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CHALLENGES AND SUGGESTIONS: BREAKTHROUGH DEVICES PROGRAM FOR CLINICAL DIAGNOSTICS
Gary Spitzer, MD
PRESENTATION ABBREVIATIONS
AV – Analytical Validation
CV – Clinical Validation
CU – Clinical Utility
RCT – Randomized prospective trial
PRS – Prospective-retrospective study
POS – Prospective observational study
PRECISION MEDICINE TESTING TUMOR TISSUE OR PRODUCTS FOR TREATMENT DECISIONS
1. The role of precision medicine in day-to-day healthcare unfortunately is relatively limited.
2. It is more than just identifying a target for a drug ( DRUG COMPANION DIAGNOSTICS)
3. Equally important is to determine biological/genomic subtypes which may require less or more treatment, or identifying benignfrom malignant tumors, identify futility . Identify patient who are not localized , surgery incorrect treatment
SOME IMPORTANT GAPS OTHER THAN DRUG COMPANION DIAGNOSTICS OR SCREENING
De-intensified therapy Prostate Cancer intermediate and High Grade ( Remove hormonal therapy) Myeloma elderly patients who can avoid transplant Lung nodules which are benign to prevent biopsies Breast nodules which are benign to prevent biopsy Identify positive sentinel node biopsies patients better Early detection of futile therapy in stage 4 disease Identify better early failure or success of BCG therapy in Bladder Cancer . Identify patients with high risk of early systemic disease , or with small volume systemic disease , in need of systemic
therapy not local therapies Radiation for DCIS Thyroidectomy for thyroid nodules Identification of malignant skin lesions Radiation if pathological CR Etc. : However many validation endpoints may require long follow up with Prospective data : need careful thought
regarding surrogate endpoints
OXFORD DEFINITION OF A COMPANION DIAGNOSTICS
Laboratory tests and test kits used to determine the suitability of patients for tailoredor targeted forms of therapy, e.g.,
therapies that act on unique biochemical pathways or that require specific genotypesor mutations.
GENOMIC TESTING FOR EARLY STAGES OF CANCER is currently only routinely performed for breast cancer (after all these years)
After all these years we still do not routinely stratify tumors by aggressiveness which can identify a significant number of tumors that can be spared overtreatment that would otherwise result in long term consequences
• Lung Cancer• Prostate Cancer• Melanoma• Colon Cancer• Thyroid Cancer
VERY FEW BIOTECHNOLOGY LABS ARE PROFITABLE : THE INDUSTRY IS IN JEOPARDY
Genomic Health (NASDAQ:GHDX) recorded a $1.1 million profit during the third quarter, something it's been shooting for as it's improved its bottom line for each of the last nine consecutive quarters. But the profit only came on a non-GAAP basis, in which the company subtracted out the expenses associated with its recently announced collaboration with Biocartis. On a GAAP basis, Genomic Health lost a still-reasonable $2.2 million
CONCEPT: BREAKTHROUGH PATH FOR GENETIC AND GENOMIC TESTING TO MANAGE TREATMENT OF CANCER
The FDA has been innovative and able to get numerous drugs to market in extraordinary time frame on the basis of single arm studies, but with the requirement of Post Marketing Data
• This approach should be applied to breakthrough innovations in genetic and genomic profiling of tumors
The FDA is only the way we can remedy the slow death of small biotech innovation in genetic and genomic profiling
BREAKTHROUGH DEVICE DESIGNATION
A genomic signature that provides prognostic information for a cancer patient such that the information helps clinicians personalize the benefit-risk profile of a variety of therapeutic options and treatment strategies.
A genetic test capable of identifying DNA mutations using blood from cancer patients may offer patients a more convenient, non-invasive sampling method compared to surgery, which has the potential for serious risks. Sponsors should indicate which marketing application type (PMA, 510(k), or De Novo request) they intend to submit and include a rationale for this approach in support of their Breakthrough Device designation request.
