Title: The UK Clinical Research Network - has it been a success for dermatology clinical trials?

Transcription

1 Author's response to reviews Title: The UK Clinical Research Network - has it been a success for dermatology clinical trials? Authors: Kim S Thomas (kim.thomas@nottingham.ac.uk) Karin Koller (Karin.koller@ntlworld.com) Katharine Foster (Katharine.foster@nottingham.ac.uk) Jo Perdue (jo.perdue@nottingham.ac.uk) Lisa Charlesworth (lisa.charlesworth@nottingham.ac.uk) Joanne R Chalmers (joanne.chalmers@nottingham.ac.uk) Version: 2 Date: 10 June 2011 Author's response to reviews: see over

2 Response to reviewer s comments MS: The UK Clinical Research Network - has it been a success for dermatology clinical trials? Kim S Thomas, Karin Koller, Katharine Foster, Jo Perdue, Lisa Charlesworth and Joanne R Chalmers Thank you for taking the time to consider our manuscript. We have endeavoured to take into account all of your comments in our revised submission, and have addressed the issues point by point below. Comments from Associate Editor Thank you for your thoughtful comments. To address your specific points: Comment 1: It would be unhelpful if the availability and desirability of local infrastructure support adversely shaped the geographical conduct of trials. If your important point could be given greater emphasis I think that would be appropriate. Thank you. This concept has now been given greater prominence in the paper by adding the following sentence to the conclusion section. This will be facilitated if the newly evolving structures allow easy and transparent support across the whole country, rather than encouraging competition between geographical regions. Page 9, para 6. Comment 2: I found the chronology of the two case studies confusing at first and had to go back to the first one to see how it fit with the second. The following sentence has now been added to the methods section in order to clarify this point.

3 These case studies are presented in chronological order based on the time at which support from the Clinical Research Networks was first accessed. Page 3, para 3. Comment 3: I wasn t sure how you got from the aspiration of the first statement (wanting all clinicians to recruit a few patients) to the reality of the second (not enough time and resource at recruiting centres to deliver the trial). If you could make this clear in the paper, that would be helpful. We agree that our initial aspirations for the UK Dermatology Clinical Trials Network were not entirely met in the PATCH cellulitis trial. Our feeling is that this was for two main reasons: 1. The UK DCTN was first established in order to encourage dermatologists to work together to answer important questions about the treatment of rare skin conditions that could not adequately be answered by studies conducted in a limited number of centres. According to this model, each centre would be encouraged to recruit a limited number of patients per year, thus making recruitment something that could be more easily incorporated into normal clinical practice. In hindsight, the PATCH cellulitis trial was a poor candidate to test this model, since cellulitis is a common condition and recruitment would probably have been more successful had we conducted the trial in a smaller number of well-resourced centres. However, our decision to engage the whole Network at this time was a deliberate decision based on the fact that this was a new network of enthusiastic people, and we wanted to involve as many members as possible in our first Network trial. The UK DCTN has since opened additional studies looking at rare skin conditions (bullous pemphigoid and pyoderma gangrenosum), and these trials are recruiting well using the model of many recruiting centres entering just a handful of participants each. 2. Secondly, the UK DCTN was first conceived prior to the introduction of the EU Clinical Trials Directive and the associated increase in regulatory controls around the design and conduct of non-commercial, Phase IV clinical trials. This meant that much more was required of our recruiting clinicians in terms of documentation and tracking of documents than had originally been anticipated, and made it far harder for busy clinicians to get involved. The following sentence has been added to the paper in order to clarify this.

4 This trial was intended to test the ability of the Network to recruit into trials by identifying just a few patients from many centres; thus allowing busy clinicians to engage in research in a meaningful way, without over burdening any one site. As a result funding for the trial was limited to a trial manager and an administrator at the coordinating centre, but no dedicated research nurses at recruiting sites. Whether such a model is possible in the current regulatory climate, and for a condition such as cellulitis, which is often seen by specialties other than dermatology, is unclear. Subsequent UK DCTN trials of rare skin conditions that are being treated by dermatologists are proving more successful in this regard ( Page 5, para 3. Comment 4: There is an A missing in the following sentence - Indeed, related trial (PATCH II) was closed at this time... Thank you, this has now been amended in the revised paper. Reviewer comments (Haleema Shakur) Comment 1: The UK Clinical Research Network has substantial UK public funding and whether it is fulfilling its objectives has to be scrutinized. The question as to whether it is contributing to the success of dermatology trials is therefore very important. Thank you. No changes required. Comment 2: From this report it is not clear what exactly the responsibility of the UK Clinical Research Network is. Did the networks act in troubleshooting mode after a failure of a trial recruitment plan, or were they brought in to sustain and support existing recruitment strategies? The remit and function of the research networks has now been made clearer in the background section: The overall objectives of these networks are: i) to introduce effective systems to speed up the regulatory approval process; ii) to provide infrastructure to support clinical research activities; and iii) to facilitate access to appropriate patient populations. Page 3, para 1. It is possible that our paper gives a misleading impression of the role of the networks as the trials that we have described were two of the first to access the additional infrastructure support, and were ongoing at the time that the networks were established.

