Safe innovation: On medical device legislation in Europe and Africa

Contents lists available at ScienceDirect

Health

Policy

and

Technology

journal homepage: www.elsevier.com/locate/hlpt

Safe

innovation:

On

medical

device

legislation

in

Europe

and

Africa

Carmelo De Maria

_{, Licia Di Pietro}

_{, Andrés Díaz Lantada}

_{, June Madete}

_,

Philippa Ngaju Makobore

_{, Mannan Mridha}

_{, Alice Ravizza}

_{, Janno Torop}

_,

Arti Ahluwalia

a_{ResearchCenterE.Piaggio– UnivesityofPisa,LargoLucioLazzarino1,56122Pisa,Italy} b_{DepartmentofIngegneriadell’Informazione– UniversityofPisa,Pisa,Italy}

c_{MechanicalEngineeringDepartment– UniversidadPolitécnicadeMadrid,Madrid,Spain} d_{DepartmentofElectrical&ElectronicEngineering– KenyattaUniversity,Nairobi,Kenya} e_{UgandanIndustrialResearchInstitute,Kampala,Uganda}

f_{SchoolofTechnologyandHealth– RoyalInstituteofTechnology,Stockholm,Sweden} g_{BioIndustryParkSilvanoFumero,Turin,Italy}

h_{InstituteofTechnology– UniversityofTartu,Tartu,Estonia}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Availableonline9February2018

Keywords:

Medicaldevicesregulation Standards

Africa Europe

OpenSourceMedicalDevices

a

b

s

t

r

a

c

t

Objectives: Theprincipalmotivationforregulatingmedicaldevicesistoprotectpatientsandusers. Com-plyingwithregulationsmayresultinanincreaseindevelopment,manufacturingand servicecostsfor medicalcompaniesandultimatelyforhealthcareprovidersandpatients,limitingtheaccesstoadequate medicalequipment.Ontheotherhand,poorregulatorycontrolhasresultedintheuseofsubstandard devices.Thisstudyaimsatcomparingthecertificationroutethatmanufactureshavetorespectfor mar-ketingamedicaldeviceinsomeAfricanCountriesandinEuropeanUnion.

Methods: We examined and comparedthe currentand future regulationsonmedical devices inthe EuropeanUnionandinsomecountriesinAfrica.Contextuallyweproposedfutureapproaches toopen design strategiessupportedbyemergingtechnologiesasameanstoenhanceeconomicallysustainable healthcaresystemdrivenbyinnovation.

Results: AfricanmedicaldeviceregulationshaveanaffinitytoEuropeandirectives,despitethefactthat thelatterareparticularlystrict.Severalstateshavealsoimplementedorharmonizeddirectivesto med-icaldeviceregulation,orhaveexpressedinterestinestablishing themintheirlegislation.OpenSource MedicalDevicesholdagreatpromisetoreducecostsbutdoneedahighlevelofsupervision,tocontrol theirqualityandtoguaranteetheirrespectforsafetystandards.

Conclusion: Harmonizationacrossthetwocontinentscouldbeleveragedtooptimizethecostsofdevice manufactureandsale.Regulatedopendesignstrategiescanenhanceeconomicallysustainableinnovation.

© 2018FellowshipofPostgraduateMedicine.PublishedbyElsevierLtd. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense. (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction

A medical device can be described as any means of improv-ing or monitoring patient health that acts on the body in a non-metabolicfashion. Thiswide definitionincludes electromedi-calequipment,implantablemechanicaldevices,diagnosticdevices, andeveneverydaylifeobjectssuchasband-aidsandglasses [1] .

∗ _{Correspondingauthorat:ResearchCenterE.Piaggio– UnivesityofPisa,Largo} LucioLazzarino1,56122Pisa,Italy.

E-mailaddress:[email protected](A.Ahluwalia).

Acrosstheworld,countriesregulatetheplacementofsuch de-vices on themarket through legislationthat sets the responsibil-ities ofthe manufacturers by referring to technicalrequirements. Technicalrequirementsareusuallymadeavailabletothe manufac-turers asdocumented technicalstandards ornorms. Those docu-ments providespecifications, guidelinesorcharacteristics, includ-ing testing methods and acceptance criteria, for the design and manufacturingofmedicaldevices.

Medicaldeviceregulationsvarygreatlyacrosstheworld, rang-ing from comprehensive to poor. Moreover, over the past two decades,thenumber,range,andcomplexityofmedicaldeviceshas

https://doi.org/10.1016/j.hlpt.2018.01.012

increased resulting in the proliferation of regulatory documents and procedures to encompass these changes. Coupled with this, the differencesin regulations betweencountriesoblige manufac-turersto preparea differentdossierforeach country,which con-stitutes a lengthy andcostly process,leadingto a disincentiveto medicaldevicecompaniestosellinsome countries.Theyarealso a deterrent to innovationand the developmentofnew products. It hasbeen estimatedthat developinga medicaldevice fromthe idea tothe market hasa costof around$31million fora low-to moderate-risk device, andaround $94 million forhigh-risk prod-ucts [2] .

The worldwide market for medical devices is increasing, but accessto them variesaccordingtothe socio-economic and polit-icalstatusofeachcountry [3] :aroundonemillionpatientsdie ev-eryyearduetothelackofadequatemedicalequipment [4,5] . Re-dressingthisimbalanceisacomplexproblem,whichmanyAfrican nations are tryingto solve [6] .Promotinginternational standards andstreamlining theregulatory process could reduce the legisla-tive burden, lower costs andremove unnecessary delays to new productsreachingpatientsinAfrica.

