Chapter 6. Future Research

During the peer review process, the contents of this report proved to be controversial because of the surprise to find well established therapies not strongly supported by evidence from

controlled trials. These surprises point to the need for studies concerning apparently established

therapies. For instance, peer reviewers were surprised that doxycycline, one of the most favored

anti-bacterials used in the treatment of acne, had so little evidence of superior efficacy in English

language controlled trials.

For researchers investigating acne therapies, this evidence synthesis points to a number of

recommendations. Given the many different treatments for acne, it would be impossible to

compare new therapies with one another.  The research community must lay out a chain of

evidence across therapies that would enable clinicians to make rational choices. A core factor in

this strategy is to choose an anchor of evidence. For instance, for mild to moderate acne, inert

control and benzoyl peroxide suggest themselves as candidates for comparison. For severe acne,

isotretinoin may be the appropriate comparison.

The question of bacterial resistance suggests further questions: To what extent must

“established” therapies (both clindamycin and erythromycin were two of the few treatments that

had evidence of Level A documenting their efficacy) be revisited? To what extent must multi-

drug therapy be used, in place of monotherapy? To what extent must P. acnes baseline status be assessed by generalists?

Future trials should address the following methodological issues:

•	Explicit description of how patients are recruited for a study, and from what population they are chosen.

•	Explicit exclusion and inclusion criteria, using a standard method for describing patient characteristics, such as acne severity, acne duration, prior therapy, and colonization with

P. acnes.

•	Stratified randomization by acne severity, sexual maturity, race, and sex, as appropriate based on the sample.

•	Explicit method of randomization.

•	Psychometric measurement for quality of life at baseline and at termination.

•	Explicit assessment of patients’ acceptability of treatment.

•	Explicit and standard method of lesion counting.

•	Explicit and standard method of severity rating.

•	Explicit and standard method of compliance monitoring.

•	Explicit procedures to ensure consistent outcome assessments across investigators especially in multi-site studies.

•	Sample size assessment to be made before the study, with an explicit statement regarding the minimal difference desired by either the investigator or the patients.

•	Statistical analysis to use at least analysis of covariance with baseline lesions as the covariate or analysis of variance with discrete assessment of severity as a factor.

•	Standard followup periods, including post-therapy.

•	Percentage change with respect to baseline within each patient as the primary acne outcome.

•	Subgroup analyses by sexual maturity, acne severity, sex, race, and prior therapy.

While the information contained in this report will be useful in selecting specific treatments

for their documented effectiveness, there is still much work to be done to define the best

approach to management of acne in an individual patient based upon their 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.

•	More information about psychological outcomes and costs related to treatment.

•	Attention to the issue of bacterial resistance.

Research is needed to define what the sequence of acne therapy (first-line, second-line, and

third-line) ought to be. This research needs to take into account baseline characteristics that we

have discussed, as well as treatment effectiveness and side effects. Patient and physician

preferences must be elicited explicitly. Although we have defined 'sequence' in terms of level of

care, other categorization may be useful, like 'active' and 'maintenance'. In any event, attention

needs to be made to a therapeutic strategy, not just to drug efficacy.

	A question posed by many experts at the start of this project – “When should acne be

referred to a dermatologist”? – still stands, and requires explicit research. This research involves

assessing the relative outcomes of patients cared for by primary care physicians and by

dermatologists for patients with equally severe acne. British researchers (e.g., Trial 11208) have put together networks of primary- care providers, but they have not explicitly compared outcomes

of primary- care providers with those of dermatologists. We recommend that a controlled trial be

considered that would compare the outcomes (acne and psychological) of patients treated on

basis of a clinical practice guideline by primary- care providers with the outcomes of patients

cared for by dermatologists. The guideline would have to account for prognostic characteristics

that we have outlined, and would have to take into account the myriad of treatments that we have

summarized. A formal decision analysis could then be performed, utilizing the causal model

detailed in this report.

Another area for further research is the optimal duration for acne therapy.  The time points in

the trials we reviewed had more to do with study design and resources then consideration of

therapeutic effect.  Furthermore, consistent time points for outcome assessment would allow for more direct comparison of results from multiple trials. An outcome not captured in the current

literature is the relative speed of therapeutic action.  A treatment that works more quickly would

be more desirable than a treatment that is equally effective but takes longer to reach

effectiveness.

It has been suggested that future research would do well to focus on more severe cases of

acne. including those that have been resistant to treatment.  These cases are more likely to cause

scarring, and cause the most frustration for patients and physicians.

Industry plays a major role in acne research. Of the 145 trials (out of 274) that reported

funding, 127 were pharmaceutical company funded, and an additional 113 trials mentioned other

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

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

influence on the nature and scope of the trials on acne. Such requests could be used as a tactic to

encourage pharmaceutical companies to support trials that, not only establish the efficacy vs

safety of their product, but provide clinicians with the evidence they need to make rational

therapeutic decisions.

Acne is a prevalent condition which can lead to significant morbidity. A variety of therapies

are effective, but further research is needed to define which patients might be expected to benefit

the most from specific schedules of treatment.