[Litigation ADR Questionnaire – India] CIVIL LITIGATION accompanied by an outline setting out the entire 1. In what language(s) may court proceedings be conducted? What arrangements can be made for Pre-action measures may be in the nature of a translation/interpreter services? request to court for grant of temporary injunctions
male circumcision for Hiv prevention
WHO TecHnical advisOry GrOup On innOvaTiOns in Male circuMcisiOn: evaluation of
two adult devices
male circumcision for Hiv prevention
WHO TecHnical advisOry GrOup On innOvaTiOns in Male circuMcisiOn: evaluation of
two adult devices
WHO Library Cataloguing-in-Publication Data Male circumcision for HIV prevention : WHO Technical Advisory Group on Innovations in Male Circumcision : evaluation of two adult devices, January 2013 : meeting report.
1.HIV infections - prevention and control. 2.Circumcision, male – therapeutic use. 3.Circumcision, male – instrumentation. 4.Circumcision, male – methods. 5.Surgical instruments – adverse effects. 6.Risk factors. 7.Program development. 8.Guideline. 9.Adult. I.World Health Organization. ISBN 978 92 4 150563 5 (NLM classification: WC 503.4) World Health Organization 2013
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Professor Kasonde Bowa
Mr Edgar Makona
Associate Professor of Urology UNZA & CBU SOM Honorary National Focal Point Consultant Urologist UTH Global Youth Coalition on HIV/AIDS Inaugural Dean CBU School of Medicine P.O. Box 14907, 00800, Nairobi Head MC Unit University Teaching Hospital UNZA School of MedicineP.O. Box 50110, Lusaka, Zambia Dr Timothy Hallett
Ms Emily Miesse-Gumkowski
Development Engineer Imperial College London North Haven, CT 06473, USA South Kensington Campus, London SW7 2AZUnited Kingdom Dr Timothy Hargreave
Dr Pius Musau
Urological Surgeon 20 Cumin Place Edinburgh EH9 2JX Department of Surgery Moi University, School of MedicineNandi Road - P.O. Box 5455, 30100Eldoret, Kenya Dr Theobald Hategekimana
Dr William Potter
Stapleford Scientific Services University Teaching Hospital (CHU) P.O. Box 254, Kigali, Rwanda Professor John Krieger
Dr Christopher Samkange
Department of Urology University of Washington Institute of Continuing Health Education 1959 N.E. Pacific University of Zimbabwe Seattle, WA 98195, USA College of Health Sciences, Harare, Zimbabwe Dr Ira Sharlip
Dr Helen Weiss
Urological Surgeon Chair, American Urological Association Task Force Head of IDE and Reader in Epidemiology and on Male Circumcision International Health San Francisco, CA, USA London School of Hygiene and Tropical MedicineKeppel Street, London WC1E 7HT, United Kingdom Dr Stephen Watya
P.O. Box 25974
Ms Melanie Bacon
Dr Emmanuel Njeuhmeli
Scientific Program Manager Senior Biomedical Prevention Advisor National Institutes of Health (NIH) Global Health Bureau/Office of HIV/AIDS 9000 Rockville Pike Technical Leadership & Research Division Bethesda, Maryland 20892, USA 1300 Pennsylvania Avenue, MW, Washington D.C, USA Dr Naomi Bock
Dr Jason Reed
HIV Prevention Branch, Division of Global Senior Technical Advisor HIV/AIDS, Centers for Global Health Office of the US Global AIDS Coordinator Centers for Disease Control and Prevention 2100 Pennsylvania Ave, Suite 200 1600 Clifton Rd. Atlanta, GA 30333, USA Washington DC 20037, USA Ms Agnes Chidanyika
Dr Renee Ridzon
Technical Specialist United Nations Population Fund (UNFPA) Consultant to BMGF P.O. Box 2530, DK - 2100 Copenhagen, Denmark Ms Celeste Sandoval
UNAIDS, Geneva, Switzerland
Dr Rachel Baggaley
Ms Julia Samuelson
Acting Coordinator Male Circumcision Focal Point Key Populations and Innovative Prevention Key Populations and Innovative Prevention Department of HIV/AIDS Department of HIV/AIDS Dr Gaby Vercauteren
Ms Irena Prat
Department of Essential Medicines and Department of Essential Medicines and Pharmaceutical Pharmaceutical Policies Dr Buhle Ncube
Dr Emil Asamoah-Odei
Male Circumcision Focal Point Programme Manager HIV/Sexually Transmitted Infections Regional Office for Africa (AFRO) Dr Nuhu O Yaqub
Maternal, Newborn, Child Adolescent Health
Ms Nita Bellare
Dr Doris Mugrditchian
Key Populations and Innovative Prevention Key Populations and Innovative Prevention Department of HIV/AIDS Department of HIV/AIDS Dr Timothy Farley
Dr Nicolas Magrini
Head, Drug Evaluation Unit Nyon, Switzerland WHO Collaborating Centre in Evidence-Based Research Synthesis and Guideline DevelopmentEmilia Romagna Health and Social Care Agency Viale Aldo Moro, 21, 40127 Bologna, Italy acknowledgments
WHO would like to thank all the participants of the WHO
could be held in a timely manner. The principal writers of this Technical Advisory Group on Innovations in Male Circumcision, in report were Tim Farley, Doris Mugrditchian and Julia Samuelson. particular, the co-chairs, Timothy Hargreave and Stephen Watya. We also express our thanks for funding support from the Bill and WHO would also like to acknowledge all the researchers who Melinda Gates Foundation and the US President's Emergency have shared data, published or confidential, so that this meeting Plan for AIDS Relief (PEPFAR).
Department of Essential Medicines and Pharmaceutical Policies failure modes and effects analysis Global Harmonization Task Force human immunodeficiency virus Instructions for Use International Organization for Standardization US President's Emergency Plan for AIDS Relief prequalification serious adverse event Technical Advisory Group on Innovations in Male Circumcision Joint United Nations Programme on HIV/AIDS Visual analogue score Voluntary medical male circumcision World Health Organization executive summary
The World Health Organization (WHO) Technical Advisory
in about one year as more experience with use of the device Group on Innovations in Male Circumcision (TAG) met at accumulates in diverse programmatic settings outside the context WHO headquarters in Geneva in January 2013. The focus of the meeting was a review of the clinical performance of two specific male circumcision devices (PrePex and ShangRing) as The PrePex (elastic collar compression) device had been part of the product review in the WHO Prequalification of Male evaluated in eight studies conducted in Rwanda, Uganda and Circumcision Devices Programme. This review was based on Zimbabwe involving about 2400 device placements. The range clinical data collected in the context of the Framework for clinical and scope of these studies met the criteria established in the evaluation of male circumcision devices (WHO), which stipulates WHO Framework for clinical evaluation of devices for male a progressive series of clinical studies to establish the efficacy, circumcision. About 7% of clients could not have the PrePex safety, acceptability and clinical performance of the device when device placed for various anatomical and technical reasons but used by trained mid-level providers. The evaluation was also would have been eligible for conventional surgical circumcision. informed by the failure modes and effects analysis conducted Circumcision was successfully completed using the PrePex in by WHO for the collar clamp and elastic collar compression 99.5 % of clients on whom the device was successfully placed. type devices. The meeting discussions also provided inputs on Adverse events occurred in 1.7% of clients, the majority of programmatic considerations for guidance under development on which were mild or moderate. Serious adverse events occurred the use of devices, information gaps and research needs.
in 0.4% of clients, some of whom required prompt intervention to prevent potentially serious long-term sequelae. Over half The ShangRing (collar clamp) device had been evaluated in five of these serious events were due to device displacement or to studies in Kenya, Uganda and Zambia, involving almost 2000 device removal (including self-removal) secondary to pain or device placements. These clinical studies met the minimum discomfort. These cases resulted in pain, swelling and occasional requirements necessary before a device can be considered for blistering of the partially necrosed foreskin tissue, requiring prequalification. The overall estimated proportion of clients not urgent intervention by a skilled surgeon to prevent severe local or eligible for male circumcision with the ShangRing device was systemic infection and/or permanent disfigurement of the penis. about 1%. In about one of every 200 clients, it was not possible In the studies conducted to date, appropriate surgical facilities to complete the circumcision procedure with the device alone. have been available, and all cases were successfully managed Some men required immediate conversion to conventional with no long-term sequelae. Client instructions must clearly surgical circumcision to avoid any serious complications. The describe safe use of the device, symptoms that may develop with conventional surgery was performed by a person experienced device displacement or early removal, as well as the possible in standard surgical circumcision who was available on site, serious outcomes and surgical interventions that may be needed together with appropriate instruments and supplies. The data if instructions on abstinence and wound care are not followed. demonstrated that the ShangRing was efficacious and safe Similarly, PrePex providers must be appropriately trained to when used by suitably trained and equipped providers, with a recognize the rare serious complications that can occur if the circumcision success rate of over 99%. No serious adverse events device is displaced and must ensure that such clients are rapidly occurred in 1983 successful device placements. A total of 20 men provided appropriate management. (1.0%) experienced moderate adverse events. All adverse events were managed with, at most, minor intervention and resolved, On the basis of the clinical evaluation, the TAG concluded that leaving no long-term sequelae. The adverse event rates were the requirements for clinical studies necessary before a device is similar to those observed with conventional surgical circumcision. considered for WHO prequalification had been satisfactorily met. The TAG considered the device to be clinically efficacious in male The TAG considered the ShangRing to be clinically efficacious circumcision and safe for use among healthy men 18 years and and safe for use in healthy men age 18 years and older, when older when used by trained mid-level providers in public health performed by trained providers in public health programmes. programmes, provided that surgical backup facilities and skills Skills and surgical facilities should always be available to safely are available within 6–12 hours to manage events that could convert technical failures of device placement to a conventional lead to serious complications. The TAG based its conclusion on procedure. The TAG based its conclusion on the data currently the data currently available. This conclusion must be reassessed available and recognized that this is only one component of the in about one year as more experience and data accumulate with prequalification assessments. This conclusion must be reassessed use of the device in diverse programmatic settings outside the context of studies.
