Methods report on the development of the European S3 guidelines for the treatment of acne

Authors


A. Nast: E-mail:alexander.nast@charite.de

I Introduction

This methods report provides a comprehensive description of the development process behind the European S3 Guidelines for the Treatment of Acne.

The Guidelines itself was developed according to the standard operating procedures (see Appendix A) of the European Dermatology Forum (EDF), and the underlying methodology incorporated the quality criteria contained within the Appraisal of Guidelines Research & Evaluation (AGREE) Instrument, as well as the recommendations of the Cochrane Collaboration, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, and the German Association of Scientific Medical Societies (AWMF).

The European S3 Guidelines for the Treatment of Acne was created using a structured development process comprising a systematic search of the literature within the relevant databases, a systematic evaluation of the search results, and a consensus conference based on formal consensus methodology (nominal group technique).

II Methods

II.1 Nomination of experts

Individuals were nominated to the expert panel – referred to henceforth as the EU Guidelines Group – by the guidelines group of the EDF or by the European Academy of Dermatology and Venereology (EADV). To be nominated as an expert, an individual had to satisfy at least one of the following criteria:

  • 1 Extensive clinical experience in the treatment of acne.
  • 2 Relevant publications in the field of acne.
  • 3 Relevant experience in evidence-based medicine.

Emphasis was placed on selecting a representative panel of experts from throughout Europe.

Representatives from various interest groups were involved in an external review of the Guidelines. Although extensive efforts were made to find a patient representative, these were ultimately unsuccessful due to the current lack of patient organizations in this field. Patients were, however, invited to participate in the external review.

For a detailed overview of participating experts, see Appendix C.

II.2 Selection of relevant interventions and key questions

As evidence-based guidelines are strongly limited by issues of feasibility, the key questions to be addressed must be chosen carefully. In its initiation meeting, the EU Guidelines Group discussed which interventions and questions should be considered and subsequently reached a consensus regarding the main focus of the Guidelines. The EU Guidelines Group decided that suitable treatment options should be presented in a clinical treatment algorithm, taking into account the type of acne and the severity of disease. Interventions were selected according to the following criteria:

  • 1 Clinical relevance.
  • 2 Intervention had to be available/licensed in Europe either as a monotherapy or a fixed dose combination.
  • 3 Used for the treatment of acute acne.

Treatment options consisting of more than two topical components were not included because of the likelihood of reduced patient adherence and/or because of a limitation in the feasibility of discussing all possible combinations and sequences. Fixed dose combinations were considered as long as they were licensed in a European country. In future versions of the Guidelines, aspects such as maintenance treatment (step 2) and the treatment of acne scarring, as well as skin care (step 3) should be considered.

II.3 Check for existing guidelines and systematic reviews

Using existing systematic reviews or guidelines as a basis can greatly facilitate the work of a guidelines group. We thus performed a search for these sources in MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and the Guidelines International Network (G-I-N) Database. Standard Google searches were also performed. We refrained from conducting a systematic search at this point and stopped searching for certain interventions as soon as we had found a high quality source of information.

Existing systematic reviews were assessed using the Methodology Checklist 1: Systematic Reviews and Meta-analyses published by the Scottish Intercollegiate Guidelines Network (SIGN) (see Appendix E). Existing guidelines were checked to determine whether they addressed the relevant questions agreed upon during the initiation meeting. All information retrieved from these reviews and guidelines was verified against the original publications and a grade of evidence was assigned to each trial.

II.4 Literature search/update based on existing systematic reviews

To find relevant trials, we performed systematic searches of the databases MEDLINE and EMBASE (for search strategies see Appendix B). For topical and systemic treatments, our search covered the period from 1 January 1999 through 10 March 2010, whereas for laser and light treatments it covered the period from 1 January 2007 through 13 April 2010. The beginning dates of our searches were based on the search periods used by the various systematic reviews considered in our Guidelines, whereas the end dates are the days upon which our own searches were conducted. All search results were verified by two independent assessors (AS and SR). In case of disagreement, a third assessor (AN) was involved and the conflict resolved through discussion. Reasons for excluding a study based on its abstract were as follows:

  • 1 No original data.
  • 2 No human data.
  • 3 No clinical data.
  • 4 Not dealing with the management of acne.
  • 5 Not in English (exception: selected German-language publications identified by hand search).

After the search results were screened and agreed upon by the two (or, in some cases, three) assessors, the bibliographical information was transferred to an EndNote database and the full texts were obtained if available.

II.5 Standardized inclusion/exclusion and data extraction

Identified literature was evaluated by the two assessors (AS, SR) using a standardized Literature Evaluation Form (see Appendix D) comprising three parts (A, B, C). Both evaluators had been trained in using the Literature Evaluation Form for critical literature evaluation. The data generated by the two assessors were compared with each other, and any discrepancies were reviewed by a third assessor (AN) and resolved through discussion.

