Chapter 3. Results: Summary of Literature

	Our results fall into two categories: This chapter addresses assessment of the literature and the evidence; the next chapter provides an exhaustive review of the evidence comparing specific

pairs of choices of acne therapy. Chapter 5 reports our answers to the specific questions.

Literature Search and Abstract Review

	Results from the searches and the abstract review process were maintained in databases

developed in ProCite® (Acne Citations Database and Acne Deletions Database). A summary of the search results is provided in Table 1. The bulk of the searching was completed in January and

February of 1999, with final searches of PubMed and CENTRAL completed in April 1999. A

total of 4,749 citations were identified. Of these, 1,558 were uniquely identified; that is, not

previously included in the Acne Citations Database. From the results of the initial PubMed and

CENTRAL searches, the search director removed citations dealing only with excluded topics

(e.g., rosacea) and, because resources did not allow for translation of articles, citations that were

published in languages other than English. A listing of these removed citations was reviewed by

one of the principal investigators. Subsequent search results were limited to English language

publications and were reviewed by the principal investigators to identify citations for inclusion in

the abstract review. Through these processes 829 citations were identified to be included in the

abstract review process.

	We were unable to review 7 citations as they did not have abstracts and we were unable to

retrieve the full articles. Of the 822 citations we could review, 460 (56 percent) were classified as

eligible for full article review while 362 (44 percent) were determined to be ineligible for full

article review. The majority of abstracts were excluded as not addressing management of acne

(291 [80 percent]); the next most common exclusion was no original data (75 [21 percent]).

Much smaller numbers of abstracts were excluded as not in English language (6), human data not

included (4), only addressing excluded topics (5), and as duplicate publications not caught during

searching and retrieving process (4).

Article Review

	From the abstract review process, 460 citations were identified for inclusion in the article

review phase. Because of this large number, and with consensus from the technical experts, it

was decided to focus on the controlled trials. Eligible trials were those where the individuals

followed in the trial were definitely or possibly assigned prospectively to one of two or more 

treatment arms using either random allocation or a quasi-random method of allocation (e.g., date

of birth). Of the 460 citations, 331 were identified as reports of controlled trials by the Cochrane

Collaboration (citations included in CENTRAL) or by one of the abstract reviewers (for citations

from MEDLINE® and other sources). 

	We were unable to retrieve, and, therefore, unable to complete article review of 12 articles.

Of the remaining 319 articles reviewed, 23 (7.2 percent) contained descriptions of more than one trial. Each trial was quality assessed and abstracted separately. There were 351 trials for which a

review was completed. 

	A total of 77 trials (21.9 percent of trials) were excluded during the article review process.

The reasons for exclusion are presented in Table 2. The final review thus included 274 trials

from 250 articles. (See Appendix H for included and excluded trials.)

	As the article review process progressed, we realized that many studies had multiple time

points of outcome assessment (e.g., 2, 4, 6, 8, 10, 12, 14, and 16 weeks in a single trial). It was

not feasible to continue collection, or data entry, in this manner nor did it seem likely to add to

the value of the evidence synthesis. We conferred with our technical experts on an ad hoc basis

and included a proposal for dealing with the time points in a formal request for feedback. Based

on this, abstraction of outcome data was collected for the time points corresponding to the

following time periods: 

•	Short term—Longest time interval up to and including 6 weeks (≤ 6 weeks);

•	Mid term—Longest time interval up to and including 12 weeks (>6 to ≤12 weeks); 

•	Long term—Longest time point reported by study, if greater than 12 weeks; and 

•	Post-therapy—Any time period reported after stopping of treatment. 

Description of the Acne Literature

General Trial Information

	Of the 319 articles reviewed, 296 presented single trials while 23 articles reported multiple

trials: 18 articles presented two trials; three articles presented three trials; one article presented

four trials; and one article presented six trials.

	Figure 2 shows the count of the 274 trials included by publication year. As illustrated in the graph, the number of controlled trials published has generally increased since the mid-1970s. 

	Study validity is often divided into two parts: external validity and internal validity.  Internal validity is the extent to which the methods of the study lead one to trust the results of the study. 

External validity is the extent to which one may generalize the results beyond the study.

	Our method of summarizing methodological strengths and weaknesses is presented in

Volume 2 (see Description of the Evidence Tables). Trials that had only strengths numbered 45 (16 percent). Trials that had only weaknesses numbered 106 (39 percent). Trials that had a mix of

strengths and weaknesses numbered 107 (37 percent). The remaining 22 (8 percent) were of

intermediate quality or did not provide enough information to make a determination.

	Funding source is important for assessing bias and in generalizing trial results. Explicit mention of funding source was made in 145 of the trials (53 percent). Of these, 8 were federally

funded, 10 reported some other source of funding, and 127 out of 274 trials (46 percent) were

drug-company sponsored. We were able to determine additional types of support by drug

companies in 113 of the trials, including those where funding source was not clear.  Twelve (4

percent of the trials) had a drug-company employee as first author, 38 (14 percent of the trials)

had a drug-company employee as co-author, 38 (14 percent of trials) supported the trial by

providing medication and one trial (0.4 percent of trials) noted analytic support. 