BREAKTHROUGH 510 K CLEARANCE IS POTENTIALLY THE WAY TO ENCOURAGE SMALL LABS TO COME TO THE FDA
1. MUST CLEARLY DEMONSTRATE HOW THE SAFETY AND EFFICACY TRANSLATES INTO CLINICAL UTILITY IN THE INTENDED USE POPULATION 2. IF THE CONNECT BETWEEN SAFETY AND EFFICACY AND CLINICAL UTILITY IS CLEAR, THE REVIEW SHOULD INCLUDE COVERAGE CONSIDERATION BY CMS3. BREAKTHROUGH CLEARANCE SHOULD BE WITHIN THE FINANCIAL RESTRAINTS OF SMALL COMPANIES
Perception: consultant costs to prepare such a submission is 250,000+4. REAL-WORLD POST-MARKETING STUDIES TO DEMONSTRATE IMPROVEMENTS IN OUTCOMES THROUGH PRECISION MEDICINE SHOULD BE A CONDITION OF CLEARANCE AND COVERAGE
CHALLENGES / SOLUTIONS
CHALLENGE: COMPANIES NEED TO DECIDE THE CLINICAL UTILITY ENDPOINTS BEFORE INVESTING IN DEVELOPMENT OF A GENOMIC SIGNATURE OR NEW PRECISION MEDICINE TEST SOLUTION: FROM THE DISCOVERY SET: A CLINICAL CONSULTANT WITH UNDERSTANDING OF TEST
PERFORMANCE DEVELOPMENT OF THE INTENDED USE AND DISCOVERY DATA A PRESUB MEETING WITH THE FDA SHOULD OCCUR FOR FEEDBACK REGARDING THE STRENGTH OF THE
DISCOVERY DATA , IF IT HAS THE POTENTIAL TO REACH WHAT THE FDA WOULD CONSIDER CLINICAL UTILITY (SURROGATE END POINT) FOR A PROSPECTIVE CLINICAL VALIDITY STUDY WITH A REALISTIC TIME FRAME
CHALLENGE: CMS MACS DO NOT HAVE THE BAND CLINICALLY TO EVALUATE GENOMIC SIGNATURES OR OTHER PRECISION MEDICINE TESTS SOLUTION: IF THE FDA AGREES THE DISCOVERY SET IS PROMISING FOR THE INTENDED USE THE
PROSPECTIVE VALIDATION WILL GO FORWARD AND IT POTENTIALLY BE GIVEN BREAKTHROUGH STATUS WITH HIGH OPPORTUNITY FOR COVERAGE.
CHALLENGES / SOLUTIONS PROBLEMCHALLENGE: CAN WE USE CLINICALLY VALIDATED DATA THAT WOULD SUBSTITUTE FOR INITIAL CLINICAL UTILITY? SOLUTION: REALLY ONLY 2 AVENUES AFTER DISCOVERY AND A TEST IS LOCKED DOWN TO ESTABLISH CLINICAL VALIDITY
PROSPECTIVE RETROSPECTIVE FROM A TRIAL : RARELY MATERIAL AVAILABLE
PROSPECTIVE OBSERVATIONAL IN THE INTENDED USE POPULATION IF THE OUTCOME IS IN A REASONABLE SHORT TIME FRAME
CHALLENGE: EVEN A PROSPECTIVE OBSERVATIONAL SINGLE ARM STUDY REQUIRES MILLIONS STRETCHING THE VIABILITY OF SMALL COMPANIES IF THEY DO NOT GET REIMBURSEMENT AFTER IT SOLUTION: BREAKTHROUGH CLEARANCE AND COVERAGE
CHALLENGE: THE COST OF A PMA GIVEN THE MANUFACTURING DOCUMENTATION IS BEYOND MOST COMPANIES SOLUTION: THE 510 K MECHANISM MAY NOT BE
THIS IS IN LINE WITH BREAKTHROUGH DEVICE GUIDANCE Discussion and agreement between FDA and the sponsor regarding goals of interactions and feasibility of response timelines;
Use of summary tables to document points of agreement and previous interactions.
May need external input : SME NIH NCI.
THIS IS IN LINE WITH BREAKTHROUGH DEVICE LANGUAGE It should describe the balance of premarket and, as applicable, post market collection of clinical and nonclinical data.