Part A of the Literature Evaluation Form lists the exclusion criteria for clinical trials of interventions that the EU Guidelines Group had chosen for consideration in the Guidelines (see Table 1: Interventions included in the guidelines). The exclusion criteria were based on those used by Lehmann et al. (2001):1

Table 1.   Interventions included in the guidelines
Systemic treatmentsTopical treatmentsLaser and light treatments
Antibiotics
 • Erythromycin
 • Clindamycin
 • Tetracycline
 • Doxycycline
 • Minocycline
 • Lymecycline
Antibiotics
 • Erythromycin
 • Clindamycin
 • Tetracycline
 • Nadifloxacin
Intense pulsed light
IsotretinoinAzelaic acidPhotodynamic therapy
Hormone therapyBenzoyl peroxideBlue light
ZincRetinoids
 • Adapalene
 • Isotretinoin
 • Tretinoin
Laser
 Fixed combination
 • Adapalene/BPO
 • BPO/clindamycin
 • Erythromycin/tretinoin
 
  • 1 Does not address management of active acne.
  • 2 More than 20% of the patients have chloracne, acne venenata, acne fulminans, acne necroticans, acne agminata, or rosacea.
  • 3 Patients differed at baseline (for example, occupational acne).
  • 4 Surrogate outcome measures only (for example, sebum production, propionibacterium acnes colony counts).
  • 5 No original data.
  • 6 Article not in English.
  • 7 Fewer than 10 patients per study arm.
  • 8 Not a controlled, prospective trial.
  • 9 No objective efficacy data (nota bene: added by the EU Guidelines Group).

Part B of the Literature Evaluation Form was designed to assist the assessors in evaluating the methodological quality of each trial and to assign each trial a grade of evidence. If methodological weaknesses, such as the use of co-medication or the presence of baseline differences, were identified during part B, it was still possible to exclude the trial in question.

Part C of the Literature Evaluation Form was designed to allow the assessors to extract outcome data on efficacy and safety from the included trials. The extracted data were summarized in evidence tables using MS Excel spreadsheets according to the methodology described in Part C.

II.6 Evidence tables

II.6.1 Categorizing included studies according to acne type

To address the demands of clinical practice, we categorized the included studies according to acne type. Because there is no widely accepted method for classifying acne severity or type, we chose to differentiate between comedonal acne; mild to moderate papulopustular acne; severe papulopustular acne/moderate nodular acne; and severe nodular acne/conglobate acne. Whenever possible, the different severity scales and definitions of acne types used in the included studies were harmonized to make the populations more comparable and provide valid evidence with a narrower focus on distinct clinical questions (for example, ‘What is the best drug for comedonal acne?’). If disease severity or acne type was not reported in a given study, we nevertheless classified and included it for later data extraction as long as lesion types and lesion counts at baseline were provided. In such instances, we classified >15 inflammatory lesions (IL) on the face in papulopustular acne and >6 nodules on the face in conglobate acne as severe disease.

To provide a good overview of the available evidence on different types of acne, we generated separate evidence tables for comedonal acne, papulopustular acne and conglobate acne. Because very few trials to date have focused on comedonal acne or on conglobate acne alone, most of the trials that examined these (alongside other) acne types can also be found in the table for papulopustular acne. In short, trials could be categorized as having examined more than one acne type (and could thus be included in more than one table) if they included patients with different types of acne. To provide valid evidence for the different acne types, we generally favoured using a percentage reduction in the respective lesion count (see below) as an outcome measure. Only if such information was unavailable did we take other outcome measures into account, such as the Leeds Score/Burke-Cunliffe score, or mean acne severity (MAS) score.

  • 1 Comedonal acne: A trial on comedonal acne was categorized as such by our group if: (a) it had been designated in this manner by its authors and/or (b) this designation could be confirmed by patient baseline data provided in the study (comedone count, few or no inflammatory lesions). Because only very few studies have focused solely on comedonal acne to date, indirect evidence was generated by means of looking at the percentage reduction in non-inflammatory lesions (NIL). If a given study was categorized by methodologists as a trial on comedonal acne and no reduction in NIL was reported, other outcome measures, such as the MAS score, could be taken into account.
  • 2 Papulopustular acne: A trial on papulopustular acne was categorized as such by our group if: (a) it had been designated in this manner by its authors and/or (b) this designation could be confirmed by patient baseline data provided in the study. For papulopustular acne, the EU Guidelines Group agreed that the percentage reduction in IL was the outcome measure that would provide the best evidence. If this information was unavailable, the second and third choice outcome measures were the percentage reduction in papules (PA) and the percentage reduction in pustules (PU), respectively. If none of this information was available, the assessors relied on the total lesion count (i.e. the NIL count plus the IL count) or, similar to the approach taken with comedonal acne, an alternative outcome measure, such as the Leeds score.
  • 3 Nodular/conglobate acne: A trial on nodular/conglobate acne was categorized as such by methodologists if: (a) it had been designated in this manner by its authors and/or (b) it reported the nodule or cyst count over time, as well as relevant numbers of these lesions at the beginning of the trial. As was the case with comedonal acne, the assessors found comparatively few studies that focused solely on conglobate acne. The percentage reduction in nodules (NO) or cysts (CY) served as an outcome measure. Alternative outcome measures were the same as those described above for comedonal acne and papulopustular acne.

II.6.2 Description of the evidence tables

Generally speaking, pooling information by means of evidence tables jeopardizes the integrity of results unless some elementary rules are applied to the columns of the tables (selection commented on in the following):

Author: gives the name of the first author and year of publication. In cases where data obtained from the same patient sample were analysed and the results presented in two publications, the first authors of each publication are given.