	Generalizability also depends on the extent to which results are replicated in multiple locations. The trials spanned the world: Of the 274 included trials for which data are available, continental Europe accounted for 74 (27 percent); United Kingdom, 56 (20 percent); North

America,124 (45 percent—includes United States, 118 [43 percent], Canada, 5 [2 percent], and

Mexico, 1 [0.4 percent]); Asia, 10 (4 percent); Middle East, 2 (1 percent); Oceania, 5 (2 percent);

Africa, 1 (0.4 percent); and Iceland, 1 (0.4 percent) for a total of 31 different countries (and one

unknown). Although the whole world is represented, patients from American/British

Commonwealth countries comprise two-thirds of the trials. 

	Generalizability is influenced by replication in multiple locations within a trial. Most trials

were performed at one study site. Of the 251 trials for which data are available, 177 (71 percent) were single-site, 65 (26 percent) were multi-center, single-country, and 9 (4 percent) were multi-

country.

	Finally, generalizability is greatly affected by how subjects (patients) are enrolled into a trial. The further away from being a randomly chosen patient and the more selected a subject is

through the clinical-care process, the less likely the study patient is to represent other patients. Of

274 trials, fully 203 (84 percent) gave no information regarding patient selection. Of those trials

providing information (71), 45 (63 percent) stated that patients were “recruited” (although rarely

with further details), and 19 (42 percent) stated that patients were selected as consecutive visitors

to the clinic. Seven trials (3 percent) mentioned other methods. Whether subjects were recruited

through a dermatology practice, a general practice, or from the general population is also an

important consideration. It was rarely possible to determine this with any specificity in the trials

reviewed.

	Within trials, it is important that the arms be similar in arm comparability, judged on the basis of baseline patient characteristics. For 103 (38 percent) of the trials arm comparability

could not be determined. In 90 trials (33 percent) the arms were definitely comparable, and 76

(28 percent) were judged as maybe comparable. Only 5 (2 percent) provided enough evidence to

conclude that the arms were not comparable. Further details concerning baseline patient

characteristics are provided in the next section (Patient Characteristics).

	Trial design is important for internal validity as well. Most of the trials used standard, two- arm, parallel trial designs (259 [94 percent]). Only 15 (5 percent) of the trials used a cross-over

design, where patients serve as their own controls over time, 30 (11 percent) were parallel trials

with split-face design, where patients serve as their own controls spatially; and 22 (8 percent)

were parallel trials with matched controls. While both cross-over and split-face design have the

potential to control for baseline characteristics in the most patient-specific manner, it is crucial

that, for cross-over studies, there be a wash-out period, and that, for split-face studies, the

investigator should anticipate contamination of the opposite side of the face.25 For the most part, we were unable to determine this type of detail from the trials.

	Treatment assignment is important for internal validity, with randomized assignment being the current gold standard. Relatively few trials (56, or 20 percent) gave enough information to

conclude that the patients were randomly assigned, and 175 (64 percent) were stated to be

randomized, with no further details. The rest either used deterministic methods of assignment—

i.e., the treatment was assigned using an attribute known by the investigator, such as date of birth

or hospital identification number (9, or 3 percent)— or gave no information at all (34, or 12

percent).

	Treatment blinding is also important for maintaining high internal validity. Only 27 trials (10 percent) gave enough details to convince the abstracters that patient blinding was properly

performed; 180 (66 percent) made a statement that blinding was performed, but with no further details; and 45 (16 percent) were explicit that patients were not blinded as to their treatment. Similarly, 41 trials (15 percent) convincingly demonstrated that the enrolling or treating

physician was adequately blinded, while 177 (64 percent) only said that they were blinded, and

22 (8 percent) were clearly not blinded.

	Compliance of patients with therapy is crucial in determining efficacy or effectiveness, and especially so with topical treatment. Seventy-four trials (27 percent) provided evidence that

patients’ compliance was addressed prospectively from trial onset. A further 17 (6 percent)

discussed compliance retrospectively, 17 (6 percent) made statements suggestive of their concern

about compliance, and 8 (3 percent) clearly ignored compliance. Fully 148 trials (54 percent)

gave no indication one way or the other of this concern, and for 9 (3 percent), compliance

monitoring was not applicable.

	Trials varied in mode of treatment administration: 101 trials (37 percent) included systemic therapy, 183 trials (67 percent) included topical facial therapy, and 25 (9 percent) addressed other

areas, like the back and chest. (Percent sums to greater than 100 percent because trials could

address multiple areas.)

	Trials excluded a variety of ancillary therapies used by all trial participants. The excluded

ancillary treatments included other medications (110, or 40 percent), soaps (44, or 16 percent),

and diet (9, or 3 percent); 129 trials (47 percent) mentioned ancillary therapy, but gave no details.

A variety of other therapies were mentioned as being explicitly excluded: radiation therapy, sun

bathing, unspecified powder, scalp shampoo, among others. We judged 124 trials (45 percent) as

providing evidence that subjects received similar ancillary treatment. Seven trials (3 percent)

clearly provided asymmetric ancillary therapy—that is, the groups did not receive the same

treatment, besides the treatment that was the focus of the trial. Fully 119 (43 percent) gave no

information at all.

	In terms of study execution, 45 trials (16 percent) had major losses to followup, while 107 (39 percent) had minor losses. Ninety-one trials (33 percent) documented virtually no such losses,

while 31 (11 percent) did not provide enough data for an assessment. Beyond losses to followup,

7 trials (3 percent) reported protocol departures; 44 (16 percent) had minor such departures but 

122 (45 percent) provided too little information to make any assessments. We judged 203 trials

(74 percent) to have followed their design in execution and only 4 (1 percent) to definitely not

have followed the plan, but this could not be determined for 14 trials (5 percent). 

