide clinicians with the evidence they need to make rational therapeutic

decisions.

The heterogeneity of the literature makes it very difficult to pool any results, and, therefore,

precludes quantifying the conclusions. We focused on assessing the level of evidence available for any treatment comparison, and we based all assessments of the efficacy of a treatment in

terms of comparisons with other treatments, including placebos. Improvements relative to

baseline were commonly seen for both active treatments and placebo treatments. This suggests

that acne may improve spontaneously and mitigates against drawing conclusions about efficacy

from the results of a single arm of a trial, even if large and statistically significant differences

were documented with respect to baseline status.

Generally, controlled trials provide limited information on side effects.  Readers are

cautioned to check other sources for side effect data such as drug inserts.

Finally, the nature of acne itself may be changing.  A number of our technical experts

expressed concern about bacterial resistance of P acnes, especially to clindamycin and erythromycin. This issue has major consequences for treatment recommendations and for future

research.

		Table 15.  Levels of evidence for comparison by treatment class

Treatment class	Number of comparisons

by evidence level

	A	B	C	Total

Cleanser (topical)	0	0	6	6

Keratolytic (topical)	1	9	10	20

Anti-bacterial (topical)	3	20	11	34

Anti-bacterial/keratolytic (topical)	2	19	19	40

Retinoid (topical)	4	11	8	23

Anti-bacterial/retinoid (topical)	0	2	2	4

Anti-bacterial (oral)	1	22	25	48

Anti-bacterial (oral)/keratolytic

(topical)	0	1	2	3

Anti-bacterial (oral)/retinoid

(topical)	1	1	1	3

Retinoid (oral)	0	1	8	9

Anti-androgen	2	6	15	23

Other	0	10	27	37

			TOTAL	14	102	134	250

		Some arms are represented more than once because they employed more than one treatment.

Table 16. Comparisons with Level A evidence

Treatment class	Index	Severity	Target treatment	Relative efficacy	Comparator Treatment	Evidence Level	Comments

Keratolytic	B.07.02		Aluminum chlorhydroxide/sulfur

(topical)	>	Vehicle (topical)	A	

Anti-bacterial

(topical)	C.01.01	Mild/mod	Clindamycin (topical)	>	Vehicle (topical)	A	Clindamycin phosphate and

hydrochloride results

combined

	C.03.01	Mild/mod	Erythromycin (topical)	>	Vehicle (topical)	A	Especially inflammatory

	C.08.01	Mild/mod	Tetracycline (topical)	=	Vehicle (topical)	A	

Anti-bacterial/k

eratolytic

(topical)	D.01.01		Benzoyl peroxide (topical)	>	Vehicle (topical)	A	

	D.01.09	Mild/mod	Benzoyl peroxide (topical)	=	Benzoyl peroxide (topical)	A	

Retinoid

(topical)	E.01.02		Adapalene (topical)	=	Tretinoin (topical)	A	Evidence B that adapalene

more effective for

non-inflammatory

	E.02.01	Mild/mod	Isotretinoin (topical)	>	Vehicle (topical)	A	

	E.03.03		Motretinide (topical)	=	Tretinoin (topical)	A	

	E.05.01	Mild/mod	Tretinoin (topical)	>	Vehicle (topical)	A	Evidence type A for

non-inflammatory; type B for

inflammatory.

Anti-bacterial

(oral)	H.08.01		Tetracycline (oral)	>	Placebo (oral)	A	

Anti-bacterial

(oral)/retinoid

(topical)	J.01.02		Oxytetracycline (oral)/vitamin A

(topical)	=	Oxytetracycline (oral)	A	

Anti-androgen	M.01.05	Mod/sev	Cyproterone/ethinyl estradiol

(0.05) (oral)	=	Cyproterone/ethinyl estradiol

(0.035) (oral)	A	

	M.04.09	Mild/mod	Norgestimate/ethinyl estradiol

(oral)	>	Placebo (oral)	A	

Note: Some arms are represented more than once because they employed more than one treatment.

	Table 17. Comparisons with Level A side effects evidence

Treatment class	Index	Target treatment	Side effects	Comparator treatment	Side effects	Relative side effects	Level of evidence	Comments

Anti-bacterial

(topical)	C.01.04	Clindamycin

(topical)	Withdrew:

0/264	Erythromycin

(topical)	Withdrew

(0.4%:

1/252)	=	A	

Retinoid

(topical)	E.02.01	Isotretinoin

(0.05%)

(topical)	**	Vehicle	**	>	A	Erythema and

peeling scores give

significant P-values

between arms

	E.03.03	Motretinide

(topical)	**	Tretinoin	**	>	A	Local reactions

	E.05.01	Tretinoin

(topical)	**	Vehicle	**	>	A	Local reactions

	E.05.04	Tretinoin

(topical)	Erythema

(27%: 48/181);

scaling

(29%:52/181)	Azelaic acid	Erythema

(15%:

27/177);

scaling

(14%:

24/177)	>	A