Regulatory Evaluation of Radiation Therapy Tumor … · Radiation Therapy Tumor Imaging and Evaluation Gerald Sokol ... • For particle beams relevant pre-clinical radiobiology

ITART MEETING 2010 1

Regulatory Evaluation of Radiation Therapy Tumor Imaging and Evaluation

Gerald Sokol MD, MSc, FCPCDER/DODP/FDAUSUHS


This presentation does not reflect the opinions of the FDA or any other government organization


FDA Campus @ White Oak, Silver Spring, Maryland


The most terrifying words in the English language are:

I'm from the government and I'm here to help."

Ronald Reagan


Summary

Regulatory background of drugs and devices

Use of surrogate markers Why and why not Radiation therapy

devices and protocols should be reviewed.

Regulatory experiential pitfalls in the review process.

Regulatory Process Admonitions


“Jerry if you keep playing around with drugs, medical oncology and radiation oncology you will amount to nothing”

Juan Del Regato 1980


FDA TODAY21 U.S.C. § 393

* * *“(b) MISSION.—The Administration shall—

“(1) promote the public health by promptly and efficiently reviewing clinical research and

taking appropriate action on the marketing of regulated products in a timely manner;


FDA Oncology Drug Approval

FDA – U.S. Food and Drug Administration Dept of HHS – Executive Branch

Created by Congress because of prior unsafe drugs being marketed

FDA charged by Congress to evaluate all new prescription drugs seeking marketing in the U.S.

Federal Laws govern these activities


Drug Development Focal Points -FDA Meetings

Phase Format Intent (FDA concerns)

Pre-IND / IND T-con, FTF, none Ph 1 design – FDA safety -population and dosing

EOP1 Tcon, FTF Ph 2 design – FDA safety -population and dosing

EOP2 FTF Ph 3 design – FDA safety, study design & analysis

Pre-NDA FTF(face to face)

Results; format & content of reports; time frame of submission; priority?


Communication is the Key



Statutory DefinitionsStatutory Definitions

DRUGDRUG----Articles recognized in the United States Articles recognized in the United States Pharmacopeia, Homeopathic Pharmacopeia of Pharmacopeia, Homeopathic Pharmacopeia of the United States, or National Formulary, the United States, or National Formulary, intended for use in the intended for use in the diagnosis, cure, diagnosis, cure, mitigation, treatment, or prevention of diseasemitigation, treatment, or prevention of diseasein man or other animals, (other than food) in man or other animals, (other than food) intended to affect the intended to affect the structure or any functionstructure or any functionof the body of man or other animals...of the body of man or other animals...

21 U.S.C. 21 U.S.C. § § 321(g)(1)321(g)(1)


NEW DRUGNEW DRUG --Any drug (except a new animal drug or Any drug (except a new animal drug or an animal feed bearing or containing a new animal an animal feed bearing or containing a new animal drug) the composition of which is such that such drug) the composition of which is such that such drug is drug is not generally recognizednot generally recognized, among experts , among experts qualified by scientific training and experience to qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, evaluate the safety and effectiveness of drugs, as as safe and effective for use under the conditions safe and effective for use under the conditions prescribed, recommended, or suggested in theprescribed, recommended, or suggested in thelabeling thereof...labeling thereof...21 U.S.C. § 201(p)21 U.S.C. § 201(p)

Statutory Definition Statutory Definition -- New Drug New Drug


Device “…an instrument, apparatus, implement, machine, contrivance,,

implant, in vitro reagent, other similar or related article, including any component, part, or accessory, which is-recognized in the official National Formulary, of the US Pharmacopeia, or any supplement to them, intended for the use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure, function or the body of man or other animals and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes”

1998-FFDC Act, Section 201 (321)


FDA - Oncology Drugs

Office of Oncology Drug Products – OODP Three FDA - Oncology Drugs divisions

DDOP- Chemotherapy drugs for CancerDBOP- Biologic oncology therapies BLAsDHDP-HematologyDMIP- Medical Imaging


The IND Process

FDA determination that:Human subject exposure to an unreasonable

and significant risk of illness or injury;Unqualified clinical investigators; Misleading, erroneous, or materially

incomplete investigator brochure; Incomplete information to assess the risk to

subjects; orDeficient plan or protocol


Basis for New Drug Approval

Demonstration of efficacy with acceptable safety in adequate and well-controlled studies CFR 314 - NDA Regulations