The HIV Department at the WHO headquarters convened
male circumcision (1), published in 2012, describes the clinical a meeting of the WHO Technical Advisory Group (TAG) on evaluation pathways required to provide sufficient evidence of Innovations in Male Circumcision in Geneva, Switzerland, 29–31 efficacy and safety of a new male circumcision device. These January 2013. The purpose of the meeting was to provide programmatic and technical updates and to evaluate and advise on the clinical efficacy and safety of two devices for adolescent • initial studies to establish safety and acceptability; and adult male circumcision that have formally entered the • at least two independent randomized control ed trials comparing WHO prequalification process. The three-day meeting brought the device against an established method of circumcision together members and observers of the TAG along with the WHO performed by providers skil ed to offer either method of male Secretariat and staff from the HIV Department, the Department circumcision in settings of intended final use; and of Essential Medicines and Pharmaceutical Policies, the WHO • at least two field studies of procedures involving relevant Regional Office for Africa, and the Intercountry Support Team.
populations, types of facilities and performed by suitably trained and qualified mid-level or non-physician providers in settings of intended final use. In March 2007, responding to compelling evidence from three The information generated from these studies forms the basis for randomized controlled clinical trials confirming the results from WHO to assess and provide advice on the use of a device in adult ecological studies, WHO and the Joint United Nations Programme and adolescent VMMC programmes for HIV prevention in high on HIV/AIDS (UNAIDS) issued recommendations that medical HIV prevalence, resource-limited settings.
male circumcision be considered as part of a comprehensive HIV prevention package in countries with generalized epidemics. WHO also established the Prequalification (PQ) of Male Since then, 14 countries in east and southern Africa have Circumcision Devices Programme for HIV Prevention in the taken action towards the scale-up of voluntary medical male Department of Essential Medicines and Pharmaceutical Policies circumcision (VMMC) for HIV prevention. (EMP). The TAG reviews the clinical data on a specific product and advises the Department of EMP whether the evidence Modelling studies indicate that national male circumcision demonstrates that a specific device is efficacious in removal of programmes will have the greatest public health impact in these the foreskin and safe for use in the intended population. The 14 priority countries, averting up to 3.4 million HIV infections Department of EMP assesses the product to see that it meets through 2025, and will provide the largest cost-saving (USD international standards (through a review of the product dossier) 16.5 billion) if services are scaled up rapidly. However, currently and inspects the manufacturing site(s) to assess the adequacy recommended surgical methods for adult male circumcision and effectiveness of the manufacturer's quality management involve considerable time and skill. Thus, innovations in the system and the correct implementation of their documented procedure, including male circumcision devices, have been under study over the past few years.
By the end of 2012, three manufacturers had entered the PQ In 2008 and 2009 initial consultations reviewed the landscape of Programme; sufficient data was judged to be available on two technologies for male circumcision. In 2010 the WHO established devices—the ShangRing and PrePex. The TAG was, therefore, a Technical Advisory Group on Innovations in Male Circumcision convened in January 2013 to review all available data on these (henceforth "the TAG") for the purpose of reviewing and devices, to advise on the clinical evaluation component of PQ and advising the WHO on innovations in male circumcision, including highlight programmatic considerations in the use of each device devices. The Framework for the clinical evaluation of devices for and to advise on priority research needs. declaration of interests
The objectives of the meeting were to: At the beginning of the meeting, the WHO secretariat explained the reasons for the written and verbal declarations of interests • update the TAG on the: and summarized the pertinent interests that had been declared – status of devices in the WHO PQ of Male Circumcision in writing prior to the meeting. All participants were invited to Devices Programme declare verbally to the group any other conflicts, or potential – device risk assessments and conflicts, of interest. No other members stated any current or potential conflicts of interest that might affect their impartiality, – development of guidance on use of devices and issues from judgment or advice. Review of the declarations by the secretariat the research that will inform the guidance. and the TAG chairs identified no significant conflicts or potential • review all available clinical research findings on two male conflicts of interest that would disqualify or restrict participation. circumcision devices for adolescents and adults, specifically the PrePex and the ShangRing, to inform prequalification The primary types of potential conflicts were due to participants' involvement on research teams that had or were currently • advise the WHO on: studying one or more devices, involvement in modelling studies and a declared advocacy of "cautious optimism in favour" of – review of study requirements for clinical evaluation of devices. One participant had been previously employed by a devices of the same category; company that worked on the development of male circumcision – operational and programmatic considerations on use of devices, two currently or previously worked on male circumcision devices to be addressed in the guidance; device technologies, and one worked with and currently consults – additional technical innovations that WHO should assess, for the Bill and Melinda Gates Foundation, which has supported or should stimulate further development of, to improve device development and research. coverage and/or accelerate scale-up of male circumcision in priority countries; and – priority research to further advance work on male circumcision for HIV prevention.
meeting process and roles of participants
The TAG is comprised of international y recognized experts
including representatives of research institutes, clinical scientists,
statisticians, medical device regulators and programme managers
in the field. The TAG is composed of members and observers.
Members of the TAG are experts appointed because of their
expertise in the field and are involved in the formulation of
recommendations. Observers from col aborating partners with
an interest in expanding male circumcision programmes for HIV
prevention represent the perspective of their institutions as wel
as contribute their technical knowledge. Observers do not directly
participate in formulating the advice and recommendations
of the TAG. Given the nature of the meeting documents that
were reviewed, TAG participants agreed to strict standards of
confidentiality and submitted signed confidentiality agreements.
programme and tecHnical updates
wHo Hiv department progress during 2012 WHO also convened a small expert group to conduct a risk
and planned guidance
analysis of devices in mid-2012. The outputs of this exercise (see below) helped to identify key potential risks associated with use of devices. WHO is preparing guidance on the use of devices for The WHO Secretariat provided programmatic updates on the adolescent and adult VMMC for HIV prevention in accordance work of the WHO HIV Department during 2012. WHO remains with the WHO guideline review processes. fully committed to identifying and assessing priority technical innovations in male circumcision, including devices that have The conclusions of this TAG meeting will inform several guidance the potential to: products on devices and device use, in particular: • make the male circumcision procedure safer, easier and quicker • The WHO PQ Programme component on clinical safety and than current methods; efficacy of the ShangRing and PrePex devices. This is one • facilitate more rapid healing and/or entail less risk of HIV part of the full product review and contributes to the decision transmission or acquisition in the immediate post-operative whether or not to prequalify a particular device. A summary report will be provided on the clinical evaluation of each specific device.
• be used safely by (mid-level) health-care providers with a shorter period of training than required for conventional • Programmatic and operational considerations in the WHO surgical male circumcision; and guidance on use of devices for adolescent and adult VMMC for HIV prevention.
• be more cost-effective for male circumcision scale-up than standard surgical methods.
The WHO also sought inputs from the TAG on additional technical considerations, including a review of the clinical Given that a number of devices were available on the market, the evaluation requirements to demonstrate equivalent efficacy and WHO, with the inputs of the TAG, had produced the following safety of a similar product, further research to be catalysed, and guidance products to inform evaluation and use of devices: additional promising technologies that should be considered.
