Evidence Report/Technology Assessment

Number 17

Prepared for:
Agency for Healthcare Research and Quality
Department of Health and Human Services
U.S. Public Health Service
2101 East Jefferson Street
Rockville, MD 20852

http://www.ahrq.gov/

Contract No. 290-97-006

Prepared by:
Johns Hopkins Evidence-based Practice Center
Harold P. Lehmann, M.D., Ph.D.
Principal Investigator
John S. Andrews, M.D.
Co-Principal Investigator


Karen A. Robinson, M.Sc.
Victoria L. Holloway, M.D., M.P.H.
Steven N. Goodman, M.D., Ph.D.
Investigators

AHRQ Publication No. 01-E019

September 2001

ISBN: 1-58763-059-01
ISSN: 1530-4396

This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other equality enhancement tools, or as a basis for reimbursement and coverage policies. Endorsement by the Agency for Healthcare Research and Quality (AHRQ) or the U.S. Department of Health and Human Services (DHHS) of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers -- patients and clinicians, health system leaders, and policymakers -- make more informed decisions and improve the quality of health care services.

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

Director	John M. Eisenberg, M.D.
Center for Practice and	Director
Technology Assessment	Agency for Healthcare Research
Agency for Healthcare Research	and Quality
and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service.

Acne is a common condition, particularly in adolescents and young adults, with potentially significant physical and psychological morbidity from scarring and from adverse effects of treatment, as well as significant economic burdens. The purpose of this review was to provide a comprehensive review of the literature on acne management.

The following reference databases were searched: CENTRAL database of the Cochrane Collaboration (1948 through April, 1999), MEDLINE (1966 through April, 1999), OLDMEDLINE (1960 through 1965), PsycINFO (1887 through June, 1999), and CINAHL (1982 through June 1999). The CENTRAL search strategy was (acne-vulgaris*.me OR acne*.tw). Similar strategies were used for the other databases. The MEDLINE strategy combined, using a Boolean AND, a topic-specific strategy (acne vulgaris [mh] OR acne* [tw]) with a strategy designed to retrieve all controlled trials. Reference lists from key articles were hand reviewed.

In consultation with our partners and technical experts, the following questions were formulated: What treatments are effective? What is the responsiveness of first-line, second-line, and third-line treatments? What are the side effects of treatment? Controlled trials of acne therapy were sought that presented original, human data, written in English.

Identified articles were screened by independent reviewers in an abstract review process to determine eligibility for full article review. Eligible articles were reviewed serially by two or more abstracters who sought methodological and outcome data. The unit of analysis was the comparison between pairs of treatment arms. Comparisons were qualitatively synthesized into conclusions for which there were varying levels of evidence.

Our searches identified 4,749 articles. After full article review, 250 articles reporting results of 274 controlled trials were included, from 31 countries. Of trials included, 74 percent reported data on subjects' age, 13 percent reported on phase of care at study entry, 8 percent reported on race, and none reported on sexual maturity rating. Investigators used 25 assessment schemes to classify acne severity, and 505 distinctly named outcomes over 4 periods of followup (usually <3 months). Two trials addressed psychological effects and 43 provided data concerning treatment compliance. None reported on cost. Only eight trials stratified results by patient demographics and none by degree or type of prior therapy. 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 101 (37 percent). The remaining 22 (8 percent) were of intermediate quality or did not provide enough information to make a determination.

There were 250 pairwise comparisons of over 140 treatments. In grading the strength of evidence, there were 14 comparisons with Level A, 102 with Level B, and 134 with Level C evidence regarding effectiveness of treatment for acne. The Level A comparisons suggested the greater effectiveness of topical clindamycin, erythromycin, tetracycline, tretinoin, and norgestimate/ethinyl estradiol over vehicle in mild-to-moderate acne; the greater effectiveness of benzoyl peroxide and aluminum chlorhydroxide/sulphur over vehicle in unstated acne severity; and equal effectiveness among topical tretinoin, isotretinoin, and motretinide. The following Level A conclusions demonstrated equivalence: Benzoyl peroxide at various strengths was equally efficacious in mild/moderate acne; adapalene and tretinoin were equally efficacious in unspecificed severity; motretinide and tretinoin were equally effective; adding vitamin A to oxytetracycline conferred no added efficacy; cyproterone was equally effective at two different doses. For side effects data, 88 comparisons provided evidence for withdrawals, severe side effects, or side effects in more than 10 percent of subjects in at least one arm. There were 10 comparisons of Level A strength.

Despite the large number of English-language controlled trials regarding acne therapy, their methodological limitations prevent our ability to evaluate the comparisons among therapies, and may limit the conclusions that others may draw in the future from this evidence base, even when coupled with expert knowledge. Multiple treatments, inconsistent information about baseline characteristics, and heterogeneity of assessment schemes and outcomes make it difficult to synthesize the evidence about best approaches to acne management. For future research to provide results for comparison, standardization among researchers is needed in these different areas. Research is needed to define the optimal sequence of acne therapy, and to define the relative roles of specialists and generalists in the care of acne.

This report was developed using accepted evidence-based techniques; however, as in other areas of research, the methodology was necessarily constrained by issues of feasibility and practicality so that, for example, the analysis was limited to clinical trials reported in the English language. Nonetheless, this report is a systematic effort to collect and summarize the available evidence on the management of acne and represents a potentially powerful resource for the field. As with any systematic review, to be accurate and comprehensive, the generation of guidelines requires additional information, such as expert opinion, to put the evidence into context.