In 1992,theEuropean Union (EU),the UnitedStates of Amer-ica(USA),CanadaandJapanconceivedtheideaofaninternational partnershipbetweenmedicaldevice authoritiesandregulated in-dustry.In 1993,theGlobal HarmonizationTask Force(GHTF) was born with the goal of standardizing medical device regulations worldwide.TheGHTFwasdisbandedin2011andtheInternational MedicalDeviceRegulatorsForum(IMDRF)wasconceived"asa fo-rumtodiscussfuturedirectionsinmedicaldevice regulatory har-monization".TheIMDRF,whichincludesmedicaldeviceregulatory authorities of Australia, Brazil, Canada, China, EU, Japan, Russia, Singapore, South Korea, andUSA,with theWorld Health Organi-zation (WHO)asofficialobserver,iscurrentlydeveloping interna-tionallyagreedupondocumentsrelatedtoawidevarietyoftopics affectingmedicaldevices [7] .

The path to harmonization is still far from completion; nev-ertheless,severalAfrican countrieshaveorientedtheir regulatory processesformedicaldevicesontheEUsystem.Inthispaper,after outlining the EU regulatory framework, we will analyse the reg-ulatory landscape in a number of African countries in which at leasta representative ofthe AfricanBiomedicalEngineering Con-sortium (ABEC, http://abec-africa.org ) is present. The consortium wasfoundedin2012withthemissionofpursuingcapacity build-ing inBiomedical Engineeringfor sustaininglocal healthcare sys-tems.TodateABECiscomposedof16memberinstitutionsfrom8 countries. Among thesecountries, we selectedfivefromdifferent geographicalregions,forbetterdescribingdifferencesand similar-itieswithEUlegislation.

Finally,wewillsuggestpossiblesolutionsforreducingthecosts ofdevelopingsafe,effectiveandquality medicaldevicesfor guar-anteeingaffordableandequitablehealthcareforAfricancitizens.

Europeanregulationformedicaldevices

In orderto place a medicaldevice on theEU market, specific European Directiveshave to be met. The regulatory processes of medicaldevicesarebasedontheMedicalDeviceDirective(MDD), which consistsof three coredirectives for safetyregulations and marketing ofmedicaldevices:theActiveImplantable Medical De-vice Directive (AIMDD 90/385/EEC), the Medical Device Directive (MDD 93/42/EEC)and theIn Vitro DiagnosticMedical Device Di-rective(IVDMDD98/79/EC) [8] .

The newEuropeanRegulation wasrecently published [9] : this newRegulation(EU2017/745)willsubstitutethecurrentDirectives aftera3to5yeartransitionperiod.

Asproof ofcompliance tothestrictsafetyrequirementsofthe Directives,manufacturershavetoapplyaCEmarkontheirmedical

devices.TheCEmarkcanbeseenasadeclarationofthe manufac-turerthattheproductiscomplianttotherelevantlegislations in-cludingthoserelatedtosafety.TheCEmarkingconsistsofseveral processesthatstartfromthemanufacturer’schoiceofthe confor-mityassessmentroute,whichitselfdependsontheclassificationof themedicaldevice [10] .Italsoaddressestheevaluationof intrin-sicriskandexpectedbenefit.Accordingtotheintendeduse,length oftimeused,interactionwiththehumanbodyandothertechnical characteristics,thedeviceisconsidered moreorlessriskyforthe patientandthereforeclassified.Byapplyingtheclassificationrules ofAnnex IX ofthe MDD 93/42/EEC all medical devicesare indi-viduallyplacedinoneoffourclasses(Class I,IIa,IIb andIII,with ClassIII as the highestrisk class). In cases where a medical de-viceoritsfeaturescanbeclassifiedaccordingtoseveralrules,the highestpossibleclassmustbeapplied [11] .Whilethe4-level clas-sificationstructure still holds,thenewRegulation isevenstricter asseveralnewdevicesare nowplacedinthe highestclass (Class III)withrespecttotheiroldIIaorIIbpositions.

Regardlessofthe classofthe device,all medicaldevicesmust be compliant to the EssentialRequirements of the directives, in-tended to enhance patient and user safety and improve device traceability throughout its useful life: some differences between currentMDDandfutureRegulationalsoapplytotheEssential Re-quirementsinasmuchasamoreprecisedefinitionhasbeen ap-plied. The core requirement on risk-benefit balance is unaltered butthere are newdetailed requests regarding validation,clinical proofofbenefitanddesignfortheintendeduser.

Currently MDDs in Europe are enforced by Notified Bodies (NBs),whichare independentcommercialorganizationsthat pro-videauditingservicesformedicaldevices,andhavetheabilityto issue the CE Mark. There are 50 active NBs in Europe [12] , and companiesarefreetochoosetheNBamongstthosedesignatedto coverthe particular class ofdevice underreview. After approval, post-market surveillance functions must be provided to the NB [13] .ThisapproachismaintainedbythenewRegulation,although stricterrulesforNBsmayleadtoareductionintheirnumbersin the near future. For all classes, excluding Class I non-sterile de-vices,themanufacturerhastogiveprooftoaNBthat their prod-uctfulfils theserequirements,e.g. byapplyingrelevantstandards. AlistofharmonizedstandardsisprovidedbytheEuropean Com-mission [14] .ThenewRegulationgivespowertothe Commission toharmonisestandardsfrom internationalorganizationsandalso toissueCommonSpecificationswherenostandardsareavailable. Incaseofasuccessfulcertificationprocedure,somecountriesalso requirethat the manufacturer orauthorised representative regis-tersthedevicewiththelocalNationalRegulatoryAuthority(NRA), a competentpublic agency that can enforce legislation.Tobetter understandtheConformityAssessmentRoutes, Table 1 liststhe ap-pliedAnnexes,andtheexpectedchangesinthenewRegulation.

