National Institute For Health And Care Excellence Guidance Research Articles

Venous thromboembolism management and the new NICE guidance: what the busy GP needs to know.

This article summarises the 2020 National Institute for Health and Care Excellence (NICE) venous thromboembolism (VTE) guidelines, which are also covered in Royal College of General Practitioners (RCGP) Essential Knowledge Updates (EKU) e-learning. This article focuses on rapid detection and treatment, changes in recommendations around anticoagulation, and implications for primary care practice.1 Individual signs and symptoms have a low positive predictive value (PPV) for VTE, making the clinical diagnosis difficult. For example, one primary care study found 77.8% of patients with a pulmonary embolism (PE) were breathless at time of assessment and 59.8% had chest pain, but only 29.5% were tachycardic and 28.0% had calf pain.2 The PPV of unilateral leg swelling ≥2 cm is just 27% for deep vein thrombosis (DVT).3 Reassuringly, the absence of any clinical signs suggestive of DVT in low-risk patients has a negative predictive value of 97%.3 To help exclude a PE on clinical grounds, the NICE now recommends using the PERC rule (Pulmonary Embolism Rule-Out Criteria) among selected low-risk patients.4 A patient must score zero to exclude a PE. One external validation study including over 8000 patients found that a PERC score of 0 had a false negative rate of just 1.0% (95% confidence interval [CI] = 0.6% to 1.6%) in low-risk patients.4 It is important to note that the PERC score was developed in emergency departments and is yet to be externally …

Removing hospital-based triage from suspected colorectal cancer pathways: the impact and learning from a primary care-led electronic straight-to-test pathway

BackgroundThe 2-week wait referral pathway for suspected colorectal cancer was introduced in England to improve time from referral from a general practitioner (GP) to diagnosis and treatment. Patients are required...

Fluid and electrolyte therapy in childhood diabetic ketoacidosis management: A rationale for new national guideline.

Fluid and electrolyte therapy in childhood diabetic ketoacidosis (DKA) management has been controversial. Previous National Institute for Health and Care Excellence (NICE) 2015 guidance advocated a restricted fluid regimen while more recent guidelines have advocated a more liberal approach to fluid replacement in DKA. At the core of the debate is the need to avoid developing cerebral oedema as a complication. Although subtle asymptomatic cerebral oedema is common in children presenting in DKA, clinically apparent cerebral oedema is rare and has been reported in approximately 0.5%-1% of DKA cases in children. Recent research evidence has shown that there was no clear evidence of a difference in rates of clinically apparent cerebral injury in children in DKA managed with a range of fluid volumes and rates of rehydration. In view of this, NICE has updated its guideline. In this paper, we review literature evidence underpinning the current understanding of the pathophysiology of cerebral oedema in children and discuss the rationale for the new NICE guidance.

Preoperative patient blood management during the SARS-CoV-2 pandemic.

Preoperative patient blood management during the SARS-CoV-2 pandemic.

2020 NICE guideline update: Good news for pregnant women with type 1 diabetes and past or current gestational diabetes.

In December 2020, the National Institute for Health and Care Excellence (NICE) reviewed the evidence and updated their recommendations on intermittently scanned (commonly known as Flash) and Continuous Glucose Monitoring (CGM) during pregnancy for women with type 1 diabetes (1). The NICE guidelines now recommend offering CGM to all pregnant women with type 1 diabetes to help them meet their pregnancy glucose targets and improve neonatal outcomes. Their evidence review, based on the CONCEPTT randomised trial (2) and a Swedish observational study (3) found that, compared to capillary glucose monitoring, CGM resulted in more women achieving their blood glucose targets, fewer caesarean sections and fewer neonatal intensive care admissions.

Wound healing: what is the NICE guidance from the UK?

Alteration of wound healing increases the risk of a patient's morbidity and mortality. This can lead to scarring, infection, malignant transformation and a reduction in quality of life. Management of wounds costs the UK an estimated £5.3 billion annually which is paid for by the state, with further financial burden due to health related productivity loss. Wound care is managed by a broad spectrum of different health professionals leading to different standards of care. For example, only 16% of lower leg wounds have either an ankle-brachial pressure index measurement or Doppler scan. Due to this variation in wound care, we have summarised all available NICE guidelines and guidance up to February 2021 on the topic of wound healing listed in the National Institute for Health and Care Excellence (NICE) archives. The goal is to provide an easy to access summary of wound care interventions. Our search provided us with 18 technology appraisals related to wound healing which have been summarised.