• Framework for clinical evaluation of devices for male circumcision (1), which: prequalification of male circumcision
– outlines the clinical pathway for assessing suitability of a device, including the minimum requirement for WHO consideration of efficacy and safety (two comparative The WHO PQ of Male Circumcision Devices Programme studies in different settings and two field studies in settings undertakes a comprehensive assessment of the applications of intended use); submitted by device manufacturers through a standardized procedure based on international best practices and WHO PQ – lists ideal device characteristics and potential evaluation requirements, which include three main components: – provides suggestions for the stepwise introduction of a new • Review of the application form with summary information device, with scale-up in mind; and about the product – highlights regulatory considerations and the WHO • Review of the product dossier, including review of clinical • Use of devices for adult male circumcision in public health HIV • Inspection of the manufacturing site(s).
prevention programmes: conclusions of the WHO Technical Advisory Group on Innovations in Male Circumcision (2), which The role of the TAG in the PQ of Male Circumcision Devices provided initial conclusions based on limited evidence on the Programme process is review of the clinical safety and efficacy use of the PrePex device in early 2012.
of the device based on clinical evidence generated within the clinical evaluation framework described earlier. – As the data reviewed were from a series of three clinical studies conducted in only one low-resource country To date, three devices—namely the PrePex, ShangRing and (Rwanda), the TAG concluded that additional studies were AlisKlamp—have entered the WHO PQ Programme. The needed before advice could be generalized beyond Rwanda.
manufacturer of a fourth device, the TaraKlamp, has expressed During 2012 the WHO PQ of Male Circumcision Devices interest but has not yet submitted an application. Review of the Programme reviewed two device products and responded PrePex device has moved the most swiftly through the stages to requests from manufacturers of two other devices. More of PQ and is the closest to meeting clinical evaluation and other details on PQ are noted below. The link to the PQ documents requirements. Once a product has been prequalified, it will be included on a list of devices published on the WHO web site (see above). This paves the way for procurement by UN agencies, WHO Member States, donors and other interested purchasers. or process) of the device to the PQ Programme. It is not the Prequalification does not imply WHO approval to import or to use manufacturer but rather the WHO programme that decides what the device in any particular country, as this the prerogative and constitutes a "significant" change in the design of the product or responsibility of the national regulatory authorities. the manufacturing process, and if a re-evaluation is needed.
The main points from discussions that followed these updates included: technical update 1: risk analysis of male
• The steps in the PQ process require significant staff time and financial resource investments. The WHO held a technical consultation in Geneva, 6–7 August – These financial resources have been provided by donors and 2012, to reach consensus on the classification scheme for male the public sector, and the manufacturer is not charged by circumcision devices and to conduct a risk analysis on of devices. WHO for work performed for PQ of a product.
Three categories of in-situ devices (i.e. devices that remain in – The process can take many months before the manufacturer place for some period of time) for adolescent and adult male satisfactorily meets requirements. It involves the circumcision were agreed upon based on their mechanism of manufacturer submitting complete documentation, responding to requests for clarification, and implementing suggested corrective actions following WHO site inspections.
• Clamp, with subcategories: a) collar clamp (e.g. ShangRing); b) • A PQ decision is time-limited. WHO will arrange for the vice clamp (e.g. TaraKlamp) products and manufacturing sites included in the WHO list The mechanism of action consists of rapid, tight compression of prequalified male circumcision devices to be reassessed between hard surfaces to achieve haemostasis. Compression at regular intervals. Prequalified diagnostic products are is sufficient to prevent slippage of tissue such that the foreskin reassessed usually every three to five years, or sooner if can be removed at the time of, or soon after, application of warranted, such as in the case of reports of product defects. If, the device. Part or all of device is left in situ for more than 24 as a result of reassessment, it is found that a product and/or hours. Injection with local anaesthesia is required.
specified manufacturing site no longer complies with the WHO • Ligature compression (e.g. Plastibell for infants) requirements, such products and manufacturing sites will be The mechanism of action consists of a rapid, tight compression removed from the list. Failure of a manufacturer to participate between a hard surface and a non-rigid ligature that is tied to in the reassessment procedure also will lead to removal from hold the foreskin in place between the hard surface and the the list. For prequalified devices the same principle will be ligature. Compression is sufficient to achieve haemostasis and applied, with re-inspection occurring sooner as indicated, prevent slippage of tissue such that the foreskin can be removed including for a new product and manufacturer.
at the time of, or soon after, application of the device. Part or • A PQ decision can be retracted if concerns with safety are all of the device is left in situ for more than 24 hours. Local substantiated. Once a product is prequalified, International anaesthesia is required. The compression force and the security of Organization for Standardization (ISO) 13485 requires the knot depend on the provider.
the reporting of serious adverse events and post-market • Elastic collar compression (e.g. PrePex). surveillance. Since national adverse event monitoring systems The mechanism of action consists of slow compression are often weak, the TAG urged the standardization of post- between an elastic ring and a hard surface that is sufficient to market surveillance and that countries improve the reporting of occlude circulation and produce tissue ischaemia. Part or all adverse events. PEPFAR will collaborate with WHO to support of the device and the foreskin are left in place for more than national programmes in post-market surveillance of the use of 24 hours, thereby causing ischaemic necrosis of the foreskin. male circumcision devices.
The device and the foreskin are removed at a later date. Such • The manufacturer must report, in addition to serious adverse devices can be applied without the need for injected local events, change(s) in the design or manufacturing (material The consultation then used the Failure Modes and Effects Analysis Tables 1 and 2 summarize the results of the risk analysis of two procedure (FMEA) which is one of the techniques specified in male circumcision device categories. ISO 14971, the international standard for the application of risk management to medical devices, to systematical y analyze, Some key points for programme introduction were noted. As evaluate and propose control measures on use of devices. devices are rolled out from study to field conditions and with According to ISO 14971, the manufacturer is responsible for broader use, more failures and failure modes can be expected establishing, documenting and maintaining a continuous process to occur. When the device is procured and used in a programme of risk management/quality feedback for the lifetime of a device, supported by a government or donor, it is more likely that including identifying hazards associated with a medical device, safety will be monitored through standardized serious adverse estimating and evaluating the associated risks, control ing these event (SAE) reporting than when it is procured and used by the risks and monitoring the effectiveness of these controls. Feedback private sector. User instructions are critical. Clinicians will need information is obtained from the market in the form of customer to be educated not to use devices that have not been clinically complaints and proactive post-market surveil ance as well as evaluated and are not prequalified. Devices that fail should be internal y from production processes, if a problem is encountered sent back to the manufacturer for analysis.
before the product or lot reaches the market.
The WHO consultation applied the FMEA technique to a device technical update 2: clinical evaluation of
category: identifying failure modes associated with the specific the prepex and the shangring devices
device category, quantifying the risk and identifying actions to mitigate risks. The exercise focused on device categories for use The TAG conducted a detailed review of all available clinical in adolescents and adults (rather than infants) and on those that safety, efficacy and acceptability data on two male circumcision had entered the WHO PQ Programme. The FMEA technique takes devices for adolescents and adults, the ShangRing and the into account three factors: PrePex. Data on the safety and efficacy of the PrePex were available from eight studies conducted in three countries in • potential severity of an outcome (consequence of the harm) east and southern Africa (Rwanda, Uganda and Zimbabwe). • frequency of occurrence (per client procedure) and These studies included an initial safety and efficacy study, two • detectability of any potential failure (ease with which the randomized comparative trials, two completed field studies and failure can be detected at time of deployment or while the interim analyses from two ongoing field studies. Safety and device is in situ). efficacy data for the ShangRing included data from five studies conducted in three countries (Kenya, Zambia and Uganda). Data Individual scores were assigned to each potential failure mode from studies conducted in China were summarized (3–6), but for each of the three factors, using a scale of 1 to 5. A total the TAG decided these data were not directly relevant to the risk score was calculated by multiplying the individual factor population where the intervention is prioritized. In addition, it scores (highest score possible risk score is 125). A risk score of was not clear whether the version of the device used in these 25 or above was considered by the participants as a priority, studies was the same as that used in the African studies. warranting that actions to mitigate risk be identified. Such actions could be through: • Provider instructions, warnings and contraindications on use• Client information on use• Specification of the device (in its design and/or the material(s) • Process and quality controls in manufacturing
1. shangringThe ShangRing is produced by Wuhu Snnda Medical Treatment Figure 1: The original design of the ShangRing is Appliance Technology Co. Ltd, Wuhu City, China. It is a shown at the top (7). The design used in the minimal y invasive method for boys and adult men undergoing African studies is shown at the bottom (8).
circumcision for phimosis or electively and was first described in the international literature in 2008 (7). The ShangRing is a col ar clamp circumcision type of device. The device consists of two concentric plastic rings that sandwich the foreskin of the penis. The mechanism of action consists of a rapid, tight compression of the foreskin between the hard surfaces to achieve haemostasis. The compression is sufficient to prevent slippage of tissue such that the foreskin can be removed at the time of device application. The device must be sterile. Anaesthetic injection is required.
