How the post trial acess issue has progressedthroughout the world in recent years

Fanny Nascimento Moura Viana

Sanitary point of view on post-trial access

DEVELOPMENT OF A NEW MEDICINEDEVELOPMENT OF A NEW MEDICINE

DRUG DISCOVERY

PRE-CLINICAL

Synthesis Identification of targets

In vitro testing

Pharmaco dynamics

Pharmaco kinetics

Toxicology

DEVELOPMENT OF A NEW MEDICINEDEVELOPMENT OF A NEW MEDICINE

Pharmaco techniques Clinical Trials

Approval/ registration Postmarketing

Formulation Phase I Phase IIIPhase IIApproval/

registration Phase IV

USE OF MEDICINES IN BRAZILUSE OF MEDICINES IN BRAZIL

In In BrazilBrazil, , productionproduction, marketing , marketing andand use use ofof medicines medicines cancan onlyonly bebe mademade afterafter grantinggranting sanitarysanitary registrationregistration byby thethe MinistryMinistry ofof HealthHealth..

SituationsSituations wherewhere unprovenunproven medical medical therapiestherapies is is permittedpermitted::

ClinicalClinical TrialsTrials

CompassionateCompassionate UseUse

ExpandedExpanded Access Access

PostPost trialtrial AccessAccess

CLINICAL TRIALSCLINICAL TRIALS

INSTANCE FOR APPROVAL OF CLINICAL TRIALS IN BRAZILINSTANCE FOR APPROVAL OF CLINICAL TRIALS IN BRAZIL

ETHICSETHICS

CEPsCEPs/CONEP/CONEP

HEALTH HEALTH SURVEILLANCESURVEILLANCE

LEGISLATION FOR REGULATORY LEGISLATION FOR REGULATORY CLINICAL TRIAL IN HUMANSCLINICAL TRIAL IN HUMANS

Law 6360/76 Law 6360/76 –– HEALTH SURVEILLANCEHEALTH SURVEILLANCE

RDC 39/2008Clinical Trials

R CNS 196/1996Humans

R CNS 292/1999Foreign cooperation

R CNS 301/2000Placebo

RDC 305/2002TSEs/ BSE

RDC 68/2003TSEs/ BSE

R CNS 346/2005CEP-CONEP

R CNS 251/1997Thematic area: new drugs

R CNS 340/2004Human Genetics

RDC 81/2008Import

R CNS 370/2007CEP-CONEP

IN 04/2009GCP

RDC 17/2010GMP

APPROVAL OF CLINICAL TRIALS IN BRAZILAPPROVAL OF CLINICAL TRIALS IN BRAZIL

-- SponsorSponsor-- CRO/ORPCCRO/ORPC

DOSSIERDOSSIER CEP(IRB)CEP(IRB)

JUDGEMENTJUDGEMENT

DOSSIER + IRB JUDGEMENTDOSSIER + IRB JUDGEMENT

EXPANDED ACCESSEXPANDED ACCESS

WithWith thethe adventadvent ofof thethe AIDS AIDS epidemicepidemic, , AIDS AIDS activistsactivists demandeddemanded whatwhat theythey calledcalled

““expandedexpanded accessaccess,,”” arguingarguing thatthat AIDS AIDS patientspatients whowho werewere notnot enrolledenrolled in a in a clinicalclinical trialtrial shouldshould

bebe allowedallowed to to taketake experimental experimental drugsdrugs underunder thethe supervisionsupervision ofof theirtheir personalpersonal physiciansphysicians..

(GROOPMAN, J., 2006)(GROOPMAN, J., 2006)

In In BrazilBrazil, , thethe conceptconcept ofof ExpandedExpanded Access Access waswas defineddefined in 1999:in 1999:RDC 26RDC 26 ((decemberdecember 17)17)

EXPANDED ACCESSEXPANDED ACCESS

ConceptConcept

SponsoredSponsored processprocess ofof providingproviding newnew productproduct, , promisingpromising, , notnot yetyet approvedapproved in in thethe NationalNational HealthHealth

SurveillanceSurveillance AgencyAgency, , whichwhich is inis in phasephase III III developmentdevelopment in in BrazilBrazil oror in in thethe country country ofof originorigin, for , for patientspatients withwith seriousserious

illnessesillnesses andand lifelife threateningthreatening, in , in thethe absenceabsence ofof satisfactorysatisfactory therapeutictherapeutic alternativesalternatives availableavailable in in thethe country, country, withoutwithout

additionaladditional costcost to to thethe patientpatient..

