Prolonged Adverse Events Following Photodynamic Therapy: Regulatory Implications

January 2014 | Volume 13 | Issue 1 | Original Article | 62 | Copyright © January 2014

Stuart J. Anderson MBBS FRACGP FACCO FARGP,a Howard K. Steinman MD,b Jason D. Mazzurco DO MS,c and Anthony J. Dixon PhD MBBSd

aMaffra Medical Group, Maffra, Vic, Australia
bDermatology, Texas A&M Health Science Center College of Medicine, Scott & White Clinic, Temple, TX
cInternal Medicine, Division of Dermatology, Michigan State University, College of Osteopathic Medicine, Ypsilanti, MI
dCutaneous Oncology, Australasian College of Cutaneous Oncology, Belmont, Victoria, Australia

OBJECTIVE: To determine whether field photodynamic therapy (PDT) of actinic keratoses (AKs) using a novel preparation of 5-aminolevulonic acid (ALA) would result in fewer subsequent invasive skin cancers developing on the face.
DESIGN: A prospective multi-center randomized controlled trial. The protocol was approved by the Bond University Human Research Ethics Committee in accord with the TGA’s Clinical Trial Notification Scheme. The trial was registered (12609000025235) on the Australian New Zealand Clinical Trials Registry.
SETTING: Six centers in four states in Australia.
PROTOCOL: Two treatments of ALA PDT, 2 weeks apart for each patient. Controls were observed. Patients were followed up with biopsies of any suspicious lesions every 6 months for 2 years.
MAIN OUTCOME MEASURE(S): Development of new skin cancers.
RESULTS: The trial was suspended after 3 months and closed after 6 months after ethics committee approval was withdrawn on the basis of a breakdown in trial governance. Over the following 2 years, some investigators noted and formally reported the continued occurrence of serious adverse events in excess of those described with other approved cutaneous PDT treatments. USA dermatologists with experience managing AKs with FDA approved ALA products subsequently confirmed prolonged and severe adverse events in 6 of the former trial intervention patients.
DISCUSSION AND CONCLUSIONS: Adverse effects experienced by patients using the investigational ALA PDT appeared more severe than those experienced when an FDA-approved ALA product is used. We believe the former should be further evaluated for safety. It is of concern that this ALA product and lamp could be promoted and used widely in Australia following these reports of significant adverse events and continued lack of TGA approval.

J Drugs Dermatol. 2014;13(1):62-66.


Photodynamic therapy (PDT) has become an established option in the management of actinic keratoses (AKs) and other skin diseases. Cutaneous PDT has predominantly involved the use of methyl aminolevulinate (MAL) and 5- aminolevulinate (ALA). Products containing MAL and ALA are applied to the affected skin and a light source is then applied to the skin for an illumination following an incubation period. ALA and MAL are absorbed and intracellularly converted to protoporphyrin IX, a light-reactive intermediary protein. Activation of protoporphyrin IX by the PDT light source creates free radicals which is the essential to the mechanism of action.
Lehmann1 compiled a literature review of PDT for AKs. Complete response rates using MAL for AKs ranged from 69% to 93% at 3 months. This non-invasive treatment option is associated with minimal risk of scarring. Phototoxic reactions that often occur during treatment rapidly heal to produce excellent therapeutic and cosmetic results. The side-effects of therapy are predominantly local phototoxic effects (burning, stinging and prickling sensations). These adverse events are usually mild-to moderate in intensity, of short duration, and easily managed. Lehmann concluded that overall, the efficacy and low risks afforded by this therapy resulted in high patient preference in clinical trials. The efficacy and side effect profile of PDT is broadly similar with MAL and ALA.2 Active ALA has been demonstrated to be effective when compared with vehicle control.3 More importantly, no prolonged or permanent adverse events have been reported to date following treatment with either ALA or MAL.
Tierney mailed a questionnaire to 45 patients who received PDT for AKs in 2005-2006.4 Patients compared PDT with other options.PDT was found to have equivalent or improved recovery times, cosmetic outcomes, patient satisfaction and preferred as a treatment for AKs. In particular, duration of adverse events was significantly shorter in patients managed with PDT compared with cryotherapy or surgical excision. Kaufmann demonstrated that both cryotherapy and PDT are very effective in treating AKs, with patients generally preferring PDT, which produces better