Accepted Article
Appropriate analysis and presentation of data in wound healing studies: should we
a
publish individual patient data? 1
Günalp Uzun, MDa; Mesut Mutluoglu,MDb; Senol Yildiz, MDa
Department of Underwater and Hyperbaric Medicine, Gülhane Military Medical Academy,
b
06100, Etlik, Ankara, Turkey
Department of Underwater and Hyperbaric Medicine, GMMA Haydarpasa Teaching Hospital, 34668, Kadıköy, Istanbul, Turkey
Keywords: individual patient data, meta-analysis, epidermal growth factor Running head: Appropriate analysis and presentation of data *Correspondence: Dr. Günalp Uzun
GATA Sualtı Hekimligi ve Hiperbarik Tıp AD. 06100 Etlik, Ankara, Turkey Tel: +90 312 304 4796 E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/wrr.12237
1 This article is protected by copyright. All rights reserved.
Accepted Article
To the Editor, Wound healing is a dynamic and intricate process comprising a complex interaction of multiple cellular and molecular factors. Of these, growth factors are among the leading research subjects. The use of intralesional human recombinant epidermal growth factor (hrEGF) in wound healing, has gained popularity recently and several studies, mostly company-sponsored, have been conducted.1 We have observed an intense promotion strategy for hrEGF in Turkey lately, targeting both the wound care market and the scientific committee through exclusive introductory lectures delivered at wound healing centers and wound care meetings. We, therefore read with great interest the study by Gomez-Villa et al.2, yet would like to express some of our reservations on the analysis and presentation of data. First, sample size was calculated based on the assumption that 40% of the patients on
the standard treatment and 85% of the patients on the EGF treatment would heal in 8 weeks. However, The European Wound Management Association (EWMA) recommends at least 12 weeks of study period in clinical trials where the primary end point is wound closure.3 Indeed,
in the current study, none of the patients (0%) in the standard treatment arm and only 25% (4/16) of patients in the hrEGF treatment arm displayed complete wound closure. Based on these results, our calculations revealed that the minimum sample size in each group should have been 24 (alpha error: 0.1; power: 0.8). Furthermore, additional comparison at 12 weeks
and at the long-term would have provided convincing evidence to support the conclusion made by the authors. Second, the authors compared “average healed area” between the groups to
demonstrate the efficiency of rhEGF over standard management. Yet, this is not a reliable method to compare healing rates between patient groups with significantly different baseline ulcer are levels (19.2 ± 15.7 cm2 in the hrEGF group and 11.9 ± 11.8 cm2 in the placebo group). Instead, “ulcer area reduction rate” is a well-known and widely used method of 2
This article is protected by copyright. All rights reserved.
Accepted Article
comparison in the wound healing literature.3 Did or would the authors consider comparing healing rates using this method? Third, cost effectiveness should be an important factor in comparing the efficacy of
different modalities in wound healing. Given the $1,200 cost of a single vial (75µg) of hrEGF in Turkey, a treatment protocol as described by Gomez-Villa et al.2 would sum up to a total amount of $28,800 (24 applications in 8 weeks). Treatment cost during the same duration (8 weeks) with negative pressure wound therapy and hyperbaric oxygen therapy in Turkey, on the other hand, would cost around $5,000 ($250 per application) and $1,200 ($30 per application), respectively. The high cost of hrEGF must be considered before its use in chronic wounds. Preferably, the use of growth factors in wound healing should be reserved to wounds that fail to heal with standard measures.4 Finally, individual patient data from small sample size studies, such as the current one,
may be published online as a supplement. The fact that the majority of these studies report only a summary of available data (mean, median, standard deviation, confidence interval, etc.), poses a barrier to researchers willing to replicate the study analyses or perform further investigation.5 Furthermore, meta-analysis studies, which actually combine the results from different studies, of individual patient will allow more accurate estimation of treatment effectiveness or identifying subgroups of patients more likely to benefit or not from any given treatment modality.6 Wound Repair and Regeneration, in this regard, may encourage the authors to share individual patient data. Designing and conducting a prospective randomized clinical trial in patients with
chronic wounds is challenging. We applaud the efforts taken by the authors of this study and hope that our remarks provide guidance for future researches in the wound healing field.
3 This article is protected by copyright. All rights reserved.
Accepted Article
REFERENCES
1. Tiaka EK, Papanas N, Manolakis AC, Georgiadis GS. Epidermal growth factor in the treatment of diabetic foot ulcers: an update. Perspect Vasc Surg Endovasc Ther 2012;24:37–44.
2. Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A, Teran-Soto JM, FabianVictoriano MR, Kresch-Tronik NS, et al. Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: A randomized doubleblinded controlled trial. Wound Repair Regen 2014;22:497–503.
3. Gottrup F, Apelqvist J, Price P. European Wound Management Association Patient Outcome Group. Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care 2010;19:237-68.
4. Langer A, Rogowski W. Systematic review of economic evaluations of human cellderived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res 2009;9:115.
5. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.