	As a summary statement regarding external validity, we judged only 4 trials (1 percent) as being generalizable to the general population; 11 trials (4 percent), to more specific populations;

and 9 (3 percent), to local populations. The great majority (152, or 55 percent) do not give

enough data, while the remainder can be generalized only to the referral population (22, or 8

percent) or to any group beyond the study participants (76, or 28 percent).

Patient Characteristics

	For those patient characteristics determined from exclusion criteria, no study mentioned

sexual maturity rating (Tanner stage) and 66 (24 percent) did not explicitly mention any

exclusion criteria based on patient characteristics. Table 3 shows the breakdown of other

exclusion criteria. Acne severity was the basis of exclusion most of the time: 79 trials excluded

patients with “severe” acne, while 82 trials excluded patients with “mild” acne. Other morbidity,

pregnancy, and young age were the other most cited exclusion criteria. 

	Based on the patient characteristics used as exclusion criteria, all studies included adolescents

and young adults (see Table 3). Specific ages for participants in trials were also collected.

Pooling the studies for which mean and standard deviations are available yields a pooled mean of

21 years and a pooled standard deviation of 5 years. This mean is consistent with the age groups

implied by the exclusion criteria. The average range was 15 to 32 years, the overall minimum

stated in age ranges was 8 years and the maximum was 72 years.

	Table 4 supplies the number of trials providing information for each patient characteristic:

age, sex, race, skin type, diet, duration of disease, insurance status, prescription plan, source of

care, practice setting and phase of care. One trial reported on patients’ diets, none reported on insurance status or the availability of a prescription plan.  Few studies reported on skin type or

disease duration. Most studies reported on the sex of patients, but 70 (26 percent) omitted this

essential baseline characteristic. 

	Eight trials stratified their results.  Trials 35, 293, 111, and 277 stratified by gender. Trials

350, 16, 222, stratified by acne severity, and Trial 55 stratified by location.

Acne Severity

	As stated above, regarding exclusion criteria, acne severity was the most important patient

characteristic, and it is the characteristic our experts raised most often in deciding on individual

treatment profiles. In the process of reviewing the literature, 25 different methods of assessment

for acne severity were identified. These methods were varied and included lesion counting on all

or part of the face, comparison of the patients to a photographic standard, and comparison of the

patients to a text description. Many trials did not report their method of assessment. The way in

which severity was reported also differed between studies. Many used terminology, “mild,

moderate or severe.” Others used numerical scores such as 1-4, 0-10, etc. Neither terminology

nor score was necessarily consistent across studies; so what was termed “grade 2 acne” in one

trial might have been classified as “grade 6” according to a grading system in a different trial. 

	In our synthesis, an effort was made to standardize the reporting of acne severity so that more

accurate comparisons could be made between trials. Terminology used here is the standard

“mild, moderate, severe.” Each trial was reviewed for the acne severity of the patients included in

that study. The reported severity was converted to a “Combined Acne Severity Classification” as

follows: 

	1.  Trials Reporting Lesion Count

	The Combined Acne Severity Classification was derived from the mean lesion counts and

standard deviations reported in the studies. The definitions are:	

•	Mild acne—Fewer than 20 comedones, or fewer than 15 inflammatory lesions, or total lesion count fewer than 30.

•	Moderate acne— 20-100 comedones, or 15-50 inflammatory lesions, or total lesion count 30-125.

•	Severe acne—More than 5 cysts, or total comedo count greater than 100, or total inflammatory count greater than 50, or total lesion count greater than 125.

	Severities included in the trial were based on the mean lesion count plus or minus 2 standard

deviations. When no standard deviation was provided in the study, then only the grade of the

mean was used.

	2.  Trials Reporting an Acne Severity Grade

	Two reviewers evaluated each grading system that was described in detail. These grading

systems, a few of which were frequently referenced, were converted to the Combined Acne

Severity Classification based on how the grading system compared with the above

definitions. This conversion was straightforward in articles that used scoring based on

calculations from lesion counts. Some conversions, such as the ones from photographic

assessment or from text descriptions, required judgement.

	3.  Trials Reporting Both Lesion Count and an Acne Severity Grade

	In some instances, studies reported both lesion count and a severity grade. In this case, the lesion count was used to determine the Combined Acne Severity Classification.

	4.  Trials With No Reference to Assessment Method

	In some trials, severity terminology was used with no reference as to how severity was

actually assessed. In these instances, the severity stated by the author was kept as the

combined acne severity classification.

	When no other information was provided, the exclusion criteria were used to determine the

Combined Acne Severity Classification. Patients included were assumed to be all of those not

excluded, using the definitions above to categorize the patients.

	See Table 5 for comparison of the Combined Acne Severity Classification and frequently

cited severity grading systems. See Figure 3 for the distribution of the Combined Acne Severity

Classification among the trials included in the review. The trials were distributed as 21 percent

(58) in mild/moderate category, 49 (18 percent) in moderate/severe category and 51 (19 percent)

in moderate category. Only about 5 percent of the trials had patients classified at either end of the

scale, as either mild or severe. We were unable to classify severity in about 22 percent (59) of the

trials.

Source of Care 

Practice Setting

	From our model of acne care (Figure 1), we needed data conditioned on source of care or

practice setting. No trial noted self-care or HMO as setting of care, 8 (3 percent) were performed

at a health clinic, 21 (8 percent) at a private practice, and 195 (71 percent) of the trials cited study

clinic/hospital as practice setting. Miscellaneous sites included schools or student centers and one

military clinic. 

