# Presentation: 442660

## Regulatory Background

- Edwin Rock, MD, PhD
- Medical Officer
- Office of Oncology Drug Products
- Food and Drug Administration

## Outline

- Requirements for Drug Approval
- Cancer Approval Endpoints
- Primary Brain Cancer Approvals
- Questions to Panel

## Requirements for Drug Approval

- Labeling		1906 Pure Food
- 				& Drug Act
- Safety 		1938 Food, Drug,					& Cosmetic Act (FDC)
- Efficacy 		1962 FDC Amendments

## Endpoints Supporting Approval

- Regular approval ~ Clinical benefit
- Longer life
- Favorable effect on valid measure
- 	of how patient feels or functions
- Favorable effect on accepted surrogate
- Accelerated approval ~ Surrogate
*reasonably likely* to predict clinical benefit

## Accelerated Approval

- Serious or _*life-threatening*_ disease
_*Improvement*_ over available therapy
- Surrogate endpoint _*reasonably likely*_ to predict clinical benefit
- Requires _*confirmation*_ of benefit

## Oncology Surrogates

- 	_For Regular Approval_	      _Disease_
- Durable complete response	        Acute leukemias
- Partial response (PR)		        Advanced breast
- Disease free survival (PRS)	        Adjuvant breast
- 	_For Accelerated Approval_
- Response rate with duration	        Solid tumors

## Survival

- Time from randomization to death
*Strengths*
- Unambiguous, daily assessment
- Not subject to investigator interpretation
*Limitations*
- Requires large sample size, long follow-up
- Cross-over therapy may wash out effect
*Trial design considerations*
- Randomized trials required to show an effect
- Likelihood and magnitude of survival benefit

## Radiographic Response Rate

*Strength*
- Treatment “entirely” responsible for tumor reduction  (contrast survival or PFS w/ natural history component)
*Limitations*
- Need for response duration component
- Issues: CR’s vs. PR’s vs. SD; burden of disease
*Trial design considerations*
- Only endpoint reliably assessed in single arm trial
- Prospectively identified, acceptable response criteria
- Complemented by symptom improvement

## Progression-Free Survival

- Time from randomization to progressive disease or death
*Strengths*
- Smaller size & shorter follow-up than for survival
- Differences not obscured by secondary therapy
- Deaths included in events
*Limitation*
- Greater potential for bias than with survival endpoint
*Trial design considerations*
- Randomized, blinded trials required to show an effect
- Must evaluate at baseline and regularly on follow-up:
- 	all patients with same tool / schedule / sites of disease

## Symptom Palliation

*Strength*
- Patient’s perspective
*Weaknesses*
- Missing data confound interpretation
- Multiple endpoints affect statistical power and plan
- Unblinded assessments invite observer bias
*Trial design considerations*
- Randomized, blinded trials required to show an effect
- Requires hypothesis driven, valid instrument
- Associated tumor response supportive of clinical benefit

## Brain Cancer Approvals

- _Drug__	_		    _Year_	     _Endpoint_
- Nitrosoureas	   1970’s	     Response rate
- Gliadel wafer	    1996	     Survival
- Temozolamide	    1999	     Durable CR
- 				    2005	     Survival

## Temodar (temozolamide) Indications

- Anaplastic astrocytoma after nitrosurea & procarbazine
- Basis of accelerated approval:
- Single-arm trial (54 patients); 22% response rate; **5 CR’s**, 7 PR’s
- Median response duration 50 weeks, **CR duration 64 weeks**
- Newly diagnosed glioblastoma multiforme
- Basis of approval (and conversion of above accelerated approval):
- EORTC randomized trial (573 patients)
- Standard fractionated XRT versus XRT with daily Temodar (75 mg/m2)
- 	during XRT followed by 6 cycles maintenance Temodar over 6 months
- Median survival 14.6 months (T + XRT) vs. 12.1 months (XRT alone)
- Hazard ratio 0.63 (95% CI 0.52-0.75); log-rank, P < 0.0001

## Gliadel Wafer Indications

- Recurrent glioblastoma multiforme as adjunct to surgery
- Basis of approval:
- Randomized, placebo-controlled trial of Gliadel vs. placebo implants in 222 glioma patients who  progressed following surgery and radiation
- Median survival 7.4 months (Gliadel) vs. 5.5 months (placebo)
- Of 143 patients with GBM, median survival 6.4 vs. 4.6 months
- Newly diagnosed high-grade malignant glioma
- 	as an adjunct to surgery and radiation
- Basis of approval:
- Randomized, placebo-controlled trial in 240 patients with newly-diagnosed, high-grade glioma undergoing resection craniotomy
- Median survival 13.9 months (Gliadel) vs. 11.6 months (placebo)
- Hazard ratio 0.73 (95% CI 0.56-0.95); log-rank, P < 0.05

## Workshop Agenda

- _Potential Endpoints_	  _Questions_
- Imaging Based 		  Analytic Validity
- Patient Reported 		  Clinical  Relevance
- _General Discussion_
- Utility of individual endpoints?
- Utility of composite endpoints?
- Endpoint development?

## Acknowledgements

- AACR
- Mark Mendenhall
- Eleanor Mayfield
- FDA
- Linda Burbank
- Dianne Spillman