# Presentation: 200128

## Evaluation of new drugs and devices for cancer: the FDA perspective

- Gerald Sokol MD, MS, FCP
- CDER/FDA
- USUHS
- gerald.sokol@fda.hhs.gov

## The most terrifying words in the English language are: I'm from the government and I'm here to help."  Ronald Reagan

## My Charge

- An expensive new radiotherapy treatment should be tested by the RT investigators in the same way as an expensive new drug treatment-including the issue of surrogate endpoints
- Sokol, FDA

## Summary

- I Regulatory background of drugs and devices
- II Use of surrogate markers
- III Why and why not radiation therapy devices and protocols should be subject to regulatory review.
- IV Regulatory experiential pitfalls in the review process and regulatory process admonitions
- Sokol,FDA

## The reviewer in his natural habitatSokol, FDA 

## Slide 6

## The “White Oak” Consolidation

## The New FDA Consolidation

## FDA - Oncology Drugs

- Office of Oncology Drug Products – OODP
- Three divisions
- DDOP- Chemotherapy drugs for Cancer
- DBOP- Biologic oncology therapies BLAs
- DMIHP- Medical Imaging and hematology
- Sokol, FDA

## Communication is the Key

## 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, T- con) | Results; format & content of reports; time frame of submission; priority? |

## Requirements for Drug Approval

- U.S. Statutes –Congress
- Labeling	1906 Pure Food & Drug Act
- Safety 	1938 Food, Drug, and Cosmetic _Act _
- Efficacy 	1962 FDC Amendments
-                                                Harris-Kefauver
-  FDAMA Amdnts. 1997
- Code of Federal Regulations (CFRs)
- Regulations from FDA provide interpretation of the laws

## Drug Approval Tracks

- FDA Modernization Act 1997 (FDAMA):
- CFR 312 subpart E regulations
- To expedite development for life-threatening illnesses
- Fast track
- process for meeting FDA -unmet med need
- Priority review
- Determined by FDA after NDA submitted
- 6 month NDA review time frame for products addressing unmet medical need

## Drug Approval Tracks

- Accelerated approval “CFR 314 subpart H”
- 1992
- Special Protocol Assessment
- agreement between FDA and sponsor on clinical protocols for phase 3 studies forming primary basis for demonstrating efficacy for NDA; 45 day clock

## 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

## Advisory Committees (ODAC)

- When the decision is tough
- Consultative (collegial)
-  Represents academic and community input
- Non-binding but usually comports with final decision
- Public airing

## 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)

## Comparison of features of drugs and devices

***Drugs***
- Pure molecule
- Toxicology/pharmacology
- Short half-life
- Long market life
- Ineffective
- Wrong drug/dose/route
- National Drug Code coding system

***Devices***
- Complex components
- Biocompatibility
- Short to long life
- Usually mode of ineffectiveness thought of as failure
- Use related error
- Broad codes being replaced by a new nomenclature under IH development

## Drugs vs Devices

***Drug***
- 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***
- Broad 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

## Device Classification

- Risk based
- Class I: common, low risk devices
- General controls
- Most exempt from premarket review
- Class II: more complex, moderate risk
- General controls and special controls
- Premarket Notification [510(k)]
- Class III: most complex, highest risk
- Supported by valid scientific evidence
- Premarket Application (PMA)

## Submission Types

- Pre-market notification 510(k)
- Pre-market application (PMA)
- De novo classification
- Investigational device exemption (IDE)
- Humanitarian device exemption (HDE)
- Analyte specific reagent (ASR)** **
- Product development protocol (PDP)
- Pre-IDE

## 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.

## Review Questions

- Is the intended use claim supported by the data provided?
- Do the data demonstrate the device to be effective for its recommended use?
- Do the benefits of using the results outweigh the risks of a false positive or false negative results?
- Is it necessary to restrict use of the device to certain types of laboratories or facilities?
- What additional information should be included in the directions for use?

## Types of Device Interfaces

- Device is drug or radiation delivery vehicle
- Device delivers drug & contributes function
- Radiation Device and other devices- e.g.-hyperthermia (RF, ultrasound, UHF), implants, internal dosimeters etc)
- Presence of both results in unintentional increased risk of adverse event (AE)

## Regulatory History

-  Until 1976, all combinations were regulated as drugs.
-  1976 – 1990, combinations were assigned to CDER or CDRH via informal process.
- 1990, Safe Medical Devices Act legally recognized drug-device combinations. Lead Center should be assigned based on primary mode of action.
-  1991, Intercenter Agreement on how to assign combinations.
-  2002, formation of Office of Combination Products per Medical Device User Fee and Modernization Act of 2002.
- Director from CDRH (Mark Kramer). – Associate Director from CDER (Patricia Love).