Care Provider	

	Eight trials (3 percent) noted generalist as source of care while 68 trials (25 percent) were

determined to have care provided by dermatologists.  In 157 trials (57 percent) the source of care

could not be determined beyond study clinic.

Outcomes

	Discrete outcomes are those in which investigators report the proportion of subjects achieving a categorical outcome (i.e., “improved”). Continuous outcomes are based on a quantitative measure of an attribute in each subject (e.g., mean number of lesions). Table 6 shows

the distribution of outcomes. 203 (74 percent) of trials had continuous outcomes, and 80 percent

(221 trials) had discrete outcomes. 

	Table 7 shows the distribution of outcomes by outcome type. There were 1,237 outcomes. Of

these outcomes, 888 (72 percent) concerned the assessment of acne lesions, and 335 (27 percent)

were classified as outcomes of adverse events or side effects. Almost all trials (269, or 98

percent) trials had data on acne outcome, while no trials had data on economic outcomes. Only 2

trials (0.7 percent) had data on psychological outcomes, and only 43 trials (16 percent) provided

some data on treatment compliance.

	The 19 outcomes shown in Table 8 account for more than half the data. There were 505 acne

outcomes, lumping together multiple time points for individual outcomes within a trial. Of these,

142 (28 percent) concerned severity, 211 (42 percent) concerned lesions counts, and 152 (30

percent) were overall assessments.  Percentage change with respect to baseline counts accounted

for 73 (36 percent) of the lesion count outcomes. Of the 83 trials (31 percent) where location of

count was mentioned, 25 (29 percent) simply said “face,” 11 (13 percent) stated “entire face,”

and the remainder used 39 other descriptors, such as “5 cm worst area” or “selected area.” Table

9 lists the various descriptors of count location.

Treatments

	For purposes of summarizing the data and for organizing the results, the treatments were

divided into a number of classes. This classification was completed by consensus of our technical

experts.  The basis for the division was (1) similarity of pharmacological mechanism, and (2)

similarity of perceived severity for which the treatment would be prescribed. For the first reason,

anti-bacterials were grouped together, regardless of the specific class of antibiotic. For the

second, topical and oral antibiotics were separated because most physicians would treat topically

first, before using systemic therapy. Our goal in separating these classes was to find if the

literature supported this established use. 

	The classes shown in Table 10 represent the classes, based on the data available. The classes

comprising first-line therapy are Cleanser, Keratolytic, Anti-bacterial (topical), and

combinations. Second-line therapy includes Retinoid (topical), Anti-bacterial (oral), and

combinations. Referral treatment includes Retinoid (oral) and Anti-androgen. The class Other

includes treatments not classifiable in the previous classes, and Inert refers to placebos, vehicles,

and other interventions used as controls for presumed effective acne treatment.

	Table 11 lists all of the treatments studied in the trials included in this report.  The table

includes a brief description, the classification, and the availability of the treatment.  Table 12

summarizes the trials as comparisons, grouped by the class assignment of the evaluated

treatment: target and comparator. There were 251 comparisons in the two- and three-arm trials.

				Figure 2. Number of trials published per year

Figure 3. Distribution of trials by combined acne severity classification 

Table 1. Summary of search results

		Number of citations

Source	Date	Retrieved	Unique	Eligible

for 

abstract

review	Unable to abstract

review	Eligible for article

review

						ALL	CTs

CENTRAL

Issue 4 1998	Jan 25, 1999	460	460	375		211	211

PubMed

core	Jan 27, 1999	820	312	228		115	55

OLDMEDLINE	Feb 8, 1999	512	512a	126	5	87	39

HealthStar	Feb 25, 1999	1,342	5a	0		0	0

PsycINFO®	Feb 25, 1999	65	65a	25		16	1

CINAHL®	Feb 26, 1999	125	125a	15		0	0

PubMed

supplemental

search for cost 	Feb 26, 1999	28	25a	6		5	0

PubMed

core	Apr 7, 1999	835	18	18		10	10

CENTRAL

Issue 1 1999	Apr 27, 1999	523	30	30	1	13	13

Hand Searching

reviews	July 1999	39	6	6	1	3	2

TOTAL	4,749	1,558	829	7	460	331

a  Listing reviewed by PIs to identify those to be included in abstract review process

Column Headings:

Source -Name of database searched and, where applicable, version of database and type of search.

Date - Date search completed.

Number of citations: Retrieved - Total number of citations retrieved by search.

Number of citations: Unique - Total number of citations retrieved minus those citations previously retrieved.

Number of citations: Eligible for abstract review - As noted with asterisks, in some cases the PIs reviewed the listing of uniquely retrieved

citations to identify those to be included in the abstract review process.  The number in this column reflects the citations identified in this

manner. 

Number of citations: Eligible for article review - Number of citations from abstract review process deemed eligible for article review.  This

column includes the total number of citations as well as the number of controlled trials (CTs).

