# Presentation: 721384

## FDA Review : Cisplatin / Epinephrine Gel (CEG) in the Treatment of Head and Neck Cancer

## Outline of FDA Presentation

- Regulatory overview
- Medical review findings
- Statistical review findings
- Summary and  introduction of questions

## FDA Cisplatin-Gel NDA Review Team

- Project Managers	Dianne Spillman
- 			Dotti Pease
- Medical			Gregory K. Frykman, M.D.
- 			Grant Williams, M.D.
- Statistics		Rajeshwari Sridhara, Ph.D./Jasmine Choi, M.S.
- 			Gang Chen, Ph.D.
- Chemistry&		Haripada, Sarker, Ph.D.
- Manufacturing 		Eric Duffy, Ph.D./Hasmukh Patel, Ph.D.
- Pharmacology&	 	Doo Y. Lee Ham, Ph.D.
- Toxicology 		David Morse, Ph.D.
- Clinical 			Sophia Abraham, Ph.D.
- Pharmacology 		Atiqur Rahman, Ph.D.
- D. Scientific		 Khin U, M.D.
- Investigations

## Requirements for New Drug Approval

- 1962 efficacy amendment to Federal Food, Drug and Cosmetic Act
- Adequate and well controlled trials
- Clinical benefit

## Basis of Oncology Drug Approvals

- Prior to mid-1980s, approvals based on RR
- Mid 1980s: Requirement for survival or improvement in symptoms
- Subsequently, RR or other tumor endpoints sometimes accepted on case-by-case basis

## Full Approval Based on RR or other Tumor Endpoints

- Disease free survival
- Complete responses
- Consideration of response rate should include response duration and treatment toxicity
- Legitimacy of RR is enhanced by correlation with improvement in tumor-related symptoms

## Oncology Drug Approvals Supported by RR or TTP

- Cutaneous lesions of Kaposi’s Sarcoma or Cutaneous T cell lymphoma

## Approvals Based Primarily on Tumor-Related Symptoms

- Photofrin for obstructing esophageal cancer (1995)
- Photofrin for obstructing lung cancer (1998)
- Mitoxantrone (1996)

## FDA meetings with Applicant

- 1994: RR not accepted as clinical benefit
- Clinical trials :
- Randomized, blinded assessment of improvement in individual problems.

## FDA Reservations about Protocol

- Preventive goals
- questions about legitimacy of goals
- advantage for Cisplatin Gel based on differential dropout, not on a difference in event rate
- FDA analyses exclude preventive goals
- 1-point change on palliative scale

## FDA Clinical Review  

## Study Design

- Main Objectives
-  Compare the effect on tumor volume
-  Assess achievement of primary treatment goal

## Key Design Features

** ****Stratified**
** ****Randomized**
** ****Double-blind**
** ****Placebo-controlled**
** ****Powered to Detect ORR Difference**

## Study Design

**Stratification**
- 	Stratum 1				0.5 - 5.0 cm3
- 	Stratum 2				>5.0 - 20.0 cm3
- 	Stratum 3				20.0+ cm3

## Submitted Clinical Data 

-  414-94-2	  III	110	US, Canada	HNSCC
-  514-94-2	  III	115	Europe/Israel	HNSCC
-  516-99-PK	  16	US, Europe	HNSCC
-    39-92-2	    I	  45	US			Solid Tumors
-  403-93-2	   II	  67	US			Solid Tumors
-  503-93-2	   II	  59	Eur./S. Africa	Solid Tumors

## Correspondence with Applicant
 “Symptomatic response” strongly recommended as primary efficacy endpoint (12/97)

 Agreed that Primary analysis will be symptom improvement; tumor responses to be supportive. (12/97)

 Agency will require a strong correlation between patient benefit and tumor shrinkage in individuals. (5/00)

 Improvement in one point may not be sufficient evidence of clinical benefit. (5/00)

-  “**Symptomatic response” *****strongly***** recommended as primary efficacy endpoint (12/97)**
** ****Agreed that Primary analysis will be symptom improvement; *****tumor responses to be supportive.***** (12/97)**
** ****Agency will require a *****strong correlation***** between patient benefit and tumor shrinkage in individuals. (5/00)**
** ****Improvement in *****one point may not be sufficient***** evidence of clinical benefit. (5/00)**