5 We have made it clearer in the paper that future studies should approach the networks at an early stage so that the networks and research teams can work together to ensure recruitment success from the outset....all new studies are now assessed for adoption onto the NIHR portfolio at an early stage, and a designated lead network is identified as part of the application process through the NIHR Coordinated System for gaining NHS Permissions ( This process ensures that the needs of studies are evaluated prior to initiation of the research activity, and negotiations with other networks are facilitated by experienced network staff familiar with the process. Page 8, para 5. This point has also been strengthened on page 6, paragraph 6, when we discuss the impact on trials that approach the networks at an early stage: Both of the trials described in this paper were ongoing at the time that resources became available through the NIHR Clinical Research Networks, which meant that the role of the research networks in these trials was primarily troubleshooting. Future trials will work more collaboratively with the research networks, and will benefit greatly from both the systems and the personnel that are now in place. This was demonstrated clearly with another of our dermatology trials that was adopted onto the UK CRN portfolio more recently (the BEEP feasibility study Barrier Enhancement for Eczema Prevention (6). In this case, support was available from the outset from both the CLRN and MCRN, and the trial quickly recruited in excess of its target in three hospitals across the region. Comment 3: The presentation of the recruitment data to illustrate UK Clinical Research Network success might be misleading. Using the media to bring the trial to the attention of the target population was probably the most important factor in improving recruitment which was the investigator initiative. The additional staff to support the Trial Manager when there was a deluge of interest could have been provided by any agency providing temporary staff or was there any special expertise which the Network offered which could not be offered by any other? It is certainly the case that advertising and wider publicity for both of the trials was one of the key reasons for the eventual success of both of these trials. This is a point that we make throughout the paper and again in the concluding paragraph and abstract, so hope that we haven t presented a confusing message in this regard. We agree that the support provided by the research networks could have been provided by outside agencies, but this is the big benefit of having a dedicated research infrastructure in place, in that it means that support can be accessed quickly as and when required, rather than all individual research teams having to independently organise emergency support and / or contingency planning. In addition, the requirement

6 for GCP training for trial-related staff means that it is generally not possible to simply appoint temporary staff through normal agencies, making temporary support via clinical research agencies a relatively costly undertaking. No changes required. Comment 4: The conclusion needs to focus more on what the Network contributed to the success or otherwise of the trials. The Network had no input into bringing the awareness of the trial to the public or did they? It also mentioned the availability of experienced and extremely dedicated research teams who constantly strove to ensure that the trials were of high quality and delivered to target. I have a vision of the Network having a group of expert people sitting around waiting for a call for help. More information on how the Network is organised to be able to provide such expert support should be given in this report. We have tried to make this point clearer in the conclusion. We were trying to imply that the trial teams were themselves extremely dedicated in delivering the trial, and that is was the partnership between the trialists and the networks that allowed this to be translated into recruitment success. We did not mean to imply that the research networks themselves employ dedicated experts to advise on trial design and conduct (although of course this is a role that the Clinical Studies Groups fulfil in a slightly different capacity). The conclusion section has been amended as follows:: The additional resource allocated to the trials highlighted in this report meant that both studies recruited to target and that two important clinical questions can now be addressed. However, it is clear that simply increasing resources is not sufficient in isolation. Neither of the trials would have benefited from the increased financial support without the availability of experienced and extremely dedicated research teams who strove to ensure that the trials were of high quality and delivered to target. Success was driven by the genuine partnership between the research teams and the flexibility of network support. Comment 5: It might be more useful to use the case studies to illustrate how support was accessed as many investigators might find that information more useful. Also, highlight the objectives of the Network and use the case studies to illustrate how the Network achieved their objectives and together were able to deliver the two trials. Thank you for this suggestion, we have now added the following paragraphs:

7 The objectives of the NIHR research networks have been stated more fully in the background section: The overall objectives of these networks are: i) to introduce effective systems to speed up the regulatory approval process; ii) to provide infrastructure to support clinical research activities; and iii) to facilitate access to appropriate patient populations. Page 3, para 1. Further information on how to access the networks has been added to the discussion section: For multi-centre trials that require support at a national level, negotiating local arrangements can be time-consuming and potentially fragmented. Further streamlining of the application process in line with other regulatory approvals in order to avoid duplication of effort is required. Indeed, this is now emerging and all new studies are now assessed for adoption onto the NIHR portfolio at an early stage, and a designated lead network is identified as part of the application process through the NIHR Coordinated System for gaining NHS Permissions ( This process ensures that the needs of studies are evaluated prior to initiation of the research activity, and negotiations with other networks are facilitated by experienced network staff familiar with the process. Page 8, para 5.