It is estimated that 45 million people in the United States have acne vulgaris, with a prevalence of approximately 85 percent in the population 15-24 years of age. The disease is more common and more severe in males than in females. Morbidity primarily comes from the lesions themselves, which may be painful and tender, as well from scars left by nodules and cysts. Morbidity may be generated by adverse effects of treatments as well. Psychological morbidity has been noted. It is estimated that consumers spend $100 million per year in over-the-counter remedies. Coupled with loss of productivity and unemployment, the direct cost of acne may exceed $1 billion per year in the United States.

Three questions were addressed in the literature abstraction:

Evidence was sought for several subpopulations by acne severity, gender, and race/ethnicity; by outcome (e.g., response to treatment and acne sequelae); and cost.

Working with our partners, the American Academy of Dermatology and the American Academy of Pediatrics, as well as with the American Pharmaceutical Association, the Departments of Dermatology and Pediatrics at Johns Hopkins School of Medicine, the Cochrane Collaboration, and the Society for Investigational Dermatology, we assembled a team of technical experts.

The questions for consideration were developed through discussions with our technical experts, as well as through preliminary searches of MEDLINE and MicroMedex and a review of consumers' questions submitted to a major consumer health Internet Web site (InteliHealth^TM).

The following reference databases were searched: CENTRAL database of the Cochrane Collaboration, MEDLINE (accessed through PubMed), OLDMEDLINE, PsycINFO, and CINAHL. The CENTRAL search strategy was (acne-vulgaris*.me OR acne*.tw). Similar strategies were used for the other databases. The search strategy for PubMed combined, using a Boolean AND, a topic-specific strategy (acne vulgaris[mh] OR acne*[tw]) with a strategy designed to retrieve all controlled trials. Reference lists from key articles were reviewed by hand. All unique controlled trials of acne therapy were sought that presented original, human data and were written in English.

Identified articles were screened by independent reviewers in an abstract review process to determine eligibility for full article review. Eligible articles were reviewed serially by two or more abstracters who sought methodological and outcome data.

Studies were qualitatively assessed in terms of methodological strengths and weaknesses. Studies were also classified by the level of acne severity in study patients at enrollment. A combined acne severity classification was created that integrated the 25 schemes found in the literature.

The unit of analysis was the comparison between pairs of treatment arms. Comparisons were qualitatively assessed by addressing methodological issues, by addressing commonality of outcomes across studies, and by addressing results and their statistical significance between arms. The evidence was assessed in terms of strength at Levels A, B, or C as follows:

• A -- At least two trials of acceptable quality show moderate to strong statistical evidence for a clinically meaningful endpoint and effect.
• B -- Evidence is of modest strength, such as when only one trial addresses a comparison, several trials have different qualitative conclusions, large differences are not statistically significant, or poor trial quality prevents accepting strong statistical evidence at face value.
• C -- Evidence does not permit coming to any scientific conclusion because of a paucity of the evidence, conflicting evidence, or very poor quality evidence.

• The literature is extremely heterogeneous, severely limiting the number of meaningful conclusions that can be drawn. The 274 trials included reports from 31 countries. There were 140 treatments. There were 505 distinctly named acne outcomes over four periods of followup (usually <3 months). There were 250 pairwise comparisons.
• Evidence for subpopulations is either not available or reported in such a varied manner as to prevent meaningful integration. Of the trials, 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. Only eight trials stratified their results: four by gender, three by acne type or severity, and one by study location.
• Evidence for quality-of-life outcomes and cost is not available. Two trials assessed psychological effects and 43 trials provided anecdotal data on treatment compliance. None reported on cost.
• Of 250 comparisons, only 14 had evidence of Level A. These comparisons demonstrated the efficacy over vehicle or placebo control of aluminum chlorhydroxide/sulphur, topical clindamycin, topical erythromycin, benzoyl peroxide, topical isotretinoin, tretinoin, oral tetracycline, and norgestimate/ethinyl estradiol. Level A conclusions demonstrating equivalence include: Benzoyl peroxide at various strengths was equally efficacious in mild/moderate acne; adapalene and tretinoin were equally efficacious in unspecified severity; motretinide and tretinoin were equally effective; adding vitamin A to oxytetracycline conferred no added efficacy; cyproterone was equally effective at two different doses. There were 102 comparisons with Level B evidence and 134 with Level C evidence.
• The literature is not organized to differentiate responses to first-line, second-line, or third-line (referral) therapy. 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.
• Regarding side effects, evidence was gleaned for 88 primary comparisons. Of these, 10 provided evidence at Level A. These involved, primarily, adverse local reactions of retinoids. Because of appropriate exclusions, important side effects, like the teratogenicity of isotretinoin, were not documented in these trials.

There is still much work to be done to define the best approach to management of acne in an individual patient based upon his or her specific characteristics. Until this work is done, the process of care for patients with acne vulgaris will remain highly individualized, based upon the experience of the patient and the treating physician. The effectiveness of a more evidence-based, stepwise approach that incorporates several therapies at different points in time still needs to be documented.

Future research on the treatment of acne vulgaris would benefit from:

• Population-based studies with detailed information about subjects including age, race, gender, sexual maturity rating, and previous treatment of acne.
• Consistent case definitions and methods for assessing acne type and severity.
• Greater consistency in outcomes across studies so that trials are comparable.
• Standards for assessment of clinical outcomes.
• Assessment of outcomes at time points distant from treatment.
• Explicit assessment of patients' acceptability of treatment.
• More information about psychological outcomes and costs related to treatment.
• Attention to the issue of bacterial resistance.

This report was developed using accepted evidence-based techniques; however, as in other areas of research, the methodology was necessarily constrained by issues of feasibility and practicality so that, for example, the analysis was limited to clinical trials reported in the English language. Nonetheless, this report is a systematic effort to collect and summarize the available evidence on the management of acne and represents a potentially powerful resource for the field. As with any systematic review, to be accurate and comprehensive, the generation of guidelines requires additional information, such as expert opinion, to put the evidence into context.