Ability to generate product labeling that Defines an appropriate patient population for

treatment with the drug Provides adequate information to enable safe and

effective use – prescribing of the drug Analogous rules for Biologics - BLA


FDA Oncology Drug Approval

LIVE BETTER – Measure QOL - PRO LIVE LONGER – Measure Survival (OS) SAFER – Controlled study comparison

These are Clinical Benefit Endpoints LESS EXPENSIVE

NOT PURVIEW OF FDA

Demonstrate these endpoints= Full Regular Approval

Risk / Benefit Assessment (in context of the disease)


Two Types of Drug Approval:Regular or Accelerated

Endpoints Supporting Regular Approval Regular Approval

Demonstrate Clinical BenefitLonger life Better life (relief of tumor-related Sx) - PRO

Requires a valid measure of how a patient feels or functions

Favorable effect on established surrogate


Accelerated Approval (AA)

Only applies in the setting of a new drug for a serious or life-threatening illness:

Improvement over available therapy Study may use a surrogate endpoint,

reasonably likely to predict clinical benefit

Requires confirmation of benefit

Fed Register 1992


Approval and tumor assessment endpoints (8

Regular Approval – RA If Clinical Benefit shown (live longer, better, safer) - or - Benefit on Established surrogate - (DFS, Heme CR)

Accelerated Approval - AAFor Serious or Life Threatening illnesses Show meaningful therapeutic benefit over existing therapy or

improved patient response over available therapy May be based on a surrogate endpoint which is reasonably likely

to predict clinical benefit - or a clinical endpoint other than survival or irreversible morbidity• Confirmatory Trial commitment is required


Devices


510(K)

Predominant type of submission

Substantially equivalent to FDA cleared devices currently on the market

Traditional, Special and Abbreviated

Analytical performance

Might require clinical performance data


PMA First of a kind Have to demonstrate safety and effectiveness Analytical and clinical performance Manufacturing inspection Bioresearch monitoring inspections Panel track and non-panel track Modular, real-time, expedited etc.


Regulation of Radiotherapy Devices

Why radiotherapy trials and devices should be regulated• In a way radiation is similar to a drug• We must prove safety and efficacy with evidence based

methodology relative to a given treatment and to alternative treatments

• We must define acute, subacute, and chronic toxicity and determine ways to mitigate them (labeling as for a drug)

• Need to define how radiation interacts with other drugs, and physiological processes over the appropriate time period

• Need to define the economic and cost benefits of new technology (not the purview of the FDA)


Evaluation of a Radiotherapy Device

• Physics (beam quality, reliability, software, dose distribution, scatter, neutron contamination, penumbra, etc.)

• Patient interface-safety (table weight, immobilization, emergency shut-offs, efficiency, accessibility, etc)

• For particle beams relevant pre-clinical radiobiology likely to reflect biological effect.

• Follow-up for acute, subacute and long term toxicity• Ultimately the safety and efficacy of combinations of

radiation, drugs or radiation of different biological effectiveness, fractionation or geometric distribution.


Why radiotherapy device regulation is difficult


Evaluation of Radiotherapy Device Trials-Issues Frequent incomparability of animal data Discerning the variable effects of fractionation, dose,

timing, breaks, field size, beam energy, device-cobalt vs linac.

Differing radiotherapy practice (which nodes, big pelvic fields vs. little, CRT vs IMRT, beam energy effect

Patient variation (previous rx, m/f, fat vs thin, old vs. young, co-morbidities) etc

Drug/drug interactions-protection, sensitization, barrier disruption (BBB), biologics, cytotoxics, timing, sequencing etc.


Drugs vs DevicesDrug Specific indication-dose,

side effects Defined drug/drug

interactions Clear cut warning and

precautions Pharmacogenics

developing (personalized medicine)

Effect and side effects are generally acute

Organ effects well described and reversible

Device No specific indications No specific dose Side effects dependent on

dose/fractionation schema/site treated

XRT/drug interactions less well defined (drug effects xrt-xrt effects drug disposition)

“Radiogenetics” in its infancy

Effects and side effects are acute, subacute and chronic

Organ effects evolve over time


Targeted Agents vs. Cytoxics The MTD may not be the optimal therapeutic dose Cytostatic vs. cytotoxic-may require life-time Rx Less toxic Unique endpoints required for targeted agents May require PD endpoints in pre-clinical and phase I studies

rather than response Epts May have more limited or heterogeneous molecular basis of

activity The mechanism of action may not effect the tumor as much

as the stroma or parenchyma.


