October 17-19Ottawa, Ontario, Canada

DIA Annual Canadian Meeting 2016

Stephen F. Amato, PhD, MBA, RACManaging Director, East Coast Operations, Cardinal Health Regulatory SciencesAssociate Professor of Regulatory Affairs and Market Access, Northeastern University

Personalized or “Precision” Medicine and Companion Diagnostics – Potential Regulatory Implications

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Statement of Purpose and Approach

Gain a specific understanding of how personalized medicine applications, including companion diagnostics (Dx) will be

regulated by FDA

Statement of Purpose

To support these objectives, a comprehensive regulatory landscape assessment based on FDA’s past companion

diagnostic assessments, current guidance as well as FDA outcomes for past companion diagnostic technologies was

conducted

Approach

Is the technology platform utilized in the same way for example for infectious disease and oncology applications? (i.e. is it utilized as an identification tool in both types of cases)

Is the technology platform utilized in the clinical decision-making process? (i.e. is it a laboratory developed test?)

What are the benefits and risks involved in incorporating the technology platform into the therapeutic process? (potential issue –number of steps involved in process)

Key Questions to Consider

+How are Companion Diagnostics Defined from FDA’s Perspective?

Premise of Companion Diagnostic Development and Clinical Utility

New biotechnology and knowledge of pathogen and tumor molecular biology antigen presentation provides opportunities to improve therapeutic decision making and new vaccine and/or drug developmentThe established molecular heterogeneity of human diseases requires the use of new diagnostic approaches to the development and evaluation of therapeutics since genotypic patient differences may significantly impact clinical outcomes

Types of Companion Diagnostic Biomarkers

Predictive biomarkersMeasured before treatment to identify who is likely or unlikely to benefit from a particular treatment – binary outcomes – “yes” or “no”

Prognostic biomarkers• Measured before treatment to indicate long-term

outcome for patients untreated or receiving standard treatment

• Marker of disease aggressiveness or disease aggressiveness in context of standard or novel treatment

Predictive & Prognostic Diagnostic Biomarkers

Most infectious disease and/or oncology treatments benefit only a minority of patients to whom they are administeredBeing able to predict which patients are or are not likely to benefit would • Save patients from unnecessary toxicity, and enhance their

chance of receiving a drug that helps them• Control medical costs • Improve the success rate of clinical drug development

Types of Validation for Prognostic and Predictive Biomarkers

Analytical validation– Accuracy, reproducibility, robustnessClinical validation– Is the biomarker correlated with a clinical endpoint?Clinical utility– Does use of the biomarker result in patient benefit?

• By informing treatment decisions• Is it actionable?

In vitro Diagnostic Products (IVD’s) From FDA’s Perspective

In vitro diagnostic products (IVD's) are:– reagents, instruments, and systems

used in diagnosis of disease or otherconditions

– in order to cure, mitigate, treat, or preventdisease

– intended for use in the collection,preparation, and examination of specimenstaken from the human body

[21 CFR 809.3]

• Companion diagnostics (IVDCDs) are aspecial class of IVDs

• Provides information that is essential for the safeand effective use of a corresponding therapeuticproduct – Currently FDA does not address vaccineor neoantigen companion diagnostic regulations

• Drugs and their companion diagnostic tests referto each other in their labels

• FDA currently approved IVDCDs: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm

Companion In Vitro Diagnostic Products (IVDCDs) From FDA’s Perspective

• December 2014: In vitro Companion DiagnosticDeviceswww.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm262327.pdf

• July 2016: Principles for Co-development of an in Vitro Companion Diagnostic Device with a Therapeutic Product

www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm407297.htm

Current FDA Guidance on Regulation of IVDCD Products

Prospective Co-Development of Drugs and IVDCD’s

1. Develop a completely specified genomic classifier of the patients likely to benefit from a new drug

2. Establish analytical validity of the classifier3. Use the completely specified classifier in the

primary analysis plan of a phase III trial of the new drug

11IND

CDER

CDRH

• Development of paired therapeutic products and diagnostic devices with interdependent uses (e.g., a drug and a companion diagnostic)

• Biomarker discovery and test development can occur anytime during the drug development process

• Safety and efficacy of the new drug (“clinical utility”) and new Dx is typically demonstrated in the same clinical trial.

• Goal is simultaneous approval of the drug and diagnostic –vaccines/neoantigens not yet addressed

IDE Approval

Co-development of IVDCDs With Clinical Therapeutics

Labeling Features Important for IVDCDsRegardless of FDA status

• Analytical validity– Does the test measure the correct analyte?– Does the test measure the analyte reliably?– Precision, reproducibility, sensitivity, specificity, etc.– Cutoff/reference range

• Risk dependent:The extent of analytical validation required for a pivotal trial exceeds

what is required for feasibility studies.• The context in which the device is used

Clinical laboratory, point-of-care setting• Intended use/Indications for use:

– Clinical purpose (diagnosis, prognosis, monitoring)– Target population for whom the test is intended

+ Potential IVDCD FDA Pathways

FDA Policy for IVDCD Clinical Trials

• Significant risk (SR IVD): An IDE is required for an investigation even if there is an IND for use of thedrug, or if the drug is IND exempt

• Non-significant risk (NSR IVD): An IDE is not required, and cannot be accepted for review– The trial still has to comply with the abbreviated

requirements– Some information on the test may be requested in the IND– A presubmission with CDRH is recommended

IDE Regulation (21 CFR 812)

• Regulatory submission that permits clinical investigation of devices/IVDs

• An approved IDE permits a device to be shippedlawfully for the purpose of conducting investigations of the device without complyingwith other requirements of the Food, Drug, and Cosmetic Act (Act) that would apply to devicesin commercial distribution.