Table 2. Reasons for exclusion of trials

Reason for exclusion	Number of

trials	Percent of

trials

excluded

(n=77)	Percent of all

trials reviewed

(n=351)

Not management of acne	16	20.8	4.6

No human data	1	0.1	0.3

Excluded topics only: more than 20% of patients have

chloracne, rosacea, venanta, fulminans, necroticans, or

agminata	1	0.1	0.3

Surrogate measures only (e.g., sebum production, P acnes colony counts) 	12	15.6	12.0

No original data	7	9.1	2.0

Not in English	4	5.2	1.1

Fewer than 5 patients	2	2.6	0.6

Unable to abstract data	4	5.2	1.1

Study design not controlled	30	39.0	8.5

	Total	77	

		Table 3. Exclusion criteria cited by trials

Patient characteristic cited as exclusion	Number of trials using criterion

(percent)a 

Type of acne

Nodulocystic	23 (8%)

Pustular 	5 (2%)

Inflammatory	5 (2%)

Comedonal	15 (5%)

Secondary	30 (11%)

No exclusion based on type	237 (86%)

Severity of acne

Severe	79 (29%)

Moderate	10 (4%)

Mild	82 (30%)

No exclusion based on severity	124 (45%)

Age

< 31 days	49 (18%)

31 days to 10 years	39 (18%)

11 to 14 years	21 (7%)

15 to 18 years	1 (0.4%)

19 to 34 years	0 (0%)

35 to 54 years	28 (10%)

> 54 years	35 (13%)

No exclusion based on age	223 (81%)

Sex

Female	5 (2%)

Male	14 (5%)

No exclusion based on sex	255 (93%)

Other conditions

Pregnancy	63 (23%)

Lactation	39 (14%)

Allergy	45 (16%)

Other comorbidity	68 (25%)

No patient characteristic based on exclusion criteria mentioned	66 (24%)

		a A trial may appear several times.

		Table 4. Patient characteristics provided by trials

Patient characteristic	Number of trials

providing data (%)

Tanner stage	0 (0%)

Age	204 (74%)

Sex	200 (73%)

Race	23 (8%)

Skin type	6 (2%)

Diet	1 (0.4%)

Disease duration	40 (14%)

Insurance status	0 (0%)

Prescription plan	0 (0%)

Source of care	222 (81%)

Practice setting	220 (80%)

Phase of care	36 (13%)

Table 5. Comparison of combined severity grading with frequently cited grading systems

Combined Acne Severity

Classification	Allen274	Burke and

Cunliffe 

(Leeds)275	Cook276	Lucky230	Michaelssona20 9	Pochi67	Pillsbury10

Mild	0

	0	0	None	0-3	Mild	1

				Very mild	4-20		

	2	0.25-0.5	2	Mild			

Moderate	4	0.75-1.5	4	Moderate	20-30	Moderate	2

	6		6				

Severe	8	2.0-10.0	8	Severe	>30	Severe	3

				Very

severe			4

a  Michaelsson severity scores based on Cook’s descriptions and using the following assumptions:

	Cook 0= 3 papules

	Cook 2= 20 comedones and 10 papules

	Cook 6= 30 papules

Table 6. Distribution of continuous and discrete outcomes

	Number of trials		Number of outcomes per trial	Total number of outcomes

		Average	SD	Median	Range	

Continuous	203	6.3	4.5	6.0	1-21	1,282

Discrete	221	2.9	3.1	2.0	1-35	637

	1,919

SD - Standard deviation

			Table 7. Outcome types

Outcome type	Total number of

outcomes

(percentage of

outcomes)	Number of

trials

(percentage

of trials)

Acne	888 (70%)	269 (98%)

Adverse effects	335 (26%)	174 (64%)

Psychological effects	8 (1%)	2 (1%)

Compliance	43 (3%)	43 (16%)

Cost	0 (0%)	0 (0%)

	TOTAL	1,274	274

			Table 8. Number of trials employing outcomes accounting for just over half of reported effectiveness outcomes

Outcome name	Number of trials	Percent of total

trials

Overall change/physician	51	6%

Overall change/patient	34	4%

Inflammatory (count)	33	4%

Inflammatory change (%)	33	4%

Pustules (count)	30	3%

Papules (count)	29	3%

Comedones (count)	24	3%

Non-inflammatory change (%)	23	3%

Non-inflammatory (count)	22	2%

Total lesions change (%)	22	2%

Severity change	16	2%

Severity (cook)	14	2%

Total lesions (count)	13	1%

Pustules change (%)	12	1%

Papules change (%)	12	1%

Severity (leeds)	12	1%

Comedones change (%)	11	1%

Open comedones (count)	10	1%

Closed comedones (count)	10	1%

TOTAL	411	46%

			Table 9. Location of lesion counting

Stated region	Number of  trials

Face	25

Entire face	11

Face unspecified	4

Face excluding nose	3

5 cm diameter	2

Both sides	2

Half face	2

Left side	2

Symmetric area of face	2

2 cm worst	1

3 + c face	1

5 cm worst area	1

5cm diameter-worst	1

Above jawline	1

Back	1

Bilateral cheeks	1

Both halves (except 1/2 midline overlap)	1

Butterfly	1

Chest	1

Designated area of face, chest and/or back	1

Each side of face	1

Entire (with estimate)	1

Entire face chest & back	1

Entire face-(photos)	1

Entire face-photo	1

Face & chest & back	1

Face (unspecified)	1

Face + or - other	1

Face above jawline	1

Face/neck	1

Left cheeks	1

Neck anterior to sternomastoid muscles and face	1

One side	1

Right	1

Selected area	1

Side of face	1

Side of face (spilt face trial)	1

Well defined regions	1

Witkowski/simons	1

Worst area	1

Worst area/5cm diameter	1

TOTAL	85

				Table 10. Treatment classes

Treatment	Number of arms

Cleanser	11

Keratolytic	22

Anti-bacterial (topical)	83

Anti-bacterial/keratolytic (topical)	54

Retinoid (topical)	84

Anti-bacterial/retinoid (topical)	10

Anti-bacterial (oral)	98

Anti-bacterial (oral)/keratolytic	19

Anti-bacterial (oral)/retinoid (topical)	4

Retinoid (oral)	26

Anti-androgen	35

Other	82

Inert	130

TOTAL	659

Table 11. Description of treatments in trials reviewed

Treatment	Description	Category	Currently manufactured	U.S. availability	Number of armsa