Targeted therapies vs. cytoxic drugsDifferent toxicity profilesChronic treatment Early use in combinationDifferent benefits Blinding of trials, use of placebo


To Target or Not

Validated testing to define the target population

Treatment effect will be greater reducing sample size

Target population will be defined in product label: “redfine disease” form histopathological to molecular criteria


To Target or Not

May exclude patients who would benefit due to an unrecognized mechanism of action (such as BCR-abl, vs c-kit vs PDGFR

Targeting may limit the potential market


Imaging


Estimated Risks of Radiation-Induced Fatal Cancer from Pediatric CT:David J Brenner, Carl Elliston, Eric Hall, and Walter E Berdon. American Journal of Roentgenology AJR 2001; 176:289 – 296.


ITART MEETING 2010 37and some radiation exposure


Chest x-ray0.02 mSv (E) ~ 2.4 days of natural environmental radiation1 in 1,000,000 risk of lifetime cancer mortality

http://www.google.com/imgres?imgurl=http://pain.health-info.org/pictures/Xray%27s/Xray.chest.JPG&imgrefurl=http://pain.health-info.org/Pain%2520Pages/xray.htm&h=150&w=113&sz=544&tbnid=Ek3N5R411y0J:&tbnh=150&tbnw=113&prev=/images%3Fq%3Dchest%2Bx-ray&hl=en&sa=X&oi=image_result&resnum=1&ct=image&cd=3�


Ultrasound Imaging (US)

http://www.radiologyinfo.org/en/photocat/photos_pc.cfm?Image=hi_us-system3.jpg&pg=genus�

http://www.radiologyinfo.org/en/photocat/photos_pc.cfm?image=gen-us-thyroid.jpg&pg=genus�


Computed Tomography (CT)


A new generation of dual scanners image a patient using a CT and nuclear medicine scanner (either a PET scanner, or SPECT camera). These allow fused images. Pictured is a dedicated CT/SPECT scanner.

PET = Positron emission tomographySPECT = Single photon emission computed tomography


The resulting fused image provides very accurate anatomical and functional information.


Magnetic Resonance Imaging (MRI) scanner.

http://en.wikipedia.org/wiki/Image:Modern_3T_MRI.JPG�


Nuclear medicine, where the radioactively labeled drug is detected and imaged is playing a new role in molecular imaging and drug discovery. Nuclear medicine includes conventional radionuclides such as technetium-99m and iodine-131 and positron emitters such as carbon-11, oxygen-15 and fluorine-18.


Imaging Modalities for Tumor Delineation and Response PET FLT Targeted NanoparticlesOptical ImagingContrast enhancementMRI spectroscopy


Why is imaging so important? (1)

Monitoring an imaging metric, a biomarker, a surrogate endpoint, may shorten the time necessary to conduct a clinical trial.

An early change in this imaging metric may provide valuable information for patient management, e.g. FDG –PET in days/weeks vs CT in months.

Observing biomarkers may be more efficient than clinical endpoints.


Clinical endpoint*Overall survival,Symptom endpoints (patient defined),Disease-Free Survival, Objective Response Rate, Complete response, Progression-Free Survival, Time to Progression

*Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (May 2007)

http://www.fda.gov/CBER/gdlns/clintrialend.htm

http://www.fda.gov/CBER/gdlns/clintrialend.htm�


Why is imaging so important? (2)

In clinical trials a change, statistically significant, in an image over time can demonstrate efficacy, e.g. tumor size, tumor metabolism, or vessel diameter. If these changes have been correlated with true clinical endpoints!

For radiation therapy, both efficacy and safety depend on the accurate determination of radiation dose (energy/target mass), and imaging is essential for the denominator. Radiotherapeutics such as Bexxar®, Zevalin®, Y-90 microspheres, currently lack the level of precision and accuracy associated with traditional external beam and brachytherapy sources.


Why are we here?

Imaging has been recognized as a potential tool for drug development!

