SUU, Alm.del - 2012-13 - Endeligt svar på spørgsmål 320: Spm. om, hvorfor Sundhedsstyrelsens rapport og anbefaling vedr. partikelcenter ikke blev sendt i høring før beslutningen om et partikelcenter, til ministeren for sundhed og forebyggelse

ContentsSummary in English ....................................................................................... 2Summary in Danish ........................................................................................ 4Context ........................................................................................................... 6Request for proposals ............................................................................. 8Convening an international panel of experts .......................................... 8Tasks of the panel and of the DHMA..................................................... 9The deliberations of the panel .............................................................. 10Legal context ........................................................................................ 11The two proposals ........................................................................................ 11The Copenhagen bid............................................................................. 12The Aarhus bid ..................................................................................... 15The panel’s assessment of the two proposals ............................................... 18Estimates of the target population ........................................................ 18Equipment and facilities ....................................................................... 19Safety issues ......................................................................................... 20Delivering clinical services .................................................................. 20Research strategies ............................................................................... 21Leadership, governance and national collaboration ............................. 22Recommendations ........................................................................................ 23Appendix A – Terms of reference ................................................................ 24Appendix B – Criteria .................................................................................. 27Appendix C – Abbreviations ........................................................................ 29

Summary in EnglishProton radiotherapy uses charged particles to deliver precision high-energybeams of particles to destroy cancer cells, and seems particularly suitable forchildhood cancers, as there is a potential to reduce side-effects such as sec-ondary cancers. The increase in potential demand as well as the rising costsof treating patients abroad and the requirements to treat malignant disease ina timely fashion, underscores the need to establish a national center for parti-cle radiotherapy in Denmark.At the request of the Danish Ministry of Health, a technical assessment onthe establishment of one, single national Danish center has been carried outby the Danish Health and Medicines Authority aided by an internationalpanel of experts in the field.Joint bids were received from two consortia: One proposal is to place thecenter adjacent to the Royal Hospital (Rigshospitalet) in Copenhagen; thisproposal was submitted by the hospital, the University of Copenhagen andthe Capital Region. The other proposal is for a national center for particleradiotherapy integrated into the new university hospital being constructed inSkejby outside of Aarhus; this application was submitted by the hospital, theUniversity of Aarhus and the Region of Central Denmark.The Copenhagen group proposes a compact proton therapy facility solution.It is argued that proton delivery technologies have advanced considerably,and compact solutions have matured. A single room compact proton facilitywould be placed in a new small building as an extension to the existing De-partment of Radiotherapy at Rigshospitalet, with the aim of being able totreat 450 patients annually from the first year, ramping up to 900 patientsannually.The proposal for a national center for particle radiotherapy in Aarhus envis-ages using commercially available technical solutions to match the overallvision and strategy for the national center to be built on a building plot nextto the Department of Oncology at the new Aarhus University Hospital. Thefacility would be equipped with a proton accelerator and two treatment gan-tries, with a view to treating 1,500 patients annually after a ramping-upphase.Given the strong scientific traditions, multi-disciplinary collaborations andsolid data registries in the country, the panel finds that Denmark has a spe-cial obligation to ensure that the center becomes a truly national center en-suring a strong collaboration with referring departments. While the clinicalneed for proton radiotherapy is bound to increase in the near future, the pan-el did however advise not to rush the establishment of the Danish nationalcenter of proton radiotherapy, as efforts to do so in other countries havebackfired.Based on currently available evidence, the panel estimates that proton radio-therapy may be relevant in roughly 10-15% of all radiotherapy indications.

With roughly 12,000 new radiotherapy cases per year this corresponds to apotential annual case load of 1,200-1,800, of which proton radiotherapywould be indicated on a routine basis for a case load of around 200.The panel found that the choice of equipment should be driven in the firstplace by strategic considerations. The panel underscored the need to estab-lish a single, truly national center for particle radiotherapy, and that such acenter should be flexible and expandable. The panel found that the Aarhusgroup presented the best implementation plan to allow for adjustments asexperience grows, with annual capacity for new patients in the first two gan-tries reduced at 333 for 2017, and 666 for 2018, to allow for clinical imple-mentation.The panel found that a national particle radiotherapy center would need tofocus on clinical research in areas with a potential benefit, and found that theAarhus bid best addressed these issues, as they worked from an algorithm tolist sites which would be treated with protons and presented a realistic strat-egy of selecting candidate sites for protocols strongly based in their researchtradition and their existing participation and leadership of several Danishmulti-disciplinary cancer groups.The panel found the Aarhus group presented a convincing proposition tolead a national center of particle radiotherapy, with a designated future lead-er of a multi-disciplinary group, and having demonstrated their leadershipthrough national and international collaborations. The panel also found theAarhus group proposed a proper governance structure to ensure collabora-tion and ownership amongst all referring and contributing departments.After reviewing the proposals to host a Danish national center of particle ra-diotherapy, and considering the best available evidence in the field, the panelrecommends:- That a single, national center of particle radiotherapy be establishedat Aarhus University Hospital- Not to start, or give the appearance of starting, an equipment selec-tion process too early and to ensure collaboration between the hostinstitution, relevant authorities and expert advisors in establishingthe top-level specifications for the equipment- To project realistic capacities for the center, taking into accountramping up of staff and facility, and based on expected treatmentprotocols and number of fractions to be delivered per year- That a strategic business case be developed to prepare for a properbudgeting model and subsequent tender for constructing and procur-ing equipment for the national center- That governance structures be established to ensure a continuedstrong national clinical and scientific collaboration in the field ofparticle radiotherapy

Summary in DanishVed protonterapi anvendes ladede partikler til at lave høj-energi præcisions-stråling der kan nedbryde kræftceller. Partikelterapi er særligt egnet til be-handling af kræftsygdomme i barnealderen, da behandlingen kan reducerebivirkninger som f.eks. sekundære kræftsvulster. Behovet for etablering af etnationalt center for partikel stråleterapi i Danmark understreges af den øgedeefterspørgsel og de stigende udgifter ved behandling af patienter i udlandet,kombineret med patientrettigheder for hurtig og rettidig behandling.På begæring af Ministeriet for Sundhed og Forebyggelse er der foretaget enfaglig vurdering af placeringen af ét nationalt center i Danmark, i regi afSundhedsstyrelsen og med rådgivning fra et internationalt panel af eksperterpå området. To ansøgninger blev vurderet: I den ene ansøgning, som er ind-sendt af Rigshospitalet, Københavns Universitet og Region Hovedstaden,foreslås centeret placeret ved Rigshospitalet. I den anden ansøgning, som erindsendt at Aarhus Universitetshospital, Aarhus Universitet og RegionMidtjylland, foreslås centeret placeret i tilslutning til det nye universitets-hospitalsbyggeri ved Skejby.I ansøgningen fra Rigshospitalet foreslås et kompakt protonterapianlæg. Derargumenteres for at protonteknologien har undergået en betydelig udvikling,og at tiden er moden til en kompakt løsning. En kompakt protonterapiløsningmed ét rum ville blive placeret i en ny, lille bygning, der kan placeres som enudvidelse af den nuværende Radioterapiklinik på Rigshospitalet, med enmålsætning om at kunne behandle 450 patienter årligt fra første år, og senereudvidelse til 900 årligt.Forslaget om at etablere et nationalt center for partikelterapi i Aarhus omfat-ter anvendelsen af relevante kommercielt tilgængelige teknologier der kanmatche den overordnede vision og strategi for centreret, der foreslås opførtpå en ledig byggegrund ved den onkologiske afdeling ved det nye AarhusUniversitetshospital. Partikelcenteret vil blive udstyret med en protonaccele-rator og initialt to behandlingsrum, med den målsætning at behandle 1.500patienter årligt efter en indkøringsfase.I betragtning af de stærke videnskabelige traditioner, det veletablerede multi-disciplinære samarbejde og de robuste dataregistre i landet, finder panelet atDanmark har en særlig forpligtelse til at sikre at centeret bliver et ægte nati-onalt center der sikrer et stærkt samarbejde med henvisende afdelinger.Selvom det kliniske behov for protonterapi vil stige i den nærmeste fremtider det dog samtidig panelets anbefaling at man ikke skal forcere etableringenaf det danske nationale center, da tilsvarende hastværk i andre lande har gi-vet bagslag.Baseret på tilgængelig viden har panelet vurderet at protonterapi kan værerelevant i ca. 10-15 % af alle tilfælde hvor stråleterapi er indiceret. Med år-ligt ca. 12.000 nye strålepatienter i Danmark svarer dette til et potentielt år-