16-epiestriol-3-allyl ether	Epimer of the estrogenic metabolite estriol	AA	No	No	1

Acidic syndet bar	A detergent that is not a soap, condensed from

synthetic detergent	C	Yes	Yes	1

Adapalene	A topical retinoid-like compound	R	Yes	Yes	15

Alitretinoin	A natural retinoid with actions similar to all-trans-

retinoic acid (tretinoin).	R	Yes	Yes	1

Aluminum chlorhydroxide	Astringent and antiperspirant properties	C	Yes	Yes	3

Aluminum chloride	Used in manufacturing, antiperspirants,

andastringents	C	Yes	Yes	1

Azelaic acid	Naturally-occurring, saturated, straight-chained

dicarboxylic acid	K	Yes	Yes	8

Bar soap	The sodium or potassium salts of long chain fatty

acids	O	Yes	Yes	1

Benzoyl peroxide	Antibacterial, mildly comedolytic, and sebostatic

agent	AB, K	Yes	Yes	74

Buttoxethyl nicotinate	Used in topical agents as a rubfacient (to cause

redness)	O	Yes	Yes	1

Chloramphenicol	An antimicrobial agent	AB	Yes	Yes	7

Chlorhydroxyquinoline	Topical antibacterial, antifungal agent	AB	Yes	Yes	2

Cimetidine	H2-receptor antagonist	O	Yes	Yes	2

Clindamycin	A lincosamide antimicrobial agent	AB	Yes	Yes	21

Clindamycin hydrochloride	A lincosamide antimicrobial agent	AB	Yes	Yes	6

Clindamycin phosphate	A lincosamide antimicrobial agent	AB	Yes	Yes	27

Clobetasol  propionate	The most potent topical corticosteroid available	O	Yes	Yes	1

Comedone extraction	Office procedure	O	Yes	Yes	3

Cotrimoxazole	Antibacterial agent comprised of trimethoprim

(dihydrofolate reductase inhibitor antimicrobial

agent) and sulfamethoxazole (an intermediate-acting

sulfonamide)	AB	Yes	Yes	4

Cyproterone	An antiandrogen with progestogenic activity	AA	Yes	No	16

Dapsone	A sulfone antibiotic	AB	Yes	Yes	2

Delta-0.2%-chlormadione	A progestogen structurally related to progesterone	AA	Yes	No	1

Delta-5%-chlormadione	A progestogen structurally related to progesterone	AA	Yes	No	1