The device is applied by placing the inner ring over the shaft of the penis at the height of the coronal sulcus. The foreskin is everted over the inner ring and then clamped in place and crushed by the outer ring. The foreskin distal to the device is then cut away. The device is removed at seven days by releasing the clamped outer ring, gently separating the inner ring from the healing wound, and then cutting the ring in two places to remove it from the shaft of the penis. The original device used in China is shown on the top in Figure 1. It was available in different diameters, ranging from 13 mm to 40 mm in 2 or 3 mm increments. The device used in all the African studies is depicted at the bottom in Figure 1. It differed from the original design only with regard to the mechanism to secure the outer ring—the threaded locking mechanism in the original design was replaced with a ratchet that facilitated positioning and adjustment of the device over the everted foreskin. Also, the device was available in 26 mm to 40 mm diameter sizes in 1 mm increments. The correct device size is selected based on measurement of the penile circumference at the level of the coronal sulcus with a specially marked tape. 2. prepexTMThe PrePexTM is produced by Circ MedTech Limited in Israel. Figure 2: The PrePex device The device was specifically designed to be used by mid-level providers in resource-limited settings and to avoid the need for local anaesthesia during device placement. The device is an elastic collar compression type of device. It consists of an inner ring placed under the foreskin at the level of the coronal sulcus and an elastic O-ring that is aligned and released over the groove of the inner ring using an applicator (Figure 2). Blood flow to the foreskin is restricted by compression of the elastic ring on the inner ring, resulting in ischemia and necrosis of the foreskin. The device and necrotic residual foreskin are removed at seven days. Since there is neither cutting nor crushing of live tissue that would result in intense pain, there is no need for injectable local anaesthesia. The absence of bleeding means that there is no need for suturing and the device does not have to be sterile at the time of use.
process of evaluation of study data on
• Successful circumcision was defined as removal of sufficient foreskin such that the coronal sulcus was visible with the penis in a flaccid (non-erect) state. Circumcision failures included clients who needed an additional intervention to complete the retrieval of the evidence circumcision and those with insufficient foreskin removed. The proportion of successful circumcisions was computed only on In preparation for the TAG meeting, WHO staff searched clients on whom the device was successfully placed.
the PubMed database for all published studies on the two • Procedure time was computed for devices as the sum of the circumcision devices and contacted investigators known to be preparation and procedure times for placement and removal, studying the devices in African countries. WHO staff reviewed not counting the time period between the two. Times were all published reports. Investigators made available to WHO measured from start of the surgical procedure to completion of secretariat confidential final reports from completed studies and wound dressing (first to last touch) for conventional surgery or interim reports from ongoing studies for review by the TAG. WHO to end of device placement (last touch) for device application, secretariat extracted key features of each study into a standard but did not include the time for induction of anaesthesia, format and compiled these to report the most important clinical where used. Removal times were measured from first touch to outcomes regarding safety and efficacy of the device in different completion of wound dressing after device removal.
populations and in the hands of different providers. During the latter part of 2012, a subgroup of the TAG reviewed and • Time to complete wound healing was defined as the number commented on all data available. WHO sought clarifications from of days from the date of conventional surgical circumcision the study investigators where necessary. or device placement (not from the date of intended or actual device removal) to the first date when complete wound As the review of the clinical data by the TAG informs the epithelialization was observed. Not all study teams used development of guidance on use of devices, the process followed identical definitions of complete wound healing, and the long was similar to that recommended by the WHO Guideline intervals between visits in some studies prevented a precise Development Committee, including specifying outcomes of estimate of the duration of healing. interest. The evaluation criteria were in line with those identified • Pain was measured in most studies using a Visual Analogue in the Framework (1). External audits conducted either on Score (VAS) with a range of 0–10, where 0 corresponds to "no behalf of the study sponsor or by a team designated by the WHO pain at all" and 10, to "worst pain imaginable", with clients secretariat independently verified the quality of the research shown pictograms for six different rating levels (Figure 3), with study and the completeness of the data and reports.
text usually translated into the local language. Depending on the study and the follow-up schedule, the pain assessments standardization of the priority outcomes were made at specified time points, such as before or during device placement; specified times after placement; while The TAG meeting evaluated the devices on the basis of the wearing; before, during and after removal; and at selected following critical outcomes and definitions: follow-up visits. Additionally, some studies assessed the • Eligibility for male circumcision with the device. All men duration of the pain. Not all studies assessed pain at the same must be screened for medical eligibility for circumcision, in time points; the most comparable times have been selected particular the absence of any penile abnormalities and current in order to facilitate comparisons between devices and with genital infections. For a particular device, use may be further conventional surgical circumcision.
restricted due to: a) additional anatomical reasons, such as Figure 3: Visual analogue pain scale and pictograms phimosis (inability to retract the foreskin), a narrow foreskin opening or a short frenulum; or b) technical reasons that preclude device placement such as unavailability of a correct device size or inability to complete the device placement procedure. Therefore, device eligibility was defined as the proportion of men who met the criteria for conventional surgical circumcision, who were also eligible for circumcision with the specific device and in whom the device could be successfully placed. definitions and classification of adverse events • AEs resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, or operation, or Although there had been attempts to standardize terminology any malfunction of the investigational medical device; and, and classification of adverse events (AEs) in studies of • Any event resulting from use error or from intentional misuse conventional male circumcision and circumcision devices, the of the investigational medical device.
classification schemes evolved as more information about the types and timing of AEs became available. The different In consideration of the above international definitions and the mechanisms of action of the devices and the differences from importance of ensuring a uniform classification that can be conventional surgical circumcision techniques have led to applied to clinical research on male circumcision, the WHO TAG differences in the types of AEs and characterization of the AEs. closely followed GHTF definitions and the following principles This required that all observed AEs be reviewed and classified by (for the two circumcision devices for which data were available the TAG in a uniform manner. In doing so, the TAG was guided by for review as well as other devices that may become available internationally recognized principles and definitions of AEs and with different mechanisms of action): serious adverse events (SAEs).
• Any untoward medical occurrence, unintended disease or The Global Harmonization Task Force (GHTF) (9) and the injury, or untoward clinical signs (including an abnormal International Organization for Standardization define an AE as: laboratory finding) in subjects, users or other persons, whether "Any untoward medical occurrence, unintended disease or injury, or not related to the conventional surgical procedure or to the or untoward clinical signs (including an abnormal laboratory medical device used for performing or assisting in the male finding) in subjects, users or other persons, whether or not circumcision procedure was considered an AE. related to the investigational medical device". This definition • Any AE that was definitely not related to the circumcision includes events related to the investigational medical device or procedure or to handling or operating the medical device was the comparator and events related to the procedures involved.
not considered further.
In addition, an SAE is defined as an AE that: • Any AE that satisfied the GHTF definition of an SAE was considered a serious adverse event (SAE).
1) led to a death; or, • Any AE not classified as an SAE but that required an 2) led to a serious deterioration in the health of a patient, user, intervention by a health care provider or medication (parenteral, oral or topical) was considered a moderate AE.
a. resulted in a life-threatening illness or injury • All other AEs were considered mild AEs. None of these events b. resulted in a permanent impairment of a body structure or would require any intervention.
In order to compile AEs over the different clinical studies and c. required inpatient hospitalization or prolongation of circumcision procedures, each AE was classified according to its existing hospitalization underlying cause or clinical presentation. It is important to note d. resulted in medical or surgical intervention to prevent that the classification adopted is designed to assess and compare permanent impairment to body structure or a body function.
complications that occurred during the clinical research on male circumcision devices. While the overall principles underlying the The International Organization for Standardization document classification are likely to apply to programmes, the details will 14155 additionally defines an adverse device effect as an AE have to be assessed for relevance in classifying AEs that occur in related to the use of an investigational medical device, which male circumcision programmes. Table 3 lists all AEs observed to date according to category. clinical evaluation of the shangring
Some clients with moderate or severe phimosis required a small dorsal slit to be made in the foreskin to facilitate eversion over 1.Overview of the studies the inner ring (range across studies of 10%-28% of men). The spontaneous detachment study showed that, if the device The TAG reviewed clinical data on the safety, efficacy and is not removed as scheduled at seven days, the device begins acceptability of the ShangRing from studies conducted in China to detach spontaneously and may come off without removal by and three countries in Africa. Table 4 summarizes the studies a medical provider. Partial detachments appear to be painful, conducted in five sites in Africa (in Kenya, Uganda and Zambia). cause discomfort as the partially detached device may snag and Early studies in China demonstrated that the device was safe cause tearing of tissue and bleeding. Therefore, the device should when applied under local anaesthesia by skilled providers in ideally be removed at seven days.
Chinese study participants (ages 5 to 95 years across studies), resulted in a neat and complete circumcision, and was potentially faster and simpler than conventional surgical circumcision, as no The overall mean placement time was 6.4 (SD 3.8) minutes, suturing was required for haemostasis or wound closure. These excluding the time for injection and induction of local studies formed the basis for proceeding in a stepwise manner to anaesthesia. The mean removal time was 3.1 (SD 1.8) minutes. clinical research in African countries where public health male The total of the mean placement and removal times (mean circumcision programmes are being implemented.
10.3 minutes) was less than the mean procedure time in the In its review of evidence, the TAG placed emphasis on the studies randomized comparison with conventional surgery in Kenya and conducted in the African region, which provided directly relevant Zambia (mean 20.3 minutes). information on the clinical performance of the device when used in public health HIV prevention programmes: two initial safety and efficacy studies, two randomized controlled trials and Adverse events in all the African ShangRing studies combined two field studies. All the studies conducted in Africa with the are summarized in Table 5. Based on a total of 1983 successful ShangRing device used the same device design, which differed device placements, there were: from the original device only with regard to the mechanism to • no SAEs—proportion 0.0% (95% confidence interval secure the outer ring (see Figure 1). Safety and effectiveness of the ShangRing device have been studied only in men age 18 years and older. There was consensus among the TAG members • a total of 20 moderate adverse events—proportion that the range and scope of the studies conducted on the 1.0% (0.6%-1.6%) and ShangRing met the requirements set forth in the Framework.