The number in parentheses refers to the bibliography in the end of the full guidelines text’.

= number: Gives the number of patients after randomization.

S = severity: Gives a grade of severity (1, 2 or 3) according to the description of disease severity in the study or, if no such description was available, according to our own calculation using the lesion count at baseline or the scale/score given in the study for the baseline population (for example, Burke-Cunliffe/Leeds score).

D = duration: Gives the duration of the study in weeks. In cases where a study lasted substantially longer than 12 weeks, the assessors generally attempted to extract data on outcomes at 12 weeks (or as close to this point as possible). In such cases, two numbers are shown in this column: the first number gives the overall length of the study in weeks, whereas the second number gives the point in time at which outcome data were extracted.

Summary of efficacy: NIL, IL, NO, CY or their components (papules, pustules, open or closed comedones) were taken into account. We defined a difference as a ≥10% reduction in lesion count compared with baseline.

Summary of safety: To provide meaningful data on safety, we followed a pragmatic approach by looking, first, at the three most common related adverse events/local side effects; second, at differences in drop-out rates due to adverse events; and, third, at the conclusions about safety drawn by the authors of each publication [conclusion of author (coa)]. If no such data were available, it was impossible to give a comparative statement on safety. It was also difficult to provide such statements in cases where the number of patients with adverse advents was low.

A written summary of efficacy and safety was provided for sequential treatments or combinations with more than two drugs, for comparisons of verum vs. vehicle, or for comparisons of different concentrations of the same drug.

Drop-outs: Gives the number of drop-outs due to adverse events if available.

Grade of evidence: Each trial included in the Guidelines was evaluated with regard to its methodological quality and assigned a grade of evidence according to the grading system used in previous guidelines.2,3

  • A Randomized, double-blind clinical trial of high quality (for example, sample-size calculation, flow chart of patient inclusion, intention-to-treat (ITT) analysis, sufficient sample size)
  • B Randomized clinical trial of lesser quality (for example, only single-blind, limited sample size: at least 15 patients per study arm)
  • C Comparative trial with severe methodological limitations (for example, not blinded, very small sample size, no randomization)

II.6.3 Level of evidence (LE)

In addition to assigning a grade of evidence to individual trials, the assessors assigned levels of evidence to the various treatment options. The levels of evidence, which can be regarded as an overall rating of the available efficacy data for each treatment option, were defined as follows:

  • 1Further research is very unlikely to change our confidence in the estimate of effect. At least two trials are available that were assigned a grade of evidence A and the results are predominantly consistent with the results of additional grade B or C studies.
  • 2Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. At least three trials are available that were assigned a grade of evidence B and the results are predominantly consistent with respect to additional grade C trials.
  • 3Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Conflicting evidence or limited amount of trials, mostly with a grade of evidence of B or C.
  • 4Any estimate of effect is very uncertain. Little or no systematic empirical evidence; included trials are extremely limited in number and/or quality.

One trial with a grade of evidence of A equals two trials with a grade of evidence of B.

In all cases, it was possible for the EU Guidelines Group to modify the level of evidence assigned to a particular treatment option based on individual clinical assessments of a trial’s findings or in the event of conflicting findings among several studies (see, for example, comedonal acne: 3.3.1, 7.2.5, 5.6.1, 10.1; papulopustular acne: 1.4, 3.3.1, 4.2.3).

II.7 Consensus conference

The consensus conference took place in Dubrovnik, Croatia, on 11–12 May 2010. The conference was chaired by Prof. Berthold Rzany, who is an AWMF-certified moderator of consensus conferences. Prior to each consensus vote on a recommendation, the existing evidence was presented to the group and discussed with regard to efficacy, safety, patient preference, practicability and additional factors, such as antibiotic resistance and the results of pathophysiological reasoning.

II.8 Strength of recommendation

To avoid any potential confusion, standardized phrases were used to express the strength of a recommendation throughout the Guidelines. These were as follows:

  • 1is strongly recommended
    Good efficacy data, reasonable safety profile (especially regarding the benefit/harm ratio), good patient acceptance and a high level of evidence with direct evidence.
  • 2can be recommended
    Good efficacy data, reasonable safety profile (especially regarding the benefit/harm ratio), good patient acceptance, limitations pertaining to the level and directness of evidence.
  • 3can be considered
    Efficacy is lower than that of interventions that received a greater strength of recommendation; or: directness of evidence is insufficient or lacking; or: there were specific pathophysiological factors that led to a downgrade.
  • 4is not recommended
    Insufficient efficacy or less favourable benefit/harm ratio.
  • 5may not be used under any circumstances
    Harmful intervention with very unfavourable benefit/harm ratio.
  • 6a recommendation for or against treatment X cannot be made at the present time
    Due to a lack of evidence, it is impossible to make a recommendation for or against treatment X at the present time. Insufficient data from clinical trials; promising case reports or expert opinions may exist.

II.9 External review

The European S3 Guidelines for the Treatment of Acne underwent an extensive external review. From 13 May through 30 June 2011 the guidelines was available online for comments and amendments. This period of online availability was announced using the following mailing lists: EDF Board, EDF Guidelines Committee, EDF Members and the UMES Board.

