Mastering NICE submissions: The three pillars for HST and STA success 

Securing a positive recommendation from the National Institute for Health and Care Excellence (NICE) is a critical milestone for pharmaceutical and biotech companies aiming to achieve market access in the UK. NICE’s evaluations determine whether new health technologies are both clinically effective and cost-effective for use within the National Health Service (NHS). 

Two primary appraisal routes exist: the Single Technology Appraisal (STA) and the Highly Specialised Technologies (HST) evaluation. The STA process is typically used for technologies that address more common conditions, while the HST route is reserved for treatments targeting very rare diseases. 

This article series will delve into the three foundational pillars of a successful NICE submission: robust clinical evidence, a comprehensive evidence review, and a strong health economic model. By mastering these elements, companies can enhance their chances of a favourable outcome, facilitating timely access to the UK market and delivering value to patients and the healthcare system alike. 

Pillar 1: Strong Clinical Evidence:  

NICE places the highest value on data that demonstrate a clear, patient-relevant benefit derived from well-designed clinician trials. Where these standards are achieved, even in very small cohorts, first-in-class or high-cost medicines can be judged clinically effective for routine use within the NHS. Conversely, short follow-up, unvalidated surrogate endpoints or standard of care (SoC) misalignment can delay routine commissioning until more robust data are secured. 

Do’s – What works and why  

Validated, meaningful endpoints give confidence in real-world impact 

Voretigene neparvovec is a one-off adeno-associated-viral gene therapy that inserts a functional RPE65 gene to restore retinal phototransduction in people with biallelic RPE65-mediated inherited retinal dystrophy. The key challenge in the submission was persuading NICE that evidence from only 31 patients and using the novel multiluminance-mobility test rather than standard visual-acuity measures, was robust enough to reflect real-world benefit. Yet because this endpoint captured functional navigation in everyday lighting, the committee accepted it as clinically meaningful and NICE recommended the one-off gene therapy, within its marketing authorisation, for routine use.¹ 

Aligning with SoC upfront prevents costly delays 

Baricitinib is an oral JAK-1/2 inhibitor for adults with moderate-to-severe rheumatoid arthritis (RA) who have not responded to conventional or biologic disease-modifying antirheumatic drugs (DMARDs). The submission’s key challenge was to show cost-effectiveness across four distinct RA subgroups, each with different NHS comparators including the low-cost option rituximab. To address this, the company mapped every subgroup to its relevant comparator and supported each comparison with data from four pivotal randomised control trials (RCTs) plus a network meta-analysis (NMA). NICE ultimately recommended baricitinib for all subgroups except the one in which rituximab already provided equivalent benefit.² 

However, when head-to-head RCTs are not feasible, compelling data can still suffice. Larotrectinib, a tissue-agnostic TRK fusion inhibitor for various cancers, had no head-to-head comparator data, but showed high response rates in a single-arm study. Larotrectinib was recommended for use within the Cancer Drugs Fund, indicating that strong signals of efficacy in high unmet need settings can still be accepted as sufficient evidence, albeit with commitments to collect further data. ³ 

Early, structured long-term follow-up helps address uncertainty 

Onasemnogene abeparvovec is a single-dose AAV9 gene therapy that delivers the missing SMN1 gene to infants with spinal muscular atrophy (SMA) Type 1, aiming to halt motor-neuron loss. The key challenge in the NICE submission was the short 18- to 24-month follow-up from the pivotal trial, leaving uncertainty about whether the early survival and motor-milestone gains would last and whether late safety issues might emerge. To address this, the company launched two long-term extension studies, LT-001 and LT-002, to track durability and safety out to 15 years. Interim results from these studies helped justify approval under a managed-access agreement despite residual uncertainty. ⁴ 

Common pitfalls to avoid:  

• Do not rely on “hand-picked” or suboptimal evidence when better data could be obtained. NICE’s independent Evidence Assessment Group (EAG) will scrutinise the submission and may flag cherry-picked analyses or omission of unfavourable studies.  

• Avoid overemphasising surrogate endpoints without support and ensure that any claims of superiority are backed by statistically robust data.  

• Never ignore the comparator issue: submissions have faltered because the comparator in the model was not reflective of UK practice, even when the new drug’s own efficacy was proven.  

In summary, present a compelling, contextually relevant evidence story: one that convinces NICE that patients will substantially benefit under real-world NHS conditions.  

