This document provides an overview of radiopharmaceuticals, including their history, clinical considerations, and regulatory frameworks. Key points include: - Radiopharmaceuticals have been used to treat disease since the late 1890s and their applications have expanded significantly in recent decades. - They can be used as free inorganic forms or conjugated to biomolecules to target specific cells and tissues. - Clinical considerations include potential adverse effects, challenges with dosimetry calculations, and risk of secondary malignancies. - Both the US and EU have regulatory frameworks for radiopharmaceutical approval and clinical trials, though requirements can vary between countries. Early engagement with regulators is recommended.

1. GETTING AHEAD OF THE EVOLVING
LANDSCAPE IN RADIOPHARMACEUTICALS
MARCH 4, 2020

2. M A K I N G T H E C O M P L E X S E A M L E S S
AGENDA
• Radiopharmaceuticals: history, radiobiology, clinical considerations
• Overview of the regulatory framework in US and EU
• Oncology Trial Management
• Imaging Advancements
• Take-Home Points
2

3. RADIATION HISTORY
CLINICAL CONSIDERATIONS
RADIOBIOLOGY

4. M A K I N G T H E C O M P L E X S E A M L E S S
BRIEF TIMELINE OF RADIATION
• 1895: Roentgen discovers X-rays
• 1896: Radiation used to treat cancer
• 1896: Becquerel discovers natural radioactivity
• 1898: Marie Curie discovers radium
• 1934: Frederic Joliot-Curie, Irene Curie- discover and artificially produce radionuclides
• 1937: Perrier and Segrè discover Technitium 99
• 1943: Electron linear accelerators available
• 1951: Iodine 131 medical use
• 1958: Captain William Briner establishes NIH Radiopharmacy
• 1950s: Clinical use of medical linear accelerators
• 1975: PET developed
• 1978: Board of Pharmacy Specialties establishes U.S. Nuclear pharmacy
• 2001: PET/CT developed
• 2017: 177Lu dotatate (Lutathera®) approved
4

5. M A K I N G T H E C O M P L E X S E A M L E S S
RADIOPHARMACEUTICALS IN TREATING DISEASE
• Radionuclide concepts:
‒ Application of particulate nature of radiation
‒ Extended and declining radiation dose rate
‒ Non-uniform and relatively uncontrolled distribution
of radioactivity throughout body
‒ Undesired systemic absorbed dose to distant non-
targeted organs
• Radionuclide advantages
‒ Easy targeting and treatment of tumor cells
‒ High LET radionuclides effectively kill radioresistant
hypoxic cells
‒ Lower whole body absorbed dose
‒ Can be delivered in free inorganic form or
conjugated to peptide/antibody/small biomolecules,
or encapsulated in liposomal nanoparticles.
5
Hall E, Radiobiology for the Radiologist, 2000

6. M A K I N G T H E C O M P L E X S E A M L E S S
RADIONUCLIDE THERAPY IN TREATING DISEASE
• Approaches of targeted
radionuclide therapy:
‒ Nuclear membrane receptor
‒ Cell Membrane Receptors
‒ Radionuclide labeled antibody
‒ Nanoparticles labeled with
antibody and radionuclides
‒ Liposomes labeled with specific
ligand and/or encapsulated with
radionuclides
‒ Radionuclide labeled base analog
6
Kumar C et al., International Journal of Radiation Biology, 2016

7. M A K I N G T H E C O M P L E X S E A M L E S S
NEW ERA OF RADIOPHARMACEUTICALS
• Radioisotopes used for therapy
‒ Free inorganic form
• ⁸⁹SrCl2: bone metastases
• ³²P: lung, ovarian, uterine, and prostate cancer
• ¹³¹I: treatment of thyroid cancer
‒ Radionuclides conjugated to peptide/ antibody/small
molecules/ or encapsulated in liposomal
nanoparticles
‒ Membrane/ receptor/antigen/ extracellular antigen
• ¹³¹I- A33: metastatic colorectal carcinoma
• EGFR ⁹ºY/¹³¹I/¹⁷⁷Lu/²¹³Bi-cetuximab: breast and
lung carcinoma
‒ Cytoplasm
• ¹³¹I/¹⁸⁸Re-liposome: solid tumors
7

