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Registro de contrastes e radiofármacos: Requisitos de segurança e eficácia e tecnologia farmacêutica. Drug market authorization: contrast media and radiopharmaceutical - Safety requirements and effectiveness and pharmaceutical technology. Ministrante/Speaker: Ayse Baker - GE Healthcare 22 de junho de 2016 / June 22nd, 2016

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Disclaimer The information contained and views expressed in this presentation are based on public information and presenter's knowledge

• Contrast Media • Molecular Imaging • Regulatory Pathways • Therapeutics vs Diagnostics • Generics

Overview of Imaging Agents

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Contrast Agents

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Contrast media ,sometimes called contrast agents or dye are chemical substances (imaging agents) used in : • Medical X-ray (XR) • Magnetic Resonance Imaging (MRI) • Computed Tomography (CT) • Ultrasound Two commonly used contrast media are: • Iodine containing contrast medium (CT) • Barium containing contrast medium (CT) • Gadolinium containing contrast medium (MRI)

Contrast Media X-Ray/CT

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• MRI contrast agents are a group of contrast media used to improve the visibility of internal body structures in magnetic resonance imaging (MRI).

• The most commonly used compounds for contrast enhancement are gadolinium-based.

Source : http://www.magnetic-resonance.org/ch/13-01.html

• Contrast media used to improve the visibility of internal bodily structures in X-ray-based imaging techniques: • computed tomography (CT)

• Radiocontrast agents used are typically: • iodine compounds. • barium compounds.

Ultrasound

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• Scattering properties of gas bubbles compared with blood cells have made microbubble ultrasound contrast agents important tools in ultrasound diagnosis

• Commercially available ultrasound contrast media are gas-filled microbubbles administered intravenously

Source : http://www.wjgnet.com/1007-9327/17/28.pdf

Radiopharmaceuticals

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• A radioactive compound used for in-vivo imaging via external detection • typically no pharmacological effect

• Limited exposure in patients • few doses/lifetime

• Short-lived products • shelf life in hrs/days

• Methods • Positron Emission Tomography (PET) • Single-Photon Emission Computed Tomography

(SPECT)

Molecular Imaging SPECT and PET

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Techniques used to used to visualize, characterize and measure biological processes in living systems. • Positron Emission Tomography (PET) • Single-Photon Emission Computed

Tomography (SPECT)

Molecular Imaging – Targeted SPECT

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• Targeted molecular imaging techniques have provide accurate and specific diagnosis of disease information.

• The use of molecularly targeted imaging probes is needed depending on different imaging modalities.

Regulatory Pathways

Same development pathway as pharmaceuticals

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Therapeutics vs Diagnostics

Phase Therapeutic Diagnostic

RDRC approval NA • Limited first-in-human studies

• Gain pharmacokinetic, metabolism, dosimetry data

Exploratory 5–30 subjects 5–30 subjects

Nontherapeutic doses Non-diagnostic doses

PK, metabolism, PK, metabolism, dosimetry

Reduced preclinical toxicity data requirements

Reduced preclinical toxicity data requirements

Source http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691464/

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Therapeutics vs Diagnostics

Phase Therapeutic Diagnostic

Phase 1 Healthy volunteers (except oncology)

Healthy volunteers

Evaluate safety Evaluate safety

Dose selection Dose selection

General PK/PD General PK

Evidence of efficacy, if possible

• Record tissue distribution (whole-body studies) for dosimetry and protocol design

• Studies with excess unlabeled tracer—“worst case scenario”

Source http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691464/

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Therapeutics vs Diagnostics

Phase Therapeutic Diagnostic

Phase 2 Several hundred patients Refine dose, imaging protocol, and analysis criteria to support phase III

Show efficacy in target population

Gain additional PK if necessary

Evaluate safety and side effects

Gain additional efficacy and safety data

Controlled studies, closely monitored

• Define population and clinical setting for phase III

• Use formulation that will be marketed; if not, may need bridging study

Source http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691464/

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Therapeutics vs Diagnostics

Phase Therapeutic Diagnostic

Phase 3 Several hundred patients Demonstrate efficacy and safety

Controlled and uncontrolled trials

Efficacy by confirming principal hypothesis

Show benefit–risk ratio based on efficacy and safety in large population

Recommends use of different investigators, centers, readers for blinded reads to improve generalization

Phase 4 Post-marketing studies Post-marketing studies

Monitor safety data Monitor safety data

Source http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691464/

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• Radioactive products with short half- life (minutes to hours)

• The types of radiopharmaceutical preparation vary from • simple dispensing of individual patient doses • ready-for-use radiopharmaceutical through the

assembly of products from sterile, pre-tested 'kits' of reagents to complicated chemical syntheses.

