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Door Evert Jan van Lente.

Inleiding

De Koninklijke Nederlandse Academie van Wetenschappen (KNAW) heeft een adviescommissie ingesteld met de opdracht: hoe kan wetenschappelijk onderzoek op het gebied van geneesmiddelen bijdragen aan duurzame, zinvolle en betaalbare zorg. Het rapport hierover verscheen onlangs (KNAW (2026). Wetenschap als recept. Het belang van wetenschap voor passende geneesmiddelenzorg. Amsterdam, KNAW” (hier te downloaden)), Dit rapport richt zich op beleidsmakers, zorgverleners, onderzoekers, patiëntenorganisaties, zorgverzekeraars en onderzoekfinanciers. Het rapport geeft een volledig overzicht over het proces van ontwikkeling, goedkeuring en toezicht. Het beschikbaar maken van passende, nieuwe geneesmiddelen en het bewaken van het gebruik daarvan zijn terecht een gebied van toegepaste wetenschap. De wetenschappelijke benaderingen die in de verschillende fasen van een nieuw product worden beschreven worden al toegepast, maar zouden kunnen worden geïntensiveerd en gerichter worden ingezet. Een groot deel van het proces vindt op Europees niveau plaats. De vraag is hoe met behulp van de wetenschap invloed uitgeoefend kan worden op de kwaliteit en veiligheid van geneesmiddelen. Dit artikel bespreekt het onderzoek dat al wordt uitgevoerd door Europese en nationale instellingen en gaat in op de complexe randvoorwaarden die een uitdaging vormen voor wetenschappelijke methoden.

Ontwikkelingen

De ontwikkelingen op dit terrein zijn zeer dynamisch. Gepersonaliseerde therapieën, nieuwe cel- en gentherapieën en kunstmatige intelligentie spelen een steeds belangrijkere rol. In het verleden richtte onderzoek naar nieuwe geneesmiddelen zich voornamelijk op grote patiëntengroepen, zoals patiënten met hart- en vaatziekten en diabetes. Grote, hoogwaardige gerandomiseerde, gecontroleerde studies zijn hiervoor bij uitstek geschikt. Tegenwoordig zijn er steeds meer weesgeneesmiddelen en geneesmiddelen die op basis van hun potentieel belang voor patiënten een versneld goedkeuringsproces doorlopen (Break-Through” geneesmiddelen). Dat leidt ertoe dat goedkeuring van nieuwe geneesmiddelen zich vaak op studies baseert, die de werking ervan met surrogaat parameters, kleine onderzoekspopulaties en soms zonder controle groep (zouden moeten) bewijzen. Dit is onderzocht: de Society for Clinical Trials (SCT) heeft een studie gepubliceerd van goedkeuringen door de Europese Geneesmiddelen Agentuur (EMA) van 2020 tot 2023. In deze periode werden 227 nieuwe geneesmiddelen goedgekeurd. Daarvan had 30,4 % de status van een weesgeneesmiddel, 23,3 % werd in een versneld proces goedgekeurd. 54,6 % baseerde uitsluitend op surrogaat parameters en 69% op klinische parameters. De harde uitkomstmaten, zoals “gewonnen levensjaren” en “gewonnen jaren met een goede levenskwaliteit”, kunnen in de studies, die slechts enkele jaren omvatten, niet of niet voldoende aangetoond worden. Er werden producten goedgekeurd, die de primaire uitkomstmaat niet konden aantonen. De EMA beargumenteerde voor de goedkeuring in deze gevallen meestal met het geheel van evidentie, secundaire eindpunten of klinische beoordeling (zie alhier). De EMA wordt vaak bekritiseerd vanwege de lakse criteria, maar deze beslissingen worden genomen door vooraanstaande deskundigen van alle nationale geneesmiddelenagentschappen in de EU.