• a total of 43 mild adverse events—proportion 2.2% 2. shangring study results The ShangRing device is designed to avoid the need for haemostasis during surgery and to clamp the skin edges firmly together to fuse as part of the healing process. Because of The overall estimated proportion of clients eligible for the tight clamping mechanism, local injectable anaesthesia conventional male circumcision who were also eligible for is required before device placement and then the foreskin Shang Ring circumcision and in whom the device could be is cut away distal to the device. The greatest proportion of placed was 98.8%. The proportion of clients eligible for moderate AEs was associated with pain during the anaesthetic Shang Ring circumcision was 99.6%, due to a small number of administration and device placement, requiring additional clients excluded for minor foreskin abnormalities (e.g. short medication for control in some instances, pain while wearing the frenulum) that precluded device placement. These men could be device, or partial device detachment or minor wound disruption circumcised using a conventional surgical approach. Shang Ring before device removal. Nevertheless, complications requiring device placement procedures were started in 1998 clients and intervention were rare (less than 1 in every 100 procedures).
were completed in all but 15 (99.2%) due to correct ring size not being available at the time of the procedure (8), the foreskin It is important to note that the seven clients (0.4%) in whom slipped from the outer ring (3), the foreskin was too short (1) or the device placement procedure was started but could not be damaged (2), or the outer ring could not be closed (1). completed were all immediately converted to conventional surgical circumcision. Had facilities not been immediately successful circumcision available to safely complete the open circumcision (sterile field, Circumcision was achieved in all clients on whom the device was sutures or electrocautery for haemostasis and sutures for wound successfully placed with the exception of three men (0.15%) who closure), complications that would have resulted in serious were considered to have insufficient skin removed. adverse events might have occurred. A small number of wound disruptions occurred several weeks after device removal; these were clear departures from the normal healing process.
In the randomized controlled trial comparing ShangRing with A person experienced in standard surgical circumcision must, conventional surgery, there were no serious AEs, 2 moderate AEs therefore, be available on site, together with appropriate (both in the surgery arm) and 23 mild AEs (15 in the ring arm and instruments and supplies. 8 in the surgery arm) in 197 ring placements and 198 surgical • Circumcision using the ShangRing was demonstrated to be safe circumcisions, P=0.40. and successful in over 99% of clients.
• Healing is by secondary intention. It requires about one Healing following male circumcision with the ShangRing device week longer than after conventional surgery. The TAG is by secondary intention and takes about one week longer considered that there is a risk of HIV acquisition if men than with surgery. In the comparative study, the mean time to engage in unprotected sex before the wound is healed, but complete healing was 44.1 (SD 12.6) days following ShangRing the magnitude of risk is unknown. While this is also true of placement compared with 38.9 (SD 12.6) days following surgery circumcision by conventional surgery, because of the longer (mean 5.2 days longer, 95% confidence interval 2.7–7.7 days). healing time, the group stressed the importance of good Thus, ShangRing circumcision requires a longer period of post- counselling about sexual activity and condom use. circumcision sexual abstinence than standard surgical methods.
• Adverse events associated with ShangRing procedures were rare. In a total of 1983 successful device placements, there were no deaths or serious adverse events (95% confidence The ShangRing device requires injectable local anaesthesia interval 0.0%–0.2%). The most common AEs were related to before placement. The pain experienced during device placement pain. All AEs were managed with, at most, minor intervention and in the post-operative period is similar to that reported after and resolved with no long-term sequelae. Although definitions conventional surgery. Men reported some pain while wearing the of serious and moderate AEs in the three randomized device and a somewhat higher rate of pain during erection than controlled trials that demonstrated the efficacy of male at comparable times after conventional surgery. There is a risk circumcision for HIV prevention in Kenya, South Africa and of minor injury to the penis from the device itself and discomfort Uganda are not directly comparable to those adopted in the from catching or snagging the device while wearing it. Partial device studies, the proportions are in a similar range—0.0% detachment of the devices is associated with some discomfort and pain, but this is rare if the device is removed as scheduled • Phased implementation with careful monitoring and reporting at seven days. There is short, transient discomfort and pain as of device events and AEs is recommended in order to the device is removed. In one study local anaesthetic spray was better understand the frequency of technical failures of the used prior to removal. This seemed to lessen but not completely ShangRing and how best to manage such failures.
– Programmes must conduct active surveillance of the Key points on the shangring made by the TaG first 1000 clients to identify and record AEs based on (Programmatic considerations are included in the next section).
standardized definitions. The active surveillance may change to passive surveillance after the first 1000 clients, if the The TAG reviewed clinical data on the safety, efficacy and incidence of events is reassuringly low as determined by acceptability of the ShangRing device from five studies independent review. Ongoing reporting of serious adverse conducted in three African countries that resulted in device events as part of post-market surveillance will need to be placements on nearly 2000 men. • The TAG considered the ShangRing to be clinically efficacious • The TAG advised that the clinical studies necessary before and safe for use in men 18 years and older, when the a device is considered for prequalification by WHO per procedure is performed by trained providers in public the Framework for clinical evaluation of devices for male health programmes. Skills and surgical facilities should circumcision (2012) have been satisfactorily conducted. be available to safely convert technical failures of device • The evaluation, and thus advice on use, is currently limited to placement to conventional procedures. The TAG recognizes data on healthy males 18 years and older, as data were not that this conclusion on clinical efficacy and safety is only one available on men under 18 years or on men living with HIV. component of the prequalification decision. The TAG based • A small proportion of men were not eligible for device its conclusion on the data currently available. This conclusion use. Provision of or referral to conventional surgical male must be reassessed in about one year as more experience with circumcision would be needed. Some of the cases required use of the device accumulates in diverse programmatic settings immediate conversion to a conventional surgical circumcision. outside the context of studies.
clinical evaluation of the prepex
2.0 (SD 0.8) minutes, placement procedure 1.5 (SD 1.0) minutes, removal preparation 0.4 (SD 0.2) minutes and removal procedure 1. Overview of the studies 2.0 (SD 1.1) minutes. In the two comparative studies, the mean total procedure time (placement preparation and procedure time and removal preparation and procedure time) was 5.7 (SD 1.4) Table 6 summarizes the eight studies conducted in three minutes compared with 19.2 (SD 3.9) minutes for conventional countries, Rwanda, Uganda and Zimbabwe (interim analyses on two ongoing field studies were included). The device was first clinically tested in Rwanda in a study that established the natural history of the necrotic process in 50 volunteers. A second study investigated alternative forms of topical anaesthesia at the time AEs occurred in 42 men in whom the device was successfully of placement before a formal randomized comparison with the placed (1.7%); the majority of AEs were mild or moderate, dorsal slit conventional surgical approach was made. The next while 9 (21%, or 0.4% of device placements) were considered study to be completed was a field study in Rwanda in which serious, as prompt surgical intervention was required to prevent the device was placed and removed by trained nurses instead potential serious long-term sequelae. The nine adverse events of physicians. In order to comply with the requirements in the categorized as serious resulted from device displacements during sexual activity, masturbation, erection, possible placement , a second series of studies was independently error, or accidental dislodging by another person; early removals conducted in Zimbabwe, starting with a small safety study (including self-removals) secondary to pain; meatal injury at followed with a randomized comparison and a second field study. removal; and difficult removal due to necrotic tissue everted 2. prepex study results over the elastic ring requiring surgical intervention, and wound dehiscence. Some of the displacements were associated with painful oedema, blistering and swelling as the blood flow returned to the partially necrotic foreskin and required prompt The overall estimated proportion of clients eligible for surgical intervention to remove the foreskin and avoid serious conventional male circumcision who were also eligible for PrePex infection or injury to the penis. No mechanical device failures circumcision and in whom the device could be successfully placed were reported.
was 92.6%. The proportion of clients considered eligible for PrePex circumcision was 94.1%, due a number of clients excluded for phimosis, narrow foreskin opening, tight frenulum, or small Healing following male circumcision with the PrePex device is wounds on the foreskin or penile shaft. PrePex placement by secondary intention and takes about one week longer than procedures were started in 2268 clients and were completed in with surgery. In the comparative study in Rwanda, the mean time all but 38 (98.3%) due to narrow foreskin opening (16), tight to complete healing was 38.0 (SD 12.1) days following PrePex or short foreskin (15) or adhesions (4), and three clients with a placement compared with 23.0 (SD 7.5) days following surgery penis circumference size outside the range of available ring sizes. (mean 15 days longer, 95% confidence interval 12 to 18 days). In the comparative study in Zimbabwe, the difference in healing successful circumcision times was less pronounced, but interpretation of the data from A total of 2417 PrePex devices were successfully placed in the this study is limited by the absence of follow-up visits between eight studies. For a large majority of clients (99.5%), the PrePex days 7 and 42 post-procedure in the surgical circumcision arm. circumcision was successful, leaving a neat circumferential The overall mean healing time after placement recorded over wound resulting in a final cosmetic appearance without suture five studies was 42.3 days (standard deviation 7.8 days). Almost marks. Circumcision had to be completed by conventional all men healed by 8 weeks. Thus, healing following PrePex surgery in a total of 12 clients (0.5%)—four removed the circumcision requires a longer period of post-circumcision sexual device themselves on Day 1 , two returned to the clinic on Day 2 abstinence than standard surgical methods.