To reach more patients, the external review was also announced on two forums (http://www.acne.org, http://www.acneassasin.com).

In addition, every participant was encouraged to invite all potentially interested parties to review and comment on the guidelines by participating in the external review process.

III Results

III.1 Nomination of experts

The experts were nominated by the EDF and EADV. For a detailed overview of the participating experts, see Appendix C.

The Division of Evidence Based Medicine at Charité– Universitätsmedizin Berlin was chosen as a methodological centre because of its experience in guidelines development in dermatology, such as the European S3 Guidelines for the Treatment of Psoriasis.

III.2 Selection of relevant interventions and key questions

In an initiation meeting in Paris on 19 March 2009, the EU Guidelines Group decided which interventions would be considered in the European S3 Guidelines for the Treatment of Acne (Table 1: Interventions included in the guidelines).

Later in the course of the project, after the final makeup of the Group had been established, all members confirmed the choice of interventions.

The Guidelines is based on a clinical algorithm that focuses in particular on the various treatment options for different types of acne. Efficacy, safety and patient preference were taken into account for each of the included treatment options, and these aspects were assessed based on suitable publications. In addition, aspects such as pathophysiology and antibiotic resistance were taken into account.

It would have gone beyond the scope of this Guidelines to consider the pricing and reimbursement regimes in every European country. The difference in these are too large, as are those in patients’ willingness and ability to pay for medication, and in the availability of generics. This and other European guidelines are therefore always meant to be treated as a source for national and local adaption, and pharmacoeconomic considerations should be taken into account at these levels.

III.3 Check for existing guidelines and systematic reviews

As described in detail in section 2.3, a non-systematic search was performed to identify existing guidelines, consensus papers and systematic reviews.

The following consensus paper and guidelines were identified and provided to the EU Guidelines Group as a basis for discussion:

  • 1 Consensus paper Gollnick et al. Global acne alliance.4
  • 2 German acne guidelines.5
  • 3 French acne guidelines.6
  • 4 US acne guidelines.7

None of these guidelines assesses the available evidence with respect to the different acne types (S3). Because of this, the EU Guidelines Group used them for orientation purposes only and did not adapt them for use in the European S3 Guidelines on the Treatment of Acne. However, the clinical algorithm from the consensus paper from 2003 from the Global Acne Alliance was adapted as the basis for the algorithm used in the Guidelines.

The following systematic reviews were identified:

  • 1 Arowojolu AO, Gallo MF, Lopez LM, Grimes DA, Garner SE. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev 2009, Issue 3. Art. no: CD004425. DOI: 10.1002/14651858.CD004425.pub4.
  • 2 Garner SE, Eady A, Popescu CM, Newton J, Li Wan Po A. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev 2003; (1): CD002086.
  • 3 Haedersdal M, Togsverd-Bo K, Wulf HC. Evidence-based review of lasers, light sources and photodynamic therapy in the treatment of acne vulgaris. J Eur Acad Dermatol Venereol 2008 Mar; 22: 267–78.
  • 4 Hamilton FL, Car J, Lyons C, Car M, Layton A, Majeed A. Laser and light therapies for the treatment of acne vulgaris: systematic review. Br J Dermatol 2009; 160: 1273–85.
  • 5 Lehmann HP, Andrews JS, Robinson KA, Holloway VL, Goodman SN. Management of Acne. Rockville, MD: Agency for Healthcare Research and Quality 2001. (Evidence Report/Technology Assessment, 17; AHRQ publication no 01-E019).
  • 6 Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol 2005; 153: 395–403.
  • 7 Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the treatment of acne vulgaris: a review. Br J Dermatol 2008; 158: 208–16.
  • 8 Thielitz A, Abdel-Naser MB, Fluhr JW, Zouboulis CC, Gollnick H. Topical retinoids in acne – an evidence-based overview. J Dtsch Dermatol Ges 2008 Dec; 6: 1023–31.
  • 9 Williams H, Bigby M, Diepan T, Herxheimer A, Naldi L, Rzany B. Evidence-based dermatology, 2nd edn, Apr 2008; Web tables. URL: http://www.blackwellpublishing.com/medicine/bmj/dermatology/pdfs/web_tables_15.doc. (last accessed: 17 May 2010).
  • 10 Worret WI, Fluhr JW. Acne therapy with topical benzoyl peroxide, antibiotics and azelaic acid. J Dtsch Dermatol Ges 2006 April; 4: 293–300.

After the quality of these systematic reviews had been evaluated (see SIGN checklists in Appendix E), the reviews listed below were chosen to be used as a basis for the present Guidelines (Table 2: Overview of available sources of evidence).