RoutesforCEmarking

Tobetterunderstandthenecessarystepsthatleadtothe assig-nationof the CE marking, four practical examples are described, eachreferringtodifferentdeviceclassorsubclass.

Consideringclass IMedical Devices, three CE Marking Routes areavailableasshownintheexamplesin Fig. 1 :

• oneforaClassIsterileMedicaldevice(ClassIs,e.g.aPersonal ProtectionKit);

• oneforaClassIMedicalDevicewithmeasuringfunction(Class Im,e.g.asphygmomanometer);

Table1

ComparisonbetweenMDD93/42/EECandRegulation2017/745.Note:ECtype-examinationistheprocedurewherebyaNBascertainsandcertifiesthatarepresentative sampleoftheproductionfulfillstherelevantprovisionsofthisDirective.

Directive93/42/EEC Regulation2017/745

ClassIII • AnnexII(complete)

• orECTYPE-EXAMINATION(AnnexIII)andonthe following:

1. Verificationofconformitytotype(AnnexIV) 2. Productionqualityassurance(AnnexV)

– AnnexIX(complete)

OR

– AnnexX(type)andAnnexXI(Productconformity)

ClassIIb(implantable) • AnnexII(withoutSection4)

• orECTYPE-EXAMINATION(AnnexIII)andoneofthe following:

1. Verificationofconformity(AnnexIV) 2. Productionqualityassurance(AnnexV) 3. Productqualityassurance(AnnexVI)

– AnnexIX(complete)

OR

– AnnexX(Type)andAnnexXI(Productconformity)

ClassIIb • AnnexII(withoutSection4)

• orECTYPE-EXAMINATION(AnnexIII)+oneofthe following:

1. Verificationofconformity(AnnexIV) 2. Productionqualityassurance(AnnexV) 3. Productqualityassurance(AnnexVI)

– PartofAnnexIX(withoutchapter2)

OR

– AnnexX(Type)andAnnexXI(Productconformity)

ClassIIa • AnnexII(withoutSection4)

• orDeclarationofconformitybasedontheTechnical Documentation(AnnexVII)+oneofthefollowing: 1. Verificationofconformity(AnnexIV)

2. Productionqualityassurance(AnnexV) 3. Productqualityassurance(AnnexVI)

– PartofAnnexIX(Chapter2perfamily)

OR

– TechnicalDocumentationreferredtoAnnexIandII+partof AnnexXI

ClassIs(Sterile) DeclarationofconformitybasedontheTechnical Documentation(AnnexVII)+(onlyforsterility)oneofthe proceduresreferredtoAnnexII,IV,VorVI

– PartofAnnexIX(withoutchapterII) OR

– AnnexXI(Productconformity)

ClassIm(measurement) DeclarationofconformitybasedontheTechnical Documentation(AnnexVII)+(onlyforsterility)oneofthe proceduresreferredtoAnnexII,IV,VorVI

– PartofAnnexIX(withoutchapterII) OR

– AnnexXI(Productconformity) ClassI DeclarationofconformitybasedontheTechnical

Documentation(AnnexVII)

DeclarationaccordingtoArticle19afterdraftingthe documentationreferredtoAnnexIandII

Custom AnnexVIII AnnexXIII

Fig.2. AssessmentprocedureforaClassIIaMedicalDevice,e.g.aContactlessThermometer.Adaptedfrom[15].

For these devices the route is self-declaration or self-certification asdescribed inAnnex VII Module A, EC Declaration ofConformity.Themanufacturerensuresandformallydeclares,via a writtenstatement,that theproducts meettheapplicable provi-sionsoftheMDD.

Fig. 2 shows an example of how a Class IIa contactless ther-mometerarrivesonthemarket.Themanufacturerdeclares confor-mitywiththeprovisionsoftheMDDandRegulations(AnnexVII) andensuresthat theproductcomplies withrelevantessential re-quirements.However, forClassIIaproducts,thisdeclarationmust bebackedupinallcaseswithconformityassessmentbyaNB us-ingAnnexII,IV,VorVI.

ThedefibrillatorisclassifiedasaClassIIbmedicaldevice– the assessmentroutetomarketisschematizedin Fig. 3 .Manufacturers ofClassIIbdevicesmayalsochoosethefullqualityassuranceroute (AnnexII)includingassessmentofthetechnicaldocumentationby aNBforatleastonerepresentativesampleforeachgenericdevice groupforcompliancewiththeMDD(AnnexIISection7).

ClassIIIincludeshigh-riskdevicesandthoseawaitingaproper classification. Ahip-jointimplant isclassifiedasa ClassIII medi-caldeviceandthediagramin Fig. 4 illustratesitsroute-to-market. Permanent monitoring during the lifetimeof high-risk devicesis conductedbyspecialisedinstitutions.