FDA’s Critical Path Initiative (2004)Go to: www.fda.govSearch on: The Critical Path

Imaging is not only a research tool when used to monitor change in drug development, it is essential for safety and efficacy as well.

http://www.fda.gov/�


What will I discuss?1. FDA wants good science in clinical trials!

2. FDA RulesRegulationsGuidance

3. Other Activities (DIA, NCI, RSNA)


Imaging Checklist (1a)

Select the imaging task and modality first, detection or measurement.

Ho = There is no cancer observed (detection task),

Ho = There is no significant difference (measurement task).


Imaging Checklist (1b)

Detection involves multiple observers (readers) and use of Receiver Operating Characteristic (ROC) curves, (plots of sensitivity vs specificity),

Measurement involves monitoring change over time, with quality control essential.

Talk to a medical physicist!


Imaging Checklist (2)

Train the qualified readers, prospectively!Use standard images to “calibrate” readers, either physically together, or with a detailed protocol. This should minimize adjudication.

This protocol should specify data collection, viewing conditions, image scoring and other criteria.


Imaging Checklist (4)Technical Issues-Phantom

Select phantom that will be used to testequipment relevant to the clinical metricsbeing used.

Many phantoms exist, new ones always beingdeveloped, a phantom can be designed for agiven trial and mass produced. (Make surephantoms are also tested and validatedcollectively.)


Imaging Checklist (5)Technical Issues- Drug

Imaging metric requires knowledge of drug amount.

How can you assure that the drug quantity is accurate?

This is highly critical for SUV*studies and trials where the patient is monitored over time. NIST** traceability would add value and credibility to the trial.

* Standard uptake value** National Institute of Standards and Technology


Imaging Checklist (6)Technical Issues The Patient-Phantom Relationship

Quantitative Imaging is not only dependent on the (1) imaging equipment, but on the (2) quantity of the drug, (3) within the patient.

Phantoms provide a surrogate for the patient for standardization, but anthropometric measurements need to be identified and made for each patient.


A few examples of phantoms:

Micro CT phantomsWater- Calibration of Hounsfield Unit (HU) WireLow contrastHigh contrast

Fluoroscopy Dose phantomCT Dose phantomMammography Phantom


Phantoms are an essential quality control (QC) Tool

Monitoring change in imaging equipment performance is done with phantoms because humans are neither standard nor always available.

And its unethical to use humans for repeated imaging.


Differences in reader’s criteria and display settings will influence volume estimate

Variability in radiologist drawn boundaries


History of Imaging Criteria

World Health Organization (1970’s)

Response Evaluation Criteria in Solid Tumors – RECIST (2000)

3-dimensional volumetric analysis (current)


Anatomy in 2DBaseline

8 Weeks

WHO: Bi-linear Measurement (1970’s)RECIST: Linear Measurement (2000)


-50

-40

-30

-20

-10

0

% Change

1 2

Measurement technique

Percentage Change in the measurement

RECIST Volume

- 3 %

- 40 %

baseline

30 days

Diameter = 17.7 mm

Diameter = 17.1 mm

Volume = 886 mm3

Volume = 525 mm3

RECIST vs. Volumetrics

Bensheng Zhao, MSKCC


STD

LUNG

BONE

Three differentreconstruction algorithms


FDA Rules- RegulationsCenter for Drug Evaluation and Research (CDER)

21 CFR* 312 Investigational New Drugs21 CFR 314 New Drug Applications21 CFR 315 Diagnostic Radiopharmaceuticals21 CFR 361.1 Radioactive Drug Research Committee

* Code of Federal Regulations


FDA Rules- Imaging Guidance(CDER)

Developing Medical Imaging Drug and Biological ProductsPart 1: Conducting Safety Assessments (July 2004)

Developing Medical Imaging Drug and Biological Products Part 2: Clinical Indications (July 2004)

Developing Medical Imaging Drug and Biological ProductsPart 3: Design, Analysis, and Interpretation of Clinical Studies (July 2004)Guidance for Industry, Investigators, and Reviewers

Exploratory IND Studies (January 2006)

Search on www.fda.gov

http://www.fda.gov/�


FDA Rules- Regulations

Center for Biologic Evaluation and Research (CBER)21 CFR 601 Biological Products, Licensing (BLA*)21 CFR 601.3 (Biologics) Diagnostic Radiopharmaceuticals

Center for Devices and Radiological Health (CDRH)21 CFR 800 Medical Devices (PMA)**21 CFR 900 Mammography21 CFR 1000 Radiological Health (Electronic Products)

* Biologics Licensing Application**Premarket Approval


FDA Rules- Medical Device and Combination Product Information

In addition to drugs and biologics, medical devices have there own set of rules and regulations.