FDA intends to work with the sponsor so that the plan is developed in a manner that is least- burdensome and predictable, while allowing for some measure of flexibility and adjustments as appropriate
IN LINE WITH BREAKTHROUGH DEVICE LANGUAGE
SAFETY AND EFFICACY ARE EQUIVALENT TO CLINICAL UTILITY
FOR IVD PRODUCTS, THE SAFETY OF THE DEVICE RELATES TO THE IMPACT OF THEDEVICE'S PERFORMANCE, AND IN PARTICULAR ON THE IMPACT OF FALSE NEGATIVE AND FALSE POSITIVE RESULTS, ON PATIENT HEALTH.
UNACCEPTABLE FALSE POSITIVES OR NEGATIVES : PATIENT IS EITHER UNDERTREATED OR OVERTREATED
THE FDA HAS BETTER BANDWIDTH THAN THE LOCAL MACS TO EVALUATE THIS
COVERAGE WITH POST MARKETING REQUIREMENTS FOR MOLECULAR
DIAGNOSTIC TESTS
BEFORE PRESUB MEETING WITH FDA, LAB SUBMITS TECHNOLOGY USED ON DISCOVERY SET TO APPROVED BODY FOR ANALYTICAL VALIDATION ( LABs FEEL THERE IS A DUPLICATION OF CLIA AND THE AV REQUIRED BY THE FDA)
COMPANY PERFORMS DISCOVERY SET AND PRESENTS TO FDA IF DATA IS DERIVED FROM APPROPRIATE INTENDED USE POPULATION AND AV IS SATISFACTORY .
IF FDA APPROVES THAT NEED AND DATA COULD FILL AN UNMET NEED THE PROSPECTIVE VALIDATION DATA WOULD BE GIVEN BREAKTHROUGH STATUS ( THIS WOULD FACILITATE CONTINUED INVESTMENT)
ON COMPLETION OF PROSPECTIVE VALIDATION BREAKTHROUGH DEVICE REVIEW PROCESS COMMENCES
IN LINE WITH BREAKTHROUGH DEVICE LANGUAGE FDA may consider the amount of data that may be collected in the postmarked setting, rather than premarket, and the level of acceptable uncertainty in the benefit-risk profile at the time of approval.
In all FDA premarket approval decisions, there is some degree of uncertainty about the benefits and risks of the device.
We may not have definitive answers to all questions relating to the benefits and risks of the device at the time of approval because the time and cost of such data collection would adversely affect public health by significantly delaying the availability of medical devices that may improve the health of patients
A particular device may require clinical studies that enroll thousands of subjects to more fully assess all risks, such as rare adverse events. The degree of uncertainty that FDA accepts at the time of approval depends on, among other factors, the probable benefits of the device.
BREAKTHROUGH CLEARANCE AND COVERAGE WITH POST-MARKETING REQUIREMENTS :2
510 CLEARANCE IDENTIFIES CLINICAL UTILITY
FDA REVIEW SUBMITTED TO CMS CENTRALLY FOR COVERAGE DECISION
COVERAGE DECISION GRANTED ALONG WITH FDA SUGGESTED POST APPROVAL REAL WORLD ENDPOINTS
THIS DATA CAPTURE HOPEFULLY FISCALLY POSSIBLE BECAUSE OF ADEQUATE MONETARY COVERAGE.