Radiopharmaceuticals - CMC Unique considerations

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• Pharmacology/Kinetics • clearance of radiotracer to determine dosimetry

distribution. • Dosimetery studies

• Bio-distribution study performed in rats or mice • Imaging may provide additional information • Calculations performed fitting animal data to

models, and performing theoretical calculations • Provides human radiation dose estimates for all

normal organs

Non-Clinical Considerations

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Source https://humanhealth.iaea.org/HHW/NuclearMedicine/Conferences/IPET2015/Presentations/Tuesday/06_Plenary_Session_5_-_M1/05_Schwarz-iPET_US_Revision_10-6-15.pdf

• Design Standard of Truth (SOT) • Challenging - to source data • Pathology used as SOT • Sourced from biopsy and/or surgery

• Population • Ethnicity • Pediatrics can be waived if intended use is for conditions

in adult or elderly populations. • Outcomes

• Proof of safety including radiation exposure(dosimetry) • Sensitivity and Specificity

Clinical Considerations

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Phase 3 Clinical Study Considerations

• “Charter” to describe: • Image acquisition • Image interpretation • Data archiving

• Special image interpretation considerations: • Readers generally masked to

clinical data • “Locked” reads (can not be

altered) • Multiple “independent” readers

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• Control of manufacture (CMC) • regional multi-site consistency • multi-dose vial supply

• Clinical utility and value • Patient care pathways

• therapy or patient management decision making using precision diagnostic imaging techniques.

• Risk benefit balance • Radiotracers vs availability of other diagnostic

modalities

Key focus areas

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Health Authority Review Timelines

Source http://ip-science.thomsonreuters.com/m/pdfs/transparent-reg-agencies.pdf 21

Health Authority Meetings

Region Health Authority

Purpose

US

recommendations to sponsors relating to the development, review or post approval changes

EU

recommendations to sponsors relating to the development, review or post approval changes

Japan

recommendations to sponsors relating to the development, review or post approval changes

Good communications between HA and the sponsor is essential for successful product development & approval 22

FDA NDA Review Timelines

Source http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM378227.pdf 23

Post Marketing Activities

Health Authorities continue to assure product safety and efficacy even after a product is approved which include

post-marketing adverse event

reporting

post-marketing study

commitments (Phase IV studies)

Renewals

Lifecycle Management

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Post marketing safety reporting

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• Reporting is on a periodic basis, frequency defined by health authorities

• In Europe the EMA publish a list of active substances (EURD list) with defined safety reporting frequencies and a harmonised assessment process.

• Radiopharmaceuticals typically have positive risk benefit profiles, with few adverse events being reported.

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Generics

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Source : from “ Clinical Drug Development & Marketing Application Process” presentation by Andrew Jiang and Ayse Baker at Harvard School of Public Health on 15 September 2015

Generics

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Medical Imaging and Drug Development

Code of Federal Regulations (CFR) Legislation ( Law) FDA Guidance

21 CFR 312 Investigational New Drugs http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=312

Developing Medical Imaging Drug and Biological Products Part 1: Conducting Safety Assessments (July 2004) http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071600.pdf

21 CFR 314 New Drug Applications 21 CFR 314 New Drug Applications http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=314

Developing Medical Imaging Drug and Biological Products Part 2: Clinical Indications (July 2004) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071603.pdf

21 CFR 315 Diagnostic Radiopharmaceuticals 21 CFR 315 Diagnostic Radiopharmaceuticals http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=315

Developing Medical Imaging Drug and Biological Products Part 3: Design, Analysis, and Interpretation of Clinical Studies (July 2004) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071604.pdf

21 CFR 361.1 Radioactive Drug Research 21 CFR 361.1 Radioactive Drug Research Committee http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Oncology/ucm093322.htm

New Contrast Imaging Indication Considerations for Devices and Approved Drug and Biological Products ( December 2009) http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM195951.pdf

21 CFR Part 211—SPECT https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=211&showFR=1

Exploratory IND Studies (January 2006) http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078933.pdf

21 CFR Part 212—PET http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=212

Clinical Trial Imaging Endpoint Process Standards (Guidance for Industry) March 2015 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm268555.pdf

PET Drugs — Current Good Manufacturing Practice (CGMP) ( December 2009) http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070306.pdf

ANDA Submissions Code of Federal Regulations (CFR) Legislation ( Law)

FDA Guidance

21CFR314.92 Drug products for which abbreviated applications may be submitted. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.92

ANDAs: Stability Testing of Drug Substances and Products Questions and Answers May 2014 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm366082.pdf

21CFR 314.94 Content and format of an abbreviated application. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.94

PET Drug Applications — Content and Format for NDAs and ANDAs • Fludeoxyglucose F 18 Injection • Ammonia N 13 Injection • Sodium Fluoride F 18 Injection August 2011 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm078738.pdf