## FDA Oncology Drug Approval

- Clinical trials:
- When we do not know which therapy is better
- Patients are fully informed of the uncertainty about which therapy is better and give consent
- We can compare one treatment with another in a controlled way
- Today’s “standard” therapy was last year’s investigational treatment

## FDA Oncology Drug Approval

- Controlled clinical trials:
- Can be verified, repeated if necessary
- Can allow us to be convinced a new therapy is effective – or it is not.
- Allow us to compare how well tolerated -
- (how safe) a new therapy is versus a standard
- Efficacy with Safety => Approval

## Approval and tumor assessment endpoints 

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

## Approval and tumor assessment endpoints 

- AA uses tumor assessment endpoints
- 	_Magnitude_ and _consistency _of effect important
- RR + TTP may achieve AA
- TTP _alone_ unlikely to be sufficient
- RR + TTP with hormone Rx – breast cancer may => RA
- CRs with Duration – Hematologic cancers may => RA
- 	Endpoints and FDA Oncology Drug Approvals
- 	Johnson, Williams, Pazdur
- 	Journal of Clinical Oncology 2003; 21:1404-1411
- Disease - Endpoint – Drug - Approval

## DEFINITIONS

- Clinical end point: a characteristic or variable that reflects how a patient feels, functions, or survives.
- Surrogate end point: a biomarker or endpoint that is intended to substitute for a clinical endpoint. A good « correlate » may not make a good « surrogate ». A surrogate endpoint is expected to predict clinical benefit (or harm) or lack thereof.
- To speed up clinical trials, decrease cost, and improve efficiency
- Ref: Biomarkers Definition Working Group, Clin Pharmacol Ther 2001, 69: 89

## VALIDATION OF SURROGATE ENDPOINTS

## Slide 33

## Slide 34

## Surrogate and true endpoint must be correlated

## Effects of treatment on surrogate and on true endpoint must be correlated

**Effects of treatment on surrogate and on true endpoint must be correlated**

## Evaluation of a Radiotherapy Device

- Physics (beam quality, reliability, stability, 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 and protocol 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, ionizing modality.
- 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.

## Surrogate Markers for Radiotherapeutic Device

- Combination of supporting documentation
- Medical literature
- Clinical trials-phase I,II
- Disease state and study specific
- Example-Whole body biodistribution imaging for Bexxar and Zevalin

## 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)
- Determine in comparative trials the superior therapy

## Radiotherapy Surrogates

***	******	******Safety surrogates vs. Efficacy surrogates***
- Safety
- –QOL measures (Fact-lung, prostate, GU etc.)
- biomarkers-TGF-beta (fibroscan)
- patient reported outcome measures
- CTC-NCI criteria,
- electronic (resistance measures of fibrosis, lung densitometry for fibrosis or pneumonitis
- acute phase reactants
- vascular imaging by ultrasound
- radio/pharmacogenic alterations
- lymphocyte mutation
- marrow reserve by imaging
- site specific criteria such as nutrient absorbent tests, cardiac impedance/ejection evaluations
- Site specific evaluation of performance status-cns-time to cns progression of disease-etc, etc
**All evaluated over multiple time points**

## Evaluation of a Radiotherapy Device

***Surrogate markers for efficacy***
- Survival in a randomized study is the gold standard
- TTP, PFS, QOL improvement (pain, function, organ preservation, decreased skeletal related event free survival etc.)
- Endpoints must be pre-defined, accepted for the trial and the Agency-(tumor response alone (PR) is not generally acceptable alone.)
- Pet scan response parameters
- PSA acceleration (Int. J. Radiaton Onc, Nov, 2006)

## Jerry Sokol’s New Product Admonitions

***Now is now and then was then-***times change and new data may abrogate old decisions and experience
***Bridge over the River Kwai-***It’s easy to become enamored with your project and forget the real enemy
***The tail wags the dog-***when there appears to be a great financial advantage to a new product, be sure the reasons for its existence are valid beyond profit.
***Eminence is not evidence*** -famous names do not a study make and does not supersede evidence

## Jerry Sokol’s Admonitions Cont.

***For every ying there’s a yang*** -IMRT may increase a local dose but increase whole body dose with resultant increase in second radiation induced neoplasms.