8. M A K I N G T H E C O M P L E X S E A M L E S S
RADIONUCLIDE THERAPY CLINICAL CONSIDERATIONS
• Radiation induced bystander effect:
‒ Complex phenomenon
• Abscopal effect
• Radioresistance and recurrence
• Possible acute sequalae:
‒ nausea
‒ vomiting
‒ sialadenitis
‒ radiation sickness
‒ temporary painful swelling of metastases
‒ bone marrow suppression
‒ thyroid storm (¹³¹I)
• Late sequalae/ secondary malignancies
‒ pneumonitis and lung fibrosis
‒ fertility disorders
‒ leukemia and secondary neoplasms
(lower risk than chemotherapy and external beam radiotherapy)
8
Kumar C et al., International Journal of Radiation Biology, 2016

9. M A K I N G T H E C O M P L E X S E A M L E S S
RADIONUCLIDE THERAPY: DOSIMETRY
Activity (A)
Becquerel
Curie
Bq
Ci
3.7×1010 Bq
1000000 Bq
Absorbed Dose (D)
Gray
Erg per gram
Rad
Gy
Rad
1.0 × 10−4
Gy
0.010 Gy
Equivalent Dose (H) Sievert Sv 0.010 Sv
9
Air
Exposure (C/kg)
The amount of
ionization in air due
to gamma (X) rays
Material
Absorbed Dose (Gy)
The amount of
irradiation energy
absorbed in material
Human Body
Equivalent Dose (Sv)
The magnitude of effects
on the human body
Isotope
Activity (mCi)
The amount of
radiation in units
of decay
Dosimetry calculations
• In clinical practice, remains difficult, calculated absorbed radiation doses to
tumor not always matching observed response
• Requires more attention to allow better assessment of tumor dose and to
account for exposure of the normal tissues and environment
Hoefnagel C et al., International Journal of Biological Markers, 1993

10. M A K I N G T H E C O M P L E X S E A M L E S S
RADIOPHARMACEUTICAL APPROVALS
UNITED STATES EUROPE
10
FDA-Approved Radiopharmaceuticals
• Carbon-14 urea (PYtest)
• Gallium-67 citrate
• Indium-111 pentetreotide (Octreoscan™)
• Iodine-123 iobenguane (MIBG, AdreView™)
• Iodine-125 iothalamate (Glofil®-125)
• Iodine-131 human serum albumin (HSA,
Megatope)
• Iodine-131 iobenguane (MIBG, Azedra®)
• Iodine-131 sodium iodide diagnostic capsules
• Iodine-131 sodium iodide solution (HICON®)
• Lutetium-177 dotatate (Lutathera®) *
• Radium-223 dichloride (Xofigo®)*
• Samarium-153 lexidronam (Quadramet®)*
• Strontium-89 chloride (Metastron™)
• Technetium-99m (Radiogenix ™ System)
• Thallium-201 chloride
• Yttrium-90 chloride
• Yttrium-90 ibritumomab tiuxetan (Zevalin®)*​
EMA-Approved Radiopharmaceuticals
• Fluorine-18 florbetapir (Amyvid™)
• Fluorine-18 fluciclovine (Axumin™)
• Copper- 64 chloride (Cuprymina)
• Lutetium-177 dotatate (Lutathera®) *
• Lutetium-177 chloride (Lumark)
• Lutetium-177 chloride (EndolucinBeta)
• Tilmanocept (99mTc Lymphoseek)
• Florbetaben (18F) Neuraceq
• Samarium-153 lexidronam (Quadramet®)*
• Edotreotide- 68Ga (SomaKit TOC)
• Flutemetamol- 18F (Vizamyl)
• Radium-223 dichloride (Xofigo®)
• Yttrium-90Y Chloride (Yttriga)
• Yttrium-90 ibritumomab tiuxetan (Zevalin®) *​

11. REGULATORY
CONSIDERATIONS

12. M A K I N G T H E C O M P L E X S E A M L E S S
REGULATORY – KEY MESSAGES
• Regulatory frameworks exist in US and EU for radiopharmaceuticals
• Regulatory pathway is defined by the type of product, intended use
and identified risks
• Consult regulations and recent guidances
• Consider engaging regulators early in development
12