Integrating research and evidence-based guidance into prescribing practice

The College of Paramedics and the Royal Pharmaceutical Society are clear that they require advanced paramedics, as non-medical prescribers, to review and critically appraise the evidence base underpinning their prescribing practice. Evidence-based clinical guidance such as that published by the National Institute for Health and Care Excellence (NICE) is recommended as the primary source of evidence on which paramedics should base their prescribing decisions. NICE guidance reflects the best available evidence on which to base clinical decision-making. However, paramedics still need to critically appraise the evidence underpinning their prescribing, applying expertise and decision-making skills to inform their clinical reasoning. This is achieved by synthesising information from multiple sources to make appropriate, evidence-based judgments and diagnoses. This first article in the prescribing paramedic pharmacology series considers the importance of evidence-based paramedic prescribing, alongside a range of tools that can be used to develop and apply critical appraisal skills to support prescribing decision-making. These include critical appraisal check lists and research reporting tools

Integrating research and evidence-based guidance into prescribing practice

The College of Paramedics and the Royal Pharmaceutical Society are clear that they require advanced paramedics, as non-medical prescribers, to review and critically appraise the evidence base underpinning their prescribing practice. Evidence-based clinical guidance such as that published by the National Institute for Health and Care Excellence (NICE) is recommended as the primary source of evidence on which paramedics should base their prescribing decisions. NICE guidance reflects the best available evidence on which to base clinical decision-making. However, paramedics still need to critically appraise the evidence underpinning their prescribing, applying expertise and decision-making skills to inform their clinical reasoning. This is achieved by synthesising information from multiple sources to make appropriate, evidence-based judgments and diagnoses. This first article in the prescribing paramedic pharmacology series considers the importance of evidence-based paramedic prescribing, alongside a range of tools that can be used to develop and apply critical appraisal skills to support prescribing decision-making. These include critical appraisal checklists and research reporting tools.

What is ‘chronic primary pain’ and why is NICE guidance on it causing controversy?

The latest guidance from the National Institute for Health and Care Excellence (NICE) marks a step-change in the assessment and management of chronic pain conditions. For the first time, the guideline divides chronic pain into two different pathways: one with an identifiable underlying cause, and one without. The latter has been termed “chronic primary pain”, and includes conditions such as fibromyalgia, […]

PMU50 A Review of Exceptional Circumstances Marketing Authorisations Granted By the European Medicines Agency

Certain conditions are so rare that it is not possible to collect comprehensive efficacy and safety data for new therapies. In these situations, or where it is unethical or unfeasible to collect such information, marketing authorization (MA) under exceptional circumstances (EC) may be a pathway to market approval in Europe. This study reviewed therapeutic medicines authorised under EC, and the subsequent health technology assessment (HTA) decisions made in England by the National Institute for Health and Care Excellence (NICE). Medicines currently licensed under EC were identified from the EMA website. Data on indication, orphan status, clinical trial design, and post-authorisation obligations were extracted from the European Public Assessment Reports. HTA decisions were identified from the NICE website. Twenty-eight therapeutic products granted EC authorisation were identified. Five of these were withdrawn: three for commercial reasons by the marketing authorisation holder, one for being unable to provide the additional efficacy and safety data requested, and one for being unable to reproduce clinical efficacy in a further study. The majority were for treatment of genetic disorders (75%) or cancers (14%), and 82% of therapies were designated orphans at the time of MA. At least one randomized controlled trial was included in 54% (15/28) of authorisations as a pivotal clinical trial; 93% of these were placebo-controlled. NICE has appraised only 14% (4/28) of the therapies authorised through EC, all of which reached positive decisions, and all of which were for paediatric conditions. The exceptional circumstances pathway provides an opportunity for the approval of drugs for which applicants cannot reasonably be expected to generate comprehensive efficacy and safety data, such as for very rare genetic disorders. Those drugs assessed by NICE have been approved for use, and several more have NICE guidance currently under development.