- Clinical Endpoints

## Dosing Regimen

- _Pre-Amendment V_
-  0.5 mL gel/cm**3** of tumor volume
-  Injection volume based on initial tumor
-   dimensions
-  Single injection technique
-  62 patients enrolled

## Dosing Regimen

- _Post-Amendment V_
-  0.25 mL gel/cm3 of tumor volume
-  Tumor volume recalculated each visit
-  Injection by “fanning” or “grid” technique
-  163 patients enrolled

## Study Design

-  Key Eligibility Criteria
-  Recurrent or Refractory SCC of the Head & Neck
-  At least one course of therapy:
- chemotherapy, radiotherapy, surgery or biological  		response modifier therapy
-  Primary or metastatic lesions allowed
-  Exclude systemic disease, arrhythmias

## Study Design

- Study Phases

## Study 414 Results

- Number of Centers, Location, Duration
- 			    44 Centers
- 			US and Canada
- 		15 Jun. 1995 - 22 Mar. 2000

## Study 514 Results

- Number of Centers, Location, Duration
- 			     28 Centers
- 			Europe and Israel
- 		21 Jun. 1995 - 22 Mar. 2000

## Study 414 & 514 Results

- Demographics
- Patients enrolled on to each study appeared reasonably equally distributed between the arms and strata for:
- 				Age
- 				KPS
- 				Histological Grade
- 				Prior therapy
- 				Ethnicity

## Study 414 Results

- Treatment Delivered

## Study 514 Results

- Treatment Delivered

## Study 414 ResultsReason for Termination

## Study 514 ResultsReason for Termination

## Study 414 Results

- Efficacy Analysis - Active Arm
-      **OR            ****20/62 (32.3%)***
**  ****CB                ****3/51 (5.9%)**
** ****CB+OR         ****2/51 (4.0%)**
- * Only 3/20 ORs were treated with the protocol-
-   specified dose and schedule

## Study 514 Results

- Efficacy Analysis - Active Arm
-   **OR       ****13/57 (22.8%)***
**CB        ****10/54 (18.5%)**
**CB+OR    ****5/54 (9.3%)**
- *Only 6/13 ORs were treated with the protocol-
-   specified dose and schedule

## Study 414 & 514 Results

- Blinding Adequacy Questions
-  Differential toxicity
-  Differential dropout
-  Local Hair loss
-  Yellow-colored Eschar
-  Reflux
-  Possibility of Direct Observation
-  Sleeve Removal Potential

## Study 414 & 514 ResultsCauses of Dosing Errors

- 	Measurement Error
- 			Inherent error
- 			Small Lesions Amplify Uncertainty
- 			Local Tissue Disruption
- 	Calculation Error
- 			Dose Calculation
- 			Missing Data
- 			 Injection in the Absence of Tumor Size
- 	Administration Error
- 			Incorrect Dosing (reflux, PI discretion)

## Study 414 ResultsActual Dose vs. Planned Dose

## Study 514 ResultsActual Dose vs. Planned Dose

## Study 414 & 514 ResultsInternal Consistency Concerns

-  Missing Data
-  Patient and PI Palliative Benefit Score
-    Inconsistent
-  Palliative Benefit Inconsistent with
-    Local Toxicity
-  Palliative Benefit Inconsistent with Tumor
-    Size

## Study 414 & 514 ResultsLocal Toxicity Parameters

-  Bleeding/Hemorrhage
-  Erythema
-  Erosion
-  Eschar formation
-  Necrosis
-  Swelling
-  Ulceration

## Study 414 & 514 Safety  

-  Six cases of stroke
-  One case of complete blindness
-  Inadvertant direct injection into vital organs
-   cannot be excluded.