Table 2.   Overview of available sources of evidence
ReferencesUsed as source of evidence forEnd date of literature searchInclusion criteriaDatabasesNo of included/excluded studies
Arowojolu8Hormonal antiandrogens29 Jan 2009RCTs of combined oral contraceptives and facial acne in any languageCENTRAL, MEDLINE, EMBASE, POPLINE, LILACS, ICTRP, ClinicalTrials.gov, unpublished trials, hand search25/58
Garner9Minocycline19 Nov 2002Open trials, RCTs of minocycline for acne vulgaris in any languageMEDLINE, EMBASE, Biosis, Biological Abstracts, International Pharmaceutical Abstracts, Cochrane Skin Group’s Trial Register, Theses Online, BIDS ISI Science Citation Index, National Research Register, Current Controlled Trials, Bids Index to Scientific and Technical Proceedings, hand search29/46
Haedersdal10Laser and light treatmentsMar 2007RCTs and CTs, optical treatments, at least 10 individuals for each tested intervention, English articlesPubMed, Cochrane Library19/8
Hamilton11Laser and light treatments31 Jul 2008RCTs of light and laser treatments for acne vulgarisCENTRAL, MEDLINE, EMBASE, CINAHL, PsycInfo, LILACS, ISI Science Citation Index, Dissertation Abstracts International, unpublished trials, grey literature, Google Scholar, Copernicus25/201
Lehmann1All included topical and systemic treatments1999Acne vulgaris combined with a Boolean AND, a topic-specific strategy, CTsCENTRAL (1948 – April, 1999), MEDLINE (1966 – April, 1999), OLDMEDLINE (1960 – 1965), PsycINFO (1887 – June, 1999), CINAHL (1982 – June 1999), hand search274/4499
Simonart12Topical antibiotics1966 to Dec 2003RCTs, CTs, topical treatment with erythromycin or clindamycin in inflammatory acne, >6 patients, English articlesMEDLINE, EMBASE, PubMed, Current Contents, textbooks, reference lists45/5
Simonart13Oral tetracycline1962 to Mar 2006Clinical trials, oral tetracyclines for the treatment of inflammatory acneMEDLINE, PubMed, Current Contents, reference lists, specialist textbooks35/22
Thielitz14Topical retinoidsNo information available, probably 2007Topical retinoids in acne, English or German articlesMEDLINE via PubMed71/no information available
Williams15All included interventions2007Search terms ‘acne’, ‘RCT’, and the medicationsPubMed, EMBASE141/no information available
IsotretinoinEnd 200813/1
Worret16Topical benzoyl peroxide, antibiotics and azelaic acidNo information available, probably 2006No information availableNo information availableUnclear, probably 32/no information available

Using the Literature Evaluation Form, the methodologists evaluated a total of 256 studies (without duplicates) that had been included in the systemic reviews. Of these studies, 184 trials were ultimately included and 72 were excluded (among which were four articles that could not be obtained). For more details, see Fig. 1 Overview of included and excluded articles and the systematic reviews in which they were cited.

Figure 1.

 Overview of included and excluded articles and the systematic reviews in which they were cited.

III.4 Literature search/update based on existing systematic reviews

We performed a systematic literature search for each included intervention (see Appendix B for search strategies). As mentioned in section 2.4 above, the beginning dates of our searches were based on the search periods used by the various systematic reviews considered in our Guidelines. For topical and systemic treatments, our search covered the period from 1 January 1999 through 10 March 2010, whereas for laser and light therapies it covered the period from 1 January 2007 through 13 April 2010.

Our search generated 1576 hits, including 161 on laser and light treatments. After screening all abstracts, the two independent assessors determined that 259 publications were eligible for a more detailed evaluation. Some of these 259 publications were included by hand search.

III.5 Standardized inclusion/exclusion and data extraction

The publications retrieved in the literature search were evaluated systematically using parts A–C of the Literature Evaluation Form. A total of 515 articles were evaluated using part A of the Literature Evaluation Form (five articles could not be obtained). Of these articles, 283 clinical trials fulfilled our inclusion criteria, whereas 232 did not and were excluded. The remaining 283 studies were further evaluated using parts B and C of the Literature Evaluation Form and the relevant information was transferred to MS Excel tables, which are available online (http://www.acne-guidelines.com). Data from the systematic reviews were transferred directly into the tables and later checked for errors.

III.6 Classification of evidence

A level of evidence was assigned to each clinical question based on the available trials. The following levels of evidence for relevant key questions were applied; low levels of evidence indicate a need for more high-quality research in these areas. The distribution of studies for each grade of evidence is displayed in Table 3: Distribution of grades of evidence.

Table 3.   Distribution of grades of evidence among the included trials
Grade of evidenceNumber of trials
A136
B95
C52

III.7 Consensus conference

Defining the clinical superiority of one treatment option over another was particularly challenging. Using indirect evidence from quality-of-life data, we chose to define superiority as a ≥10% reduction in the number of lesions.17

After a detailed presentation of the available data on efficacy, safety and patient preference, the recommendations were discussed during the consensus conference.

The detailed voting results are available at the dEBM. Of the 41 recommendations put up for a vote, 59% passed with absolute consensus (i.e. 100% agreement), 39% passed with a strong consensus (>75%) and only 2% passed with a majority between 50% and 75% partial vote.

III.8 External review

The European S3 Guidelines for the Treatment of Acne was made available online for commenting for 7 weeks. All national societies were invited to comment and to pass on the invitation to their members. In addition, the mailing list of the EDF was used. The EU Guidelines Group received and evaluated 65 comments (see http://www.acne-guidelines.com), of which 37% led to changes in the text. Individuals or organizations that posted comments that were ultimately rejected were provided with an explanation of why their comments had not been considered further.