Pillar 2: Comprehensive evidence review 

A NICE submission is far more than one or two pivotal trials. The committee expects a comprehensive review of all relevant evidence, delivered through systematic literature reviews (SLRs) that cover four core domains: a clinical SLR to capture every pertinent study of efficacy and safety, and an economic SLR to identify published evidence on health-related quality of life (HRQoL) to gather utility data for quality adjusted life years (QALY) calculations, published cost-effectiveness studies and UK-specific resource-use and cost inputs. Synthesising these sources lets the dossier set the full context (disease burden, unmet need, and current care patterns) and ensures NICE has the complete picture. A meticulous, transparent SLR also signals credibility, showing the company is not withholding data and is committed to an objective appraisal of its technology. 

Do’s – What works and why  

Mapping every relevant comparator and triangulating multiple evidence sources ensures the submission is grounded in real practice 

Nusinersen treats 5q spinal muscular atrophy, where the relevant comparators were best-supportive care for type 1 infants and “no disease-modifying therapy” for later-onset types.  The challenge with the submission was that its two placebo-controlled trials covered only a subset of UK patients and lacked an untreated arm. To fill the gaps, the company supported two placebo-controlled trials with the UK SMA-REACH registry and a matched natural-history cohort to contextualise trial findings and populate model transitions for BSC, the only relevant comparator at the time. This triangulation allowed NICE to see how nusinersen performed against the full spectrum of UK care, leading the committee to call the package “comprehensive and appropriate for decision-making” and to recommend the drug for presymptomatic SMA and for types 1–3 under a managed-access agreement.⁵ 

Using formal NMAs where head-to-head data are sparse delivers transparent, evidence-based comparisons 

The submission for daratumumab + lenalidomide + dexamethasone in untreated transplant ineligible multiple myeloma faced the challenge of five distinct UK comparators. As the main trial only supplied direct evidence against lenalidomide + dexamethasone, the company included an NMA of all other UK-relevant comparators (two bortezomib-based and two thalidomide-based triplets). NICE assessed the NMA as “fit for purpose,” supporting a positive recommendation despite no direct trial data versus the most common comparators. ⁶ 

Incorporating patient-centric and quality-of-life evidence demonstrates that trial gains translate into everyday value 

During the NICE submission for venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukaemia, the company bolstered the pivotal CLL14 trial with UK-specific stakeholder evidence, highlighting the burden of lifelong chemo-immunotherapy and confirming that the main comparators (FCR and BR) generate significant long-term side effects. NICE judged the stakeholder-rich evidence “suitable for decision making” and recommended venetoclax + obinutuzumab for adults with a 17p deletion or TP53 mutation, or for those without these mutations when FCR or BR are unsuitable.⁷ 

Pitfalls to avoid:  

• A common mistake is performing an SLR that misses important studies. Competitors, clinicians, or NICE’s EAG might point out omitted trials or data, potentially undermining your submission. Searches must be up to date and designed with a robust methodology to ensure all relevant evidence is identified and nothing important is overlooked.  

• Avoid over-reliance on favourable data while ignoring conflicting evidence; NICE values transparency and will have access to public domain data in any case.  

• Poor documentation of your review methods is another pitfall, if the EAG cannot follow how you arrived at your included evidence, they may suspect bias.  

The goal is a comprehensive, well-documented evidence base that underpins your clinical and economic arguments, leaving no major unanswered questions about “what evidence is out there?” 

Pillar 3: Strong health economic model 

Cost‐effectiveness decides whether strong clinical data translate into NHS funding. NICE therefore expects a transparent economic model that mirrors real-world care, uses conservative, evidence-based inputs, and rigorously tests uncertainty. Just a single unsupported assumption can push the incremental cost effectiveness ratio (ICER) above the threshold and sink an otherwise promising therapy. 

Do’s – What works and why  

Calibrate cure or long-term survival states only when clinically justified to keep ICERs credible 

Gilteritinib is an oral FLT3 inhibitor for relapsed or refractory acute myeloid leukaemia. The modelling challenge was projecting long-term post-transplant survival and the company’s initial assumption that all patients alive at three years were “cured” risked overstating benefit. By limiting the cure state to those who actually underwent stem-cell transplant and recalibrating survival curves with UK registry data, the revised model produced ICERs that NICE judged as credible, enabling routine NHS use. ⁸ 

Model real-world dosing and stopping rules so costs mirror NHS practice 

Eculizumab treats atypical haemolytic uraemic syndrome but carries very high drug costs. The modelling challenge was how to reflect real-world dosing and stop-rules for a drug that can exceed £300,000 per patient per year if given indefinitely. By incorporating three-month response reviews and tapered lifelong dosing to reflect how UK clinicians would stop or reduce treatment the ICER’s were nearly halved. This enabled NICE to recommend the therapy; however, funding was conditional on a national protocol for starting and stopping eculizumab for clinical reasons and a research programme with robust methods to evaluate when stopping treatment or dose adjustment might occur. ⁹ 