## Study 414 & 514 Summary  

-  Concerns about Study Conduct
-  Concerns about Blinding
-  Concerns about Internal Consistency
-  Modest ORR
-  Minimal Benefit with OR
-  Smaller Lesions Respond Better

## Study 414 & 514 Summary  

-  Local Toxicity Greater than Placebo
-  Stroke and Blindness were Observed to be
-    Associated with IntraDose and Placebo
-    Administration
-  Clinical Value of Local Treatment in the
-    Presence of Regional or Systemic Progression

## FDA Statistical Review  

## Areas of Major Statistical Problems

- Two co-primary efficacy endpoints: objective tumor response and patient benefit, in both randomized studies (Studies 414 and 514)
- Association between objective tumor response and patient benefit

## Objective MTT Response

## Objective MTT Response - Study 414

## Objective MTT Response -Study 514

## Graph of Survival Data

## Clinical Patient Benefit

## Patient Benefit

- Sponsor / Per Protocol Analysis: Palliative and Preventive Treatment Goals selected by investigators, not patients
- Patient Benefit Algorithm
- Palliative Goals measured on a scale of 1-4
- Decrease in score by 1 point (  1) is benefit
- Preventive Goals measured as met or not met
- Different Goals for each patient

## Patient Benefit Algorithm

## Clinical Benefit - Study 414 and Study 514:  Sponsor Analyses

## Pooled Analysis Not Acceptable

- When both studies have failed to demonstrate clinical benefit
- Inflates type I error
- Causes Imbalance in Randomization
- The patient population differs between the two studies
- Selection pattern of treatment goals differs between the two studies
- Can only be used as supportive evidence and not primary evidence

## Treatment Received - Study 414

## Treatment Received - Study 514

## Preventive Goals - Investigator Assessment

## Patient preventive Benefit 

- The preventive Benefit was discredited by the FDA, because:
- Differential pattern in number of treatments administered between IntraDose and Placebo arms
- Potential for bias in assessment
- Potential for unblinding
- Not interpretable
- Incidence within 8 - 12 weeks period not established
- Almost all the benefitters that the sponsor has claimed in the US Study are based on achievement of preventive goal

## Investigator Assessment of Change in Palliative Treatment Goal Score  Study 414

## Investigator Assessment of Change in Palliative Treatment Goal Score   Study 514

## Patient or Investigator Palliative Benefit Assessment - Study 414 FDA Analyses

## Patient or Investigator Palliative Benefit Assessment - Study 514 FDA Analyses

## Clinical Patient Benefit - FDA Analyses

- Study 414

- Study 514

## Clinical Patient Benefit

- Both the randomized studies _**failed**_ to demonstrate clinical patient benefit of IntraDose *versus* Placebo by Sponsor’s Analyses and FDA Analyses.
- Validity of a one-point change as a clinically meaningful patient benefit is debatable.  If one-point change is excluded, then both studies demonstrated _**< 5%**_ palliative benefit.  If one-point change is included then only 6% appear to have palliative benefit versus _25%_ who got worse in the US Study 414 and 19% appear to have palliative benefit versus _22%_ who got worse in the Europe Study.
- Per Sponsor 6/119 (_**5%**_) of IntraDose treated *versus* 1/59 (_**2%**_) of placebo treated patients attained investigator and patient specified primary treatment goals.

## Association Between Tumor Response and Patient Benefit - Study 414 Sponsor Analysis

- Association Between Tumor Response and Patient Benefit - Study 414 Sponsor Analysis

## Association Between Tumor Response and Patient Benefit - Study 514 Sponsor Analysis

## Association Between Tumor Response and Patient Benefit - Study 414 FDA Analysis

## Association Between Tumor Response and Patient Benefit - Study 514 FDA Analysis

## Association Between Tumor Response and Patient Benefit

- P-values of association between tumor response and patient benefit should be interpreted cautiously.
- The association is predominantly because of large number of patients classified as non-responders and non-benefitters
- Preferred measure of association between patient benefit and tumor response is _sensitivity_, and this was _< 50%_ in each of the studies and in the combined study data.

## Summary

- Both the randomized studies failed to demonstrate clinical patient benefit (primary endpoint) of IntraDose
- It is not evident that the objective tumor response translates into clinical benefit

## Summary of FDA Findings  

## Objective Response Rate

**Objective Response Rate**

## Primary palliative goal

**Primary palliative goal**

**Study 414**

**Study 514**

## Issues to consider

- Evaluate primary palliative goals, tumor response, and association between the two
- What is the clinical importance of other data:
- the objective response data
- other data on clinical benefit
- Accelerated Approval not a viable option