Review by the UEMS (Union Européenne des Médicins Spécialistes)

According to the standard operating procedures of the EDF (see Appendix A Standard operating procedures), the European S3 Guidelines for the Treatment of Acne was also sent to the UEMS for approval.

III.9 Participation of the relevant interest groups

Participation of patient representatives

Although extensive efforts were made to find a patient representative, these were ultimately unsuccessful due to the current lack of patient organizations in this area. Patients were, however, invited to join the external review.

Participation of further relevant disciplines

A psychologist participated in the development process. She took part in the consensus conference, the internal review, and also in writing the texts.

III.10 Implementation

Depending on further funding, an implementation project may be conducted to increase awareness and acceptance of the European S3 Guidelines for the Treatment of Acne. Because many countries are involved, each with its own health system, traditions and languages, a project like this would face a range of challenges.

III.11 Evaluation

Because no further funding for this Guidelines is available, no formal evaluation programme has been planed so far.

III.12 Funding

The European S3 Guidelines for the Treatment of Acne was funded by the EDF.

III.13 Future updates of the Guidelines

In accordance with the standard operating procedures of the EDF, the European S3 Guidelines for the Treatment of Acne will need to be updated in 3 years. Because new interventions may be licensed or relevant changes in information (for example, on adverse events) may become available before this point, the subcommittee on acne of the EDF will evaluate the need for an earlier update of particular (or all) interventions at regular intervals.

Future updates to the Guidelines may also include maintenance therapy.

III.14 Declaration of conflicts of interest

All authors completed the ‘Form for Disclosure of Potential Conflicts of Interest’ of the International Committee of Medical Journal Editors (ICMJE), which is available at the dEBM and online (http://www.acne-guidelines.com).

IV Summary

The European S3 Guidelines for the Treatment of Acne is the first in the European Union to focus on this disease. Developing evidence-based guidelines is demanding and time-consuming for all participants, especially when the process takes place at the European level. Coordinated structures and processes are essential in this context. In the present method report, we describe in detail this structured process, which was coordinated by the Division of Evidence Based Medicine at Charité– Universitätsmedizin Berlin, Germany. Two possibilities for updating the Guidelines are imaginable: (i) after a certain period (for example, 3 years); or (ii) at shorter intervals and based on continuous surveillance of the literature, which might involve updating only certain parts of the Guidelines. This latter option, which could be described as creating ‘living guidelines’, would ensure a high degree of timeliness and relevance in addition to high quality findings, but would clearly require sufficient and continuous funding.

Appendix

Appendix A Standard operating procedures

StepResponsibleTaskMonths duration
 1EDF Guidelines Committee (EDF-GC)*Decision of topic of specific guideline
Identification of potential chairperson and subcommittee members
At EDF meeting
 2EDF BoardDiscussion and approval of the choice, and level of guideline (S1. S2 or S3) as well as chairpersonVia round email
 3Chairperson guideline subcommitteeFormation of guideline subcommittee: Nomination of EDF members (50%)
Identification of possible EADV members (25% of members for the subcommittee) who could work within the subcommittee. Chairman of EDF guideline subcommittee asks EADV president for approval
Finally approval of the chairperson of the subcommittee by the group
 
 4EDF Guidelines
Subcommittee
(EDF-GSubC)
Development of a business plan (information available at B Schulze. EDF guideline secretariat) 
 5EDF BoardConfirmation of business plan and signature of the contract for financial support of guidelinesVia round email
 6Chairperson of
EDF-GC
Send information on the intended guideline to national dermatological societies 
 7EDF-GSubCStart of work on the guideline content
Identify all Existing guidelines for the specific guideline (active process: literature survey plus contact to Dermatological Societies) Select the guidelines with highest quality. Criteria for selection
1. Availability of strength of evidence
2. Availability of strength of recommendation
Evidence of mechanics of literature review (adhere to the recommendations of the Cochrane collaboration. These standards should assure high quality for the systematic literature search as well as
for the critical appraisal of the papers. For further information see http://www.cochrane.org/crgprocedures/chapter4/1.htm
Identification/nomination of EDF members for the EDF-GSubC from amongst the authors of the best guidelines
1
 8EDF-GSubCStart with literature survey0.5
 9Chairperson of EDF-GSubCConsider involvement of other disciplines and patients’ organizations1
10EDF-GSubCMeeting
 1. To decide the author of the first draft (normally the chairperson of the subcommittee) and to discuss the present guidelines, their strengths and weaknesses
2. Discuss responsibility for chapters of the guideline
3. 6 months later to discuss the draft (consensus conference)
6
11EDF-GSubCCirculate draft final version for approval among members of the guideline subcommitteeØ
12EDF-GSubC Chairperson EDF guideline committeeDeliver final version to EDF guideline committee chairperson, who forwards it to
 1. EDF board
 2. EDF guideline committee
 3. EDF membership including corporate members
 4. Board of EADV
 5. UEMS dermatology guideline group
 
13Chairperson of
EDF-GC
Send draft final version of EDF board for approval0.25 (round email)
13Chairperson of EDF-GCSend guideline for official approval to UEMS (formal approval)1