6. What does all trials registered and reported mean? http://www.alltrials.net//wp-
content/uploads/2013/09/What-does-all-trials-registered-and-reported-mean.pdf
4 This article is protected by copyright. All rights reserved.
Appropriate analysis and presentation of data in wound healing studies: should we
a
publish individual patient data? 1
Günalp Uzun, MDa; Mesut Mutluoglu,MDb; Senol Yildiz, MDa
Department of Underwater and Hyperbaric Medicine, Gülhane Military Medical Academy,
b
06100, Etlik, Ankara, Turkey
Department of Underwater and Hyperbaric Medicine, GMMA Haydarpasa Teaching Hospital, 34668, Kadıköy, Istanbul, Turkey
Keywords: individual patient data, meta-analysis, epidermal growth factor Running head: Appropriate analysis and presentation of data *Correspondence: Dr. Günalp Uzun
GATA Sualtı Hekimligi ve Hiperbarik Tıp AD. 06100 Etlik, Ankara, Turkey Tel: +90 312 304 4796 E-mail: [email protected]
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/wrr.12237
1 This article is protected by copyright. All rights reserved.
Accepted Article
To the Editor, Wound healing is a dynamic and intricate process comprising a complex interaction of multiple cellular and molecular factors. Of these, growth factors are among the leading research subjects. The use of intralesional human recombinant epidermal growth factor (hrEGF) in wound healing, has gained popularity recently and several studies, mostly company-sponsored, have been conducted.1 We have observed an intense promotion strategy for hrEGF in Turkey lately, targeting both the wound care market and the scientific committee through exclusive introductory lectures delivered at wound healing centers and wound care meetings. We, therefore read with great interest the study by Gomez-Villa et al.2, yet would like to express some of our reservations on the analysis and presentation of data. First, sample size was calculated based on the assumption that 40% of the patients on
the standard treatment and 85% of the patients on the EGF treatment would heal in 8 weeks. However, The European Wound Management Association (EWMA) recommends at least 12 weeks of study period in clinical trials where the primary end point is wound closure.3 Indeed,
in the current study, none of the patients (0%) in the standard treatment arm and only 25% (4/16) of patients in the hrEGF treatment arm displayed complete wound closure. Based on these results, our calculations revealed that the minimum sample size in each group should have been 24 (alpha error: 0.1; power: 0.8). Furthermore, additional comparison at 12 weeks
and at the long-term would have provided convincing evidence to support the conclusion made by the authors. Second, the authors compared “average healed area” between the groups to
demonstrate the efficiency of rhEGF over standard management. Yet, this is not a reliable method to compare healing rates between patient groups with significantly different baseline ulcer are levels (19.2 ± 15.7 cm2 in the hrEGF group and 11.9 ± 11.8 cm2 in the placebo group). Instead, “ulcer area reduction rate” is a well-known and widely used method of 2
This article is protected by copyright. All rights reserved.
Accepted Article
comparison in the wound healing literature.3 Did or would the authors consider comparing healing rates using this method? Third, cost effectiveness should be an important factor in comparing the efficacy of
different modalities in wound healing. Given the $1,200 cost of a single vial (75µg) of hrEGF in Turkey, a treatment protocol as described by Gomez-Villa et al.2 would sum up to a total amount of $28,800 (24 applications in 8 weeks). Treatment cost during the same duration (8 weeks) with negative pressure wound therapy and hyperbaric oxygen therapy in Turkey, on the other hand, would cost around $5,000 ($250 per application) and $1,200 ($30 per application), respectively. The high cost of hrEGF must be considered before its use in chronic wounds. Preferably, the use of growth factors in wound healing should be reserved to wounds that fail to heal with standard measures.4 Finally, individual patient data from small sample size studies, such as the current one,
may be published online as a supplement. The fact that the majority of these studies report only a summary of available data (mean, median, standard deviation, confidence interval, etc.), poses a barrier to researchers willing to replicate the study analyses or perform further investigation.5 Furthermore, meta-analysis studies, which actually combine the results from different studies, of individual patient will allow more accurate estimation of treatment effectiveness or identifying subgroups of patients more likely to benefit or not from any given treatment modality.6 Wound Repair and Regeneration, in this regard, may encourage the authors to share individual patient data. Designing and conducting a prospective randomized clinical trial in patients with
chronic wounds is challenging. We applaud the efforts taken by the authors of this study and hope that our remarks provide guidance for future researches in the wound healing field.
3 This article is protected by copyright. All rights reserved.
Accepted Article
REFERENCES
1. Tiaka EK, Papanas N, Manolakis AC, Georgiadis GS. Epidermal growth factor in the treatment of diabetic foot ulcers: an update. Perspect Vasc Surg Endovasc Ther 2012;24:37–44.
2. Gomez-Villa R, Aguilar-Rebolledo F, Lozano-Platonoff A, Teran-Soto JM, FabianVictoriano MR, Kresch-Tronik NS, et al. Efficacy of intralesional recombinant human epidermal growth factor in diabetic foot ulcers in Mexican patients: A randomized doubleblinded controlled trial. Wound Repair Regen 2014;22:497–503.
3. Gottrup F, Apelqvist J, Price P. European Wound Management Association Patient Outcome Group. Outcomes in controlled and comparative studies on non-healing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care 2010;19:237-68.
4. Langer A, Rogowski W. Systematic review of economic evaluations of human cellderived wound care products for the treatment of venous leg and diabetic foot ulcers. BMC Health Serv Res 2009;9:115.
5. Doshi P, Dickersin K, Healy D, Vedula SS, Jefferson T. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013;346:f2865.
6. What does all trials registered and reported mean? http://www.alltrials.net//wp-
content/uploads/2013/09/What-does-all-trials-registered-and-reported-mean.pdf
4 This article is protected by copyright. All rights reserved.