Het belang van het EMA

Dit onderstreept het belang van het EMA, dat via zijn gecentraliseerde autorisatieprocedure de toegang tot de Europese markt voor vrijwel alle nieuwe geneesmiddelen reguleert. In tegenstelling tot de Amerikaanse Federal Drug Administration (FDA) heeft het EMA een gedecentraliseerde structuur met een onafhankelijke raad van bestuur waarin elke EU-lidstaat vertegenwoordigd is. De dossiers voor de handelsvergunning van nieuwe geneesmiddelen worden doorgaans beoordeeld door twee EU-lidstaten met ondersteuning van EMA-deskundigen. De beslissing wordt uiteindelijk genomen door het Comité voor geneesmiddelen voor menselijk gebruik (CHMP), dat bestaat uit vertegenwoordigers van alle EU-lidstaten. Nederland is vertegenwoordigd door het College ter Beoordeling van Geneesmiddelen (CBG). De onafhankelijke vertegenwoordigers van de EU-lidstaten zijn ook rechtstreeks betrokken bij beslissingen over de eisen van het EMA aan studies, de wijze waarop bedrijven wetenschappelijk advies ontvangen, de autorisatieprocedures en het toezicht op geneesmiddelen op de markt. Bij de beoordeling van nieuwe producten worden internationaal erkende wetenschappelijke normen toegepast. De uiteindelijke beslissing over de vergunning is gebaseerd op de afweging van voordelen en risico’s en is complex en veelzijdig, en geen puur kwantitatieve kwestie met vaste drempelwaarden. Maatschappelijke aspecten spelen hierbij een rol, bijvoorbeeld of er een onvervulde medische behoefte is en de patiëntenwaarde in ruime zin. De prijs van het nieuwe product is niet relevant voor de goedkeuring ervan. Deze wordt wel meegenomen in de HTA-beoordeling (Health Technology Assessment) en is belangrijk voor de opname ervan in het zorgpakket. HTA wordt eveneens op EU niveau geharmoniseerd.

De EU heeft ook een belangrijk platform geschapen waar wetenschap, industrie, patiëntenorganisaties en regulatoren samen prioriteiten vastleggen voor onderzoek. Dit platform is het grote Public-Private-Partnership Innovative Health Initiative (IHI). Het belangrijkste doel is om medische innovatie te stimuleren, het concurrentievermogen van het Europese farmaceutische onderzoek te versterken en in te spelen op onvervulde medische behoeften.

De industrie en de EMA

Farmaceutisch onderzoek vereist aanzienlijke investeringen, die grotendeels door de industrie worden gedragen. De ontwikkeling van een veelbelovend nieuw product kost miljoenen euro’s, zonder enige garantie dat de werkzaamheid en veiligheid ervan bewezen kunnen worden. Het risico zulke kosten in het geval van mislukken af te moeten schrijven kan de overheid niet nemen. De grote farmaceutische bedrijven kunnen risicokapitaal aantrekken en zo deze studies financieren. De industrie heeft er groot belang bij om zo snel mogelijk marktgoedkeuring te verkrijgen, aangezien de winstgevende fase eindigt met het verstrijken van het patent of andere wettelijke bepalingen. Dat betekent dat het bedrijf dat het product op de markt wil brengen zeer geïnteresseerd is in het door de EMA of nationale agentschappen aangeboden wetenschappelijk advies. Maar hoe het studieontwerp uiteindelijk vastgelegd wordt, inclusief dosering, doelgroep en de duur van de therapie, wordt uiteindelijk door het farmaceutisch bedrijf bepaald. Het is niet uit te sluiten, dat hierbij ook commerciële overwegingen een rol spelen. Het is dan aan de EMA om te beoordelen of de ingediende studies een positieve balans van voordelen en risico’s aantonen. Wanneer de EMA het product op grond van onvoldoende evidentie afwijst, wordt het product niet beschikbaar voor patiënten. Een tweede grote zogeheten fase 3 studie zal in de regel niet gemaakt worden. Dit dilemma wordt duidelijk bij de beoordeling van twee nieuwe geneesmiddelen ter behandeling van Alzheimer in een vroeg stadium (zie alhier). Het is overduidelijk welke enorme verantwoordelijkheid op het desbetreffende commitee (CHMP) van de EMA rust. Door het studieontwerp bepaalt het farmaceutisch bedrijf ook hoe het product in de klinische praktijk gebruikt kan gaan worden. Afwijking van de aanbeveling van het bedrijf betekent een risico voor de artsen, omdat een ander gebruik niet door een wetenschappelijk onderzoek gedekt is.