• Focused on risk• Delegated responsibilities

A Risk-Based Approach to IVD Regulation

• Need to think about the benefits and risks of a test• For an IVD tests, it is important to think about the risks

associated with false positives or false negatives. What would happen if the test results are wrong? Are thebenefits greater than the risks of inaccurate results?– False positive: the patient would receive unneeded

treatment, be exposed to treatment risk without benefit– False negative: the patient would not receive needed

treatment.• For companion diagnostics, this will depend on the

disease, the risks of treatment with the drug, and othertreatment options (e.g., standard of care)

IVDCD Significant Risk (SR) ConsiderationsSignificant risk device (812.3(m)) means an investigational device that:Is intended as an implant and presents a potential for serious risk tothe health, safety, or welfare of a subject;• Is purported or represented to be for a use in supporting or

sustaining human life and presents a potential for serious risk to thehealth, safety, or welfare of a subject;

• Is for a use of substantial importance in diagnosing, curing,mitigating, or treating disease, or otherwise preventing impairmentof human health and presents a potential for serious risk to thehealth, safety, or welfare of a subject; or

• Otherwise presents a potential for serious risk to the health, safety,or welfare of a subject

In other words, does the use of the IVD guide patient care?(ie, patient selection)

Laboratory Developed Tests (LDT's)• LDT’’s are a type of IVD test that are designed,

manufactured and used within a single laboratory• LDT's can measure a wide variety of analytes

(substances such as proteins, chemical compounds likeglucose, or DNA), in a sample taken from humans

• While the uses of an LDT are often the same as theuses of FDA-cleared or approved in IVD, some labsmay choose to offer their own test

• The FDA does not consider diagnostic devices to beLDT's if they are designed or manufacturedcompletely, or partly, outside of the laboratory thatoffers and uses them

http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407296.htm

http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm407296.htm

Laboratory Developed Tests (LDT's)• FDA has not enforced premarket review because LDT's were

relatively simple lab tests and generally available on a limitedbasis. But, due to advances in technology and business models,LDTs have evolved significantly since initial in vitro diagnosticsregulations in 1976.

• LDTs are now more complex, and present higher risks, whichare similar to those of other IVDs with premarket review.

• FDA has identified problems with several high-risk LDTs including:claims not adequately supported with evidence; lack of appropriatecontrols yielding erroneous results; and falsification of data.– Faulty LDTs that could have led to: patients being over- or undertreated for

heart disease;– cancer patients being exposed to inappropriate Rx or not getting effective Rx;– incorrect diagnosis of autism; etc.

The 510(k) premarket notification process requires demonstration of ‘substantial equivalence’ to legally

marketed devices

In return, FDA is assured:• Any new device will not be

marketed until it complies with PMA requirements (or is down classified to Class II or I)

• Any new device claiming to be ‘similar’ to pre-amendment device is actually ‘substantially equivalent’ to said device

1976 Medical Device Amendments modified §510 of the FD&C Act to include subsection (k)• Manufacturers that register

under section 510 must provide a premarket notification to the FDA at least 90 days prior to marketing a device

The 510(k) premarket notification process is utilized to clear most but not all class II medical devices for

marketing

510(k) Premarket Notification Applies To

• Device being introduced into commercial distribution for the 1st time (unless the device has been exempt)

• Device design is based on an approved device but has been modified in a way that could impact its safety and effectiveness

• Device is marketed with new intended use

Exempt From the 510(k) Premarket Notification

• Devices for which general controls are sufficient to provide a reasonable assurance of safety and efficacy

• Pre-amendment devices, as long as: • They have not been

adulterated or misbranded• No changes in labeling or

changes in device design have been made

+Example Companion Diagnostic Technologies

TumorVaccines

• Cells• Lysates• Proteins,

peptides• Genetherapies• Idiotypicand

anti-idiotypicantibodies

Example Immuno-Therapy

From Donnelly, RAPS201320

FDA Approved Companion IVD Tests for Herceptin

Asof June 2016

Name of test analyte

Informher2/neu FISH qualitative gene amplificationPathyvysion her-2dna probe kit FISH qualitative gene amplification

Pathwayanti-her 2/neu ventana IHC Semiquantitativec-erb-2 protein

Insite her2/neu kit IHC Semiquantitativec-erb-2 protein

Spot-light Her2 CISH Kit CishSemiquantitativec-erb-2 protein

Bondoracle her2 ihc system IHC Semiquantitativec-erb-2 protein

HER2 CISH pharmaDX kit CishSemiquantitativec-erb-2 protein

INFORM HER2 DUALISH DNAProbeCocktail

ISH enumerationof ratioher2 gene andchromosome17

HERCEPTEST IHC Semiquantitativec-erb-2 protein

HER2 FISH PharmDx Kit FISH quantitative gene amplification

+ Conclusions

ConclusionsSome of the conventional wisdom about statistical analysis of clinical trials is not applicable to trials dealing with co-development of drugs and companion in vitro diagnosticsPrior FDA decisions suggest that if a technology platform is being utilized during drug/vaccine clinical development, but not therapeutically, a rationale can be written to explain that it is not a companion diagnostic productIt may be possible to position a technology platform tool as a Research Use Only (RUO) tool – especially if it is utilized for discovery of novel neoantigensAt this risk of stating the obvious, the more the technology is utilized, the more validated and powerful the tool becomes –however, this increases the risk that the tool will be considered a companion diagnostic by FDA, as many clinicians will look to the tool in their personalized medical treatment approaches

Contacts

Cardinal Health Regulatory Sciencesc/o Stephen Amato, PhD, MBA, RAC245 First Street, Suite 1822Cambridge, MA 02142P- 781-640-0553Stephen.Amato@cardinalhealth.com

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