Combine trial and real-world data to support extrapolation of durable responses 

Tisagenlecleucel is a one-off CAR-T therapy for the treatment of relapsed or refractory B-cell acute lymphoblastic leukaemia in people 25 years and under. The modelling challenge was the very limited follow-up from its single-arm trials, leaving major uncertainty about long-term survival and cure. To bridge this gap, the company used a mixture-cure model calibrated with long-term UK cancer-registry curves and ran extensive sensitivity analyses. These steps persuaded NICE to fund the therapy via the Cancer Drugs Fund with a requirement to collect real-world data. After five years of additional outcomes and model validation, NICE approved tisagenlecleucel for routine commissioning. ¹⁰ 

Pitfalls to avoid: 

• Common pitfalls include coding errors or logical flaws in the model (which EAGs often uncover), using non-transparent “black box” models that make it hard to verify results, and overly optimistic assumptions (e.g. assuming lifetime treatment benefit with no evidence, or zero mortality after cure, if not justified, these will be challenged) 

• Neglecting to include relevant comparator costs or downstream costs (like treating adverse events or subsequent therapies) can make the new treatment look artificially better and will be flagged by reviewers.  

• Not aligning with the reference case, for instance, using a societal perspective or unapproved utility measures without justification will also draw criticism.  

• Failing to account for uncertainty or presenting an ICER only under best-case conditions will not satisfy the committee’s need to understand risks.  

Ultimately, NICE will only trust an economic model that is transparent, evidence-grounded, and rigorously tested. Anything less and the chances of a positive recommendation are significantly lowered.  

Conclusion  

Mastering NICE submissions requires a holistic approach: excelling in each of the three pillars and ensuring they reinforce one another. Strong clinical evidence provides the necessary efficacy narrative, a comprehensive evidence review adds credibility and context, and a robust economic model delivers the value justification. When these elements are well-prepared and aligned, the submission will inherently fit NICE’s decision making framework and increase the chances of a positive decision.  

Remap Consulting has extensive experience guiding pharmaceutical and biotechnology companies through both pre-submission planning and the STA or HST appraisal process itself. With a proven track record of optimising NICE submissions in the UK and navigating complex HTA challenges, we can maximise your asset’s chances of a positive decision. For more information, please contact us. 

References: 

1. National Institute for Health and Care Excellence (NICE). Voretigene neparvovec for treating inherited retinal dystrophies caused by RPE65 gene mutations. Accessed 18 June, 2025. https://www.nice.org.uk/guidance/hst11 
2. National Institute for Health and Care Excellence (NICE). Baricitinib for moderate to severe rheumatoid arthritis. Accessed June 18, https://www.nice.org.uk/guidance/ta466 
3. National Institute for Health and Care Excellence (NICE). Larotrectinib for treating NTRK fusion-positive solid tumours. Accessed June 18, 2025. https://www.nice.org.uk/guidance/ta630 
4. National Institute for Health and Care Excellence (NICE). Onasemnogene abeparvovec for treating spinal muscular atrophy. https://www.nice.org.uk/guidance/hst15 
5. National Institute for Health and Care Excellence (NICE). Nusinersen for treating spinal muscular atrophy. Accessed June 18, 2025. https://www.nice.org.uk/guidance/ta588 
6. National Institute for Health and Care Excellence (NICE). Daratumumab with lenalidomide and dexamethasone for untreated multiple myeloma when a stem cell transplant is unsuitable. Accessed June 18, 2025. https://www.nice.org.uk/guidance/ta917 
7. National Institute for Health and Care Excellence (NICE). Venetoclax with obinutuzumab for untreated chronic lymphocytic leukaemia. https://www.nice.org.uk/guidance/ta663 
8. National Institute for Health and Care Excellence (NICE). Gilteritinib for treating relapsed or refractory acute myeloid leukaemia. https://www.nice.org.uk/guidance/ta642 
9. National Institute for Health and Care Excellence (NICE). Eculizumab for treating atypical haemolytic uraemic syndrome. https://www.nice.org.uk/guidance/hst1 
10. National Institute for Health and Care Excellence (NICE). Tisagenlecleucel for treating relapsed or refractory B-cell acute lymphoblastic leukaemia in people 25 years and under. https://www.nice.org.uk/guidance/ta975