RDC No. 26, December 17, 1999

COMPASSIONATE USECOMPASSIONATE USE

In cases In cases ofof researchresearch involvinginvolving situationssituations for for whichwhich therethere is no is no establishedestablished treatmenttreatment ("("HumanitarianHumanitarian use" use" oror

""compassionatecompassionate") ") couldcould bebe authorizedauthorized to release to release thethe productproduct in in anan emergencyemergency,, provided there has been approval by the provided there has been approval by the

CEP, CONEP and ratified by the SVS / MS.CEP, CONEP and ratified by the SVS / MS.

ResolutionResolution ofof NationalNational HealthHealth CouncilCouncil (CNS) (CNS) No. 251, August 7, 1997.No. 251, August 7, 1997.

COMPASSIONATE USECOMPASSIONATE USE

TheThe compassionatecompassionate use is use is alsoalso characterizedcharacterized

byby thethe use use ofof unprovedunproved medical medical therapiestherapies outsideoutside thethe

contextcontext ofof clinicalclinical trialtrial to to patientspatients withwith seriousserious illnessesillnesses andand

lifelife threateningthreatening thatthat havehave no no therapeutictherapeutic alternativealternative

registeredregistered in in thethe country, country, butbut thethe authorizationauthorization is for is for eacheach

individual individual patientpatient differentlydifferently expandedexpanded accessaccess programsprograms..

POST TRIAL ACCESSPOST TRIAL ACCESS

ContinuedContinued use use byby participantsparticipants in a in a surveysurvey afterafter thethe conclusionconclusion ofof clinicalclinical trialstrials..

DECLARATION OF HELSINKI DECLARATION OF HELSINKI

“The protocol should describe arrangements for post-study access by study subjects to interventions identified as beneficial in the study or access to other appropriate care or benefits”.

COUNCIL FOR INTERNATIONAL ORGANIZATIONS OF MEDICAL COUNCIL FOR INTERNATIONAL ORGANIZATIONS OF MEDICAL SCIENCES (CIOMS)SCIENCES (CIOMS)“Additionally, if an investigational drug has been shown to be beneficial, the sponsor should continue to provide it to the subjects after the conclusion of the study, and pending its approval by a drug regulatory authority. ”

POST TRIAL ACCESSPOST TRIAL ACCESS

ContinuedContinued use use byby participantsparticipants in a in a surveysurvey afterafter thethe conclusionconclusion ofof clinicalclinical trialstrials..

RESOLUTION NO. 196/1996 (CNS)RESOLUTION NO. 196/1996 (CNS)The search should guarantee the return of benefits gained through research to the people and the communities where they are held.

RESOLUTION NO. 251/1997 (CNS)RESOLUTION NO. 251/1997 (CNS)The sponsor should ensure access for the drug under investigation for patients who have benefited from using.

POST TRIAL ACCESSPOST TRIAL ACCESS

BENEFITS OF RESEARCHBENEFITS OF RESEARCH

SeveralSeveral benefitsbenefits to to thethe communitycommunity::

Training Training ofof healthhealth workersworkers,,

ImprovementsImprovements in in thethe infrastructure,infrastructure,

ProvisionProvision ofof standard standard treatmenttreatment availableavailable,,

ProvisionProvision ofof publicpublic healthhealth measuresmeasures, , amongamong othersothers..

TheThe benefitbenefit ofof researchresearch notnot onlyonly directlydirectly relatedrelated to to thethe researchresearch subjectssubjects whowho participatedparticipated in in thethe studystudy..

DAINESI, S. M., 2006DAINESI, S. M., 2006

POST TRIAL ACCESSPOST TRIAL ACCESS

BENEFITS OF RESEARCHBENEFITS OF RESEARCH

The subjects in the study benefited clinically have the right toThe subjects in the study benefited clinically have the right to continue receiving free medication that brought a good for your continue receiving free medication that brought a good for your health, health, beyondbeyond the benefits that the study has brought to the the benefits that the study has brought to the community.community.

JÚNIOR, B. R. S., 2007

POST TRIAL ACCESSPOST TRIAL ACCESS

TheThe responsibilitiesresponsibilities ofof thethe sponsorssponsors do do notnot endend withwith thethe

completioncompletion ofof thethe studystudy, as , as theythey shouldshould provideprovide conditionsconditions ofof

securitysecurity andand monitoringmonitoring thethe use use ofof thethe drugdrug as as longlong as as

necessarynecessary whilewhile thethe researchresearch subjectsubject is is benefitingbenefiting fromfrom thethe

experimental experimental treatmenttreatment..

JÚNIOR, B. R. S., 2007

POST TRIAL ACCESSPOST TRIAL ACCESS

RISK MANAGEMENTRISK MANAGEMENT

-- Was the safety properly evaluated in studies in the early stagesWas the safety properly evaluated in studies in the early stages??