Demethylchlortetracycline	A bacteriostatic antimicrobial agent	AB	Yes	No	6

Desogestrel	A progesten used for contraception	AA	Yes	Yes	6

Doxycycline	A tetracycline antibiotic with a broad spectrum of

activity	AB	Yes	Yes	6

E-solve	Vehicle for erythromycin/clindamycin	O	Yes	Yes	1

Electrocautery	Minimal burning of lesions via electricity	O	Yes	Yes	1

Emollient	An agent that softens or soothes the skin or irritation

of the skin	O	Yes	Yes	1

Epiestriol	Epimer of the estrogenic metabolite estriol	AA	No	No	1

Erythromycin	A macrolide antibiotic	AB	Yes	Yes	35

Erythromycin acistrate	A macrolide antibiotic	AB	Yes	No	1

Erythromycin base	A macrolide antibiotic	AB	Yes	Yes	2

Erythromycin proprionate	A macrolide antibiotic	AB	No	No	1

Erythromycin stearate	A macrolide antibiotic	AB	No	No	2

Ethinyl estradiol	An estrogen component of oral contraceptives	AA	Yes	Yes	28

Etretinate	A derivative of tretinoin	R	Yes	No	1

Fractionated human

dialyzable transfer factor	Leukocyte extract that passively transfers cell

mediated immunity	O	Yes	Yes	1

Fulguration	A form of electrocautery	O	Yes	Yes	2

Fusidin cream	A steroidal antibiotic, chemically related to

cephalosporin P	AB	Yes	No	1

Fusidic acid	A steroidal antibiotic, chemically related to

cephalosporin P	AB	Yes	No	2

Gamma-globulin	Antibodies derived from human plasma	O	Yes	Yes	1

Gestodene	A progestogen structurally related to levonorgestrel	AA	Yes	No	1

Gluconolactone	Available as part of the orphan drug, glucono-delta-

lactone and magnesium carbonate	K	No	Yes	1

Glycolic acid	An organic acid	K	Yes	Yes	3

Grenz rays	Superficial irradiation	O	No	No	6

Group therapy	A psychological method	O	Yes	Yes	1

Gugulipid	The oleoresin of the Indian herb Commiphora mukul or gum guggul.	O

	Yes

	Yes

	1

Hexachlorophene	A polychlorinated bisphenol, which is an effective

inhibitor of gram positive organisms	O	Yes	Yes	2

Hydrochlorthiazide	A thiazide diuretic	O	Yes	Yes	2

Hydrocortisone	A corticosteroid with both glucocorticoid and

mineralocorticoid activity	O	Yes	Yes	14

Hydrocortisone F	A corticosteroid with both glucocorticoid and

mineralocorticoid activity	O	Yes	Yes	1

Hydroxyquinoline	Class of agents with antibacterial, antifungal, and

deodorant properties	AB	Yes	Yes	2

Ibuprofen	A non-steroidal anti-inflammatory drug	O	Yes	Yes	3

Inactive drug	Drug with no therapeutic effect	O	No	No	1

Inocoterone acetate	A topical, 5-alpha reductase inhibitor anti-androgen	AA	Yes	No	1

Ionax	Benzalkonium chloride, coal tar, salicylic acid	K	Yes	No	1

Isoconazole nitrate	An imidazole antifungal	AB	Yes	No	1

Isolutrol	Produced in the liver and gallbladder of sharks	O	Yes	No	1

Isotretinoin	A synthetic analogue of vitamin A	R	Yes	Yes	28

Komed®	A multiingredient preparation including salicylic

acid, sodium thiosulphsulfate, and isopropyl alcohol.	K	No	No	2

Meclocycline	A tetracycline antibiotic derived from oxytetracycline 	AB	Yes	No	1

Meclocycline sulfosalicylate	A tetracycline antibiotic derived from oxytetracycline	AB	Yes	No	3

Methyl prednisolone	A corticosteroid and the methyl derivative of

prednisolone	O	Yes	Yes	5

Metronidazole	A synthetic 5-nitroimidazole	AB	Yes	Yes	4

Miconazole	An antifungal agent	AB	Yes	Yes	4

Minocycline	A tetracycline antimicrobial agent	AB	Yes	Yes	10

Motretinide	A retinoid that inhibits the secretion of sebum	R	Yes	No	5

Neomycin	An aminoglycoside antimicrobial	AB	Yes	Yes	10

Nicotinamide	The amide metabolite of niacin	O	Yes	Yes	1

Norethisterone	A synthetic progestin 	AA	Yes	Yes	1

Norgestimate	A progestogen structurally related to levonorgestrel 	AA	Yes	Yes	2

Ocimum basilicum	Oil of sweet basil herb	O	No	No	1

Oleandomycin	A macrolide antibiotic	AB	Yes	No	1

Oxytetracycline	A tetracycline antimicrobial agent	AB	Yes	Yes	8

Petrolatum	A purified semi-solid mixture of hydrocarbons

obtained from petroleum	O	Yes	Yes	2

Phenethicillin	A phenoxypenicillin 	AB	Yes	No	1

Placebo	An inert substance given as a medicine for its

suggestive effect	O	No	No	98

Polyethylene scrub	An abrasive substance used to unseat comedones and

deter formation	O	No	No	2

Polyoprepolymer-2	A mixture of glycols labeled according to average

molecular weight 	O	Yes	Yes	2

Polythionate	Therapeutically active form of sulfur	K	No	No	2

Potassium hydroxyquinoline	A mixture of potassium sulphsulfate and quinolin-8-ol

sulphsulfate monohydrate with antibacterial, antifungal,

and deodorant properties 	AB	Yes	No	2

Povidone-iodine	A broad-spectrum germicidal agent	AB	Yes	Yes	2

Propylene phenoxetol	A preservative with anti-Pseudomonas activity	AB	Yes	Yes	1

Proteolytic enzymes	A protein that  decomposes other enzymes	O	No	No	1

Pumice	An abrasive	C	Yes	Yes	1

Quaternary ammonia

complex of polythionates	Therapeutically active form of sulfur	AB	No	No	1

Quinestradol	A synthetic oestrogen	AA	Yes	No	1

Relaxation-imagery	A psychological method	O	Yes	Yes	1

Resorcinol	An aromatic alcohol 	O	Yes	Yes	8

Retinyl beta-glucuronide	Vitamin A metabolite	R	No	No	2

Roxithromycin	A macrolide antibiotic 	AB	Yes	No	2

Salicylic acid	A topical keratolytic agent	K	Yes	Yes	6

Saline	Sodium is the principle cation of extracellular fluid

and chloride is the principle anion of extracellular

fluid 	O	Yes	Yes	1

Serum gonadotrophin	Hormones supports and stimulates the function of the

gonads (LH and FSH)	AA	No	No	1

Shankhabhasma vati	A traditional Indian formulation containing minerals derived from conch shells	O