ligt patientvolumen på 1.200-1.500, hvoraf protonterapi vil være rutinemæs-sigt indiceret hos ca. 200.Panelet fandt at valget af udstyr bør bestemmes primært ud fra strategiskeovervejelser. Panelet understregede vigtigheden af at etablere ét enkelt, ægtenationalt center for protonbehandling, og at et sådant center bør være fleksi-belt med mulighed for udbygning. Panelet fandt at forslaget fra Aarhus inde-holdt den bedste plan for implementering, med plads til justeringer i taktmed øget erfaring, og med målsætning om et årligt patientvolumen i de før-ste to behandlingsrum reduceret til 333 i 2017 og 666 i 2018 for at muliggø-re implementering i den daglige klinik.Panelet fandt at et nationalt center for partikelterapi bør fokusere på kliniskforskning indenfor områder med potentiel gavn, og fandt at forslaget fraAarhus bedst imødekom disse hensyn, ved at arbejde ud fra en algoritme vedvalg af potentielle kræftformer til behandling med protoner, og ved at præ-sentere en realistisk strategi for udvælgelse af protokollerede behandlingerbaseret på eksisterende samarbejde og lederskab indenfor en række danskemulti-disciplinære cancergrupper.Panelet fandt at de aarhusianske ansøgere præsenterede et overbevisendekandidatur til at lede det nationale center for partikelterapi, med en udpegetfremtidig leder forankret i et multi-disciplinært team, og med dokumenteretlederskab i nationale og internationale sammenslutninger. Panelet fandt ogsåat ansøgningen fra Aarhus har foreslået en passende ramme for national sty-ring af centeret, der sikrer samarbejde og ejerskab blandt alle henvisende ogbidragende afdelinger.Efter gennemgang af de to forslag til placering af et nationalt center for par-tikelterapi i Danmark, og under hensyntagen til den bedste tilgængelige vi-den på området, er det panelets anbefalinger:- At der etableres et nationalt center for partikelterapi ved AarhusUniversitetshospital- Ikke at påbegynde, eller give indtryk af at ville påbegynde, en procesmed valg af udstyr for tidligt, og at sikre et samarbejde mellemværtsinstitution, relevante myndigheder og ekspertrådgivning vedkravspecifikation til udstyret- At projektere realistiske kapaciteter for centeret, under hensyntagentil indkøring af personale og faciliteter, og baseret på forventningerom behandlingsprotokoller og antal fraktioner der skal leveres per år- At en strategisk business case udvikles som forberedelse til enegentlig budgetmodel og efterfølgende udbud af anlægsopgaver ogindkøb af udstyr til det nationale center- At styringsrammerne for centeret fastlægges for at sikre et fortsatstærkt national klinisk og videnskabeligt samarbejde indenfor pro-tonbehandling

ContextProton radiotherapy (PRT) uses charged particles to provide radiotherapy,thus delivering precision high-energy beams of particles to destroy cancercells. PRT seems particularly suitable for childhood cancers, as there is a po-tential to reduce side-effects such as secondary cancers induced by radio-therapy when compared to conventional radiotherapy. In addition, the higherprecision of PRT compared to conventional radiotherapy has proven value inthe treatment of cancers growing in close proximity to sensitive healthy tis-sues such as brain, cranial nerves and spinal cord, which could otherwise notbe treated with sufficiently high doses to achieve cure.Current radiotherapy (RT) options have improved with the technologicalachievements of linear accelerators, and the integration with imaging tech-nologies such as computer tomography (CT), magnetic resonance imaging(MRI) and combined positron emission and computer tomography(PET/CT). Image-guided radiotherapy (IGRT) has considerably reduced theuncertainties related to movement of the target between treatments, and istoday considered the gold standard in RT. Intensity-modulated radiotherapy(IMRT) delivers dose distributions conformed to the target, and combinedwith IGRT have enabled treatment of tumor targets with relatively smallmargins, thus escalating doses and minimizing morbidity.With PRT, a modality with improved depth-dose characteristics has been in-troduced. Protons differ fundamentally from photons delivered by conven-tional linear accelerators, in delivering low energy deposition of radiationwhile traversing healthy issue until reaching the target depth where the max-imum energy (the Bragg peak) is deposited, with no appreciable tail. Thedepth is controlled by varying the energy of the charged protons, thus ena-bling a spread-out target area in all dimensions.Protons are potentially advantageous to photons in ensuring that nearbynormal tissues receive significantly less radiation, and thereby reducing ad-verse effects as well as delivering increased cure rate with higher radiationdoses in certain cancers. PRT is estimated to reduce the dose to normal tis-sue by a factor of two. The strongest case for PRT is for the use in childrenwith brain tumors, where the risk of secondary cancers caused by RT is ofspecial concern, due to their long life expectancy following treatment inchildhood and to their increased susceptibility to RT. From theoretical mod-els it has been estimated that the life-time risk of secondary cancers afterchildhood RT for medulloblastoma may be reduced from 30% to 4% byPRT1. Further benefits from reduced radiation morbidity with PRT may in-clude lower rates of deafness and of reduced IQ.There is a dearth of good evidence to support the clinical benefit of PRT inmost cancer types, and further evidence from basic, translational and clinical1

