An overview of nuclear medicine research in the UK and the landscape for clinical adoption

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: Nuclear medicine imaging procedures. This table shows the number of nuclear medicine imaging procedures (i.e. gamma-scintigraphy, SPECT and PET-CT scans) performed within NHS England each year for the last 5 years 1 . In addition, the number of PET-CT scans performed by NHS Scotland 2 and NHS Wales (GIG Cymru) 3 in the 2019-2020 financial year are also listed.  ISRCTN  ISRCTN31697115  Kidney function assessment with finger-prick blood tests in different people and different  settings   ISRCTN  ISRCTN32667607  A study using a response-based combination therapy of rituximab and ibrutinib in patients with  post-transplant lymphoproliferative disorder (PTLD)  ISRCTN  ISRCTN34690731  PET CT analysis of restenosis after lower limb revascularisation  ISRCTN  ISRCTN42886452  Recovery and survival of stem cell originated red cells  ISRCTN  ISRCTN45536692  Zoledronic acid in the management of malignant pleural mesothelioma   ISRCTN  ISRCTN47127434 A trial to look for markers in the tumour cells and blood which signal that trial treatments are working in a patient with triple negative breast cancer, for whom upfront chemotherapy has not provided the maximum expected benefit: PHOENIX      In the UK, a manufacturer licence (also known as Manufacturing and Importation Authorisation -MIA) granted by the UK licencing authority is required in order to manufacture products for which MA has been granted.  The obligations of the MIA holder, including compliance with the principles and guidelines of GMP, are defined in the Human Medicines Regulations 2012.  Sites are inspected regularly and issued GMP certificates upon passing the inspection.  A manufacturer licence must name the responsible Qualified Person (QP), Production Manager and Quality Controller 4  Once the MA is granted, products produced at the manufacturing sites listed within are labelled as GMP, with the MA number, and can be marketed by the MAH in the specified countries.  Although a company may hold a UK MA for a radiopharmaceutical product and be marketing it in the UK, they are not obliged to use a UK-based manufacturing site and do not need to be able to deliver the product to the whole country nor meet national demand. Manufacturer "Specials" Licence (MS)

 Article 5(1) of Directive 2001/83/EC Community Code Relating to Medicinal Products for Human
Use 5 allows countries to waive the need for MA to fulfil "special needs".  In the UK, medicines without a MA can be supplied by manufacturers that hold a manufacturer "specials" licence (MS) from the UK licencing authority.  The MHRA inspects the site regularly to ensure that facilities are operating in compliance with GMP regulations and other conditions of the licence.  A MS licence must name the responsible Production Manager and Quality Controller for the site but there is no requirement for a QP.  MHRA inspection of sites holding manufacturer "specials" licence is site-specific, as opposed to product-specific, and the products manufactured cannot be labelled as GMP.  Restrictions that come with products made under a manufacturer "specials" licence include (i) products must be used for clinical "special needs" of an individual patient as determined by the prescriber 6 . (ii) products cannot be marketed or advertised 6 . (iii) products cannot be used instead of those with a MA for reasons of cost, convenience or operational needs unless the product with a MA becomes unavailable (no longer obtainable from normal distribution channels in a reasonable time). Manufacturer Licence for Investigational Medicinal Products -Manufacturing and Importation Authorisation for Investigational Medicinal Products (MIA(IMP))  In the UK, a manufacturer licence for investigational medicinal products (also known as Manufacturing and Importation Authorisation for Investigational Medicinal Products -MIA(IMP)) is required from the UK licencing authority in order to manufacture products for investigation in a clinical trial.  The obligations of the MIA(IMP) holder, including compliance with the principles and guidelines of GMP, are defined in the EU clinical trials directive 2001/20/EC.  Sites must comply with GMP and are inspected regularly by the MHRA.  A manufacturer licence for investigational medicinal products must name the responsible QP, Production Manager and Quality Controller.  It is the QP's responsibility to ensure that each batch has been manufactured and checked in compliance with the product specification file, good manufacturing practice for medicinal products for human use regulations, and the process outlined in the clinical trial application and IMP dossier before it is released for use to the clinical trial sponsor.             7 . Most relevant to the nuclear medicine community are the NICE guidelines that set out the care and services that are suitable for most people with a specific condition or need, and those about how medicines should be managed in different settings. A typical guideline will describe the patient pathway for a particular disease or condition, make recommendations about how patients should be assessed and then managed or treated, and describe how this may change over time. Explanations of how recommendations were derived and summaries of the evidence are provided alongside guidelines. NICE guidelines cover health and care in England. In other UK countries, decisions on how these guidelines are applied are made by ministers in the Welsh Government, Scottish Government and Northern Ireland Executive. In England, clinical commissioning groups (CCGs), NHS England and healthcare providers have a responsibility to enable NICE guidelines to be applied, despite this not being a legal obligation. NICE guidelines include the use of medicines granted MA. In some circumstances, off-label use of medicines granted UK MA may be recommended, but medicines (including radiopharmaceuticals) that have not been granted UK MA will not be considered for inclusion in guidelines 7 .

NICE Guidance
NICE Guidance is produced through a number of evaluation programs that evaluate both clinical-effectiveness and cost-effectiveness of new health technologies. The choice of the most suitable evaluation program depends on the type of technology to be evaluated.