Appendix B Search strategies

Search strategy for topical and systemic treatments:

Databases: Ovid MEDLINE®, Ovid MEDLINE® In-Process, EMBASE

NoSearchesResults
 1exp acne/21 483
 2‘acne*’.ab,ti.19 622
 3exp clindamycin/31 199
 4exp erythromycin/63 620
 5exp tetracycline/56 991
 6exp benzoyl peroxide/3087
 7exp Retinoids/92 720
 8exp adapalene/705
 9exp anti acne agent/38 589
10exp isotretinoin/10 104
11exp retinoic acid/39 078
12exp azelaic acid/943
13exp antibiotic agent/586 001
14exp Antibiotics, Antitubercular/84 652
15exp doxycycline/29 314
16exp erythromycin/63 620
17exp lymecycline/500
18exp minocycline/14 784
19exp miconazole/8017
20exp drospirenone/578
21exp chlormadinone/1719
22exp desogestrel/3065
23exp antiandrogen therapy/44
24exp Androgen Antagonists/38 583
25exp cyproterone/3152
261 or 228617
273 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25807 181
2826 and 2710 986
29limit 28 to yr = ‘1999–Current’5667
30remove duplicates from 294816
31limit 30 to (clinical trial, all or clinical trial or comparative study or controlled clinical trial or meta analysis or multicenter study or randomized controlled trial) [Limit not valid in EMBASE; records were retained]4452
32from 31 keep 1–272272
33limit 30 to (‘qualitative studies (1 term high sensitivity)’ or ‘qualitative studies (1 term high specificity)’ or ‘qualitative studies (1 term min difference)’ or ‘qualitative studies (2 or more terms high sensitivity)’ or ‘qualitative studies (2 or more terms high specificity)’ or ‘qualitative studies (2 or more terms min difference)’) [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) In-Process; records were retained]1756
34from 33 keep 1–12941294
3532 or 341415

Search strategies for laser and light treatments:

Database: Ovid MEDLINE®

NoSearchesResults
 1exp Acne Vulgaris/8228
 2acne.mp.10 921
 3exp Lasers/30 379
 4laser*.mp.132 591
 5exp Light/180 295
 6light*.mp.361 725
 7intense pulsed light*.mp.361
 8photodynamic therap*.mp.7726
 9exp Photochemotherapy/10 125
101 or 210 921
113 or 4 or 5 or 6 or 7 or 8 or 9574 540
1210 and 11789
13limit 12 to yr = ‘2007 –Current’220
14limit 13 to (clinical trial, all or clinical trial or comparative study or controlled clinical trial or multicenter study or randomized controlled trial)59
15limit 14 to english55

Database: Ovid MEDLINE® In-Process

NoSearchesResults
 1acne* vulga*.mp.83
 2acne*.mp.380
 31 or 2380
 4laser*.mp.29 024
 5light*.mp.35 919
 6intense pulsed light*.mp.19
 7photodynamic therap*.mp.360
 8photochemotherap*.mp.23
 94 or 5 or 6 or 7 or 860 920
10clinical trial.mp.2287
11controlled clinical trial.mp.220
12randomized controlled trial.mp.1411
1310 or 11 or 123345
143 and 9 and 132
15english.lg.906 790
1614 and 152

Database: EMBASE

NoSearchesResults
 1exp acne/13 916
 2exp acne vulgaris/2666
 3acne*.mp.18 046
 41 or 2 or 318 465
 5exp laser/41 673
 6laser*.mp.123 298
 7exp light/59 787
 8light*.mp.264 262
 9intense pulsed light*.mp.419
10photodynamic therap*.mp.10 999
11exp photochemotherapy/1867
12photochemotherap*.mp.2579
135 or 6 or 7 or 8 or 9 or 10 or 11 or 12384 410
144 and 131299
15limit 14 to yr = ‘2007 –Current’460
16limit 15 to (‘qualitative studies (1 term high sensitivity)’ or ‘qualitative studies (1 term high specificity)’ or ‘qualitative studies (1 term min difference)’ or ‘qualitative studies (2 or more terms high sensitivity)’ or ‘qualitative studies (2 or more terms high specificity)’ or ‘qualitative studies (2 or more terms min difference)’)155
17limit 16 to english language135

Appendix C Members of the EU Guidelines Group

Each member of the EU Guidelines Group has specific responsibilities. At all stages of the guidelines process, these responsibilities need to be defined.

Project leaderBerthold Rzany ScM, MD
Division of Evidence Based Medicine (dEBM)
Klinik für Dermatologie
Charité– Universitätsmedizin Berlin
Campus Charité Mitte
Charitéplatz 1
10117 Berlin
Germany
Tel.: +49 30 450518 83
Fax: +49 30 450518 927
E-mail: berthold.rzany@charite.de
http://www.debm.de
http://www.derma.charite.de
Project coordinationAlexander Nast, MD
Adel Sammain, MD
Division of Evidence Based Medicine (dEBM)
Project office
Health record administration
Martin Hussain
Stefanie Rosumeck
Division of Evidence Based Medicine (dEBM)
Expert groupVincenzo Bettoli, MD (Italy)
Klaus Degitz, MD (Germany)
Brigitte Dréno, MD (France)
Andrew Finlay, MD (United Kingdom)
Ruta Ganceviciene, MD (Lithuania)
Harald Gollnick, MD (Germany)
Merete Haedersdal, MD (Denmark)
Alison Layton, MD (United Kingdom)
Jose Luis Lopez Estebaranz, MD (Spain)
Falk Ochsendorf, MD (Germany)
Cristina Oprica, MD (Sweden)
Thierry Simonart, MD (Belgium)
Niels Veien, MD (Denmark)
Maja Vurnek Živković (Croatia)
Christos Zouboulis, MD (Germany)
Moderation of the consensus conferencesBerthold Rzany ScM, MD