research is highly desired, as are health technology assessments includingeconomic analyses. A Danish national center for PRT is expected to recruit alarge proportion of patients into research protocols, thus also contributinghigh-quality science in the field.PRT facilities use accelerators called cyclotrons, synchro-cyclotrons or syn-chrotrons to deliver proton beams for therapy, with most operational facili-ties using either cyclotrons or synchro-cyclotrons. Development and market-ing of PRT accelerators is a dynamic and highly competitive field, with newaccelerator concepts being explored, and several vendors active in the field.Traditional multi-room PRT facilities rely on a centralized accelerator withbeam delivery to a number of treatment rooms equipped with gantries withrotational capabilities to increase flexibility in treatment planning. Newer,compact PRT systems integrate accelerator and treatment delivery systems(gantry and beam nozzle) in a single-room solution.PRT facilities are unique in their size, complexity and cost of the technolo-gy. There are currently around forty operational PRT facilities around theworld, with most of these in the USA and in Europe2. Additionally, morethan twenty are in the planning stages and will become operational withinthe next five years. Both the Department of Health in England and the Min-istry of Health, Welfare and Sports in the Netherlands have recently com-pleted review processes to select suitable centers to host PRT facilities. InScandinavia, PRT has been available for selected cases such as eye melano-ma at the Svedberg Laboratory at the University of Uppsala, Sweden. InJune 2011 construction was started of a dedicated PRT facility at the Akad-emiska Sjukhuset in Uppsala, expected to treat its first patient by 2015.Capacities in the international PRT facilities are limited, and there are highcosts involved in treating patients overseas, both in direct payments as wellas by the burden imposed on children and their families having to spend ex-tended periods of time abroad. Access to the European centers can be diffi-cult, and costs for overseas treatment in the commercially run centers in theUSA can easily exceed 1 million DKK. The increase in potential demand forPRT in the Danish population, as well as the rising costs and the require-ments to treat malignant disease in a timely fashion, underscores the need toestablish a national center for PRT in Denmark.Currently, Danish patients can be referred, and fully reimbursed, for PRTabroad, subsequent to approval by the Danish Health and Medicines Au-thority (DHMA). In 2011, fifteen patients, mostly children, were treatedabroad, and during the first nine months of 2012 twenty-two patients havebeen referred. As evidence and experience grows on the potential benefitsfrom PRT compared to conventional radiotherapy, the need for PRT in theDanish population is expected to increase.

Request for proposalsIn July 2011, the Danish Ministry of Health issued a request for proposals(RFP) to host a national center for particle radiotherapy. The RFP was issuedto two potential centers, who submitted their bids by end September 2011. InMarch 2012, the Ministry requested the DHMA to initiate a technical as-sessment on the establishment of one, single national Danish center.Joint bids were received from two consortia: One proposal is to place thecenter adjacent to the Royal Hospital (Rigshospitalet) in Copenhagen; thisapplication was submitted by the hospital, the University of Copenhagen andthe Capital Region3. This will be referred to as the “Copenhagen bid”The other application is for a national center for particle radiotherapy inte-grated into the new university hospital being constructed in Skejby outsideof Aarhus; this application was submitted by the hospital, the University ofAarhus and the Region of Central Denmark4. This will be referred to as the“Aarhus bid”.In June 2012 a meeting was convened by the DHMA, with representativesfrom the two consortia, as well as the DHMA and the Danish Ministry ofHealth. The context and framework of the technical assessment was dis-cussed, and the two consortia were invited to update and resubmit their ap-plications, taking into account the time passed since the original request forproposals, technological and commercial developments in the field, changesin the consortias’ staffing and research strategies, as well as radiation protec-tion issues. A deadline of 3 September 2012 was agreed for the updated bidmaterial.Convening an international panel of expertsTo ensure the highest level of expertise, as well as balanced and impartialadvice, it was decided to solicit the services of an international panel in theassessment of the two applications. With their bids both applicants submittednominations for this international panel. Terms of reference for this advisorypanel were developed (appendix A, see page 24) to describe the process ofthe technical assessment as well as the context and tasks of the internationalpanel. The draft terms of reference and nominations for the panel was dis-cussed at the June 2012 meeting and in subsequent bilateral consultationswith the two consortia.Early August 2012 the candidates had accepted and the panel was appointedby the DHMA, taking into consideration the nominations from the two ap-plicants in a balanced approach.The members of the international advisory panel were:3

Professor Michael Baumann, Dr.med.,Klinikdirektor, Klinik und Poliklinik für Strahlentherapie und Ra-dioonkologie, Universitätsklinikum Carl Gustav Carus, DresdenDr. Adrian Crellin,Consultant Clinical Oncologist, St James's University Hospital,Leeds, Chair of the NHS NSCT Proton Clinical Reference Panel andDH National Clinical Lead Proton Beam TherapyProfessor Jürgen Debus, Dr.med., Dr.rer.nat.,Ärztlicher Direktor, Abteilung RadioOnkologie und Strahlenthera-pie, Nationales Centrum für Tumorerkrankungen, Universitätsklini-kum, HeidelbergProfessor emeritus Michael Goitein, PhD,Harvard Medical School, Boston, MassachusettsProfessor Eric Klein, PhD,Chief of Physics, Department of Radiation Oncology, WashingtonUniversity School of Medicine, St. Louis, Missouri

Memoranda of understanding were issued by the DHMA to the panel mem-bers, who in turn submitted statements on potential conflicts of interest aswell as confidentiality statements, all of which are kept on file at the DHMA.Travel costs, lodging etc. for the panel members were covered by theDHMA, who also paid honoraria to the panel members for their services.Neither of the two bidding consortia nor any other outside parties, vendorsetc. were involved in servicing the panel’s work.Tasks of the panel and of the DHMAThe panel was asked to assist and advise the Danish Health and MedicinesAuthority on the following issues:-to describe the role of a Danish national center for PRT, in the con-text of the present services offered Danish patients, and consideringother international and regional developments in the delivery of PRTto outline a potential time frame for the establishment of a Danishnational center for PRT, considering the expected technical andcommercial developments in the field, as well as projections for thetarget population in needto balance and expand the criteria to be applied in assessing the twoapplicantsto assess the two applicants according to the weighed criteriato provide, orally and in writing, contributions to the final report onthe technical assessment

The deliberations of the panelThe updated bid documents, along with a brief guideline with suggestionsfor criteria to use in reviewing the bids, were sent to each of the panel mem-bers in early September 2012. The materials received by the five panelmembers were as listed in footnote 1-2 (see page 8) and appendices A-B (seepages 24 and 27).On 9 October 2012 an all-day face-to face meeting of the panel was held inCopenhagen. Each consortium was invited to send representatives to meetthe panel, and, at the request of the panel, it was suggested that they wouldrepresent the professional and clinical responsibilities of running the project-ed center. Each consortium met separately with the panel in equal time slots.The Copenhagen bid was represented by:----Professor Svend Aage Engelholm,Department of RadiotherapyProfessor Liselotte Højgaard,Department of Clinical Physiology, Nuclear Medicine and PETProfessor Søren Bentzen,Department of RadiotherapyDr. Jannik Hilsted,Chief Medical Officer, Rigshospitalet

Legal contextThe DHMA is empowered by the Health Act of 20085to plan publicly fund-ed specialized health services, including the detailed description of criteriaand requirements, assessment of applications, and issuing (and revoking)permit to offer such specialized services. A consultative committee, chairedby the Managing Director of the DHMA, is heard in the process. As PRTeasily fulfills the criteria for being a highly specialized service, these regula-tory requirements apply, and the DHMA is empowered to decide the place-ment of a Danish national center for PRT.The criteria currently used in assessing applications in this framework in-clude, but are not limited to, the capacity and stability of a center’s clinicalservices, its patient volume, clinical experience, and professional expertise,as well as its competency in all relevant professional and supportive fields.Further criteria are access to all required technical facilities, documentedclinical quality and prospective reporting of results to relevant national data-bases, the employment of a multi-disciplinary approach as well as safeguardsto ensure continuity of patient care. A center’s active and documented re-search, development and education, its procedures for assessing new tech-nologies and treatments and its collaboration with other hospitals and rele-vant specialized departments are also taken into account when assessing ap-plications.Additionally, the DHMA is the national radiation protection authority, regu-lating the use etc. of ionizing radiation. Based on international recommenda-tions6and national legislation7the criteria currently used in assessing appli-cations in the framework of radiation protection include, but are not limitedto, the assessment of safety for the facility and activities, optimization ofprotection against radiation risks to patients, staff, members of the public andthe environment to provide the highest level of safety that can reasonably beachieved as well as an assessment of a potential production of radioactivewaste and radioactive releases over the lifetime of the facility.These criteria also formed the basis for the panels assessment of the two ap-plications to host a Danish national center for PRT (see page 18), and to aidthe panel members in their review, a brief guideline on the applications ofthese criteria was provided by the DHMA (appendix B, see page 27).