NICE Guidance
New Pharmaceuticals with UK MA New pharmaceuticals or new indications for their use are typically evaluated through the technology appraisal programme or if indicated for an ultra-orphan disease, the highly specialised technologies programme. All medicinal products and indications considered for these programs must already have been granted UK MA or be expected to receive this within 20 months so that the NICE guidance can be published concurrently with that approval. Technologies that will remain without MA cannot be evaluated. NICE aims to consider all significant drugs and indications, and most technologies are identified by the National Institute for Health Research (NIHR) Innovation Observatory 8 . Technology appraisal is specifically designed to appraise a health technology for a single indication and is based on a review of clinical and economic evidence 9 . As of 2019, there is a charge for NICE to conduct technology appraisals or highly specialised technology evaluation. For 2019-2020 this charge ranges from £88,000 to £251,000, depending on the complexity of the appraisal 10 . Although the focus of technology appraisals is typically on new pharmaceuticals or newly licensed indications, there is flexibility for any health technology to be evaluated through this programme. The National Institute for Health and Care Excellence (Constitution and Functions) and the Health and Social Care Information Centre (Functions) Regulations 2013 11 and the NHS constitution 12 state that when NICE recommends that the NHS should fund new technology by publishing technology appraisal guidance or highly specialised technology guidance, the NHS must implement this within three months, unless NICE specifies a longer implementation period.

NICE Guidance New Medical Technologies with CE Marking
Medical technologies with CE marking, or those on course to receive a CE marking within 12 months, are typically evaluated by the NICE medical technologies evaluation programme or the diagnostics assessment programme. This includes medical devices, active medical devices, active implantable medical devices and an in vitro diagnostic medical devices. Currently, no charge is associated with products going through the medical technologies evaluation programme or the diagnostics assessment programme. When medical technologies guidance or diagnostics guidance are published, the NHS does not have an obligation to fund the recommendations made by NICE.

New Companion Diagnostics
Companion diagnostics are diagnostic tests that enable the patients that will respond best to new treatments to be identified. The NICE guide to the methods of technology appraisal states that if the sole purpose of the diagnostic test and it is essential for establishing the suitability of patients, then when a NICE technology appraisal is conducted for the therapy, the companion diagnostic can also be included 13,14 . This means the diagnostic test is incorporated into the assessments of clinical and cost-effectiveness. In addition, the diagnostic accuracy of the test for the particular biomarker of treatment efficacy should be examined. Key considerations which influence if the companion diagnostic is included in the technology assessment are: (i) how the companion diagnostic is described in the MA for the therapy. (ii) how it was used in clinical trials. The NICE guide to the methods of technology appraisal says that if there are multiple diagnostic tests available for a therapy, the NICE diagnostics assessment program 13,14 will be used to determine which should be used in the NHS. However, the NICE diagnostics assessment program has been tailored for medical devices and not medicinal products and so it is unclear if this route would be used for radiotracers.

NICE Advice
NICE advice is distinct from NICE guidance, and there are three key types of NICE advice: Evidence Summaries, Medtech Innovation Briefings and Key Therapeutic Topics. These provide objective summaries of the information available, are purely advisory and do not constitute a guidance recommendation. They are designed to support commissioners or staff considering using new technologies 15,16,17 .

Pharmaceutical (physico-chemical, biological or microbiological) tests
Information on development, manufacture and control of the active substance, precursor and finished product.
As required by the guideline on radiopharmaceuticals the non radioactive "chemical precursor" for the synthesis of PET radiopharmaceuticals was shown to comply with the Note for Guidance     [ 18 F]Fluciclovine-PET-CT detected 1 or more sites of recurrence in 57% of men with BCR. Overall, 59% (126/213) of patients had a change in management; 78% (98/126) of these were 'major' changes. The most frequent major changes were from salvage or non-curative systematic therapy to watchful waiting (25%), from non-curative systematic therapy to salvage therapy (24%) and from salvage therapy to non-curative systemic therapy (9%). At 6 months, 63% of patients had treatment that was concurrent with post-scan plans, a clinically important difference was found for 37% Teoh et al. The value of anti-1-amino-3-18F-fluorocyclobutane-1carboxylic acid PET-CT in the diagnosis of recurrent prostate carcinoma: a meta-analysis Systematic review and metaanalysis of published data about the performance of [ 18 F]Fluciclovine PET-CT in the diagnosis of recurrent prostate cancer. 6 studies were included, involving a total of 251 patients with suspected prostate cancer recurrence.
[ 18 F]Fluciclovine PET-CT had an 87% pooled sensitivity, and a 66% pooled specificity. On a perpatient-based analysis in detecting prostate cancer recurrence, [ 18 F]Fluciclovine PET-CT had an area under the receiver-operating characteristic curve of 0.93.

Proposal phase
The inclusion of a new intervention into policy is proposed by a clinician, deemed qualified to be the Policy Clinical Lead, through a preliminary policy proposal (PPP) which is developed into the final policy through a three-stage process.

Stage 1: Clinical build phase
New or amended clinical commissioning policies are developed. New policies need to be underpinned by an independent clinical evidence review, which is conducted by NICE if the technology has been granted UK MA or application is ongoing. For all other policy propositions, the Clinical Panel will set out the type of independent evidence review required. In particular, the focus is on the patient benefit offered by the drug, device or intervention, and the quality of the evidence for clinical-effectiveness. NHS England's specialised services clinical panel challenges and confirms whether a proposal has a sound evidence base.

Stage 2: Impact analysis phase
The financial and operational impacts of moving from current pathways of care to the proposed pathways are identified in the draft policy proposition and are then subject to stakeholder testing and public consultation.

Stage 3: Decision phase
For cost-neutral or cost-saving propositions, the decision is based on an assessment of clinical benefit. There is a fixed budget for new specialised service commissioning and so all specialised service propositions that require additional funding are ranked based on their relative incremental clinical benefit and incremental cost, and those providing the best value for money will be funded up to the available budget. This ranking and commissioning process is carried out twice a year by the Specialised Services Commissioning Committee and the results are published on the NHS England website.