	No

	No

	1

Silicic acid	A silicon compound that occurs naturally as opal	K	No	No	1

Sodium fusidate	A steroidal antibiotic 	AB	Yes	No	2

Sodium novobiocin	An antimicrobial which is structurally related to

coumarin	AB	Yes	Yes	1

Sookshama triphala	A traditional Indian formulation containing dried

fruits and minerals	O	No	No	1

Soybean liposome	(No description found)	O	No	No	2

Spironolactone	A synthetic steroid aldosterone antagonist	AA	Yes	Yes	7

Staphylococcal toxoid	Detoxified toxins which retain their antigenicity and

their immunizing capacity	O	No	No	1

Sulfadimethoxine	A long-acting sulfonamide 	AB	Yes	No	1

Sulfamethoxazole	An intermediate-acting sulfonamide 	AB	Yes	Yes	2

Sulfur	A pure chemical element with keratoplastic and

keratolytic, as well as antifungal, antibacterial, and

antiscabies activity	K	Yes	Yes	24

Sulfur-resorcinol salicylic

acid	A combination of a pure chemical element with

keratoplastic and keratolytic, as well as antifungal,

antibacterial, and antiscabies activity, an aromatic

alcohol, and a topical keratolytic agent	K	No	No	1

Sufur/salicylic acid	A combination of a pure chemical element with

keratoplastic and keratolytic, as well as antifungal,

antibacterial, and antiscabies activity, and a topical

keratolytic agent	K	No	No	1

Sufurated lime	A mixture containing calcium sulfate and not less

than 50% of calcium sulfide 	K	Yes	No	1

Sunder vati	A traditional Indian formulation containing dried

fruit, bark, and rhizones	O	No	No	1

Tea tree oil	Obtained by distillation from the leaves of the

Australian tea tree, it contains about 50 to 60% of

terpenes, cineole (up to 10%), and terpineol	O	Yes	Yes	1

Tetracycline	A bacteriostatic antimicrobial agent	AB	Yes	Yes	33

Tetracycline hydrochloride	A bacteriostatic antimicrobial agent	AB	Yes	Yes	17

Tetracycline phosphate	A bacteriostatic antimicrobial agent	AB	Yes	Yes	1

Tetracycline-citric acid	A bacteriostatic antimicrobial agent and excipient	AB	Yes	Yes	1

Tetracycline-novobiocin	Combination of a bacteriostatic antimicrobial agent

and a stretomyces antibiotic	AB	Yes	No	1

Thiostanin	A traditional Indian formulation containing dried

fruits, minerals and roots	K	No	No	1

Tolbutamide	A short-acting sulfonylurea 	O	Yes	Yes	1

Topical treatment	Any traetment applied directly to the skin	O	No	No	1

Tretinoin	A retinoid derived from naturally occurring all-trans-

retinol 	R	Yes	Yes	68

Triacetyl-oleandomycin	An essential trace metal	AB	No	No	2

Triclosan	An antiseptic used in cosmetics and soaps	AB	Yes	Yes	3

Trimethoprim	A dihydrofolate reductase inhibitor antimicrobial

agent	AB	Yes	Yes	3

Unfractionated human

dialyzable transfer factor	Leukocyte extract that passively transfers cell

mediated immunity	O	Yes	Yes	1

Unknown	Not able to determine what treatment was received	O	Yes	Yes	1

Untreated	Receiving no treatment	O	Yes	Yes	3

Urea	An osmotic diuretic, abortifacient, emollient,

keratolytic, and diagnostic agent	K	Yes	Yes	1

Vehicle	A substance without therapeutic action used to

administer medication	O	No	No	78

Vitamin A	A fat-soluble vitamin, it exists within the body as

retinol, retinyl esters, retinal, and retinoic acid	R	Yes	Yes	6

Vitamin A palmitate	A fat-soluble vitamin, it exists within the body as

retinol, retinyl esters, retinal, and retinoic acid	R	Yes	Yes	2

Water avoidance	Avoiding water	O	Yes	Yes	1

Zinc	An essential trace metal used topically as a drying

agent	O	Yes	Yes	4

Zinc acetate	Mild astringent with inhibitory effects on copper

absorption	O	Yes	Yes	4

Zinc gluconate	Mild astringent with inhibitory effects on copper

absorption	O	Yes	Yes	1

Zinc sulphsulfate	Mild astringent with inhibitory effects on copper

absorption	O	Yes	Yes	10

Zinc sulphsulfate monohydrate	Mild astringent with inhibitory effects on copper

absorption	O	Yes	Yes	1

Zinc sulphsulfate/citrate complex	Mild astringent with inhibitory effects on copper

absorption	O	Yes	Yes	1

Zinc sulphsulfur	Mild astringent with inhibitory effects on copper

absorption	O	Yes	Yes	2

TOTAL					859

	Table 12. Treatment comparisons

Target class		Comparator class	

														TOTAL

Cleanser (topical)	2	2	---	1	---	1	---	---	---	---	---	---	---	6

Keratolytic (topical)	7	1	2	1	4	3	---	1	---	---	---	---	1	20

Anti-bacterial (topical)	10	1	1	7	6	---	---	5	---	---	---	---	3	33

Anti-bacterial/keratolytic

(topical)	5	---	5	6	14	2	---	2	---	---	1	---	6	41

Retinoid (topical)	5	---	3	---	2	11	---	1	---	---	---	---	2	24

Anti-bacterial/retinoid

(topical)	1	---	---	1	---		1	---	---	---	---	---	---	---	3

Anti-bacterial (oral)	12	---	1	8	2	1	---	20	---	---	1	1	3	49

Anti-bacterial

(oral)/keratolytic

(topical)	---	---	---	---	---	---	1	1	---	1	---	---	---	3

Anti-bacterial

(oral)/retinoid (topical)	---	---	---	---	---	---	---	2	1	---	---	---	---	3

Retinoid (oral)	2	---	---	---	---	---	---	2	---	---	4	---	1	9

Anti-androgen	10	---	---	---	---	---	---	2	---	---	---	10	1	23

Other	16	---	1	2	5	3	---	3	---	---	---	---	7	38

TOTAL	70	4	13	26	33	22	1	39	1	1	6	11	24	250