PNS145 Access to Medicines in the United Kingdom: A Review of HTA Decisions for New Medicines

To examine Health Technology Assessment (HTA) decisions for new innovative medicines in the UK (England, Scotland, Wales, Northern Ireland). The study examined HTA decisions made between 2017 and 2020 across UK countries for innovative medicines licensed by European Medicines Agency (EMA) in 2017. The analysis was done using published documents. The decisions were classified as “recommend without restrictions,” “recommend with restrictions,” or “not recommended”. EMA approved licenses for 56 new innovative medicines in 2017. From the date of licensing the medicines in 2017 until January 2020, the National Institute for Health and Care Excellence (NICE) in England had completed the appraisal of 28 out of the 56 medicines. Out of these 28, 12 were “recommended without restrictions” 14 were “recommended with restrictions” and 2 were “not recommended”. Majority of the NICE recommendations (i.e. 21 of 26 or 81%) were done through managed access agreements. The Scottish Medicines Consortium (SMC) has assessed 31 out of the 56 medicines licensed in 2017. Out of these 31, 8 were, “recommended without any restriction”, 22 were “recommended with restriction” and 1 was “not recommended”. AWMSG in Wales follows NICE guidance and does not review a medicine if NICE is considering assessing it in the next 12 months. Northern Ireland follows HTA guidance issued by NICE or SMC and adopts a decision shortly after either has made its decision. In Northern Ireland, 37 recommendations were adopted from either NICE or SMC. These 37 include: 10 without restrictions, 21 with restrictions and 6 not recommended decisions. Adoption of HTA recommendations is low and it varies across UK countries. The number of HTA assessments resulting in “not recommended” decision was found consistently low across all UK countries. However, the number of “recommendation with restriction” is relatively high compared to the “recommendation without restrictions”.

PCN259 How Accelerated Is Patients' Access to New Oncology Products in the New Era of the Cancer Drugs Fund in England, Considering the IMPACT of the 2018 New Technology Appraisal Process

This research provides an update on a poster presented at ISPOR Europe 2018 reviewing the accelerated appraisal timetable proposed in April 2016 by National Health Service England (NHSE) and National Institute for Health and Care Excellence (NICE) to publish final guidance within 90-days of an oncology drug indication receiving its’ marketing authorisation (MA), following reforms to the Cancer Drugs Fund (CDF) in 2016. To reassess the time taken from MA to publication of final NICE guidance for new oncology Technology Appraisals (TA) against the NICE target of 90-days. Of interest is the new appraisal process (post-April 2018) which aims to streamline appraisal and regulatory timelines by introducing a ‘Technical Engagement’ step to remove issues before the Appraisal Committee Meeting (ACM). The NICE website was methodically searched to include all TAs with final guidance published before 20th May 2020 and having an ACM post 1st April 2016. Only newly licensed indications/products with MA granted by EMA before the cut-off date were included. Multiple technology appraisals (MTAs) and transition drugs which were previously in the CDF, have been excluded. Ninety-one TAs were identified across 14 cancer categories; thirteen were appraised under the new process. In total, seven (7.7%) TAs had guidance produced within 90-days of MA; two (15.4%) under post-2018 and five (6.4%) under pre-2018 process. From the 79 TAs recommending new products/indications for routine commissioning or the CDF (46 and 33 respectively), final guidance was published on average 269 days post-MA. Following MA approval, on average, patients will gain access to innovative cancer therapies within 8.4 months to improve their health outcomes. The post-2018 process has a higher proportion (54%) of final recommendations made after one ACM compared to pre-2018 process (17%). Further exploration is required to understand the barriers in meeting the 90-day post-MA target.

Effects of primary care C-reactive protein point-of-care testing on antibiotic prescribing by general practice staff: pragmatic randomised controlled trial, England, 2016 and 2017.