Africanregulationformedicaldevices

Briefoverviewofgeneralsituation

In2005,theWHOperformedastudyonthepresenceofNRAs tasked withregulating andcontrolling medicines,vaccines, blood products and medicine devices in the 46 sub-Saharan African countries. Only3ofthesecountries(correspondingto7%)hadan NRAinplace,while29(63%)hadminimaland14(30%)no regula-tions [16,17] .

Table 2 liststhecurrentstate-of-the-artofmedicaldevice reg-ulationsinthe8countrieshostingABECmembers,consideringthe presence of NRAs, directives and laws, how medical devices are classified,the presence ofa medicaldevice nomenclaturesystem aswell asthe existenceof policyor guidelinesondonated

med-icaldevices. Allof them exceptMalawi, where noinformation is available,haveanNRAtoregulateandcontrolmedicaldevices.

ThenamesoftheNRAs indicatethat theyarealsoresponsible forfoodandmedicinecontrol,asalsohappensinsome EU coun-tries(i.e.Spain)andinUSAwiththeFoodandDrugAdministration (FDA),tocitesomeexamples.TheGHTFRiskClassificationprovides afour-tiersystem,withClassArepresentinglowest-hazarddevices and Class D the highest-hazard device. The European and GHTF Classificationsare essentiallyequivalent, both basedon4 classes: devicesareassignedtoaclassaccordingtotheirintrinsicpotential harmtothepatient,intendeduseandtechnology [18,19] .

Table 2 indicates that ABEC countries orient their regulatory processes on the GHTF system. Furthermore, most of the ABEC countrieshaveimplementedorharmonizedwithEuropean direc-tivesin their legislation. Itshould be noted that despite thefact thatmostABECmembercountrieshavealreadyestablisheda ba-sisformedicaldeviceregulations,manyofthemstill havelimited capacities to do so. The limited capacities might include lack of investmentandtrainingtoimprove andmaintainknowledge and skillsofpersonnel [20,21] .

AfricanRegulationinfiveexamplecountries

Describing Africa as a whole means merging a complex and fragmented continent, characterized by different levels of politi-cal stability andsocial situations fromnorth to south, from east to west,into a singleentity. This maylead to incompleteor too general descriptions. We illustrate the regulatory landscape in 5 countrieswith ABEC members in different geographicregions in Africa.

Egypt– NorthAfrica

in-Fig.3. AssessmentprocedureforaClassIIbMedicalDevice,e.g.adefibrillator.Adaptedfrom[15].

Fig.4. AssessmentprocedureforaClassIIIMedicalDevice,e.g.anhip-jointimplant.Adaptedfrom[15].

struments.It controlstheregistration ofmedicaldevicesthrough aSpecializedCommitteeforStudyofManufacturedandImported MedicalDevicesandEquipment [23] .As Table 2 shows,Egypthas adoptedthedefinitionandclassificationofMedicalDevices accord-ingtotheEuropeanMDD93/42/EEC.Afreesalecertificate,andCE Markor FDA Approval is required to commercialize the medical deviceinthecountry.Itisimportanttonotethatlocally manufac-turedproductsmustalsobeclearlylabelledassuch.

Uganda– EastAfrica

The Ugandangovernment was ableto setup differentbodies that are responsible for the regulation of medical devices that, however,presentseverelimitations [20] .Thesegovernment

Table2

OverviewonmedicaldevicesregulationinABECcountries.

ABEC Country

NationalRegulatory

Authority Directives/Laws

Classificationof MedicalDevice

MedicalDevice nomenclature System

Policyor Guidelineson Donated medicaldevice

NorthernAfrica

Egypt EgyptianDrugAuthority (EDA)

93/42/EEC I,IIa,IIb,III No Yes

2007/47/EC

SouthernAfrica South Africa

DepartmentofHealth,South AfricaMedicinescontrol council(MCC)

No.101/1965 A,B,C,D No Yes

No.14/2015 No.15/1973

WesternAfrica

Nigeria NationalAgencyforFoodand DrugAdministrationand Control(NAFDAC)

CapN1L.F.N2004 Complianceto Classificationofthe countrywherethe deviceismanufactured

No Yes

EasternAfrica

Ethiopia FoodMedicineand HealthcareAdministration andControlAuthorityof Ethiopia(FMHACA)

No.661/2009 I,II,III,IV Nationally

developed

Yes

No.12/2013 No.9/2012

Malawi No Noinfo Noinfo No Yes

Uganda NationalDrugAuthority Chapter206_2000 Noinfo Nationally

developed

Yes

Tanzania TanzaniaFoodandDrugs Authority(TFDA)

No.1_2003 A,B,C,D BasedonGMDN Yes

Kenya PharmacyandPoisonsBoard Chapter244_2002 A,B,C,D Nationally

developed

Yes

the laboratory capacity to test the safety and performance of a number of medical devices.Thus two routes must be takenif a device ismanufacturedoutsideofthecountryandasellerwould liketomarketinUganda:

1. ProductCertification - This process requiresan assessmentof theprocess ofproduction/manufacturing andtestingofthe fi-nal integratedproduct. Itwill be checked forconsistency and quality and it will be bench-marked based on the applicable ISOstandards(seefurtherinthetext)evaluatingwherethe de-viceismanufacturedandwhereclinicaltrialswereperformed. 2. Pre-Shipment Verification of Conformity(PVoC) - This

certifi-cation involvesan assessment on whetherthemedical device complies with the applicable relevant ISO standards through testing, quality assessmentand an inspection ofa numberof sampleddevicesintendingtobeexported.Acertificateof con-formityisissueduponasuccessfulassessmentoftheexamined batch. This process is carried out by pre-shipmentagents: in this case, the UNBS entrusts the Société Générale de Surveil-lance (SGS),the Bureau Veritasand the IntertekInternational Ltd.Thissecondrouteisfaster.