13. M A K I N G T H E C O M P L E X S E A M L E S S
US REGULATORY FRAMEWORK
• US Agencies with regulatory oversight of radiopharmaceuticals
‒ Nuclear Regulatory Commission
‒ Food and Drug Administration
• Who within FDA has jurisdiction for your product?
‒ Therapeutic (e.g. 223Ra) - Office of Oncologic Diseases
‒ Diagnostic (e.g. Fludeoxyglucose 18F) – Division of Medical Imaging and
Radiation Medicine
• Approval pathways in the US
‒ New Drug Application (NDA), Biological License Application (BLA) or
Abbreviated New Drug Application (ANDA)
‒ 505(b)(1) vs 505(b)(2) (e.g. Axumin (fluciclovine 18F) and Netspot (kit for prep of
68Ga dotatate injection)
13

14. M A K I N G T H E C O M P L E X S E A M L E S S
EU REGULATORY FRAMEWORK
• Radiopharmaceuticals (therapeutics and diagnostics) are regulated as
medicinal products
‒ Legislation was introduced in 89/343/EEC and 2001/83/EC
• Conduct of a clinical trial requires an approved CTA by National Competent
Authority and approval from Ethics Committee
‒ Currently regulated under Clinical Trial Directive 2001/20/EC  transitioning to CT
Regulation ((EU) No 536/2014)
• Regulatory procedures for market authorisation in the EU
‒ National Authorisation by EU Member State
‒ Mutual Recognition Procedure/Decentralised Procedure/Centralised Procedure
14

15. M A K I N G T H E C O M P L E X S E A M L E S S
WHAT IS NEW WITH THE CLINICAL TRIAL
REGULATION (EU) NO 536/2014?
• New EU CT Regulation aims to align clinical trial requirements within
EU and to facilitate experimental use of some diagnostic RPs
• Key points to consider
‒ Manufacturing and import authorization not needed
• For use in the same hospital
• Taking part in the same clinical trial
• Based in same member State
‒ GMP requirements: No need for GMP production per Eudralex Volume 4, but
still not harmonized across EU member states
‒ Simplified labeling (primary packaging)
15

16. M A K I N G T H E C O M P L E X S E A M L E S S
CMC CONSIDERATIONS
• cGMP requirements for PET drugs in 21 CFR 212
• Eudralex-Volume 4 GMP Guidelines, Annex 3: Manufacture of
radiopharmaceuticals, specific requirements may vary depending on
the level of risk
• Some countries may require manufacturing of radiopharmaceuticals
according to Good Radiopharmacy Practice (European Association
for Nuclear Medicine), rather than GMP
16

17. M A K I N G T H E C O M P L E X S E A M L E S S
NONCLINICAL CONSIDERATIONS
• EMA recognize the need for a “targeted” approach
• FDA’s recent guidance covers microdose diagnostic RP and
therapeutic RP for oncology indications
• Toxicology studies in a single appropriate mammalian species
can suffice
• Carcinogenicity and reproductive toxicity studies are not warranted
• GLP considerations
17

18. M A K I N G T H E C O M P L E X S E A M L E S S
THERANOSTICS
• Precision medicine (“see and treat”)
• Recent Examples of Theranostic Pairs
• 131I iobenguane (Azedra®)
• 68Ga dotatate (Netspot®) 177Lu dotatate (Lutathera®)
• Co-development vs Sequential
• Recommend early & frequent interaction with
Regulators where trial is to be conducted
18
Yordanova et al., 2018

19. M A K I N G T H E C O M P L E X S E A M L E S S
REGULATORY – TAKEAWAY MESSAGES
• Regulatory frameworks exist in US and EU for radiopharmaceuticals
• Regulatory pathway is defined by the type of product, intended use
and identified risks
• Consult regulations and recent guidances
• Consider engaging regulators early in development
19