BackgroundC-reactive protein (CRP) testing can be used as a point-of-care test (POCT) to guide antibiotic use for acute cough.AimWe wanted to determine feasibility and effect of introducing CRP POCT in general practices in an area with high antibiotic prescribing for patients with acute cough and to evaluate patients’ views of the test.MethodsWe used a McNulty–Zelen cluster pragmatic randomised controlled trial design in general practices in Northern England. Eight intervention practices accepted CRP testing and eight control practices maintained usual practice. Data collection included process evaluation, patient questionnaires, practice audit and antibiotic prescribing data.ResultsEight practices with over 47,000 patient population undertook 268 CRP tests over 6 months: 78% of patients had a CRP < 20 mg/L, 20% CRP 20–100 mg/L and 2% CRP > 100 mg/L, where 90%, 22% and 100%, respectively, followed National Institute for Health and Care Excellence (NICE) antibiotic prescribing guidance. Patients reported that CRP testing was comfortable (88%), convenient (84%), useful (92%) and explained well (85%). Patients believed CRP POCT aided clinical diagnosis, provided quick results and reduced unnecessary antibiotic use. Intervention practices had an estimated 21% reduction (95% confidence interval: 0.46–1.35) in the odds of prescribing for cough compared with the controls, a non-significant but clinically relevant reduction.ConclusionsIn routine general practice, CRP POCT use was variable. Non-significant reductions in antibiotic prescribing may reflect small sample size due to non-use of tests. While CRP POCT may be useful, primary care staff need clearer CRP guidance and action planning according to NICE guidance.

Lenalidomide with Rituximab for Previously Treated Follicular Lymphoma and Marginal Zone Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of lenalidomide (Revlimid®), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of lenalidomide in combination with rituximab (MabThera®), together referred to as R2, for the treatment of adults with treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG’s critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included one relevant study, for the comparison of R2 versus rituximab monotherapy (R-mono): the AUGMENT trial. In addition, the company performed an unanchored indirect comparison of R2 versus rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and rituximab combined with cyclophosphamide, vincristine, and prednisolone (R-CVP), using data for R2 from the AUGMENT trial and pooled data for R-CHOP/R-CVP from the Haematological Malignancy Research Network (HMRN) database. During the STA process, the company provided an addendum containing evidence on only the FL population, in line with the marketing authorisation obtained at that time, which did not include MZL. The probabilistic incremental cost-effectiveness ratios (ICERs) presented by the company were £27,768 per quality-adjusted life year (QALY) gained for R2 versus R-CHOP, £41,602 per QALY gained for R2 versus R-CVP, and £23,412 per QALY gained for R2 versus R-mono. The ERG’s concerns included the validity of the unanchored comparison, the unavailability of a state transition model to verify the outcomes of the partitioned survival model, substantial uncertainty in survival curves, and potential over-estimation of utility values. The revised ERG base case resulted in ICERs ranging from £16,874 to £44,888 per QALY gained for R2 versus R-CHOP, from £23,135 to £59,810 per QALY gained for R2 versus R-CVP, and from £18,779 to £27,156 per QALY gained for R2 versus R-mono. Substantial uncertainty remained around these ranges. NICE recommended R2 within its marketing authorisation, as an option for previously treated FL (grade 1–3A) in adults, contingent on the company providing lenalidomide according to the commercial arrangement.

The ethics of grandfather clauses in healthcare resource allocation

A grandfather clause is a provision whereby an old rule continues to apply to some existing situation while a new rule applies to all future cases. This paper focuses on the use of grandfather clauses in health technology appraisals (HTAs) issued by the National Institute for Health and Care Excellence (NICE) in the United Kingdom. NICE provides evidence-based guidance on healthcare technologies and public health interventions that influence resource allocation decisions in the National Health Service (NHS) and the broader public sector in England and Wales. In this context, a grandfather clause is included when NICE does not recommend treatment with a given technology. The grandfather clause provides an exemption from the general recommendation for patients who have already started treatment with the technology in question, before the publication of the NICE guidance. In this paper we first lay out the contexts in which grandfather clauses occur in NICE guidance, and then consider ethical arguments against and in support of grandfather clauses and the continuation of treatment. We argue that NICE's current practice of automatic inclusion of a grandfather clause is ethically problematic and unfair. While the inclusion of a grandfather clause may be appropriate and justified in specific cases, we argue that inclusion of such a clause should be considered as part and parcel of the decision making process on a case by case basis, rather than adopted as the default.