The Copenhagen bidThe Copenhagen consortium proposes to place a proton therapy center adja-cent to the Royal Hospital (Rigshospitalet) in Copenhagen8. The original biddocument was developed in the spring of 2011, and submitted by Septemberof 2011. Subsequently, the bid material was updated with a volume IV, sub-mitted in August 20129.The Copenhagen bid envisages a proton radiation therapy center at Rigshos-pitalet interlinked with basic, translational and clinical research. The centershould treat all Danish children with cancer, where radiation therapy is rele-vant (approximating 50 children annually). The proton therapy center shouldalso treat adult cancer patients with cancer diseases, where proton therapy isrecognized as the best treatment internationally, i.e. patients with melanomain the eye, sarcomas in the skull base, cranio-pharyngeomas, selected glio-mas, large arteriovenous malformations, meningeomas, pituitary tumor re-lapse, acusticus neurinomas, paranasal sinus carcinomas, nasopharyngealcarcinomas, paraspinal tumors, approximating a total of 300 patients annual-ly.For many other cancer types such as malignant melanoma, head and neckcancer, lung cancer, breast cancer, prostate cancer and cervical cancer thebid states that the role of proton therapy is not finally established, but protontherapy seems to be better than conventional treatment. The consortiumtherefore proposes a comprehensive prospective clinical trial program togather evidence needed to establish the future role of proton therapy for anumber of cancer diseases.The overall aims of the Proton Therapy Center at Rigshospitalet are statedas:1. To offer cancer patients the best possible radiation therapy, includ-ing proton therapy when proven or judged advantageous, striving forcure at the lowest possible cost in terms of side effects.2. To develop a comprehensive medical physics research program onhigh-precision planning and delivery of proton therapy includingmotion management strategies, quantitation and visualization of un-certainties, adaptive strategies and use of bioeffect modeling for planoptimization and assessment of therapeutic ratio.3. To pursue basic, translational and clinical research on the technical,biological and informatics basis for personalized proton therapy.This includes research into genetic and epigenetic biomarkers fortumor and normal tissue response to radiation.4. To conduct research in molecular imaging, diagnostic imaging andimage processing as a prerequisite for fully exploiting the capabili-8

ties for spatial dose modulation with IMPT. This includes dosepainting by numbers and theragnostic imaging, where specific areasof the tumor are treated to different dose levels.5. To design, conduct and analyze the outcome of clinical trials withthe aim of developing evidence based indications and test novelstrategies for proton therapy in the multi-modality management ofdifferent cancer diseases.As many of the operational particle therapy facilities in the world today areworking without modern imaged guided technologies and possibilities foractive modulation of the beam and even without gantries, the Copenhagengroup aims for the Proton Therapy Center at Rigshospitalet to be among theabsolute world leaders for proton therapy by this research based approachcombining protons, imaging and molecular medicine.In the 2011 bid materials the proposal is for a center with clinical patienttreatment and research interlinked and integrated in one center, and situatedin one building, with shared facilities including shared coffee rooms for clin-ical and research staff, and strong collaboration with the leading researchgroups at Rigshospitalet, and at the University of Copenhagen: The Facultyof Health Sciences, The Faculty of Life Sciences, The Faculty of Pharma-ceutical Sciences and The Faculty of Science. Further strong collaborationswould be with DTU, The Technical University of Denmark with the insti-tutes IMM, Risø, Electro and BMC, and with strong collaboration with TheLund University Hospital, The University of Lund and especially theplanned future ESS, The European Spallation Source with the data center inCopenhagen.The research and clinical program would be anchored in an international set-ting with collaborative partners in Uppsala, Sweden and HIT Heidelberg,PSI, Villigen, Switzerland and first and foremost the University of Wiscon-sin, Madison, USA.The bid suggests a solution for protons only, and not a solution for both pro-tons and light ions. The expenditure to the much larger and more complexcombined facility would not be justified, it is argued, and the few availableclinical studies on the use of light ions do not show convincing results com-pared to results from the use of protons.The bid states that the Department of Radiation Oncology at Rigshospitaletis the largest in Denmark and one of the largest in Northern Europe, and thedepartment has pioneered the clinical implementation of a number of newradiation therapy technologies at the national and in several cases also theinternational level, including IMRT, gating and rotational delivery with Rap-idArc. The Department has a strong track record for dosimetric and qualityassurance studies relating to the clinical introduction of new technologies.Parallel photon and proton therapy planning are already now conducted onselected cases in the Department with the aim of supporting decision makingregarding referral to proton therapy abroad. Sharing knowledge and experi-ence with a big radiotherapy clinic will give high synergy.

The Copenhagen bid outlines a vision for the center to deliver the most ad-vanced patient treatment and the most excellent research in the triangle be-tween science, technology and bio-medicine. In this vision, a cure of cancerwithout side effects is the final goal. It is stated that especially in childrenwith cancer the center would have a beneficial treatment effect from the firsttreatments given, and that the center would be for the benefit of Danish pa-tients, while the research outcome would be for the global benefit of the pa-tients and society.In the 2011 bid materials the future Proton Therapy Center at Rigshospitaletwas projected to treat 1,000 patients per year and to be operational from2015. The costs of establishing the center was listed as requiring a sum forequipment of 450 million DKK, a sum for building of 724 million DKK anda sum for the research center of 376 million DKK (excl. VAT).However, in the updated Volume IV, completed in August 2012, the Copen-hagen bid describes a proposal for a compact proton therapy facility solu-tion. It is argued that proton delivery technologies have advanced considera-bly, and since the original bid was submitted the compact solutions have ma-tured. Now, the time is ripe for a compact solution, the bid suggests.A single room compact proton facility would be able to treat 450 patients peryears and could be established in 3 years. The cost would be around 300 mil-lion DKK and the proton machine could be placed in a new small building asan extension to the existing Department of Radiotherapy at Rigshospitalet. Itis argued that this technology would provide exactly the same patient treat-ment quality, including spot scanning, Intensity Modulated Proton Therapy(IMPT) and Image-Guided Radiation Therapy (IGRT), as the larger, tradi-tional facilities. A second treatment room could be added in the future,should the clinical need be there, whereby the treatment capacity can be ex-panded to 900 patients per year.The lower capital investment and the option for a phased expansion of ca-pacity make the proposed clinical compact proton solution, in the view of thebidders, the optimal choice for Denmark with a population of 5.5 millionpeople. From an evidence-based medicine perspective, the phased introduc-tion of proton therapy in Denmark would minimize the risk of investing in alarge, traditional facility with excess treatment capacity or with an implicitpressure to give proton therapy to patients in whom there is only weak or noevidence for a favorable cost-benefit compared to photon therapy.The bid material assesses the technical specifications of the three commer-cially available compact solutions: Mevion S250™, Varian ProBeam™ andIBA ProteusOne™ and finds all three systems to meet the clinical needs andwould provide adequate support for the research projects described in Vol-ume II of the original application. International collaboration on clinical tri-als would ensure patient enrolment already with one treatment room availa-ble. The first phase of a compact proton facility would open for patienttreatment much earlier than would be the case with a traditional proton facil-ity, and with no foreseeable drawback for the planned research program.