20. ONCOLOGY TRIAL
MANAGEMENT

21. M A K I N G T H E C O M P L E X S E A M L E S S
REGULATORY SUBMISSIONS – RADIATION
COMMITTEES
Regulatory process for radiopharmaceuticals is highly heterogeneous across different
countries
• Radiation Committee may be required
• Can significantly extend start-up timelines
21
Spain Belgium UK US
Radiation review? No Yes Yes Site-dependent
Process N/A – no additional
review required
FANC (radiation board)
review takes ~3 months
and must be completed
before EC/RA
submission
Radiation assurance
review must be
completed at least 2
months before REC
submission.
ARSAC (radiation
committee) takes ~6
weeks in parallel with
EC submission
Variable by site: some
have radiation or other
special committees,
which may be required
before IRB review or in
parallel and can take 1-6
months

22. M A K I N G T H E C O M P L E X S E A M L E S S
Regulatory process for radiopharmaceuticals is highly heterogeneous across
different countries
• Country selection highly important for FPI
• Consider risk-mitigation strategies, for example, selection of multiple countries and spread of sites
Additional considerations for site selection
• Radioactivity licenses and associated limits: impact on qualification, start-up and enrolment
• Authorization of investigator and /or site certificate by radiation committee (country-specific)
Expectations for essential documents
• Queries often relate to manufacturing and ensuring purity and quality of final product
• Ensure IB, IMPD and other documents contain sufficient detail on manufacturing and QC process
REGULATORY SUBMISSIONS
SITE SELECTION CONSIDERATIONS
22

23. M A K I N G T H E C O M P L E X S E A M L E S S
SUPPLY CHAIN
23
Peptide
manufacture
Radionuclide
manufacture
Radiopharmacy
Administration
at site
Kit manufacture
Preparation at
radiopharmacy
Radionuclide
manufacture at
radiopharmacy
Approx3weeks4-10days
Administration
at site
Kitsheldinstockat
radiopharmacy
Approx4hours
Long half-life / central manufacture Short half-life / local manufacture

24. M A K I N G T H E C O M P L E X S E A M L E S S
Some isotopes such as Gallium can be manufactured in a local radiopharmacy
• ‘Cold kits’ can be stored at the site and reconstituted as required
• Mostly imaging compounds that are manufactured in this way
Radiopharmacy should be thoroughly qualified during start-up
• Visits from CMC/QP
• Mock preparations and quality testing
Important to ensure the correct documentation is generated
• Batch records should be completed for each reconstitution
• Documentation of radioactivity and volume at preparation and administration
Some, but not all, countries require manufacturing to GRPP, rather than GMP
• Additional process validation may be required during start-up to satisfy site- or country-specific
manufacturing requirements
SUPPLY CHAIN
LOCAL RADIOPHARMACY
24

25. M A K I N G T H E C O M P L E X S E A M L E S S
SUPPLY CHAIN
CENTRAL RADIOPHARMACY
25
Dose is manufactured for administration at a specific date and time.
• Cannot be modified at a later date
• IRT system must be designed specifically to capture necessary data for
radiopharmaceutical dose manufacture
• Complex logistics involved with coordination of multiple manufacturers within a time-
critical process
Short shelf life (~4 days for Lutetium products)
• Correct import/export documents are critical to prevent delays
• Ensure country-specific requirements are adhered to, particularly when sending
cross-continent
• Mock shipments can help identify issues in transportation and/or receipt at
investigative site

26. M A K I N G T H E C O M P L E X S E A M L E S S
SITE START-UP
THERANOSTIC EXAMPLE
26
A complex collaboration between multiple parties
• Communication is critical for highly linked and interdependent processes
• Delays to one can cascade into further delays
• Identify actions on the critical path for site activation and potential bottlenecks

27. M A K I N G T H E C O M P L E X S E A M L E S S
RECRUITMENT
How do patients find the study?
• Requires close collaboration between Nuclear Medicine Physicians and Oncologists
Why do patients want to participate in the study?
• Due to manufacturing timelines for therapeutic radiopharmaceuticals, the time between
patient consent and administration of treatment can be relatively long
• Imaging studies may offer no therapeutic benefit to the patient: altruistic trial
• Consider patient understanding of radioactivity and the effect of radioactivity on their day-
to-day lives e.g. sleeping with partner, proximity to children and pets
Preventing barriers to enrolment
• Screen fail rates due to presence of receptor, stringency of imaging criteria
• For studies with multiple imaging procedures and/or complex patient management, sites
may be reluctant to treat multiple patients in parallel
27