requesting removal because of pain, discomfort or inconvenience, and in five clients the device became displaced on Day 1 (1), Day 2 (2), Day 4 (1) or Day 5 (1), following erection, masturbation, The PrePex device does not require injectable anaesthesia sexual intercourse or an assault. In one client surgery under local during placement. Comparing the pain scores is difficult anaesthesia was required to remove the band of necrotic foreskin because the pain control protocols evolved as the studies that had everted over the outer ring and prevented device progressed and more information on pain became available. In none of the studies was any injectable anaesthesia used for placement or removal of the PrePex device (excluding the men with complications that required surgical intervention). There was considerable variation in placement and removal A topical anaesthetic cream containing 5% lidocaine was first times over the different studies, with more experienced providers introduced in the Rwanda field study and has been adopted in all having lower procedure times. After the initial training and subsequent studies. familiarization process, mean placement preparation times were Summary results of the VAS pain scores in the Rwanda studies personal inconvenience wearing the device. Some of these showed that pain at the time of ring placement was minimal. The cases resulted in pain, rapid swelling and/or blistering of the period of greatest discomfort and pain was in the 3–6 hours after partially necrotized foreskin tissue, requiring urgent surgical placement, with ischaemia induced by the device. Most study intervention by a skilled surgeon in order to avert permanent participants were provided with analgesics to take as needed at disfigurement of the penis and/or severe local or systemic home after placement; pain during the early ischaemic process infection. In the studies conducted to date, appropriate appeared to be adequately controlled in a large proportion of surgical facilities have been available; all cases were clients with readily available medications such as paracetamol or successfully managed, with no long-term sequelae.
ibuprofen. There appears to be less pain while the device is worn • Client instructions must clearly describe safe use of the device, than at comparable times after conventional surgery, even during symptoms that may develop with device displacement or early erections. Study participants reported transient pain (short removal as well as the possible serious outcomes and surgical duration but quite severe) during device removal as the elastic interventions that may be needed if instructions on abstinence and inner rings were detached from the healing wound. and wound care are not followed or if the device becomes displaced (see next section).
Objectively assessing client acceptability in the early research • The PrePex device was reportedly acceptable to a large studies is difficult. However, a large proportion of clients proportion of study participants. In contrast to conventional expressed satisfaction with the aesthetic result. Pain, discomfort surgical circumcision and other circumcision devices that or user behaviour led to device displacements or early removals. have been reviewed by the TAG, the PrePex device has the Providers in at least three studies noted a strong odour in several advantage of not requiring injectable anaesthesia or suturing clients at the time of removal. Studies with the PrePex assessed at the time of placement, thus requiring less time for the loss of working days, which appeared to be fewer than following procedures and causing less pain.
conventional surgery. • PrePex providers must be appropriately trained to recognize the potential serious complications that can occur if the Key points on the prepex made by the TaG device is displaced or removed early, and must ensure that (Key programmatic considerations are noted in the next section.) such clients are rapidly assessed for appropriate management (within 6–12 hours), including referral when necessary. The TAG reviewed clinical data on the safety, efficacy and acceptability of the PrePex device from eight studies conducted • If countries decide to introduce the PrePex device into their in three countries with device placement on 2417 men. public health programme, introduction should be done in a phased approach after the device is prequalified. • The range and scope of these studies met the criteria • Careful monitoring and reporting of AEs is necessary in order established in the WHO Framework for clinical evaluation of to better understand the frequency of device displacement and devices for male circumcision.
self-removals and how risks can best be mitigated. • The TAG advised that the clinical studies necessary before a – Programmes must conduct active surveillance of the device is considered for prequalification by WHO have been first 1000 clients to identify and record AEs based on satisfactorily conducted. standardized definitions. The active surveillance may change • Evaluation and any advice are currently limited to healthy to passive surveillance after the first 1000 clients, if the males 18 years and older, as the device has not yet been incidence of events is reassuringly low as determined by evaluated for use among younger ages or among men living independent review. • The TAG considered that there is an enhanced risk of HIV • About 7% of clients eligible for conventional surgical acquisition if men engage in unprotected sex before the wound circumcision could not have the PrePex device placed for is healed, but the magnitude of risk is unknown. Therefore, various anatomical or technical reasons, including a narrow the group stressed the importance of good counselling about preputial opening or the correct device size outside range sexual activity and condom use. of five sizes produced. Circumcision was completed using • The TAG considered the device to be clinically efficacious in the PrePex in 99.5 % of clients on whom the device was male circumcision and safe for use among healthy men 18 years and older when used by trained mid-level providers • AEs occurred in 1.7% of clients; the majority were mild or in public health programmes, provided that surgical backup moderate. AEs in 0.4% were considered serious, and prompt facilities and skills are available within 6–12 hours to intervention was required to prevent potential serious long- manage events that could lead to serious complications. This conclusion is time-limited and must be reassessed in about one year as more experience with use of the device in diverse • In a small number of clients (about 1 in every 200), the programmatic settings is accumulated and reported.
device became displaced and /or was removed (including self-removal) due to client activities, pain, discomfort or programmatic considerations in developing wHo
guidance on tHe use of male circumcision devices
During the course of the meeting and the session focused on Considerations related to delivery site requirements that the TAG programmatic considerations, the TAG noted the following key identified included: points. In general, evidence on devices is currently available from use in research conditions, in which many of the providers are • The unique requirements of a device will need to be considered highly skilled. As use expands and shifts from study populations in the context of each type of service delivery site (e.g. fixed, receiving "ideal care in well-resourced settings" to more real- mobile, outreach, routine versus campaign).
world conditions, the TAG considered phased implementation • At the initial introduction of a new device, it is advised to have critical to determine the best and safest approaches for addition both conventional surgery and device methods available.
of a new device method. Pilot studies are planned in a number • A second visit is definitely required for device removal; services of the priority countries. The information from these studies will must be organized to meet the requirements of both visits. further inform the use of the devices. Implementation plans must be tailored to the specific characteristics of each device.
• The type of surgical back-up skills and facilities must be clearly specified, depending on device type, and available: Clinical skills and competencies for device placement, – "Immediate/on-site" surgical skills will be necessary at the removal and management of AEs should be available within time of ShangRing placement.
an ‘individual' and/or a ‘team'. For conversion to a surgical procedure after commencement of a device circumcision, – "Within 6–12 hours timeframe" surgical skills must be surgical staff may need skills beyond those needed to perform available during the week that men have a PrePex device in conventional surgical circumcision. Required clinical skills situ, in case of an AE requiring urgent intervention.
and training will differ according to device. For example, • Referral systems and contact numbers should be in place prior ShangRing placement requires skills similar to those required for to adding a device to any service.
conventional surgery, but more advanced skills and experience • For men not eligible for a device (such as those under 18 are required to manage the rare cases when the ShangRing years old or HIV-positive), service sites must determine if placement procedure cannot be completed; these skills should be conventional surgery is to be available on site or through a available on site. The surgical intervention necessary after PrePex functioning system of referral to services at another location. device displacement or self-removal after the ischemic process has started requires a surgeon experienced with managing • Programmes need to indicate pain management protocols for swollen tissue and abnormal foreskin anatomy. These skills and each specific device and for all stages of device use (pre-, in facilities must be available or obtainable within 6 to 12 hours. situ, at removal and post removal); these protocols must be All providers must be knowledgeable and trained to manage potentially life-threatening complications as well as the expected Male circumcision is one essential component of the "minimum and foreseeable side-effects.
package" of services, and all other components also must be available. Information should be available for providers, including a • Accurate messaging is needed on care and hygiene, possible training manual and instructions for use of the device. The EMP symptoms and management of device use, including the likely Department stated that the evaluation of the manufacturer's event of some pain. Symptoms such as pain, odour, bleeding instructions for use (IFU) is part of the PQ programme. The and swelling should be clearly described. IFU should include pictures and step-by-step instructions from • Clients must also be instructed on safe behaviours while the beginning to end (placement and removal) and should list the device is worn, including avoidance of sexual activity and equipment that is provided in procedure package and additional masturbation and the risks associated with such activity accessories that are required. The TAG asked to review the (with the PrePex risk of displacement, bleeding, swelling and IFUs prior to a PQ decision. Considering the limits of any IFU, ulceration and need for surgical circumcision).
programmes will still be responsible for the training and for developing manuals that will address specific issues such as • If a device displaces or becomes dislodged, clients must know pain management.
where to return to receive skilled surgical care or referral and transport arrangements to such care, within 6–12 hours.
Client counsel ing and education is an essential activity for good There are a number of other issues that programmes will need to clinical practice, informed consent and mitigation of risks related consider prior to introduction and use of a device, including: to client behaviours. Client instructions must clearly indicate the process and requirements of use of a specific device. Clients' • The organization of the supply chain and logistics will be partners should also be provided instructions. Points that should needed. Multiple device sizes will be required and must be be included in client instructions include the following: sufficiently stocked through good supply management and forecasting. The choice of the correct device size is likely to be • Once placed, a device must remain for seven days. In case critical for avoiding adverse outcomes, but as yet the tolerance a client desires to remove the device early, clients must be margin for using a device one size too small or too large is not instructed to return to the clinic. For the PrePex device early removal would likely require a conventional surgery to safely complete the circumcision. • Effective training and training materials will need to be • Clients must understand that wound healing may take about one week longer than following surgery, and that, until • Sterility requirements and accessories required will need to be complete healing, they should continue abstinence or use a condom to protect the wound and reduce HIV transmission • Regulations/policies will be needed on product approval in the risk. Also, the nature and appearance of secondary healing country and on which providers are permitted to perform male should be described to men.
circumcision with a device.