Kenya– EastAfrica

Medical device regulation has been a point of contention in Kenya for a while, where different bodies are given the author-ityfordifferentaspects.Until recently,thePharmacyandPoisons Boardhasbeenimplementingandenforcingsomeaspectsof med-ical device regulations based on a 2002 act of parliament. The Boardis responsibleforregistrationofmedicaldevicesthatenter themarket.TheBoarddoesnothaveitsownguidelinesbutadopts those oftheGHTF,European MDD93/42/EEC,AIMDD90/385/EEC andIVDMDD98/79/EC,andtheUSFDAandAustraliaTherapeutics

Goods Act [24] . A new Health Bill is pending and all regulatory bodieshavebeenputonhold.UnderthenewHealthBill,the Min-istryofHealthwillultimatelybethemainregulatorybody.TheBill willallow fora unifiedhealth systemthat shouldcoordinate the inter-relationship between the National Government and County Government HealthSystems. Moreover, the Bill is to provide for theregulationofhealthcareservicesandserviceproviders,health productsandtechnologiesandforconnectedpurposes,inaddition to establishing a single regulatory body for regulation of health products andhealthtechnologies. Thisregulatory body will over-seethelicensing ofhealth productsandtechnologies, andthe li-censing of manufacturers and distributors of health products. It willalsoregulatecontractorsformedicaldevicesandphysical se-curity for products including radioactive material and biological weapons.Article 31of theproposed HealthBilllooks atthe pro-curementofhealth products andtechnologies, whichwill be un-dertaken in line with the Public Procurement and Disposal Act [25] .

Nigeria– WestAfrica

pro-ducemedicaldevicesforsale inthecountry oforigin(Certificate ofManufacturerandFreeSale).Such evidencemustbe issuedby theCompetentAuthority ofthe countryof manufacture,and has to be authenticated by the Nigerian Embassy in that country. In countrieswherenoNigerian EmbassyorHighCommissionexists, anyotherEmbassyorHighCommissionofanyCommonwealthor WestAfricancountrycanauthenticate.

SouthAfrica– SouthernAfrica

South Africadoesnothaveacomprehensiveregulatory frame-workgoverningmedicaldevices.However, themarket isvery so-phisticated and it is strongly advisable that the product be FDA approvedorevenbetter, carrytheCEmark.Atpresent,only elec-tronic products (also known as electromagnetic medical devices orradiationemittingdevices) mustbe registeredbefore theycan besold,leased,used,operated,orapplied inSouthAfrica [27,28] . Thesedevicesmustberegistered withtheDepartmentofHealth, andmust havetheCE mark.FDAapprovedelectro-medical prod-uctswithouttheCEmarkarenotaccepted [28] .Theregistrationof medicaldevicesinSouthAfricaisgovernedbytheprovisionsand requirementsoftheMedicinesandRelatedSubstancesControlAct No.101of1965,andtheRegulations andGuidelinespublishedin termsthereof.CompliancewithlocalandinternationalMedical De-viceStandardsandConformityAssessmentStandardscanbeused todemonstratecompliancewiththemedicaldevicelegislative re-quirements.Theuseofthesestandardsisnotmandatory,butitis a wayto establish compliance with the regulatory requirements. The legislative framework adopts the IMDRF philosophy, and for this reason it adopted the Risk Classification System formulated by the GHTF. The Medicines Control Council is a statutory body that is appointedby the Minister of Healthfor ensuring that all products that are sold and used in South Africa are safe, thera-peuticallyeffectiveandconsistently meet acceptablestandards of quality.

Sustainableinnovationsinthemedicaldevicefield

AccesstonewproductsinAfricacanbedelayed,sometimesfor years,duetocomplex andcostlyrequirements forregulatory ap-provalinsome countries.In ordertoenableinnovationsinAfrica andinothercountrieswithanimmatureregulatorysystemwhile ensuringahighlevelofpatient protection,aswellasgivingvoice to the citizens and their needs, including those associated with rarediseases, possible alternatives have to be explored. We pro-posethat “Open Source MedicalDevices” (OSMDs), designed fol-lowingcollaborativestrategies,mayhelptoreducecostsfor devel-opingmedicaldevices,respecting theformal regulatoryprocesses, whilemaintainingatleastthesamesafetylevelsasEuropean de-vices.

Creating an OSMD means developing a medical device by sharing ideas and concepts, design files, documentation, source-code, blueprints and prototypes, testing results and all collected data, with other professional medical device designers. Advan-tages of the open procedure are its accessibility, sustainabil-ity, lower costs and, under ideal conditions, improved perfor-manceandsafetybecauseeveryonecanreview thedesigndossier [29] .

While a couple of years ago, the development of biomedical deviceswasessentiallylinked tocompaniesanduniversities,now severalexamplesofOSMDshaveappearedontheweb [30] ,on-line communitiessharegoodpractices [31] ,butseldomthesemedical devicesare designedto be compliant withsafety standards [32] . Thus,OSMDsareoftennotyetaccurateorsafeenoughtobeused aspartofthemainstreamclinicalroutines.