- •  ***The law of unintended consequence***-what looks like a benefit
-    may have adverse consequences down the line (RFA cause tumors
-    to shrink but may enhance the growth of others-(Balden et.al. 	Aliment Pharm Ther., Nov 2006)
- •   ***A pound of cure is better than an ounce of prevention –***higher
-     dose, higher response, higher side effects may be obtained by the
-     same degree with the old treatment pushed harder (are we
-     managing toxicity without a true benefit)
- •   ***A hundred thousand Frenchman can’t be wrong*** -yes they can-
-     patients and doctors misinterpret benefits and results

## Question already answered

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## Cont.

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## Cont.

- 	26. If I throw a stick, will you leave? 27. Errors have been made. Others will be blamed. 28. Whatever kind of look you were going for, you missed. 29. I'm trying to imagine you with a personality. 30. A cubicle is just a padded cell without a door. 31. Can I trade this job for what's behind door #1? 32. Too many freaks, not enough circuses. 33. Nice perfume. Must you marinate in it? 34**. Chaos, panic, & disorder-- my work here is done**. 35. How do I set a laser printer to stun? 36. I thought I wanted a career; turns out I just wanted a salary. 37. Oh I get it ... like humor ... but different

## 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
- Sokol, FDA

## FDA Oncology Drug Approval

-  How do you achieve approval ?
-  Provide substantial evidence of
-           	_Efficacy_ and _Safety_
-  What is _substantial evidence_ for Effectiveness
-  	“A & WC investigation_**s**_”  CFR 314.126
-  2 or more studies
-  	required by 1962 amend.  to FFDCA
- Source = Controlled clinical trials

## De Novo 510(k)

- For
- Low or moderate risk IVDs that have no predicate device
- IVDs with obvious or “intuitive” benefit
- Not for
- New IVDs intended to diagnose newly recognized serious diseases
- Unable to determine ways to manage risk
- Already classified

## De Novo 510(k) (2)

- Standard is “safe and effective”
- Compare to reference method or clinical diagnosis
- Identifies controls (general and special) applicable to the device to manage risk
- Classifies device into class I or II
- New classification is written and published

## Major Elements of a Submission

- Intended use/indications for use
- Device description
- Performance characteristics – analytical and clinical
- Instrument validation, if applicable
- Software validation, if applicable
- Labeling (package insert)

## Software

- Require documentation:
- Total system validation
- Describe any algorithms or cutoffs used to determine results
- Database integrity
- Cyber-security

## Post-Market Regulation

- Facility inspection
- “condition of approval”-order to perform a specific study
- Controls-e.g.-post-market surveillance, patient registries, guideline development, other recommendations
- Adverse event reporting (Medical Product Surveillance Network-”MedSun”)
- Post-market Surveillance Study order- e.g. -cohort follow-up, bench materials testing (1997PDUFA)

## 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 Benefit
- Longer 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

## Oncology Trial Endpoints (1)

- CLINICAL BENEFIT ENDPOINTS
- LIVE LONGER – Measure Survival- OS
- 	Efficacy, reassures for safety, unbiased endpt but – subsequent therapy, long time required
- LIVE BETTER – Measure QOL – PRO
- 	Important: control group + blinding needed (bias)
- 	hard to measure, scale problems, missing data
-    Drug TX. symptoms versus tumor symptoms
- 	=> COMPARISONS ARE NECESSARY
- 	**Note – These endpoints do not measure the tumor**

## Interface between Drugs and Devices-Devices and Devices

- • Types of interfaces
- • Combination product regulation
- • Device regulation
- • Why devices are important
- • Relevant features of devices
- • Examples
- Infusion pumps – Drug eluting stents – Contraceptive capsule – ACE inhibitors and dialysis-mammosite and gliocyte systems
- membranes

## Endpoints - Regular Approval 

- Survival
- QOL – PRO
- Safety improved- with efficacy
- DFS – adjuvant and leukemia settings
- _Improvements_ convey/are clinical benefits
- _Improvements_ show effectiveness
-  Demonstrate these endpoints
- 	= (Full) Regular Approval (RA)

## Accelerated Approval (AA)(Conditional)

- 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