28. M A K I N G T H E C O M P L E X S E A M L E S S
SITE LOGISTICS
PATIENT PATHWAY
28
Example screening and D1
• Patient flow must be clearly defined and scheduled in advance
• Communication is critical for time-critical processes occurring in different departments
• Support to investigative site and proactive planning is crucial to success
Screening D1

29. M A K I N G T H E C O M P L E X S E A M L E S S
DATA FLOW
Protocol
endpoints
Imaging/
dosimetry
PK/PD
EDC
Administration
and
preparation
details
ECG
Blood/ urine
radioactivity
29
Additional data must be collected in a
radiopharmaceutical trial to fully capture
protocol endpoint data:
• Preparation details (if on-site)
• Administration details
• Radioactivity of blood and urine, specific time points
• Higher volume and specificity of imaging data
Data may come from multiple different sources
e.g. Nuclear Medicine and Oncology
departments
• Implications for data entry/cleaning and monitoring
• Consistency of equipment and calibrations

30. M A K I N G T H E C O M P L E X S E A M L E S S
DATA FLOW
30
Turnaround times for obtaining, cleaning and
analyzing data must also be considered:
• Is any analysis required to determine patient eligibility or
calculate an individual treatment dose?
• Are any analyses required for dose escalation, Safety review
or other committee meetings?
• Delay in samples to be sent to central lab, as most cannot
receive radioactive products
Analysis of certain data can be lengthy, such as
dosimetry data for which calculations can take
several days
Protocol
endpoints
Imaging/
dosimetry
PK/PD
EDC
Administration
and
preparation
details
ECG
Blood/ urine
radioactivity

31. M A K I N G T H E C O M P L E X S E A M L E S S
TAKE-HOME
• Regulatory landscape is highly heterogeneous: country and site
selection is critical for start-up and FPI timelines
• Unique CMC requirements for radiopharmaceuticals need to be
considered carefully during start-up to ensure sufficient qualification
and quality control checks are in place
• Patient management can be complex and requires close
collaboration from multiple disciplinary departments
• Data flow and analysis requirements need to be identified and
adequate processes defined from the outset
31

32. IMAGING ADVANCEMENTS

33. M A K I N G T H E C O M P L E X S E A M L E S S
• Required to obtain comparable quantification in multicenter
settings
‒ Maintaining accuracy and precision of quantitation
• Uses phantom scans (NEMA) with a source of known
activity
• For diagnostic radiopharmaceuticals: PET
‒ Aim to achieve standardized uptake value (SUV) harmonization
• For therapeutic radiopharmaceuticals: planar or SPECT
‒ Aim to standardized the acquisition parameters including energy
window peaks
• Mandatory for clinical trials with dosimetry calculation and
highly recommended for SUV calculation trials
SCANNER CALIBRATION
DIAGNOSTIC AND THERAPEUTIC RADIO-PHARMACEUTICALS
33
http://www.spect.com/products-nema.html

34. M A K I N G T H E C O M P L E X S E A M L E S S
• The imaging protocol should be strictly followed by each site
• No deviation permitted, if so, the scan will not be used for calculation
(SUV, dosimetry, qualitative analysis)
• No re-scan of a patient is permitted for therapeutic imaging
• Sites should be pro-active and send images to Medpace Imaging
Core Lab asap for further dosimetry analysis if any
‒ Allowing treatment dose calculation for example
IMAGING PROTOCOL
PET/CT, PLANAR, SPECT/CT AND RADIO-PHARMACEUTICALS
34

35. M A K I N G T H E C O M P L E X S E A M L E S S
DIAGNOSTIC RADIOPHARMACEUTICALS
EXAMPLE 68Ga-DOTATOC PET/CT
35
68Ga-DOTATOC PET/CT images
(MIP, sagittal) in a patient with
metastatic small cell lung
carcinoma
Sollini et al., 2014
PET CT PET/CT
DOTATOC targets
somatostatin receptors
that are over-expressed
in some cancer