This ismainlydueto thefact thatthe open movementprizes innovation,creativityandingenuitymorethancompliancetorules

andstandards, whichare not oftenfully known andvalued, and should be considered from the beginning of the development process. Nonetheless, OSMDs hold great promise because today, thanks to thecrowd-thinking andcrowd-sourcing paradigms,the design of open products has an intrinsic revision process, driven by a virtual community,composed ofa heterogeneous and large population,whichhas becomean activeplayer intheentire pro-cessofconceptiontoproduction [33] .However,biomedicaldevices doneedahighlevelofsupervision,tocontroltheirqualityandto guaranteetheirrespectforsafetystandards.

To promote OSMDs and to boost innovation across the EU and Africa, UBORA, a project funded by the EU, aims at devel-oping a Europe-Africa e-infrastructure for open-source co-design of new solutions to face the current and futurehealthcare chal-lenges of both continents (http://ubora-biomedical.org ). Accord-ing to the project vision, exploiting new ideas and sharing of safety criteria and performance data can be an innovative solu-tion to improve the current state of healthcare in Africa. Exam-ples ofbiomedical devicesunder developmentwithin UBORA in-clude:coolersforvaccines,systemsforthesterilizationofsurgical instruments,incubators for prematurebabies, breast pumpswith cooling andpreservation systems, 4D printed splints(3D printed andthen personally modifiedto suitpatients),polymeric devices fortreatingclubfoot,CPAPdevices,preventivemethodsformalaria [34] .

TheUBORAplatformenablesapeer-to-peer evaluationand ex-pert mentorship from Academia and Industry, before submitting thedocumentationtoaNB,fortheformalcertificationroute.This doublecheckofthedesignmightthenleadtosafermedical prod-ucts becauseboth a large communityand a regulatory authority areperformingtheevaluation.

The projects available for downloading in the UBORA e-infrastructurewillbesafeandcomplianttostandards,butwillnot bedefinedasa“product”,sincemanufacturingwillrequirefurther certification;howeverproductionandmarketingwillbegreatly fa-cilitated.AnexampleofthisprocessistheGammaCardio electro-cardiograph [35] ,anopen source,certifiedmedicaldeviceproject, which can be placed on the market only by manufacturers who haveobtainedthecertification:each newmanufacturermust im-plementrepeatableandapprovedmanufacturingandcontrol pro-ceduresandgetitsowncertification.

Standards from the International Standard Organization (ISO) andtheInternationalElectrotechnicalCommission(IEC) constitute thestateoftheart,areverywidespreadandhaveproventoensure aminimumsatisfactorylevelofpatientsafety.Forthisreason,they probablyprovidethemostpreferablereferencedocumentsfor de-signingsafemedical devices.Itcan beargued that standardscan alsobeproduced anddistributedas“open” inthemedicaldevice field. Thedefinitionofopen standardshasbeenwidely discussed in the software field [36] , with an influential position taken by World Wide WebConsortium, which can beseen asa modelfor openstandards [37] .

Emergingtechnologiesandrelatedstandardizationchallenges

Several emerging technologies are synergic with open source strategiesandcanfacilitatetheemergenceofasustainablemedical industry anda moresocially-responsiblewayofinnovating medi-cal technologies. Additivemanufacturing technologies(AMTs)and smartphones andmobile technologieshave beensuccessfully ap-pliedinthemedicalfield [38,39] ,however,regulation-related chal-lengesstillexistforadequately(andsafely)exploitingalltheir po-tentials.

Forinstance, surgicaltraining, diagnostic models, personalized smart prostheses for soft and hard tissue repair and ad hoc er-gonomic appliances are already well-established biomedical ap-plications of AMTs [40] . Furthermore,in recent years, in parallel with theexpiry of severalpatents frompioneeringcompanies of the AMTs sector, thesetechnologies are undergoing a “democra-tization” process and open hardware approaches have reshaped this field, leading to collaborative design environments (e.g. the RepRap wiki, http://reprap.org ) and to the development of low-cost AMTs. In turn, this has led to the worldwide expansion of “fab-labs” ordigitalfabrication laboratories,which support inven-torsanddesignersinprototypingandsometimesinmanufacturing thefinalproducts.Thesenetworksoflaboratories,ifadequately or-ganized, can constitute a powerful tool forpromoting a delocal-ized production of medical devices and for bringing richness to remote regions, helping to shift from mass-production of medi-caldevicestomass-personalization [41] .Theteaching-learning im-plications of these fab-labs, for training a cohort of responsible biomedical engineers worldwide, capable of mentoring (together withmedical professionals)the requiredinnovations forthe suc-cessfulfutureofanopensourcebiomedicalindustry [42] ,arealso noteworthy.Iffab-labsaretoprovidenewalternatives for manag-ingthesupplychainandsupportingopensourcebiomedical prod-ucts, or if the hospitals of the future are to count on advanced engineering laboratories for promoting personalized manufacture ofmedicaldevices,severalregulatoryquestionsarise.Medical de-vice classification does not change if the device is manufactured using traditional methods or AMTs. Rethinking AnnexVIII of the MDDwithspecificguidelinestotakeintoaccounttherelevanceof these technological resources will facilitate their custom applica-tiontopatients,whileguaranteeingsafety.Forinstance,anoption for promoting AMTs and fab-labs and their synergies with open medicaldevicesisto shiftfromproduct-based toamaterial- and process-based regulation, as it is already happening in the den-tal sector [43] . For instance, we can cite the recently developed FDA Technical Considerations for Additive Manufactured Medical Devices [44] . The document provides non-binding recommenda-tionsforfulfillingcurrentFDAregulationswhenusingthese inno-vativetechniquesforthedevelopmentofmedicaldevices.Among theproposedactions,thedocumentgivesguidancefor:designand manufacturing procedures, both forgeneral and for personalized devices, software-related processes, performing material controls, post-processing steps, final device testing and validation, overall secure data management, labelling and even eco-impact assess-ment.Weenvisionasimilarorientationbutwithanextended ap-proach, soas to providean adequate regulatory environment for medical devices developed in a personalized way, taking advan-tage of open-source approaches and involving global communi-tiesof collaboratorsandmanufacturers.Besides, thecomponents, materials and processes should be traceable, for which the use of collaborative development frameworks (such as the Ubora e-infrastructure)maybeuseful.