FDA REVIEWS POST APPROVAL COVERAGE , MAYBE USER FEES HERE AND RECOMMENDS TO CMS PERMANENT COVERAGE
ALTERNATIVES TO RCT, RPS AND POSClinical validation – promising quality to suggest CU – FDA to define
FDA / sponsor agree on study(ies) to define CU prior to coverage using: Intermediate or surrogate endpoints via:
Limit coverage to defined use and user for up to 3 years with FDA periodic review – “Use and user creep”
Consider user fees for post approval data review Registries – prospective
Clinical vignette data modeling – prospective
Medicare claims data analysis (CPT and ICD-10) – retrospective
Require publication regardless of outcomes
FDA / Sponsor agree on objectives, endpoints, limited data elements
Data capture via independent registry, data modeling or claims data
Test implemented for intended useData provided to FDA
/ test developer
Coverage with Post Approval Data Collection
CMS Coverage
HOW FDA DECISION TRANSLATES TO CMS COVERAGE
FDA approved Drugs CMS Technical Direction Letter (TDL) – drugs automatically covered when in Drug Compendia – NCCN, etc Works for Part B billable drugs Established national coverage for the drug Eliminated need for individual MAC Local Coverage Determinations (LCDs)
FDA approved Diagnostics – Suggestions: Keep process simple FDA post Diagnostic Approval List & CMS issue TDL regarding coverage Establish national coverage without LCDs or NCD For cancer related diagnostics – Post in NCCN compendium For non-cancer diagnostics – Ex: Macular Degeneration, drug compliance testing – FDA Approval List or other
mechanism
DESIGNATION WITHDRAWAL
Failure to initiate and accrue data in a timely period
Failure to monitor intended use - screening vs diagnostic
Failure to demonstrate CU
THE REAL UNMET NEED
WE NEED ALL IMPORTANT STAKE HOLDERS TO IMMEDIATELY MEET AND MAKE A LIST OF UNMET NEEDS THAT PRECISION MEDICINE COULD POTENTIALLY MAKE AN ENORMOUS DIFFERENCE TO PATIENT OUTCOMES AND ABUSE OF RESOURCES FOR EACH OF THESE NEEDS WE NEED TO DECIDE WHAT CV WOULD ALLOW CENTRAL CMS TO GIVE NATIONAL COVERAGE , WITH THE PROVISO THE CV IS VALIDATED AFTER COVERAGE WITHIN 3 YEARS WE NEED ADEQUATE REIMBURSEMENT FOR THE TEST AS THE SUFFERING AND COSTS OF INAPPROPRIATE TREATMENT PALE IN COMPARISON WITH THE COSTS OF THE TESTS WE NEED MECHANISMS TO REMOVE A TEST IF IT NO LONGER PREFORMS IN THE STANDARD OF PRACTICE: This includes newly approved tests as well past approved tests WE NEED ONLY ONE MECHANISM OF APPROVAL SO ALL STAKEHOLDERS KNOW THERE IS A CONSISTENT PATHWAY TO COVERAGE WITH LEARNED PEOPLE ABLE TO EVALUATE AND SUBSEQUENTLY RECOMMEND COVERAGE THE FOLLOWING EXAMPLES AREA FEW OF MANY I COULD ADDRESS. THIS IS NOT CANCER SPECIFIC
Thank You
Questions?
EXTRA SLIDES
ALTERNATIVE BREAKTHROUGH CLEARANCE AND COVERAGE WITH POST-MARKETING REQUIREMENTS LAB ONLY MARKETS TEST TO USERS FAMILIAR WITH THE TEST AND MORE LIKELY
TO MANAGE MOST PATIENTS BY THE
LAB COLLECTS DATA FROM ALTERNATIVE USERS WHICH DO NOT USE THE TEST AND DOES NOT OFFER THE TEST TO THEM
THIS WAY IT IS NOT A RANDOMIZED STUDY, WHICH IS BEYOND MOST COMPANIES IF NOT ALL , AND NOT ASSOCIATED WITH THE PATIENT DROP OUT OF RANDOMIZED STUDIES.
REAL WORLD OUTCOMES CAN BE CAPTURED AND COMPARED BETWEEN THE TWO
POTENTIALLY THE OUTCOME OF INTEREST MAYBE CAPTURED BY CLAIMS
IF TEST IS CLEARED
FDA MAY WISH TO DEVISE A CURATING SYSTEM
SUBMIT FDA REVIEW TO CENTRAL CMS AND NCI OR NIH FOR THEM TO REVIEW COVERAGE : DO NOT LEAVE THIS TO A LOCAL MAC
IF COVERAGE GRANTED , DESIGN OF POST APPROVAL DATA COLLECTION AND ENDPOINTS FINALIZED BY FDA OR EXTERNAL REVIEW
FDA NOT CMS BE THE REVIEWER OF THE POST APPROVAL DATA
POSSIBLY USER FEES CHARGED HERE IF REIMBURSEMENT ENOUGH TO COVER IT.
REMEMBER AS DISTINCT FROM A DRUG THEY USUALLY ONLY GET ONE CHARGE : IF 3000 DOLLAR PRICE GRANTED THERE MAYBE LITTLE LEFT FOR DATA COLLECTIONS AND RECAPTURE DEVELOPMENT COSTS
IN LINE WITH BREAKTHROUGH DEVICE LANGUAGE FDA may consider the amount of data that may be collected in the postmarket setting, rather than premarket, and the level of acceptable uncertainty in the benefit-risk profile at the time of approval.