The Copenhagen bid argues that they have detailed plans, the physical loca-tion and the economical basis in place for the one room compact facility,which could be extended to a two room facility, if or when the clinical needarises. The consortium underlines their motivation, their overall researchstrategy and their required clinical and research expertise to succeed.The Aarhus bidThe Aarhus consortium proposes a national center for particle radiotherapyintegrated into the new university hospital being developed in Skejby outsideof Aarhus10. The bid document describes the design, aims and operation of aparticle radiotherapy center to be placed at the new University Hospital inAarhus.The bid states that the center would be integrated into a comprehensive in-terdisciplinary academic environment combining the clinical services of thetop university hospital in Denmark, the largest radiation oncology researchcenter in Scandinavia and the only center for accelerator physics in Den-mark.The long-term vision of the proposed National Center for Particle Radiother-apy (NCPRT) is stated as delivering frontline research-based proton therapyto all relevant Danish patients, and becoming a world leader in research andtreatment of cancer with particle based radiotherapy.The bid finds commercially available technical solutions which match theoverall vision and strategy for NCPRT. The proposed proton radiotherapycomplex is planned to be built on a 9,000 m2building plot next to the De-partment of Oncology at the new Aarhus University Hospital, and it is statedthat the plot is ready for construction to start immediately. Furthermore, thebid proposes that the 7,800 m2facility, for which comprehensive plans exist,would be equipped with a proton accelerator and two treatment gantries,with a view to treating 1,000 patients annually. The bid states that therewould be well-integrated facilities for patients and their relatives, as well asclinical staff and scientists. Research office facilities would be planned in theNCPRT building close to the clinical activities, and there would also be anexperimental particle beam facility, as well as experimental laboratories atthe neighboring Core Research Center.Future expansion would be secured through the possibility of a third gantryroom, allowing smooth expansion up to a capacity of 1,500 patients annual-ly. Should further expansion be needed, ample space would be reserved sur-rounding the facility.Aarhus University Hospital, the bid argues, would be an optimal host for aDanish national particle radiotherapy facility. The comprehensive cancermanagement at Aarhus University Hospital is highly regarded international-ly. Clinicians and scientists from Aarhus University Hospital play leading10

roles in all relevant Danish Multidisciplinary Cancer Groups and in most in-ternational scientific societies relevant for radiation oncology. The Depart-ment of Oncology hosts an internationally renowned clinical and experi-mental environment with a very high academic production; more than half ofall scientific papers from the six Danish oncology departments over the lastdecades have a first author from Aarhus University Hospital.The consortium claims a broad international network, especially throughparticipation in all radiation oncology relevant FP5, FP6 and FP7 EU re-search programs: Scientists from Aarhus University and Aarhus UniversityHospital have a long time standing special strength in accelerator physicsand particle beam radiotherapy research, where they, as partners in interna-tional research collaborations, have been responsible for the radiobiologyand dosimetry associated with major particle beam experiments, for exampleat CERN. The laboratories are equipped for radiobiological dosimetry meas-urements using refined particle beam structures. Additionally, Aarhus Uni-versity Hospital and Aarhus University host several interdisciplinary centers,which would be actively involved in the research at NCPRT.The bid argues that research activities in the center would exploit the syner-gistic effect of collaboration between existing leading major research groupsin the fields of clinical radiobiology, functional imaging, accelerator physics,medical physics, cellular and molecular oncology, nanotechnology and clini-cal research in Aarhus. The lead scientists at NCPRT, it is claimed, have astrong track record in collaborating with the Danish radiotherapy communityand the Danish Multidisciplinary Cancer Groups, and they have shown ex-cellent leadership skills in the national radiotherapy research center CIRRO,which is initiated and hosted by Aarhus University and Aarhus UniversityHospital. In addition, a unique international network exists that is associatedwith particle therapy spanning most relevant major institutions and collabo-rative groups, both throughout Europe and world-wide.A comprehensive research program is planned, the bid describes. Particletherapy is a new enterprise and while extremely promising, it requires moreclinical data for assessment of its outcome. In this new therapy area, reliableclinical studies are presently few and far between and an important missionof the new center is to help overcoming this current lack of information.With this in view it is planned to include a very large proportion of the pa-tients in clinical trials. The trials will in particular aim to establish the typesof cancers which are most suitable for particle therapy. Clinical treatmentprotocols would be established on the basis of evidence from the clinicaloutcome after proton therapy and analyzed and discussed within the rapidlygrowing world forum for particle therapy. The basic and translational re-search, conducted in the radiobiology and functional imaging programs,would aim to characterize the individual normal tissue and tumor biologyrelevant for proton therapy. These activities would be further facilitated byestablishing a particle radiotherapy dose-plan database and utilizing existingtissue and tumor bio-banks. Essentially the research in treatment delivery

and dose planning is closely allied to practice and will have as its major aimthe improvement of the precision and quality of particle radiotherapy.The planned research staff would include a director, 28 full time academicpositions, 17 technical-administrative positions and 4 visiting scientist posi-tions. Within the field of education related to the new center, the majority ofall Danish pre- and postgraduate educational activities in radiotherapy andmedical physics are located in Aarhus. Activities include national specialistcourses for oncology residents, a school for radiotherapists, a dedicated med-ical physics module at Aarhus University and the Danish Graduate School inClinical Oncology. These educational activities would be expanded to en-compass particle radiotherapy, exploiting the local accelerator expertise inthis area. In addition, core groups would be trained at international referencecenters and Danish doctors in training would be offered courses at theNCPRT.The NCPRT would be embedded with the Center for Cancer and Inflamma-tion at Aarhus University Hospital and governance enabled according to thehigh standards associated within this institution. The day-to-day manage-ment team would consist of the three directors of Clinical Management,Technical Management and Research, respectively. The national governanceof the NCPRT would be secured through a National Board, with representa-tives of key stakeholders, that is, the Ministry of Health, Danish Regions,Danish Multidisciplinary Cancer Groups and others. An International Advi-sory Board and a National Forum for Particle Radiotherapy would secure in-put from experts and collaborators in Denmark and abroad. Contact personswould be assigned at all Danish radiotherapy departments. In order to facili-tate smooth patient throughput with the maximum of communication, regu-lar meetings and video conferences, as well as the use of comparative treat-ment planning IT infrastructure, are planned between referring specialistsand the center.The construction costs are estimated in the bid material as 770 million DKK(building 295 million DDK, equipment 475 million DKK), a budget compa-rable to similar recent state-of-the-art facilities in Europe. The estimated an-nual operational costs at full operation of 1000 patients per year would be 76million DKK. The average annual research budget would be 36 millionDKK. Since construction is ready to start from today the center could openits doors to the first patients by the end of 2017 if a decision for its locationis made in 2013.The commitment of Aarhus University Hospital and Aarhus University tothe project is underlined in the bid materials, with a commitment of the insti-tutions together to have agreed to contribute initially with 50 million DKK tothe project, in addition to the value of the building plot.