Useful medical device information is available at:

http://www.fda.gov/cdrh/devadvice/

…and medical products that are combination products must be registered with the Office of Combination Products. Their website is http://www.fda.gov/oc/combination/faqs.html.

http://www.fda.gov/cdrh/devadvice/�

http://www.fda.gov/oc/combination/faqs.html�


Combination Products

Radionuclide Immunotherapeutic Pharmaceutical Imaging agent Kit-packaging E.G; Zevalin, Bexar (radiolabeled CD20

Antibodies)


Combination products

PK/PDRadiation dosimetry ToxicologyCMC (Stability, contaminants, etc) Imaging properties


Combination Products

Oncology Biologics ImagingCDRHClin pharmComplex interactive product with a

“chosen lead division”


Other ActivitiesMany other stakeholders and partners! …such as, but not limited to, theAmerican Association of Physicists in Medicine (AAPM),

American College of Radiology (ACR), Society of Nuclear Medicine (SNM), Radiological Society of North America (RSNA), American Institute of Ultrasound in Medicine (AIUM)…..

Too many overlapping, competing, uncoordinated efforts. No single imaging modality is superior for all tasks, some societies associate with one modality.


Imaging Review Charters

Comprehensive checklist for use by clinical research organizations (CRO’s)

Currently it is neither a regulation nor an FDA guidance, although FDA supports this initiative.

http://www.diahome.org/DIAHOME/Education/FindEducationalOffering.aspx?productID=14416&eventType=Meeting

http://www.diahome.org/DIAHOME/Education/FindEducationalOffering.aspx?productID=14416&eventType=Meeting�




National Institute of Standards and Technology (NIST)

Imaging as a Biomarker: Standards for Change Measurements in Therapy Workshop Summary (September, 2006)

http://www.mel.nist.gov/msidlibrary/doc/NISTIR_7434.pdf

http://www.mel.nist.gov/msidlibrary/doc/NISTIR_7434.pdf�

http://www.mel.nist.gov/msidlibrary/doc/NISTIR_7434.pdf�


RECIST- Response Evaluation Criteria in Solid Tumors

2000 guideline, replaced older WHO criteria.

Widely criticized, but pioneering effort, needs to be improved.

http://ctep.cancer.gov/guidelines/recist.html

http://ctep.cancer.gov/guidelines/recist.html�


LIDC

Lung Image Database Consortium-

Focus is on CAD (Computer assisted diagnosis)

http://imaging.cancer.gov/programsandresources/InformationSystems/LIDC

http://imaging.cancer.gov/programsandresources/InformationSystems/LIDC�

http://imaging.cancer.gov/programsandresources/InformationSystems/LIDC�


ACRIN

American College of Radiology Imaging Network

http://www.acrin.org/

http://www.acrin.org/�


IRAT Imaging Response Assessment Team

Nine funded imaging centers required to discuss experiences periodically (monthly).

Subject to funding constraints.

http://www.aaci-cancer.org/irats/about_project.asp

http://www.aaci-cancer.org/irats/about_project.asp�


The Issue *******

An imaging response must correlate with a meaningful improvement in QOL, PFS, Overall Survival i.e a meaningful biological benefit

Complete response may have superior correlation to benefit than a partial response-no matter how accurately response is measured

Drug evaluation admonitionsNow is now, then was then Eminence is not evidence 100,000 Frenchmen can’t be wrong For every ying theres a yangMechanisms of action are not always

what they seem Law of unintended conseuences is at

play


Regulatory Admonitions cont. Too much data may obuscate the issues Statistical significance does not mean

clinical significance PR, and even progression free survival

may or may not have clinical significance Bridge over the River Kwai effect-

investigators are enamored with their work


Regulatory admonitions cont

Regulatory science is an evolving practice and must grow with the multitude of new agents and devices.



Chaos, panic, & disorder-- my work here is done.

Documents

Regulatory Evaluation of Radiation Therapy Tumor … · Radiation Therapy Tumor Imaging and Evaluation Gerald Sokol ... • For particle beams relevant pre-clinical radiobiology