In all FDA premarket approval decisions, there is some degree of uncertainty about the benefits and risks of the device.
We may not have definitive answers to all questions relating to the benefits and risks of the device at the time of approval because the time and cost of such data collection would adversely affect public health by significantly delaying the availability of medical devices that may improve the health of patients
A particular device may require clinical studies that enroll thousands of subjects to more fully assess all risks, such as rare adverse events. The degree of uncertainty that FDA accepts at the time of approval depends on, among other factors, the probable benefits of the device.
1. DE-ESCALATION VALUE: 1. Remove unnecessary drug. (cost and toxicity )2. Reduce dose of a treatment modality 3. Identify indolent disease in need of no action4. Intended use population must be clearly
defined where treatment has potentially been significant with significant morbidity
DE-ESCALATION: SPECIMEN REQUIREMENT
Biobank preferably from a prospective study including patients receiving the the de-escalation approach
Accurate estimation of an adverse event , e.g. Recurrence is 5% approximately with narrow SD.
At these outcomes, adverse reactions from extra treatment are unlikely to match any small benefit from further reduction in recurrence rate
EXAMPLES OF DISEASES IN NEED OF DE-ESCALATION OF THERAPY Thyroid nodules : total thyroidectomy
Prostate Cancer : proctectomy , radiation therapy , overuse of androgen suppressive therapy
Autoimmune diseases , overuse of biologicals
2. PREVENT AN INVASIVE PROCEDURE: NEEDS A HIGH NPV FOR BENIGN DISEASE 1. Lung Nodules : Prevent dangerous biopsy
2. Breast Masses
3. Hematuria to prevent cystoscopy
4. Thyroid nodules
5. Organ transplant rejection
PREVENT AN INVASIVE PROCEDURE: NEEDS A HIGH NPV FOR BENIGN DISEASE : VALIDATION SPECIMENS This possibly could be a retrospective analysis if biobank blood is available , deidentified subjects should be selected by an independent consultant to fit the intended use .
After discovery , the validation should be performed on different specimens than the discovery cohort and review should be by an independent investigator and the company blinded to result
Tests should outperform clinical algorithms
If unavailable biobank, study would have to be prospective
NPV for benign disease would have to be above 90% with SD not exceeding < 90%
Appropriate short term follow up would be suggested
3. IDENTIFY NEWLY DIAGNOSED PATIENT WITH A HIGH LIKELIHOOD OF ADVANCED DISEASE 1 Avoids inappropriate local therapy
2 Directs them to more advanced staging procedures
4. IDENTIFY NEWLY DIAGNOSED PATIENT WITH A HIGH LIKELIHOOD OF ADVANCED DISEASE: GUIDELINES DO NOT RECOMMEND WHOLE BODY IMAGING These studies would be prospective
The PPV would have to be high (High Specificity at Sacrifice of Sensitivity )
This would mean the majority of patients reflexed to extensive staging because of a positive test would have advanced disease : cost and time effective
MEDICARE CLAIMS DATA COULD CAPTURE ADVERSE OUTCOME
TESTS TO IDENTIFY EARLY FUTILITY OF THERAPY
Early readout of ineffectiveness' before cycle 2 Reduce toxicities and cost of ineffective therapy Potentially reduce imaging costs Reduce drug development costs
TESTS TO IDENTIFY EARLY FUTILITY OF THERAPY
Test would have to very high NPV close to 100% : for patients to accept action based on result
Test would have to be resulted fast and before second cycle of therapy to reduce subsequent drug use and imaging
Test would be validated relative to usual imaging performed at 8 weeks or 12 weeks
5. TESTS TO OVERCOME AMBIGUITY OF HISTOLOGICAL DIAGNOSIS : BENIGN FROM MALIGNANT : ENORMOUS DISCORDANCE BETWEEN PATHOLOGISTS Skin
Thyroid nodules
What is more accurate
Single local pathologist’ call or the test
Comparator “ Present Gold Standard – consensus from 3 experienced Pathologist “
Population well defined , size , age etc.
