PROTO (Prostate Trials Office)

The first randomized controlled trial (RCT) was reported by the MRC in 1948 and compared streptomycin plus bed rest with bed rest alone for the treatment of pulmonary tuberculosis. The trial found that streptomycin was effective [1]. Although the value of RCTs is generally accepted (e.g. see [2]), much of the evidence presented in the area of benign prostatic disease remains observational (see Frymann et al. page 46–53). In view of the recent, rapid advances in technologies for treating benign prostatic obstruction (BPO), and their ad hoc incorporation into clinical practice before rigorous evaluation, there remains a need for strong, research-based evidence concerning the comparative safety, clinical effectiveness, acceptability and cost-effectiveness of these new treatments. It was also acknowledged that developing robust research proposals, whilst maintaining contact with current initiatives, can be a difficult task and therefore a new clinical trials office, the Prostate Trials Office (PROTO), was established. PROTO was to be a focus for developing and establishing RCTs for the treatment of BPO in the UK and would provide support for health professionals in the field. This project was funded by the NHS Research and Development Health Technology Assessment (HTA) Programme for 3 years and has been developed as a joint initiative between Southmead Health Services Trust and the University of Bristol (Department of Social Medicine), with the involvement of a wide range of clinicians and researchers in the UK. PROTO was established with the following major aims. (i) To establish databases of published and ongoing RCTs. Building on previous systematic reviews [3], a database has been established containing published RCTs for all forms of treatment for BPO. This database can be accessed via the PROTO web page ( http://www.bui. ac.uk/proto) for reviews. The database has been indexed under the three principal categories of treatment (nonmedical, medical and surgical) with pathways to major modalities. The database has been updated quarterly during PROTO’s funding. (ii) To develop core and ‘add-on’ protocols for RCTs. PROTO has followed, where appropriate, the recommendations of the Fourth International Consultation on BPH [4]. The following protocols appear in full in this supplement: (a) inclusion/exclusion criteria (core and add-on); (b) clinical measures (only urine analysis was highly recommended by the Fourth International Consultation on BPH in the core protocol). Dilemmas inherent in the measurement of prostate size and PSA testing are dealt with by Williams (page 31–35). The add-on protocol contains detailed recommendation for urodynamic technique and practice; (c) symptom, quality of life and sexual function assessment. Details of methods of symptom evaluation and recommended questionnaires are contained in Donovan’s paper (page 10–19). The IPSS is highly recommended in the symptom and quality-of-life core protocols; (d) sociodemographic data - basic data are set out for the core protocol; (e) treatment complications, the measurement of which is not yet clearly established and varies considerably between treatment types. An add-on protocol is suggested here for invasive surgical procedures; (f) economic evaluations, which need to be designed to address the particular question posed by the trial. The principles of economic evaluation are discussed in the paper by Baxter et al. (page 36–41). A basic core protocol is presented, with indications of adjustments that will need to be made for particular treatment evaluations. (iii) To provide an advice and support service (for trial design and conduct) to clinicians and researchers. During PROTO’s funding, ad hoc advice has been available to clinicians and researchers. This supplement contains three papers which discuss the principles, design, conduct and analysis of RCTs. The paper by Peters (page 3–9) describes issues in the design and analysis of RCTs. Thorpe and Neal (page 42–45) review issues relating to patient information and consent. The problems and pitfalls encountered in conducting RCTs are discussed by Chapple (page 54–57). (iv) To develop an infrastructure enabling the performance and co-ordination of RCTs by PROTO. There was simultaneous funding for PROTO and an RCT comparing the Vaportrode method with TURP, led by Fowler (Royal London Hospital). PROTO has supported the conduct of this trial by providing statistical advice, database management and will assist in the final analysis. (v) To facilitate the submission of proposals for funding of new RCTs for treatments of men with LUTS. After an unsuccessful bid to the MRC to fund an RCT comparing transurethral incision of the prostate with TURP, PROTO conducted a survey of all UK urologists (response rate 92%) to assess the feasibility of such a study [ 5]. In addition, a pilot study is underway to finalize a further application for funding in 2000. Four outline proposals were submitted to the NHS HTA programme call. One was short-listed and after the submission of a full proposal, the HTA agreed, in principle, to the funding. This study will compare pharmacotherapy with conservative management in a primary-care RCT, and pharmacotherapy with surgical management in a secondary-care RCT. PROTO will provide full support for this trial, which will commence in 2000. It is PROTO’s view that in future all new interventions (surgical, medical and nonmedical) should be evaluated in RCTs of sufficient size and methodological rigour. Initial pilot studies are required to assess issues such as safety and basic efficacy. Thereafter, all treatments should be compared with established therapies to determine their effectiveness and cost-effectiveness in multicentre pragmatic RCTs. Such a programme will expose the fewest patients to risks whilst providing rapid answers to basic questions about new methods or technologies for treating LUTS in men. These principles are best supported by organizations such as PROTO. P. Abrams, FRCS, Professor in Urology. T.A. McNicholas, FRCS, FEBU, Consultant Urologist. J. Donovan, PhD, Senior lecturer. T. Peters, PhD, Reader. A. Grant, PhD, Professor.