• Post-market surveillance will need to be set up in a standardized manner. information gaps and needs
The TAG discussed research gaps that should be addressed in the
• As full healing and resolution of scarring may take up to one near future. Over the next 12 months, PEPFAR and the Bill and year, outcomes one year after circumcision is performed with Melinda Gates Foundation will support pilot studies on the use a device should be assessed to document long-term wound of the ShangRing and the PrePex devices in VMMC programmes healing and final cosmetic result.
in most of the countries in eastern and southern Africa. These • Sizing studies are required, as the choice of the correct device pilot projects wil have monitoring components, particularly the size is likely to be critical for avoiding adverse outcomes. monitoring and analysis of AEs, which will provide more data on their frequency and more detailed information on causes of serious A brief update on ongoing/planned studies on the use of male AEs, such as PrePex displacement or ShangRing device failures. circumcision devices for infants such as AccuCirc compared with Mogen and Plastibell in Botswana, Zimbabwe and Uganda The following additional gaps regarding the use of male was provided by the WHO secretariat. TAG members expressed circumcision devices were identified: interest in moving forward infant circumcision, but WHO noted that due to limited resources the focus would be on review of • Bridging studies are required to establish performance and data when it becomes available. safety in younger populations since neither the ShangRing nor the PrePex have been evaluated in men under the age of 18 addressing other technical issues
• Since there are limited data in HIV-infected adolescent males Due to the limited time available, two items on the agenda were and adult men, it is important to document the safety of the device in such clients. Risk of HIV transmission during wound healing should be assessed through modelling studies to better • review of the study requirements for clinical evaluation of inform the consideration of risks and benefits. devices in the same category; • Studies are needed to assess the acceptability of the devices, • advise on additional technical innovations that WHO should particularly regarding the recommended period of sexual assess or should stimulate further development of in order to abstinence and the presence and management of pain, odour improve coverage and/or accelerate scale-up of medical male and urination problems while the devices are in situ.
circumcision in priority countries.
• More research is required to identify the best protocol for The TAG will address these items through telephone and managing pain at each point in the device use process.
electronic communications during the year. • The frequency of SAEs in non-study settings needs to be next steps
Key activities for the coming year include:
• Follow up with other technologies that have the potential to accelerate public health male circumcision programmes, • Complete the summary reports on the clinical performance of specifically use of the Gomco clamp and surgical adhesive; each device as part of the prequalification process; • Collate and monitor the incidence of device-related SAEs • Finalize the tables and summaries of adverse events occurring in programmes and provide regular updates to the and provide feedback to the study investigators on the classifications adopted by TAG; • Convene the next TAG meeting in early 2014 when sufficient • Review the Instructions for Use submitted by the device additional data on male circumcision devices used in manufacturers in accordance with the TAG recommendations; programmatic settings is available, and review the TAG • Incorporate feedback from the TAG into the generic guidance conclusions on the clinical performance of the PrePex and on use of devices by the Guideline Development Group; Shang Ring devices.
Table 1: Key risks of elastic col ar compression devices as
identified by WHO failure modes and risk analysis, August 2012 Potential failure
Instructions and Clear and detailed Untrained provider Excessive blood loss Penile strangulation Training and user Incorrect gauging Insufficient foreskin Device displacement Excessive bleeding Patient selection Insufficient pressure Matching components Applied pressure Septicaemic shock O-ring properties Properties of O-ring Stress relaxation Septicaemic shock O-ring properties Irritation and/or Biocompatibility (ISO Material for O-ring Adverse reactions Anaphylactic shock 10993)Specification and Ring breaks after a Damage to penis/glans Properties of inner ring Inadequate strength material testing at end of shelf-life Device design Local and systemic Contact duration Accumulation of debris Colonisation of device Instructions for Ulceration, pain Information for patients Inappropriate cleaning Choice of materials Patient instructions, Reasonably foreseeable Intercourse Device displacement Bleeding, damage to appropriate selection misuse by patient Self-removal of device Injury to self or partner penis, infection of patients (user Reasonably foreseeable Reuse of device Damage to penis, glans Design of components misuse by clinic or Table 2: Key risks of clamp col ar devices as identified by WHO failure modes and risk analysis, August 2012 Potential failure
Instructions and Clear and detailed Untrained provider Excessive blood loss Inadequate sterilization Potential infection Sterilization validation Packaging validation Packaging breached Potential infection Seal integrity testing Penile strangulation Training and user Incorrect gauging Insufficient foreskin Device displacement Excessive bleeding Patient selection Irritation and/or Biocompatibility (ISO Material for O-ring Adverse reactions Anaphylactic shock Failure after placement Design verification and foreskin removed Product testingManufacturer's quality Damage to penis, management system Outer ring too loose Device displacement and product inspection Instructions for useSpecification and Ring breaks after a Damage to penis, glans Properties of inner ring Inadequate strength materials testing at end of shelf-life Set appropriate lower Inadequate force Excessive bleeding Shock, blood loss, limit for applied Device displacement Properties of outer Ring breaks after 6–8 Excessive bleeding Supplier evaluation Inadequate strength Testing and inspection Local and systemic Accumulation of debris Colonization of device Instructions for clients Ulceration, pain, Information for clients Inappropriate cleaning Choice of materials Patient instructions, Bleeding, damage to Reasonably foreseeable Device displacement appropriate selection misuse by patient Injury to self or partner of patients (user Self-removal of device Reasonably foreseeable Reuse of device Damage to penis, glans Design of components misuse by clinic or Table 3: Classification of serious, moderate and mild adverse events for review of clinical data on device safety by the WHO TAG, 2013 Serious adverse event
Required surgical intervention to prevent permanent impairment to a body structure
or a body function
Pain or discomfort resulting in early removal Difficult removal Wound disruption requiring suturing Moderate adverse event
Required intervention or medication
Severe pain at time of, or soon after, device placement or surgery Infection requiring medication Pain or discomfort resulting in early device removal Wound disruption Difficult removal Insufficient skin removed Mild adverse event
Did not require intervention
Anaesthetic complication Pain at time of, or soon after, device placement or the surgical operation Displacement requiring repositioning Bleeding or oozing (pressure and/or dressing) Wound disruption Partial detachment Insufficient skin removed Table 4: ShangRing clinical studies in Africa Study [type of study]
Number and type of Type of providers
Safety Study (Kenya) Homa Bay District Hospital, 40 healthy HIV-negative Physicians and nurses experienced in [case series] (8) conventional surgical circumcision Spontaneous Detachment Homa Bay District Hospital, 50 healthy HIV-negative Physicians and nurses experienced in Study (Kenya) (10, 11) conventional surgical circumcision Randomized Comparison Kenya: Homa Bay District Non-physicians under supervision, with Surgery (Kenya and negative men (200 physicians and non-physicians, all with Zambia) [comparative Zambia: University allocated to ShangRing, extensive experience with surgical male trials] (12–14) Teaching Hospital (UTH), 200 to conventional circumcision (>500 surgical procedures Field Studies (Kenya and Kenya: seven sites in Homa 1256 healthy men Non-physicians and physicians, all with Zambia) [field studies] extensive experience with surgical male Zambia: Male Circumcision Centre and UTH, Lusaka Acceptability and Safety Rakai Health Sciences 621 health HIV-negative Clinical officers in sterile conditions in (Rakai) [field study] (17) Programme, Kalisizo, Rakai men, 508 of whom outpatient operating rooms Table 5: Adverse Events in all Shang Ring studies combined Type of Event
Number of device placements Serious AEs
Pain placement (PAIN) Pain leading to early removal (PREM) Wound disruption (WNDD) Insufficient skin removed (ISKR) Anaesthetic complication (ANAE) Pain placement (PAIN) Partial detachment (DETD) Wound disruption (WNDD) Insufficient skin removed (ISKR) Table 6: PrePex™ clinical studies in Africa Study [type of study]
Number and type of client
Type of providers
Safety and Efficacy Rwanda
Kanombe District and 50 generally healthy HIV- Physicians and nurse operators [case series] (18) Military Hospital, Randomized Comparison of Nyamata District 217 generally healthy men (144 Physicians and nurse operators PrePex and Surgery Rwanda allocated to PrePex, 73 allocated [comparative trial] (19) to dorsal slit surgery) Pilot Study with Nurse Kanombe District and 49 healthy HIV-negative men age Nurses Providers Rwanda [case Military Hospital, Field Study with Nurse Kanombe Military 666 generally healthy men Lower cadre nurses with no Providers Rwanda [field study] Hospital, Kigali, previous experience of PrePex Phase 1 Safety Study 53 HIV-negative men Physicians (urologists, Zimbabwe [case series] (23) Hospital, Zimbabwe general surgeons and general practitioners) and assistants (senior registered general nurses) Phase 2 Randomized 240 HIV-negative men Controlled Trial Zimbabwe Hospital, Zimbabwe [comparative trial] (24)Phase 3 Field Study Zimbabwe Harare, Kadoma and 641 HIV-negative men Nurses with physician back-up [field study] (25) Field Study, Kampala, Uganda International Hospital 634 healthy men Surgeons, medical officers, [field study] (26) clinical officers and nurses Field Study, Rakai, Uganda Rakai Health Sciences 187 HIV-negative men [field study] (27) Table 7: Adverse Events in all PrePex studies combined Type of Event
Per cent [95% CI]
Number of circumcisions Serious AEs
Displacement (DISP) Premature removal (PREM) Difficult removal (DIFR) Wound disruption (WNDD) Moderate AEs
Displacement (DISP) Premature removal (PREM) Difficult removal (DIFR) Burn blisters (BLIS) references
1. Framework for Clinical Evaluation of Devices for Male Circumcision. Geneva, World Health Organization, 2012.
2. Use of devices for adult male circumcision in public health HIV prevention programmes: conclusions of the WHO technical Advisory Group on Innovations in Male Circumcision. Geneva, World Health Organization, 2012.