Voretigene Neparvovec for Treating Inherited Retinal Dystrophies Caused by RPE65 Gene Mutations: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Appraisal

The UK National Institute for Health and Care Excellence (NICE) considered evidence for voretigene neparvovec (VN; Luxturna®) for the treatment of RPE65-mediated inherited retinal dystrophies (IRD) within its highly specialised technology programme. This paper summarises the evidence provided by the company; the appraisal of the evidence by the Peninsula Technology Appraisal Group, who were commissioned to act as the independent evidence review group (ERG); and the development of the NICE guidance by the appraisal committee. The evidence presented by the company highlighted the significant lifelong burden of IRD for patients and carers. Evidence to support the effectiveness of VN was lacking, but the available evidence showed a modest, sustained improvement across a variety of vision-related outcomes. While patients would remain visually impaired, the committee considered that VN would prevent further deterioration in vision. The modelling approach used by the company had a number of limitations and relied heavily upon a large volume of clinical expert input to produce cost-effectiveness estimates with large uncertainty around long-term effectiveness. The ERG's main concerns revolved around these long-term outcomes and the plausibility of utility values. The NICE committee were convinced that the clinical benefits of VN were important and an appropriate use of national health service resources within a specialised service. The committee concluded that a high unmet need existed in patients with RPE65-mediated IRD and that VN represents a step change in the management of this condition.

P13 Optimising paediatric intravenous fluid management plans: a quality improvement project

IntroductionIntravenous (IV) maintenance fluids are often prescribed post-surgery when enteral routes are contraindicated. Serious consequences have been documented when poor fluid management has occurred, as highlighted in the National Patient Safety Alert (NPSA) 22; reducing the risk of hyponatraemia; when administering IV fluids to children.1 In response to this, the National Institute for Health and Care Excellence (NICE) published their guidance in December 2015 regarding IV fluids in children.2 Based on NICE recommendations, a pan hospital fluid guidance was produced. Within the NICE and hospital’s own guideline it states that there should be a daily fluid management plan documented. It has been well recognised that this daily fluid management plan was not routinely been completed; hence showing non-adherence to our hospital policy and NICE recommendations.AimsPrimary aim was to improve the documentation of the daily fluid management plan; aimed at the medical staff and the secondary aim was to improve the monitoring requirements of IV fluids and documentation of these; largely aimed at the nursing staff.MethodsA simple sticker was designed and attached to continuous sheets for medical notes which had a checklist of monitoring requirements and a section for fluid balance. Additionally, 2 posters were produced; one aimed at medical staff for documenting a fluid management plan and one aimed at the nursing staff with the monitoring requirements. These posters were displayed on the paediatric surgical ward.ResultsA total of 22 patients who were prescribed IV fluids were identified for a baseline measurement, an equal number of patients were compared after the intervention. Neonates and children receiving total parenteral nutrition were excluded from the data collection. There were 41% of daily fluid management plans completed pre intervention and post intervention there were 56% completed; showing a 15% increase in completion. As regards the monitoring indications; there were increases for nursing fluid balance completed from 19% to 46%, blood glucose taken and recorded from 64% to 83% and the daily weight documented from 10% to 49%.ConclusionsThis short QI project shows that implementation of an intervention did improve outcomes across all indications investigated. The results are not as dramatic as first hoped, but this is largely due to the short time scale of 4 weeks to introduce our change and it coincided with the change-over month of junior medical staff. With further education and champions within the medical and nursing teams; further improvement is very much possible, with the main aim in reducing risk and improving patient safety.ReferencesNational Patient Safety Alert: Reducing the risk of hyponatraemia when administering intravenous infusions to neonates 2007. Available at https://www.sps.nhs.uk/articles/npsa-alert-reducing-the-risk-of-hyponatraemia-when-administering-intraveneous-infusions-to-neonates/ [Accessed 12th June 2019]NICE guidance: Intravenous fluid therapy in children and young people in hospital. Available at https://www.nice.org.uk/guidance/ng29 [Accessed 12th June 2019]

NICE public health guidance update.