Smartphone based medical applications can be simple “apps” advising users to adopt healthier life styles, mainly relying on countingsteps andallowing userstointroduce informationabout theircalorieintake.Morecomplex“apps” fordiagnosticand

thera-peuticmonitoringmakeuseofthesmartphone’ssensingelements (camera,accelerometers,microphone…),ormay,insomecases,be supportedby externalsensing-actuating kits.Theycanhelp users andmedicalprofessionalstoperformmorecomplexmedicaltasks [45] .

Themorecomplexcombinationsofsmartphones,softwareand supporting kits, are considered medical devices. Some of these appsmayevenreachClassIIIandmustcomplywithavailable reg-ulationsbeforetheyareused [46] .

TheFDAseemstohavetakentheleadintheregulationof mo-bilehealthtechnologiesandofthemedicalapplicationsof smart-phonesingeneral [47] ,whiletheEU’snewRegulationonMedical Devicesplaysmuchattentiontomedicaldevicesoftware(SW).The harmonizedstandardIEC62304definesrestrictiverulesontheSW lifecycle,forensuringsafetyrequirements.

Openhardwareapproachesandthecapabilitiesofmobile tech-nologies,especiallyofsmartphones,canopen newhorizonsinthe biomedical field as well as promoting quality healthcare for all. BothEurope,withauserpenetration ofsmartphonesalready be-yondthe64%in2017 [48] ,andAfrica,withanexpecteduser pen-etrationof mobile phones up to a 76% in 2020 [49] , can greatly benefitfromtheuseofmedicalappsandmobilehealth technolo-giesforaddressingglobalhealthissues.

Conclusion

Accesstosafebiomedical devicesensuresequitable healthcare forall and is guaranteed by regulations. However, implementing regulationsandcomplying withthem placesan economicburden ondevelopers,manufacturersandresearchers.Indeveloping coun-tries,poorregulatorycontrolresultsintheuseofsubstandard de-vices,andoftenitbecomesaconstraintforthosewantingto pro-duce, sell, oreven donate these devices. Ourfindings show that AfricanmedicaldeviceregulationshaveanaffinitytoEuropean di-rectives,despitethefactthattheyareparticularlystrict.Itwas ob-served that mostABEC countriesalreadyhave a NRAin place to control and medical devices. Most of these states have also im-plementedorharmonizeddirectivesto medicaldeviceregulation, orhaveexpressedinterestinestablishingthemintheirlegislation. Nevertheless they need adequately trained biomedical engineers forconsultation,andABECwasformedinrecognitionofthisneed. Asreportedin Fig. 5 ,harmonizingregulationsleadstomultiple benefits.Regulatory authorities willbenefit intermsof improved expertise,collaborationwithother regulatory authorities and op-erational efficiency through sharing of information and recogni-tionofestablishedregulatory authoritydecisions.Healthcare pro-fessionalswill benefitthrough the availability of moretreatment optionsinordertooptimisepatientmanagement.The biomedical industry willbenefit through theaccessto newmarkets andthe improvedabilitytocomplywithregulatoryrequirementsrelatedto devicesregistration.Patientswillbenefitthroughimprovedsupply ofdevices,access tohighquality devices that complywithstrict requirements of safety, quality and efficacy and reduced risk of useofunsafedevices.Supranational initiatives,such asthe Inter-nationalMedicalDeviceRegulatorsForumarecurrentlydeveloping internationallyagreedupondocumentstofacilitatethe harmoniza-tionofaffectingmedicaldevices.

Inaddition to harmonization, to furthersave costs and main-tainahighersafetylevel,OSMDmightbeanoption,buttheystill needcertificationtobeplacedonthemarket.Projects,suchas UB-ORA,aretryingtoconveythestrengthofthisapproachprovidinga frameworktodesignprojectswhichrespectsafetystandards.They canalsobeusedasateachingtool forcapacitybuildingoffuture biomedicalengineers.

Fig.5. Impactsofharmonization.

humanhealth improvement,aswell to asStandardDevelopment Organizations to provide support, means and expertise to OSMD designfordevelopingeconomicallysustainable, safeandeffective healthcaretechnology.

Acknowledgement

This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreementNo 731053 ,UBORA.

AuthorStatements

Funding

This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreementNo731053,UBORA.

Competinginterests

Authorshavenoconflictofinteresttodeclare.

Ethicalapproval

Notrequired.