The panel’s assessment of the two proposalsOverall, the panel finds the establishment of a single national center of PRTin Denmark to be a very worthwhile endeavor. With a population of 5.6 mil-lion inhabitants served by a well-integrated and comprehensive health-caresystem, with indeed very strong scientific and clinical traditions in clinicaloncology and radiotherapy, such a center could certainly be sustained.Given the strong scientific traditions, multi-disciplinary collaborations andsolid data registries in the country, the panel also finds that Denmark has aspecial obligation to ensure that the center becomes a truly national centerwith a strong collaboration with referring departments, to produce robust andoriginal science in the field.While the clinical need for PRT is bound to increase in the near future, thepanel does however advise not to rush the establishment of the Danish na-tional center of PRT, as efforts to do so in other countries have backfired.Estimates of the target populationBased on currently available evidence, the panel estimates that proton radio-therapy may be relevant in roughly 10-15% of all radiotherapy indications.With roughly 12,000 new cases per year with radiotherapy indications thiscorresponds to a potential annual case load of 1,200-1,800. The panel alsofound the algorithm proposed by the Health Council of the Netherlands11helpful, for grouping indications in three categories, based on expected ad-vantage of protons over photons according to set criteria in the individualclinical situation, taking into account normal tissue complication probabilitymodels.In the first category, where the expected advantage is major in favor of pro-tons, the panel would group commonly accepted indications such as curativetreatment in pediatric cases and a number of adult indications such as base ofskull and spinal chordomas and chondrosarcomas, as well as selected headand neck cancers and other difficult cases. Based on best available evidencethis population of PRT indicated on a routine basis would be roughly 15% ofall PRT cases, or an annual case load of around 200. Similar population es-timates have been done recently when planning for the national proton ther-apy service in England12.The panel found that the few Danish cases of intraocular melanoma, that arealready today being referred abroad to specialized onco-ophtalmologicalcenters, should continue to do so, as this small and highly specialized nichewould be difficult to accommodate in a Danish center.

The second category, where the expected advantage of protons is moderateor questionable, the panel would estimate at roughly 85% or an annual caseload of 1,300. These patients should be enrolled in clinical trials or protocolsto establish evidence, and a primary aim of the Danish national center shouldbe to ensure well-designed trials with adequate patient numbers. To the ex-tent that comparative trials are conducted with conventional RT arms, theprojected throughput of the PRT facility would obviously be lower.The third category, where the expected advantage of protons is small or ab-sent, should continue to be offered photon radiotherapy.Equipment and facilitiesIn general, the panel found that it would be wise not to start, or give the ap-pearance of starting, an equipment selection process too early. The legal re-quirements for equipment procurement are very demanding and failure tofollow the required procedures can badly delay a project and even derail it,as has been the case in several European countries.The choice of equipment should be driven in the first place by strategic con-siderations. Both applicants seem to accept the proposition that the equip-ment should, to the extent possible, allow the protons to be used to their fullpotential. This has many aspects, but not least of these is the ability to per-form intensity-modulated particle radiotherapy at the highest possible level.The panel would not advise the selection of an applicant based in part ontheir preference for a given device but, rather, to defer the equipment selec-tion process (and budget) until the host institution for the facility is selected.The host institution should then work with relevant authorities and outsideexperts to undertake a selection process – which must start with quite de-tailed specifications of what is desired and a balanced estimation of risk be-tween both what it currently clinically available and what is promised bymanufacturers.The panel considers it a mistake to select an institution based in part on theirpreference for a lower cost option. Indeed, when the overall cost of startingthe project up and running it for 10 to 20 years is tallied up, the initial cost ofthe equipment will fade as the running costs over a decade could sum up tosignificantly higher amounts than initial investments. Down the road it willbe seen to have been a far better decision to have picked the best availabletechnology, with capabilities of further development and upgrading as tech-nology inevitably changes.The panel underscored the need to establish a single, truly national center forPRT, and finds it important that such a center be flexible and expandable. Inthis regard the panel did not regard the proposal of the Copenhagen bid ofadding single-room solutions one at a time, as if conceptually just expandingan existing string of photon accelerators, as particularly wise, as this facilitycould easily be constrained for options to accommodate future technologicalsolutions.

Both applications have proposed very attractive designs for their facility.The size of the building is in part determined by the equipment and in partby the clinical and research activities which it houses. The vendor of theproton therapy equipment and the detailed nature of what is being boughtmust be decided before the building design can be finalized – and the panelfound it wise not to go too far down the road of building design before thattime.The panel did commend both applicants for proposing integrated PRT facili-ties with existing radiotherapy departments in full-scale university hospitals,as stand-alone PRT facilities elsewhere have shown to have difficulties en-suring continuity of patient care.In connection with the equipment, in formulating the business plan it is im-portant to appreciate that substantial staffing is needed several years beforestart of operations. They are needed to: plan and develop specifications forthe facility and especially its equipment; oversee the design and constructionof the facility; prepare the infrastructure for treatments (instrumentation,computer programs etc.); conduct acceptance tests of the equipment; andcommission it.Safety issuesThe panel found that both proposals at this stage addressed relevant safetyissues, such as shielding, safety of staff and individual monitoring. The panelfound that both applicants acknowledge and oblige to meet the requirementsset by DHMS as the regulatory authority during planning, operation and de-commissioning of the PRT facility.Delivering clinical servicesIn assessing the two proposals, the panel found both bids to have access tonecessary and relevant supportive services, including co-location of imaging,pediatric, oncological and anesthesiological services, as well as child andfamily friendly facilities and on-site guest houses.However, the panel did find that realistic projection for patient throughput isneeded. Operation of the currently available proton therapy equipment is, byand large, clumsy and inefficient, and does not approach the standards ofconventional radiotherapy. While current proton users are resigned to this,newcomers to the field are often largely uninformed and do not pressurevendors to address this problem. Ramping up of staff and facilities will taketime.The panel found that the projected volume of 450 patients per year in a one-room solution starting in 2016, as proposed by the Copenhagen bid, was un-realistic, and failed to get adequate responses to queries on this central issue.Furthermore, the panel was not convinced that the Copenhagen bid had thestaffing plans and training scenarios necessary to ramp up staffs in time for a2016 throughput as proposed. Training, including spending time at existinghigh-quality proton centers for a minimum of one and preferably more yearswould be important before operation begins. An enormous amount of plan-