De Nederlandse overheid en de EMA

De Nederlandse overheid kan de wetenschappelijke basis van de geneesmiddelenregulering op verschillende gebieden beïnvloeden. Zij kan echter geen directe invloed uitoefenen op het EMA, aangezien de vertegenwoordigers van de CBG onafhankelijk zijn. De onafhankelijkheid van de EMA van politieke invloed is ook een belangrijk kenmerk. In de Verenigde Staten heeft het FDA onder President Trump zijn onafhankelijkheid verloren en de politiek beïnvloedt FDA beslissingen. Dit brengt aanzienlijke risico’s voor de volksgezondheid met zich mee.

De overheid kan fundamenteel onderzoek stimuleren. De farmaceutische industrie deed in het verleden zelf ook fundamenteel onderzoek. Tegenwoordig vindt het fundamentele onderzoek vooral aan universiteiten of andere wetenschappelijke organisaties plaats, die meestal door de overheid gefinancierd worden. Farmaceutische bedrijven werven vaak wetenschappers van universiteiten, die met potentieel nieuwe therapieën werken om zelf nieuwe producten te ontwikkelen. Regelmatig richten wetenschappers zelf een bedrijf op (“spinn-off”) om zelf een nieuw product te ontwikkelen. Zulke spin-offs worden dan ook vaak in een later stadium door grote farmaceutische bedrijven gekocht. Grote studies en de autorisatie processen in de verschillende landen over de hele wereld kan een klein bedrijf zelf in de regel niet bewerkstelligen.

De overheid heeft de mogelijkheid fundamenteel wetenschappelijk onderzoek in Nederland te bevorderen door meer financiële middelen ter beschikking te stellen en kan invloed uitoefenen op de prioriteiten om zo maatschappelijk relevante problemen, zoals de ontwikkeling van nieuwe antibiotica, of het ontwikkelen van geneesmiddelen voor kinderen te stimuleren. Ter dekking van hogere kosten voor fundamenteel onderzoek kan een regeling op EU-niveau geïnitieerd worden, die farmaceutische bedrijven verplicht een deel van de winst die met fundamentele ontdekkingen van universitaire instituten gemaakt worden te delen met de overheid, die dit fundamentele onderzoek gefinancierd heeft. De overheid kan ook onderzoek financieren dat gefocust is op aspecten waarvoor de industrie geen interesse heeft nadat een product de toelating ontvangen heeft. Zo kan de basis voor een zinvolle dosering, differentiëring van patiëntengroepen, etc. nader onderzocht worden. De wetenschappelijke basis kan dan gelegd worden voor gebruik van het nieuwe geneesmiddel dat afwijkt van het in het goedkeuringsproces onderzochte gebruik.

Ook kan de overheid de omgeving scheppen waarin onderzoek succesvol plaats kan vinden. Daarvoor is het nodig dat gepseudonimiseerde gegevens centraal beschikbaar zijn, ook voor secundair gebruik door wetenschap of farmaceutische bedrijven. In Duitsland is het Forschungsdatenzentrum Gesundheit (FDZ Gesundheit) bij de Duitse geneesmiddelen agentuur (BfArM) opgericht om deze taken te verrichten. De FDZ Gesundheit zal ook aanvragen beoordelen. Als overheidsinstantie kan ervoor gezorgd worden, dat de hoogste standaarden voor gegevensbescherming gehandhaafd worden.