36. M A K I N G T H E C O M P L E X S E A M L E S S
DIAGNOSTIC / THERAPEUTIC RADIOPHARMACEUTICALS
EXAMPLE 68Ga-PSMA PET/CT AND 177Lu-PSMA PLANAR
36
A. Image showing multiple bone
and lymph node metastases in
a patient with metastatic
prostate cancer
B. Post-therapeutic images
showing high uptake within
lesions corresponding to those
seen on PET image
Rahbar et al., 2016
PSMA is an antigen
overexpressed by
prostate’s cancer cells
68Ga-PSMA PET 177Lu-PSMA Planar
Therapy

37. M A K I N G T H E C O M P L E X S E A M L E S S
THERAPEUTIC RADIOPHARMACEUTICALS
EXAMPLE 177Lu-DOTATATE SPECT/CT
37
Image showing primary
lesions in a patient with
pancreatic gastrinoma
invading the duodenum with
multiple hepatic metastases
Kashyap et al., 2015
After cycle 1 of therapy After cycle 6 of therapy
DOTA-TATE targets
somatostatin receptors that
are over-expressed in
some cancer
Therapy
177Lu-DOTA-TATE SPECT/CT

38. M A K I N G T H E C O M P L E X S E A M L E S S
• Advantages and disadvantages to choose SPECT/CT compared to
planar for dosimetry calculation:
THERAPEUTIC RADIOPHARMACEUTICALS
PLANAR VS SPECT/CT
38
Planar
- Short scan (30 min)
- Whole body
- Need a transmission scan (30 min)
- Less accurate for dosimetry
calculation
- Total volume of patient’s urine
has to be collected for dosimetry
calculation
SPECT/CT
- Longer scan (15 min per FOV)
- Usually head to mid-tight
- Transmission scan is provided by
the CT
- Very accurate for dosimetry
calculation
- No need to collect total volume of
patient’s urine

39. M A K I N G T H E C O M P L E X S E A M L E S S
IMAGING TIME POINTS
• For SUV calculation:
‒ Only one time point needed
• For dosimetry calculation:
‒ Between 3 to 5 time points needed
‒ Early and late time points are the most important ones
• Challenging for patient / site to acquire several images
‒ Depends on patient’s illness and pain
‒ Require several visits
39

40. M A K I N G T H E C O M P L E X S E A M L E S S
BODY PART TO BE IMAGED
• Images should focus on primary disease as
well as on disease extension body parts
• If dosimetry, images field of view should
cover all critical organs (full bladder
included)
• Two field of views usually covers the chest,
abdomen and pelvis
• Three field of views will also cover the brain
40
http://www.sfu.ca/~psa43/Project_2/data/body.jpg
175
cm
40 cm
40 cm

41. M A K I N G T H E C O M P L E X S E A M L E S S
DOSIMETRY
• Radiation dosimetry is used to estimate the absorbed dose (Gy/GBq) of a
radioactive compound in critical organs and/or tumors
‒ Helps to define a treatment dose without damaging the critical organs
‒ Helps to define a treatment dose that will treat the cancer
‒ Helps to predict a treatment dose based on a diagnostic agent using the same pharmaceutical
41
Relative radiotracer uptake (%ID/g or Bq/g) Absorbed dose value (Gy/GBq)
0
0.5
1
1.5
2
2.5
Absorbed dose per unit of injected activity
(Gy/GBq)
0
5
10
15
20
25
30
35
15 60 120 240
NormalizedOrganActivity
(MBq/g)
Mins p.i.
Normalized Organ Time-Activity Curves
Lungs Liver
Spleen Marrow
Bladder Heart

42. M A K I N G T H E C O M P L E X S E A M L E S S
CONCLUSIONS
• The following considerations are important for any
radiopharmaceutical trial:
‒ Scanners calibration
‒ Imaging protocol to be strictly followed
‒ SPECT/CT should be considered instead of planar if dosimetry has to be
calculated
‒ Imaging time points have to be defined with dosimetrist before protocol
finalization
‒ Field of view has to include source organs for dosimetry
‒ Dosimetry calculation is a powerful tool and can help physicians on their
clinical decision for treatment dose
42

43. QUESTIONS
THANK YOU