ning and preparation (in all disciplines) is needed well before operationsbegin – and, for these to be effective, considerable training/experience mustalready have been obtainedThe panel found the Aarhus group presented a realistic implementation planto allow for adjustments as experience grows. The Aarhus bid proposes toappoint the management group already in 2013 to prepare the procurementof the proton radiotherapy system and to manage the planning of the nationalcenter of PRT. Three physicists would start education, training and prepara-tion in advance, to be an active part in the installment in 2016 and treatingthe first patients in 2017. The annual capacity for new patients in the firsttwo gantries would be reduced at 333 for 2017 and 666 for 2018 to allow forclinical implementation. Decision on a third gantry would be made afterthree full years of operation.For future planning and projections of the national center for PRT, the panelfound that it would be advantageous to plan capacities for the center in theramping up phase based on expected treatment protocols and number of frac-tions to be delivered per year. In both centers’ cases there are assumptionson lower numbers of fractions used in modeled capacity than are delivered inpatients treated in USA centers currently. The evidence base for hypo-fractionated regimes should be assessed before they are assumed and moredetailed work on capacity modeling undertaken.Research strategiesThere are particular issues with regards to the conduct of clinical researchinto proton beam therapy. These include: the choice of sites to investigate;stratagems to assure an adequate number of patients to conduct a given trial;and the provision of adequate resources for long-term follow-up of treatedpatients.The panel found that the Aarhus group best addressed the issue of site selec-tion, as they worked from the Dutch algorithm in listing sites which wouldbe treated with protons and which would be considered in phase II or phaseIII trials. Furthermore, the panel found that the Aarhus group presented a re-alistic strategy of selecting candidate sites for protocols strongly based intheir research tradition and their existing participation and leadership of sev-eral Danish multi-disciplinary cancer groups.While there is no doubt that the NCPRT will be able to provide world-classclinical care for Danish patients, it is likely that, for some sites of interest, itmay be hard to provide an adequate number of Danish patients for a clinicaltrial – especially in the case of phase III trials for which the control arm islikely to dilute the number of patients receiving proton therapy. Strategies toaddress this problem will be needed and are likely to include internationalmulti-center trials and case-controlled studies with control arm patients be-ing treated at non-proton centers. The NCPRT has the exciting possibility oftaking a leading role in these efforts, but their pursuit will require substantialscientific dedication.

It is likely that an important benefit of proton therapy will be a reduction oflate side-effects. These may occur even decades after treatment and may bequite subtle and of a nature as to be easily overlooked (e.g. complications ofsubsequent surgery in or near the proton-irradiated fields). Strategies andsubstantial resources will be needed to ensure continuity of patient referral,care, and follow-upand even more so in the context of multi-center trials.While both groups identified a number of potential research areas, the panelfound that the majority of such projects proposed by both applicants do notrelate specifically to proton or particle therapy per se. Rather, they have todo with radiation therapy in general, or even related fields such as imagingand tumor biology. That is not to say that developments in many of these ar-eas would not profit patients who receive particle therapy. But it is unclearwhether putting them all under the same roof as particle therapy: would bewise for programmatic reasons; would be of help when judging progress; orwould make sense from a funding agency’s point of view.So far as the impact on proton therapy research is concerned, the panel seestwo dangers. First, non-proton related research may dilute management at-tention on, and support of, efforts that are specifically proton-related. Andsecond, in a somewhat related manner, it can have the undesirable conse-quence that, if progress on the proton therapy front were to be slow or prob-lematic, it may be less quickly noted, or may be excused by good progress inthese other areas. For that reason, proton therapy needs and deserves the fullattention of a research group. General developments in radiation therapy arehighly desirable, but they are a separate and potentially distracting problem.Strong biology and technology laboratory research as well as strong transla-tional research efforts are undoubtedly necessary to establish high qualityproton therapy in a variety of indications and to assess its value compared tobest conventional radiotherapy. However, this research needs to address spe-cific issues which are very relevant for proton treatment and currently un-solved, such as motion management, relative biological effectiveness atbeam edges, volume effects in healthy tissues, image guided intensity-modulated proton therapy approaches and, very importantly, patient stratifi-cation to the different treatment options.Leadership, governance and national collaborationThe panel found both applicants to have excellent scientists and staff in allthe key disciplines at their disposal. It is also clear that the successful appli-cant will need to boost staffing, preferably including persons with experiencein proton therapy.However, the panel found that the Copenhagen application failed to clearlyidentify the person and core leadership group which would be designated tolead the proposed center, and failed to adequately respond when queried.The current department head will be of retirement age by the time the facilityopens. Much of the research proposed in the bid is carried by experts inphysiology, nuclear medicine and molecular imaging, and the group current-

ly does not seem to include an academic medical physicist although medicalphysics will have to play a major role in the project.The panel found the Aarhus group to present a much more convincing prop-osition to lead a national center of PRT, with a designated future leader inhis early fifties, and a strong core group in place covering radiotherapy,medical physics and clinical oncology. Furthermore, the Aarhus group hasdemonstrated their leadership skills through key roles in the Danish multi-disciplinary cancer groups, and other national and international oncologicaland radiotherapy groups and societies, and they have since 2009 as leadersof the Lundbeck Foundation Center for Interventional Research in RadiationOncology (CIRRO) proven their ability to host a national center.Furthermore, the panel found that the Aarhus group proposes a sensible andrealistic governance structure to ensure collaboration and ownershipamongst all referring and contributing departments, including strategies toensure continuity of patient referral and care, with a framework to ensurefollow-up of patients over extremely long time periods.

RecommendationsAfter reviewing the proposals to host a Danish national center of PRT, andconsidering the best available evidence in the field, the panel recommends:--That a single, national center of particle radiotherapy be establishedat Aarhus University HospitalNot to start, or give the appearance of starting, an equipment selec-tion process too early and to ensure collaboration between the hostinstitution, relevant authorities and expert advisors in establishingthe top-level specifications for the equipmentTo project realistic capacities for the center, taking into accountramping up of staff and facility, and based on expected treatmentprotocols and number of fractions to be delivered per yearThat a strategic business case be developed to prepare for a properbudgeting model and subsequent tender for constructing and procur-ing equipment for the national centerThat governance structures be put in place to ensure a continuedstrong national clinical and scientific collaboration in the field ofparticle radiotherapy

Appendix A – Terms of referenceTerms of reference for an international panel convened to advise the DanishHealth and Medicines Authority on the establishment of a national center forparticle radiotherapyIn July 2011, the Danish Ministry of Health issued a request for proposals to host anational center for particle radiotherapy (PRT). The RFP was issued to two potentialcenters, who submitted their bids by end September 2011. In March 2012, the Min-istry requested the Danish Health and Medicines Authority to initiate a technical as-sessment on the establishment of one, single national Danish center.Furthermore, it has been agreed by all parties, that this technical assessment wouldoptimally be served by an international advisory panel. These terms of reference de-scribe the process of the technical assessment as well as the context and tasks of theinternational panel.IntroductionParticle Radiotherapy (PRT) uses charged particles instead of X-rays to pro-vide ra-diotherapy, thus delivering precision high-energy beams of particles to destroy can-cer cells. PRT seems particularly suitable for childhood cancers, as there is a poten-tial to reduce side-effects and secondary cancers induced by radiotherapy whencompared to conventional radiotherapy. How-ever there is currently a dearth of goodevidence to support the clinical benefit of PRT in most cancer types, and further ev-idence from basic, translation-al and clinical research is highly desired, as are healtheconomy analyses.As it is difficult to estimate how many patients will potentially benefit from PRT ascompared to conventional radiotherapy, it is not easy to plan for the present and fu-ture needs for PRT in the Danish population. Currently, Danish patient can be re-ferred, and fully reimbursed, for PRT abroad, subsequent to approval by the DanishHealth and Medicines Authority.A Danish national center for PRT is expected to recruit a large number of patientsinto research protocols, thus also contributing high-quality science in the field.ContextThe Danish Health and Medicines Authority is empowered by the Health Act of2008 to plan publicly funded specialized health services, including the detailed de-scription of criteria and requirements, assessment of applications, and issuing (andrevoking) permits to offer such specialized services. A consultative committee,chaired by the Director of the Danish Health and Medicines Authority, is heard inthe process. As PRT easily fills the criteria for being a highly specialized service,these regulatory requirements apply, and the Danish Health and Medicines Authori-ty is empowered to decide the placement of a Danish national center for PRT.The criteria currently used in assessing applications in this framework include, butare not limited to:- Capacity and stability of a center’s clinical services- Patient volume, clinical experience and professional expertise- Competency in all relevant professional and supportive fields- Access to all required technical facilities- Documented clinical quality and prospective reporting of results to relevantnational databases- A multi-disciplinary approach- Safeguards to ensure continuity of patient care- Active and documented research, development and education- Procedures for assessing new technologies and treatments- Collaboration with other hospitals and relevant specialized departments