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CarmeloDeMariaisanassistantprofessorofbioengineeringatintheDepartment ofIngegneriadell’InformazioneEngineering,attheUniversityofPisa,Italy,and affil-iatedwiththeResearchCenter“E.Piaggio.” Heisaguestprofessorin bioengineer-ingatAddisAbabaUniversity,Ethiopia,andmemberoftheAfricanBiomedical En-gineeringConsortiumsecretariat.Hisresearchinterestsareinthefocusonadditive manufacturing/rapidprototypingtechnologies,withaparticularfocusin biofabrica-tion.Hehaspublishedmorethan30papersandin2016hereceivedtheYoung In-vestigatorAwardfromtheInternationalSocietyforBiofabrication.DeMariaisalso co-founderandpresidentoftheFabLabPisa.

LiciaDiPietroiscurrentlyaresearchfellowatResearchCentreE.Piaggioof Uni-versityofPisa,Italy.ShereceivedtheBachelorandMasterDegreeinBiomedical En-gineeringfromUniversityofPisa,Italy,in2014and2017,respectively.In2016she hasenrolledanErasmusforTraineeshipprogramatHilditchGroupatMalmesbury, England,workingonherMasterThesisprojectentitled“Differentapproachesto im-provehealthcareinAfricathroughBiomedicalEngineering”.Duringthisperiod,she spentonemonthinKampala,Uganda,workingasvolunteerwithAmaltheaTrust Foundation,tohelpprovideforthesustainablemaintenanceofmedicalequipment

throughtheprovisionoftrainingprogramsfortherecipients,includingtest equip-mentandworkshopfacilities.HerresearchinterestincludesGlobalHealthwith par-ticularattentiontodevelopingcountries.Sheisworkingonmanufacturingof open-sourceandlowcostmedicaldevices,compliantwiththeInternationalstandardsto assurethesafety,qualityandperformanceofmedicaldevices.

AndrésDíazLantadaisProfessorintheDepartmentofMechanicalEngineeringat ETSIIndustriales– UPM.Hisresearchactivitiesareaimedatthedevelopmentof biodevicesusingmoderndesign,modelingandmanufacturingtechnologiesandhe incorporatestheseresultstosubjectslinkedtoproductdevelopment.Heis Edito-rialBoardMemberoftheInternationalJournalofEngineeringEducationandCDIO contactatUPM.Hehasreceivedthe“TUMadridYoungResearcherAward” andthe “TUMadridTeachingInnovationAward” in 2014andthe “MedaloftheSpanish AcademyofEngineeringtoYoungResearchers” in2015.

JuneMadeteisaBiomedicalEngineerspecializinginbiomechanics,aresearcher andsenior lectureratKenyatta Universitywithspecial interestandexpertisein collections,analysisandinterpretationofgaitdatausingvariousmotionanalysis softwareandhardware.Herresearchinvolvescombinationofthesetechniqueswith animalresearchinthefieldofeuroscience,videofluoroscopy,x-rayandCTdata. In2011–2012,shedidastudythatlookedataspecificgroupofpatientswho un-derwenttotalkneereplacement,thestudyaimedatunderstandingtherelationship betweensurgicalaccuracyandjointfunction.Sheseekstodevelopbiomechanics withinKenya.

PhilippaNgajuMakoboreisanElectricalEngineerand iscurrentlythe Depart-mentHeadoftheInstrumentationDivisionattheUgandaIndustrialResearch In-stitute(UIRI).Herteamcomprisesofelectricalandcomputerengineersthatdesign anddevelopelectronicapplicationsforHealthcare,AgricultureandEnergy.Todate theDivision’sportfoliohasover7projects,whichshesupervises,with3medical deviceprototypesintheiradvancedstages.Theseprojectshavewonboth interna-tionalandlocalawardsincludinga1stplaceInnovationAwardatthe2016World PatientSafety,ScienceandTechnologySummit.

MannanMridhaisaSeniorResearcheratKTH(RoyalInstituteofTechnology)in Stockholm.WithmeritscholarshipsacquiredM.Sc.Eng.degreefromWarsaw Tech-nicalUniversity,Ph.D.andM.Ed.degreefromLinköpingUniversityinSweden.He hasworking experiencewith teachingandresearchinBiomedicalengineeringat theUniversityofLinköping,KTH– RoyalInstituteofTechnology,Universityof Ox-fordand TokyoUniversity.Hestronglybelievesintheimportanceofpreventive healthcarethrougheducationutilizingthedigitaltechnology.

AliceRavizza,biomedicalengineer,startedhercareerasR&Dforamanufacturerof disposableplasticmedicaldevices,spendingmorethan10yearsandcovering po-sitionsfromResearchandDevelopmenttoQualityAssuranceandRegulatory.She iscurrentlyaconsultantforcompaniesandstartupsforDesign,Developmentand RegulatoryplanningofinnovativemedicaldevicesandforQualityManagement Sys-tems.SheisRegulatoryconsultantoftheUBORAprojectbasedinUniversityofPisa andregularlyholdsseminarsinvariousItalianuniversitiesaboutRegulatoryand Biocompatibilityaspectsofmedicaldevicedesign.

JannoToropreceivedhisPhDfromUniversityofTartuin2012.Hehasbeen de-velopingsmartelectromechanicalactuatorsinUniversityofTartu,Instituteof Tech-nologysince2006.HeiscurrentlyaresearchscientistofInstituteofTechnology, UniversityofTartu.In2013hejoinedasapostdocresearchertoBiosensorsand Bio-electronicsCentreinLinköpingUniversity,Sweden.Hisresearchinterestsaresmart electromechanicalpolymericactuatorsandenergyconversiondevicesutilizing mi-croporouscarbonsasactiveelectrodematerial.