This article highlights recent guidance from the National Institute for Health and Care Excellence (NICE). It highlights the organization’s response to the COVID-19 pandemic and then provides a spotlight on workplace health in the context of long-term sickness absence and capability to work. It discusses some of the actions that need to be taken by a range of stakeholders in order to implement NICE guidance in this area and aid employees in ensuring good workplace health. The NICE guidance on workplace health, discussed in this article, predates the current pandemic. Comment is made specifically on fitness for work assessments, where the COVID-19 pandemic has posed a range of unique clinical challenges.

The landscape of psoriasis provision in the UK.

Psoriasis remains one of the commonest conditions seen in dermatological practice, and its treatment is one of the greatest cost burdens for the UK National Health Service. Treatment of psoriasis is complex, with numerous overlapping lines and therapies used in combination. This complexity reflects the underlying pathophysiology of the disease as well as the heterogeneous population that it affects. National Institute for Health and Care Excellence (NICE) guidance for the treatment of psoriasis has been available since 2013, and has been the subject of three national audits conducted by the British Association of Dermatologists. This report synthesizes the results of the most recent of those exercises and places it in the context of the NICE guidance and previous audits. It clearly shows the significant burden of disease, issues with provision of services and long waiting times and the marked shift in therapies towards targeted biologic therapies.

Cannabidiol for Adjuvant Treatment of Seizures Associated with Lennox-Gastaut Syndrome and Dravet Syndrome: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

GW Research Ltd. provided two separate, but similar, submissions to the National Institute for Health and Care Excellence (NICE) on the clinical and cost-effectiveness of cannabidiol (CBD) 10mg/kg/day, trade name Epidyolex®, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). This paper highlights important methodological issues related to the company submissions, the Evidence Review Group (ERG) reports, and the subsequent development of the NICE guidance by the Appraisal Committee (AC) for the use of CBD. The company identified four randomised controlled trials (RCTs) of CBD (GWPCARE1 and GWPCARE2 for DS, and GWPCARE3 and GWPCARE4 for LGS) and an ongoing open-label extension study (GWPCARE5) as relevant to both submissions. In these RCTs, CBD in addition to current clinical management (CCM) was compared to CCM without CBD (i.e. CCM plus placebo). GWPCARE2 and GWPCARE3 were three-arm studies and compared two dosages of CBD (10mg/kg/day and 20mg/kg/day) in addition to CCM and CCM plus placebo. GWPCARE1 and GWPCARE4 compared CBD (20mg/kg/day) in addition to CCM and CCM plus placebo. Both DS patients in GWPCARE2 and LGS patients in GWPCARE3 who received 10mg/kg/day CBD in addition to CCM achieved better seizure frequency outcomes than those who received CCM plus placebo. In the company's base case, use of CBD for LGS patients resulted in an incremental cost-effectiveness ratio (ICER) of £31,107 per quality-adjusted life year (QALY) gained and, for DS patients, £36,046 per QALY gained versus CCM. The ERG considered that these ICERs were extremely uncertain and suffered from validity issues concerning model structure (e.g. patients receiving CCM moved back to baseline drop seizure frequency), input (e.g. inclusion of caregivers' QALYs), and transparency issues (e.g. hidden worksheets and coding in Visual Basic for Applications), and hence incorporated adjustments to the original base case which increased the ICERs. During the process, the European Medicines Agency (EMA) licence granted marketing authorisation for CBD only in conjunction with clobazam. Hence, the company provided evidence from this subgroup in an additional submission, which resulted in an ICER of £33,721 per QALY gained for LGS and an ICER of £32,471 per QALY gained for DS. In this submission and clarifications, the ERG was able to verify and validate most of the company's responses to the ERG's concerns. However, some issues remained regarding the face validity of model assumptions on patient pathways after treatment discontinuation. Finally, the AC recommended CBD with clobazam as an option for treating seizures associated with LGS and DS in patients aged 2years and older only if (1) the frequency of drop seizures is checked every 6months and CBD is stopped if the frequency has not fallen by at least 30% compared with 6months before starting treatment and (2) the company provides CBD according to the commercial arrangement.