TheThe effectseffects ofof thethe drugdrug are are monitoredmonitored for short for short periodsperiods andand safetysafety assessmentassessment is is relatedrelated to to thethe studystudy periodperiod andand does does notnot extendextend thethe closedclosed..

GOLDIM, J. R., 2008GOLDIM, J. R., 2008

POST TRIAL ACCESSPOST TRIAL ACCESS

TOP QUESTIONSTOP QUESTIONS

-- HowHow longlong shouldshould suchsuch accessaccess postpost--studystudy??

-- Who is Who is responsibleresponsible for for providingproviding andand storingstoring thethe productproduct in in researchresearch??

-- HowHow to monitor to monitor andand reportreport adverseadverse eventsevents outsideoutside thethe contextcontext ofof a a controlledcontrolled clinicalclinical trialtrial??

-- Does a Does a singlesingle studystudy prove prove thethe efficiencyefficiency ofof a particular a particular interventionintervention??

-- Does the individual benefits correspond to the results obtained Does the individual benefits correspond to the results obtained in the study in the study as a whole?as a whole?

TheThe superioritysuperiority ofof a a newnew drugdrug mustmust bebe provenproven throughthrough a a statisticalstatistical analysisanalysis ofof surveysurvey data data andand notnot fromfrom thethe clinicalclinical evaluationevaluation ofof a a singlesingle patientpatient..

DAINESI, S. M., 2006 / 2009DAINESI, S. M., 2006 / 2009

• For cases where there is patient benefiting from the drug under investigation,

• Best alternative therapy,• The protocol does not provide an extension of the study

DONATION OF THE DRUG

SANITARY POINT OF VIEW ON POST-TRIAL ACCESS

www.anvisa.gov.br

Criteria and procedures:– Quantitative;– Final study report;– Letter explaining the need to execute the decision

recommended by the Resolution CNS 251/97;– Medical report;– Notification CEP;– Declaration by the sponsor :

• supply of study medication and safety evaluation.

DONATION OF THE INVESTIGATIONAL PRODUCT

www.anvisa.gov.br

194177

237

197

250

213

289

229

281

221

366

243

291

220

0

50

100

150

200

250

300

350

400

2003 2004 2005 2006 2007 2008 2009

Aprovação de Estudos Clínicos ANVISA

Estudos Submetidos à ANVISA para AprovaçãoEstudos Aprovados pela ANVISA

PROFILE OF REQUESTS

0

50

100

150

200

250

300

350

No.

of p

atie

nts

incl

uded

No. of patients included 73 316 109

EXPANDED ACCESS COMPASSIONATE USE POST TRIAL ACCESS

Requests approved by ANVISA to use unregistered drugs outside the context of clinical trial in the period from January 2008 to July 2010.

EXPANDED ACCESSEXPANDED ACCESS

ANTIRETROVIRAL82%

ANTINEOPLASTIC18%

Therapeutic class of expanded access programs authorized by ANVISA from January 2008 to July 2010.

COMPASSIONATE USECOMPASSIONATE USE

68%

28%

1%

1%

2%

0,31%

ANTINEOPLASTIC

ENZYME FOR REPLACEMENT

ANTIRETROVIRAL

ANTIVIRAL DRUGS

OTHER DRUGS ACTING ON THEVISION

Therapeutic class of compassionate use authorized by ANVISA from January 2008 to July 2010.

EXPANDED ACCESSEXPANDED ACCESS and COMPASSIONATE USECOMPASSIONATE USE

Status of registration of medicinal products authorized by ANVISA for use in programs of expanded access and compassionate use from January 2008 to July 2010.

Unregistered drugs in ANVISA15 (65%)

Registered drugs in ANVISA8 (35%)

POST TRIAL ACCESSPOST TRIAL ACCESS

- The donation of non-approved drugs may have been under-reported or under-counted,-The donation post-study can is covered in a program extension, which is nothing more than an extension of the research with the same subjects recruited.

NOTIFICATION OF THE EXTENSION STUDYNOTIFICATION OF THE EXTENSION STUDY

CHALLENGESCHALLENGES

- Review of RDC No. 26, December 17, 1999 (EXPANDED ACCESSEXPANDED ACCESS) include compassionate use and donation after study;

- Procedural donation after study;

- Medical Medical reportreport;;

-- Final Final studystudy reportreport;;

-- QuantitativeQuantitative;;

-- NotificationNotification IRB;IRB;

-- SponsorSponsor: : supplysupply ofof medicationmedication, , safetysafety evaluationevaluation, , monitoringmonitoring..

SANITARY POINT OF VIEW ON POST-TRIAL ACCESS

FANNY NASCIMENTO MOURA VIANA

THANK YOU!

WWW.ANVISA.GOV.BR