Appendix D Literature evaluation form (LEF)

STUDY ARTICLE ID:REVIEWERS:
AUTHOR:YEAR:

I. ACNE ABSTRACT REVIEW FORM (INCLUSION/EXCLUSION?)

*to be specified in Part III

SYSTEMIC
 ErythromycinClindamycinTetracyclineDoxycyclineMinocyclineLymecyclineHormone therapy*IsotretinoinZinc
 □
TOPICAL
 ErythromycinClindamycinTetracyclineNadifloxacinAzelaic acidBenzoyl peroxideAdapaleneTretinoinIsotretinoin
 □
OTHER INTERVENTION
 LaserUVBlue lightPDTIPLOther
 □ □ □ □ □(specify)
Does not address management of active acne
More than 20% of the patients have chloracne, rosacea, venenata, fulminans, necroticans, agminata
Patients differed at baseline (e.g. occupational acne)
Surrogate outcome measures only (e.g. sebum production, P. acnes colony counts)
No original data
Article not in English
Fewer than 10 patients
Not a controlled prospective trial
No relevant efficacy data
DO NOT PROCEED FURTHER IF ANY ITEM ABOVE IS TICKED!
ACNE TYPE:
(tick one or more)
MildComedonal acne
ModeratePapulopustular acne
SevereNodular/cystic
  Acne vulgaris
Acne

Comments on reasons for exclusion or inclusion if these could not be explained above:

………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………

II. ARTICLE REVIEW FORM (QUALITY OF ARTICLE)

1.Randomized trial?Yes □ No □ Cannot say □
Based on random numbers, from a table or computer
2.Blinding?□ No
□ Patient
□ Enroller/physician
□ Evaluator/assessor
□ Cannot say
3.ITT□ Yes □ No □ Cannot say
Did the study follow an intention-to-treat protocol?
4.Any co-medication besides study treatment?
Yes □ No □ Cannot say □
If yes, please specify: …………………………………………………………………………………….
5.Differences in characteristics of treatment groups besides study treatment (e.g. age, gender)?Yes □ No □ Cannot say □
If yes, please specify: …………………………………………………………………………………….
6.Study size: Number of patients after randomization
      (n) = ……………
      Number of arms = ……………
 
7.Grade of evidence
 ARandomized, double-blind clinical trial of high quality (for example, sample-size calculation, flow chart of patient inclusion, intention-to-treat (ITT) analysis, sufficient sample size)
 BRandomized clinical trial of lesser quality (for example, only single-blind, limited sample size: at least 15 patients per study arm)
 CComparative trial with severe methodological limitations (for example, not blinded, very small sample size, no randomization)

III. EFFICACY

STUDY CHARACTERISTICS
Number of patients after randomization
Number of patientsNumber in arm 1 = Number in arm 2 = Number in arm 3 = Number in arm 4 = 
Intervention
name by active agent
    
Dosage    
+Dosing (Oral: μg/mg/g per unit. Topical: constituent percent)    
+Vehicle (lotion, gel, ointment, cream, other?)    
+Frequency (once daily, twice daily, other?)    
+Route (oral, topical, other?)    
Overall drop-outs
n (%) = n (%) = n (%) = n (%) = 
Drop-outs due to insufficient effectiveness? → No □→ Cannot say □
Arm 1Arm 2Arm 3Arm 4
n (%) = n (%) = n (%) = n (%) = 
Drop-outs due to adverse events? → No □→ Cannot say □
Arm 1Arm 2Arm 3Arm 4
n (%) = n (%) = n (%) = n (%) = 
Side effects/adverse events
Not reported
 Arm 1Arm 2Arm 3Arm 4
 Please specify:   
OUTCOME MEASUREMENTS
Week of evaluation (preferably 12 weeks) after … weeks?
□ Lesion count [inflammatory (IL) and non-inflammatory (NIL) lesion count]
 Arm 1Arm 2Arm 3Arm 4
 IL↓NIL↓IL↓NIL↓IL↓NIL↓IL↓NIL↓
Improvement (%)        
Significantly better? (P value + comparison arm)        
□ Lesion count was not performed – but … was performed
 Arm 1Arm 2Arm 3Arm 4
(Definition of improvement)        

Comments on quality of study/additional information you think a reader of the Guideline would like to know about this study:

………………………………………………………………………………………………………………………………………………………………

………………………………………………………………………………………………………………………………………………………………

………………………………………………………………………………………………………………………………………………………………

Appendix E SIGN checklist for included systematic reviews

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Appendix F Conflicts of interests of the members of the experts group

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Ancillary