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The application of surrogate endpoints in clinical trials


   School of Health & Wellbeing

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  Prof R Taylor  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Background to the project

Evidence for the efficacy and safety of treatments should ideally come from well-designed randomised controlled trials (RCTs) that assess final outcomes relevant to patients, such as survival and health-related quality of life.1 However, surrogate endpoints (biomarkers or intermediate outcomes) are often used in RCTs as substitutes for final outcomes; offering the advantages of faster accrual/easier to assess, thereby shortening duration, size, and cost of clinical trials.2 There has been a long tradition of regulators (US FDA and EMA) promoting ‘faster access’ to drugs/biologics with approval based on surrogate endpoint evidence.3,4

Whilst regulatory guidance increasingly recommends surrogates be limited to ‘validated’ endpoints to ensure that the effect of therapy truly reflects the effect of therapy on the final outcome(s) of interest,5 there remains a lack of clarity in the wider clinical trial community on when and how surrogate endpoints should be best used.6,7 Furthermore, reliance on surrogates is growing with the application of innovative trial methods, including adaptative and platform (including basket and multiple arm) trials.8

What the studentship will encompass:

The overarching aim of this PhD proposal is to undertake an analysis of the contemporary application of surrogate endpoints in clinical trials to inform future methodological practice.

Phase 1 of this PhD will be foundational and include: (1) review pf published trials - update previous reviews9,10 with a retrospective review of RCTs published in last 3-5 years in major general medical journals (e.g., NEJM/BMJ) and NIHR monographs to assess proportion of trials with a primary surrogate endpoint. This will include a detailed analysis of identified surrogate trial reports e.g., surrogate definition, RCT design, disease area, intervention (e.g., drug, medical device), rationale for evidence of surrogate validation, nature of surrogate, type of intervention sample size, length of follow up, type of funder and (2) survey of UK trial practice around the use of surrogates in clinical trials – UKCR CTUs, NIHR and MRC funding committees/secretariats, MHRA/NICE/SMC, and members of TMRP and HRB-TMRN will be invited to complete a web-based questionnaire/phone interviews to assess their practice/views of the use of surrogates in RCTs. Based on phase 1 and tailored to the background and skills of the PhD candidate the focus of remainder of the PhD and could take either a quantitative/statistical focus (e.g., detailed analysis if current validation/statistical methods for the handling of surrogate endpoints in clinical trials) or a health-policy focus (e.g., development of guidance for the use of surrogate outcomes in future clinical trials in context of regulatory and HTA decision making).

With extensive experience of the use of surrogate endpoints in clinical trials and HTA and healthcare policy, the supervision team is ideally placed to support this PhD. Prof Rod Taylor will be lead supervisor and will specifically coordinate the supervision for the phase 1. Prof Taylor is a member of TMRP PhD Advisory, Strategy and Outcome theme groups and is an experienced PhD supervisor, and has extensive experience in clinical trial methodology and methodological reviews. Prof Chris Weir (University of Edinburgh) will provide co-supervision and coordination of the 2nd project phase. Prof Weir co-leads the TMRP Outcomes Working Group and has extensive PhD supervision experience, and has a longstanding interest in the use of surrogate endpoints in clinical trials that includes his leadership of a previous overview of statistical approaches for evaluating surrogate outcomes in clinical trials.11

We will explore with our existing medical device/pharma company links, the possibility of industry placements/field work. In addition we anticipate that there will be a placement opportunity for the student to spend time with Prof Sylwia Bujkiewicz at University of Leicester (where she leads a research team in the area of Bayesian methods for evidence synthesis) and/or Assoc Prof Oriana Ciani, SDA School of management, Milan (who has a substantive track record on the use of surrogate endpoints in HTA and health-care policy making and is member of the TMRP Outcome working group) to develop the student statistical analysis and/or health policy analysis skills respectively and gain experience to deliver the 2nd project phase.

MRC/CSO Social and Public Health Sciences Unit (SPHSU) has a strong track record of public/stakeholder engagement in its methodological research. This doctoral proposal will ‘piggy-back’ the PPI established in our MRC Better Methods, Better Research funded study developing CONSORT/SPIRIT extensions for reporting of surrogate endpoints in clinical trials.

The successful candidate will be required to have a 2.1 honours degree in a STEM subject and a relevant Master’s degree (e.g., medical statistics/epidemiology), is desirable.

HOW TO APPLY

You are applying for a PhD studentship from the MRC TMRP DTP. A list of potential projects and the application form is available online at:

http://www.methodologyhubs.mrc.ac.uk/about/tmrp-doctoral-training-partnership/

Please complete the form fully. Incomplete forms will not be considered. CVs will not be accepted for this scheme.

Please apply giving details for your first choice project. You can provide details of up to two other TMRP DTP projects you may be interested in at section B of the application form.

Before making an application, applicants should contact the project primary supervisor to find out more about the project and to discuss their interests in the research.

The deadline for applications is 4pm (GMT) 18 February 2022. Late applications will not be considered.

Completed application forms must be returned to: [Email Address Removed]

Informal enquiries may be made to [Email Address Removed]


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend (stipend to include London Weighting where appropriate). We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

1. Pocock SJ. Clinical trials: a practical approach. Wiley, 1996
2. Bucher HC, JAMA 1999;282:771-8
3. Kordecka A, Value Health. 2019;22:884-90
4. Chen EY, JAMA Intern Med. 2020;180:912-4
5. Ciani O, Nat Rev Drug Discov. 2016;15:516
6. Fleming TR, Stat Med. 2012;31:2973-84
7. Dawoud D, BMJ. 2021;374:n2191
8. Park JJH, Trials. 2019;20:572
9. la Cour JL, BMJ. 2010, 18;341:c3653
10. Ciani O, BMJ. 2013 Jan 29;346:f457
11. Ensor H, J Biopharm Stat. 2016;26:859-79
12. Skivington K, BMJ 2021;374
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