3. Cheng Y, et al. Adult male circumcision using the Chinese ShangRing: results of 328 cases and a recommended standard surgical protocol in China. National Journal of Andrology, 2009, 15(7):584-592.
4. Yan B, et al. Circumcision with the Chinese ShangRing in children: outcomes of 824 cases [Article in Chinese, English abstract only]. Zhonghua Nan Ke Xue [National Journal of Andrology], 2010, 16(3):250-253.
5. Peng YF, et al. Standardized male circumcision with ShangRing reduces postoperative complications: a report of 351 cases [Article in Chinese, English abstract only]. Zhonghua Nan Ke Xue [National Journal of Andrology], 2011, 16(11):963-966.
6. Li HN, Xu J, Qu LM. ShangRing Circumcision versus comventional surgical procedues: Comparison of clinical effectiveness [Article in Chinese, English abstract only]. Zhonghua Nan Ke Xue [National Journal of Andrology], 2010, 16(4):325-327.
7. Peng Y-F, et al. Clinical application of a new device for minimal y invasive circumcision. Asian Journal of Andrology, 2008, 10(3):447-454.
8. Barone MA, et al. The ShangRing device for adult male circumcision: A proof of concept study in Kenya. J Acquir Immune Defic Syndr. 2011; 57(1): e7-e12.
9. Study Group 5 of the Global Harmonization Task Force (GHTF). Reportable events during pre-market clinical investigations. GHTF, 2012 10. Barone MA, et al. Randomized trial of the ShangRing for adult male circumcision with removal at one to three weeks: delayed removal leads to detachment. JAIDS Journal of Acquired Immune Deficiency Syndromes, 2012, 60(3):e82-e89.
11. The ShangRing: evaluation of healing at three time intervals and potential for spontaneous detachment [confidential statistical report and tables, study #10214]. Durham, NC, USA, FHI 360, 2011.
12. Sokal DC, et al. Randomized control ed trial of the ShangRing versus conventional surgical techniques for adult male circumcision in Kenya and Zambia (TUAC0404). Presented to the XIX International AIDS Conference, Washington, DC, 22-27 July, 2012, abstract TUAC0404 13. Sokal DC, et al. Randomized control ed trial of a minimal y invasive circumcision device, the ShangRing, versus conventional surgical techniques for adult male circumcision: safety and acceptability [submitted for publication], 2013.
14. Comparison of the ShangRing with conventional surgical methods: a randomized control ed trial (RCT10220) [confidential statistical report and tables]. Durham, NC, USA, FHI 360, 2012.
15. Sokal DC, et al. A field study of male circumcision using a minimal y-invasive device, the ShangRing, in routine clinical settings in Kenya & Zambia. [Report to The Technical Advisory Group on Innovations in Male Circumcision, World Health Organization]. Durham, NC, USA, FHI 360, 2012.
16. A prospective observational study of male circumcision using the ShangRing in routine clinical settings in Kenya & Zambia [confidential statistical report and tables, study #10278]. Durham, NC, USA, FHI 360, 2012.
17. Kigozi G, et al. The acceptability and safety of the ShangRing for adult male circumcision in Rakai, Uganda [submitted for publication], 2013.
18. Bitega JP, et al. Safety and efficacy of the PrePex device for rapid scale-up of male circumcision for HIV prevention in resource-limited settings. JAIDS Journal of Acquired Immune Deficiency Syndromes, 2011, 58(5):e127-e134.
19. Mutabazi V, et al. HIV prevention: male circumcision comparison between a non-surgical device to a surgical technique in resource-limited settings: a prospective, randomized, non-masked trial. JAIDS Journal of Acquired Immune Deficiency Syndromes, 2012, 61(1):49-55.
20. Mutabazi V, et al. One arm, open label, prospective, cohort field study to assess the safety and efficacy of the PrePex device for scale-up of non-surgical circumcision when performed by nurses in resource-limited settings for HIV prevention. Presented to the XIX International AIDS Conference, Washington, DC, 22-27 July, 2012, abstract TUAC0405 21. Mutabazi V, et al. One arm, open label, prospective, cohort field study to assess the safety and efficacy of the PrePex device for scale-up of non- surgical circumcision when performed by nurses in resource-limited settings for HIV prevention [Submitted for publication], 2013.
22. Mutabazi V, et al. One arm, open label, prospective, cohort field study to assess the safety and efficacy of the PrePex™ device for scale up of non-surgical circumcision when performed by nurses in resource limited settings for HIV prevention (Protocol RMC-03). 2012 January 10.
23. Tshimanga M, eta al. Evaluation of safety and efficacy of PrePex™ device for male circumcision in Zimbabwe. Phase I: device safety trial report. Harare, Zimbabwe, Ministry of Health and Child Welfare, 2013.
24. Tshimanga M, et al. A randomized control ed trial comparing the PrePex™ device to forceps guided surgical circumcision for rapid scale-up of male circumcision in Zimbabwe. Phase II: randomized trial report. Harare, Zimbabwe, Ministry of Health and Child Welfare, 2013.
25. Tshimanga M, et al. Evaluation of safety and efficacy of PrePex™ device for male circumcision in Zimbabwe. Phase 3: cohort field study on safety and efficacy of the PrePex circumcision device when performed by nurses. Harare, Zimbabwe, Ministry of Health and Child Welfare, 2013.
26. Galukande M, et al. HIV prevention: safety study of a non-surgical device for adult male circumcision with no injected anesthesia in a non sterile setting. Kampala, Uganda, International Medical Group, 2013.
27. Kigozi G. Acceptability and safety of the prepex device for male circumcision: Rakai (UO1 AI075115-0451). Kalisizo, Rakai, Uganda, Rakai Health Sciences Program, 2013.
annex: meeting agenda
Day 1: Tuesday 29 January 2013
Welcome and introductions Objectives and expected outcomes, review of agenda Roles of members and observers, declaration of interests Session I: Brief updates
Chair: Tim Hargreave
WHO guidance on use of devices for male circumcision Prequalification status of devices Irena Prat
Session II: Technical updates
Recapitulation of research available on male circumcision devices for adolescents and adults Bill Potter
Risk assessment of devices Clinical studies–is there a need to review requirements? Session III: ShangRing
Detailed review of research findings Tim Farley
Con't: review evidence Tim Farley
Reception (WHO D building cafeteria) Day 2: Wednesday, 30 January 2013
Session III: ShangRing (cont'd)
Session IV: PrePex
Co-chair: Stephen Watya
Detailed review of research findings Tim Farley
Con't: Review evidence Tim Farley
Discussion (cont'd) Day 3: Thursday, 31 January 2013
Session IV: PrePex (cont'd)
Session V: Implications for WHO Guidance on use of devices
Highlights of Day 1 & 2 to address guidance on use of devices: operational and programmatic considerations, and recommendations Doris Mugrditchian/
Session VI: Additional technical innovations and research
Co-chair: Steve Watya
Bridging studies and special safety studies Other male circumcision technologies including Gomco and glue For more information, contact:
World Health Organization Department of HIV/AIDS ISBN 978 92 4 150563 5 20, avenue Appia 1211 Geneva 27 Switzerland
I n f o r m a t i o n s m a t e r i a l v o m 1 7 . 0 1 . 2 0 0 8 Zysten, Fisteln und Co. Der 18. November 1686 war der aufregendste Tag im Leben des Chirurgen Charles-François Félix (1653-1703). Ein Jahr lang hatte sich sein Patient der von ihm vorge-schlagenen Operation seiner Analfistel verweigert. Nun reckte er ihm den After ent-gegen, bereit, einige schmerzhafte Schnitte zu ertragen, denn mit Betäubungsmitteln war es damals nicht weit her. Der Patient war Schmerzen gewöhnt, zeitlebens hatten ihn unzählige Leiden geplagt. Doch ein Misslingen dieser Operation, wo-