Wat de goedkeuringsprocessen bij de EMA betreft, kan de overheid ondersteunen door een versterkte inzet van het CBG bij de behandeling van dossiers van nieuwe producten. Ook ondersteuning van het onderzoek bij de EMA, hoe bij de marktautorisatie voor een product voor een kleine patiëntengroep de beste evidentie gegenereerd kan worden, eventueel ook met studies op basis van hoe het product in de klinische praktijk werkt, is denkbaar. De EMA werkt intensief aan de vraag hoe “real world evidence”, met “real world data” gegenereerd kan worden. Dit is gedocumenteerd in een recent artikel in JamaNetwork Open.

De overheid kan ook onderzoek stimuleren, dat het optimale gebruik van geneesmiddelen regelt. Hierbij gaat het om de doelgroep, de dosering en de duur van de therapie. Met wetenschappelijk onderzoek kan beoordeeld worden hoe sterk de wetenschappelijke evidentie uit de goedkeuringsstudies is en welke andere relevante studies gepubliceerd zijn. Dit kan dan in de medische richtlijnen opgenomen worden, die artsen voor het dagelijks klinische werk nodig hebben. Deze wetenschappelijke ontwikkeling kost geld en moet voldoende financiële ressources hebben.

Pakket en prijs

Op basis van de HTA beoordeling wordt beslist of het nieuwe product in het zorgpakket opgenomen wordt en welke prijs betaald kan worden. Dit is een nationale competentie en de overheid laat zich adviseren door het Zorginstituut Nederland (ZIN), dat de wetenschappelijke beoordeling maakt. De Nederlandse overheid is al zeer effectief in deze rol, omdat het prijsniveau van nieuwe geneesmiddelen in Nederland substantieel lager is dan bijvoorbeeld in Duitsland.

Kortom

Het rapport van de KNAW biedt een groot overzicht van het boeiende terrein van de geneesmiddelen evaluatie en regulering. Het is een zeer dynamisch, multidisciplinair wetenschapsgebied, dat zeer interessante en toekomstgerichte mogelijkheden voor onderzoekers biedt. Voor Nederland relevant onderzoek vindt zowel op nationaal als op Europees niveau plaats. Beleidsmakers, zorgverleners, onderzoekers, patiëntenorganisaties, zorgverzekeraars en onderzoekfinanciers moeten zich bewust zijn welke maatregelen op welk niveau effectief genomen kunnen worden.

En als bonus kan de wetenschap ons soms helpen met een advies gewoon koffie te drinken (zie alhier).

Over de auteur

De Nederlander Evert Jan van Lente is in eigen land opgeleid tot gezondheidseconoom. Hij werkt sinds dertig jaar in de Duitse zorgsector. Hij was bij de grootste verzekeraar AOK verantwoordelijk voor zorgaankoop en innovatieve projecten. Hij behartigde zeven jaar de belangen van de Duitse zorgverzekeraars in Brussel en was één jaar werkzaam bij de Europese Geneesmiddelen Agentschap (EMA). Sinds 1999 werkt hij ook als internationaal consultant in gezondheidsprojecten in het kader van de ontwikkelingssamenwerking. In al die jaren volgde hij op de voet de ontwikkelingen in zijn geboorteland.

Zoektermen op internet: 

Evert Jan van Lente, beleidsontwikkeling, KNAW rapport Wetenschap als recept 2026, passend gebruik geneesmiddelenbeleid, EMA versnelde toelatingsprocedures surrogaatparameters, CBG onafhankelijke geneesmiddelenbeoordeling CHMP, Innovative Health Initiative IHI farmaceutisch onderzoek, Real World Evidence geneesmiddelen JAMA Network Open, Zorginstituut Nederland HTA pakketbeheer, financiering fundamenteel medisch onderzoek spin-offs, Alzheimer medicatie CHMP dilemma, Forschungsdatenzentrum Gesundheit gezondheidsdata Duitsland.