Additionally, the Danish Health and Medicines Authority is the national radiationprotection authority, regulating the use etc. of ionizing radiation. Based on interna-tional recommendations and the national legislation the criteria currently used in as-sessing applications in the framework of radiation protection include, but are notlimited to:- Assessment of safety for the facility and activities- Optimization of protection against radiation risks to patients, staff, mem-bers of the public and the environment to provide the highest level of safetythat can reasonably be achieved- Assessment of a potential production of radioactive waste and radio-activereleases over the lifetime of the facility-These criteria will also form the basis for the assessment of the two applications tohost a Danish national center for PRT. Applications have been received from twoconsortia: One suggests integrating it in the new university hospital being construct-ed in Skejby outside of Aarhus; this application is submitted by the hospital, theUniversity of Aarhus and the Region of Central Denmark. The other application is toplace the center adjacent to the Royal Hospital in Copenhagen; this application issubmitted by the hospital, the University of Copenhagen and the Capital Region.To ensure the highest level of expertise, as well as balanced and impartial advice, ithas been decided to solicit the services of an international panel in the assessment ofthe two applications. Both applicants have, with their applications, submitted nomi-nations for this international panel.Composition of the international advisory panelThe panel will be composed of 5 internationally peer-recognized experts:- 3 expert(s) from the field of oncological radiotherapy, and with specific ex-perience and expertise in PRT- 2 expert(s) from the field of medical physics, and with specific experienceand expertise in PRTThe panel will be appointed by the Danish Health and Medicines Authority, takinginto consideration the nominations from the two applicants in a balanced approach.The Danish Health and Medicines Authority will cover travel, accommodation, perdiem expenses, as well as honoraria, for the panel members. Memoranda of under-standing will be issued to panel members, who will in turn be required to submitstatements on potential conflicts of interest as well as confidentiality statements.Tasks of the international advisory panelThe panel will be required to assist and advise the Danish Health and Medicines Au-thority on the following issues:- to describe the role of a Danish national center for PRT, in the context ofthe present services offered Danish patients, and considering other inter-national and regional developments in the delivery of PRT- to outline a potential time frame for the establishment of a Danish nationalcenter for PRT, considering the expected technical and commercial devel-opments in the field, as well as projections for the target population in need- to balance and expand the criteria to be applied in assessing the two appli-cants- to assess the two applicants according to the weighed criteria- to provide, orally and in writing, contributions to the final report on thetechnical assessmentThe tasks of the Danish Health and Medicines AuthorityIn reference to regulatory requirements, the Authority will:- select the members of the international advisory panel- convene, chair and keep the minutes of the international advisory panel- forward to the panel the two applicants’ submissions, as well as other mate-rials needed by the panel such as criteria and scoring tools- facilitate and prepare the assessment of the applications

The result of this process will be a report, submitted to the Danish Ministry ofHealth, describing the establishment of a national center for PRT, as well as as-sessing the merits of the two applicants to see which should receive the first Danishnational center for PRT.Time schedule (2012-2013)End of AprilMayDraft of terms of referenceMeeting to discuss process, with representatives ofapplicants, Ministry of Health, and the DanishHealth and Medicines AuthorityInvitations sent to panel members, dates bookedDeadline, submission of supplementary materialfrom the applicants to the Danish Health and Medi-cines AuthorityMaterial sent to panel membersFace-to face meeting of the panel in Copenhagen.Representatives of the two applicants invited to at-tend brief hearings, if the panel so desiresCompilation of panel contributions. Possible fol-low-up video conference(s) with panel to discussfindings and recommendationsFinal report submitted to the Ministry of Health

Brief guideline on the required evaluation regarding the establishment of aDanish center for particle radiotherapyRigshospitalet and Aarhus University Hospital are among the largest tertiary univer-sity hospitals in Denmark. Both hospitals have direct access to a large number ofhighly specialized functions and co-location of imaging, pediatric and oncology ser-vices as well as patient hotels. Both hospitals are situated in or near the city witheasy access.The international advisory panel should:-describe the role of a Danish national center for PRT, in the context of thepresent services offered Danish patients, and considering other inter-national and regional developments in the delivery of PRToutline a potential time frame for the establishment of a Danish nationalcenter for PRT, considering the expected technical and commercial devel-opments in the field, as well as projections for the target population in needbalance and expand the criteria to be applied in assessing the two applicantsassess the two applicants according to the weighed criteriaprovide, orally and in writing, contributions to the final report on the tech-nical assessment

The national planning of specialized health care services in Denmark is regulated bythe Health Care Act and a task of the National Health and Medicines Authority. Thecriteria previously used by the Authority when judging applications should, if possi-ble, be broadly applied when assessing the two applications for the national center ofparticle therapy. –The Authority would ask the panel members to consider these cri-teria when reviewing the two applications and proposing their recommendations tothe Authority. The panel can expand on the criteria, if necessary.These criteria can be summarized as follows:-Capacity and stability of a center’s clinical services, includingoRealistic timelines for development and implementation of ser-vicesoSufficient capacity to cover projected treatment needsoA clearly defined management with resources to manage the pro-grammeoA sufficient number of specialized and auxiliary staff to providethe clinical services at all relevant timesoPlans to sustain and further develop the clinical services once thecenter is establishedPatient volume, clinical experience and professional expertiseoA sufficient patient flow and volume to ensure maintenance ofskills and ongoing development of clinical servicesoA sufficient number of specialized staff to sustain a professionalenvironment that will ensure continuous development of servicesCompetency in all relevant professional and supportive fieldsoCo-location of imaging, pediatric, and oncology services

Stable and direct access to other relevant clinical services neces-sary to a high complexity of clinical casesAccess to all required technical facilities, e.g.:oCo-location and integration with existing radiotherapy infra-structureDocumented clinical quality with prospective reporting of results to rele-vant national databasesoPlans for the elaboration of relevant national clinical guidelines,patient pathways, referral criteria etc.A multi-disciplinary approachoIntegration of professions, medical specialties, technical staff etc.in patient careoPlans to ensure that decisions are based on expertise from all rele-vant fieldsSafeguards to ensure continuity of patient care, e.g.oPlans to ensure seamless care for patients and professional com-munication with caregivers and treatment providers outside thecenteroAvailability of accommodation for patients and their carersActive and documented research, development and education, e.g.:oRobust research links and infrastructure (multidisciplinary and in-ternational)oA relevant and ambitious strategy and roadmap for future clinical,physics and technological research and developmentoPlans to ensure sufficient training of staff during the implementa-tion phaseoA strategy to maintain skills and capabilityTechnological capability, e.g.:oA site which meets technical and utility service requirementsoAn accelerator meeting the needs of capacity, indications and safe-tyoProjections for technical development and upgradabilityoProcedures for assessing new technologies and treatmentsCollaboration with other hospitals and relevant specialized departments, in-cludingoRelevant plans for ensuring efficient and professional communica-tion with caregivers and treatment providers outside the centero