21CFR 314.101 Filing an application and receiving an abbreviated new drug application. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=314.101

ANDAs: Impurities in Drug Substances June 2009 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm172002.pdf

ANDA Submissions FDA Guidance Controlled Correspondence Related to Generic Drug Development Sep 2015 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM411478.pdf

ANDA Submissions – Refuse-to-Receive Standards Guidance for Industry May 2015 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm370352.pdf

How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD December 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM425662.pdf

ANDA Submissions — Refuse to Receive for Lack of Proper Justification of Impurity Limits September 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM414598.pdf

ANDA Submissions — Prior Approval Supplements Under GDUFA July 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM404441.pdf

ANDA Submissions — Amendments and Easily Correctable Deficiencies Under GDUFA July 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM404440.pdf

ANDA Submissions — Content and Format of Abbreviated New Drug Applications June 2014 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM400630.pdf

Generic Drug User Fee Amendments of 2012: Questions and Answers September 2013 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM316671.pdf

Completeness Assessments for Type II API DMFs Under GDUFA February 2016 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM321884.pdf

Self-Identification of Generic Drug Facilities, Sites, and Organizations August 2012 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM316672.pdf

Acceptability of Draft Labeling to Support ANDA Approval October 2015 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm465628.pdf

Good Manufacturing Practice (CGMP) Regulations

21 CFR Part 2ll CGMP for Finished Pharmaceuticals

21 CFR Part 212 CGMP For Positron Emission Tomography Drugs

Subpart A--General Provisions Subpart B--Organization and Personnel Subpart C--Buildings and Facilities Subpart D--Equipment Subpart E--Control of Components and Drug Product Containers and Closures Subpart F--Production and Process Controls Subpart G--Packaging and Labeling Control Subpart H--Holding and Distribution Subpart I--Laboratory Controls Subpart J--Records and Reports Subpart K--Returned and Salvaged Drug Products

Subpart A: General Provisions Subpart B: Personnel and Resources Subpart C: Quality Assurance Subpart D: Facilities & Equipment Subpart E: Control of Components, Containers, & Closures Subpart F: Production & Process Controls Subpart G: Laboratory Controls Subpart H: Finished Drug Product Controls & Acceptance Subpart I: Packaging and Labeling Subpart J: Distribution Subpart K: Complaint Handling Subpart L: Records

• Directive 2001/83/EC, as amended • Note for Guidance on Summary of Requirements for Active

Substances in Part II of the Dossier (CHMP/QWP/297/97 Rev. 1) • Note for Guidance on Development Pharmaceutics

(CPMP/QWP/155/96) • Note for Guidance on Pharmaceutical Development

(EMEA/CHMP/167068 /2004) • Note for Guidance on Manufacture of the Finished Dosage form

(CPMP/QWP/ 486/95) • Note for Guidance on Excipients in the Dossier for Application for

Marketing Authorisation of a Medicinal Product (CHMP/QWP/396951/06)

• Eudralex Vol 4: Good Manufacturing Practice, Annex 3 - Radiopharmaceuticals.

Useful References EU

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Global Contrast Media Market to Surpass $6 Billion by 2022 driven by a number of factors.

• These include increases in the number of annual computed tomography (CT)

• magnetic resonance imaging (MRI) Partnering Between Pharma and Imaging Companies Advances in Digitalization Source http://www.dicardiology.com/content/global-contrast-media-market-surpass-6-billion-2022

Looking Forward

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THANK YOU

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First angiogram-1896. The vessels in the hand of a corpse was shown by injecting a mixture of lime, mercury and petroleum

Source : http://www.learningradiology.com/museum/discoveryhome.html

http://acr.sagepub.com/content/54/5/473.full.pdf http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691464/ http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM195951.pdf http://www.dicardiology.com/content/global-contrast-media-market-surpass-6-billion-2022 http://www.academic-server.cvm.umn.edu/Radiology/student/SP_07_files/CVM6104/PDF_s/Contrast_Media.pdf http://radiology.yale.edu/patientcare/physicians/er/contrastquestions.aspx http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm142882.htm http://www.ema.europa.eu/ema/ http://ip-science.thomsonreuters.com/m/pdfs/transparent-reg-agencies.pdf http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM378227.pdf http://www.slideshare.net/shatham/molecular-imaging-with-pet-spect http://www.insideradiology.com.au/pages/view.php?T_id=54#.V1ncVLsrJD8 http://www.springer.com/us/book/9783540767350 http://pubs.acs.org/doi/abs/10.1021/bi901135x https://humanhealth.iaea.org/HHW/NuclearMedicine/Conferences/IPET2015/Presentations/Tuesday/06_Plenary_Session_5_-_M1/05_Schwarz-iPET_US_Revision_10-6-15.pdf

References

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