Throughout this ODAC briefing document, the reader will find numerous discussions about the efficacy of IntraDose® for recurrent squamous cell carcinoma of the head and neck. Frequently, these efficacy findings are formatted such that the applicant’s and FDA’s claims are juxtaposed allowing for immediate appreciation of the critical differences.

Often, the data, analysis and results presented by the medical reviewer and the applicant reveal differences ranging from relatively small and unimportant to quite large and striking. At the time of the submission of the ODAC briefing document, there is continuing ongoing discussion with the applicant regarding these differences. Sources of these differences are manifold and will be discussed herein briefly.

Numerous dosing errors were noted in the review of all patients for which the applicant claims any benefit or response. Many of these tumors were treated with substantially incorrect doses, frequently in the 10-75% range, but occasionally well over 100%. In some patients all the administered doses were incorrect. The FDA believes that the number of dosing errors influenced certain patients’ tumors substantially such that any response noted could not be counted as valid.

Other reasons for differences between the applicant’s and FDA’s findings include unverifiable 28-day duration of response and lack of 28 day DOR in the blinded phase of the study.

Clinical benefit was another key parameter to determine efficacy of IntraDose®. Clinical benefit was derived from palliative treatment goals and/or preventive treatment goals. The palliative treatment goals, which were selected by the patient, the investigator or both, were comprised of a four-point scale to reflect various degrees of symptomatic debilitation stemming from the disease. Changes in a palliative treatment goal of three or two points are almost uniformly believed to constitute an improvement clinically beneficial to a patient. A zero point change in a given treatment goal is likewise generally believed to represent no meaningful clinical benefit. There is not uniform consensus, however, on how much meaningful a degree of clinical benefit can be ascribed to a one-point change.

The following tables describe the applicant’s findings and the FDA’s most conservative analyses. The most conservative analyses count responses if each met all three of the following criteria: correct dose administration at each injection, response duration of 28 days or more and the full 28+ DOR during the blinded period. The most conservative analyses count clinical benefit claims only if more than a one-point change in a palliative treatment goal was achieved according to either the investigator’s or patient’s selection.

The first table includes a listing of each patient in both study 414 and 514 from which the applicant makes any claim. It details the key findings on each patient required to make a response and clinical benefit claim. The second table "Dosing Error Effect on Objective Response" shows the applicant’s analysis, the FDA’s most conservative analysis and the FDA’s least conservative analysis with regard to responses. The least conservative FDA analysis shows the effect on the two studies’ results when all of the incorrectly dosed patients are counted as valid responders. This represents an efficacy calculation based on the intent to treat (ITT) population. The last table entitled "1-Point Palliative Treatment Goal Improvement" shows the applicant’s analysis, the FDA’s most conservative analysis and an exploratory less-conservative calculation that intends to suggest a potential effect on each study’s efficacy results of counting all of the one-point changes in the primary treatment goal.

Clinical Review

A. Critical Differences from the Sponsor(section reserved for final review) 10

B. Detailed Review of Trials by Indication 11

IX. Overall Summary 43

1. Description/Review of the Study Protocol for 414 and 514 46
2. (Reserved for Full Final NDA review)
3. (Reserved for Full Final NDA review)
4. Regulatory History of IND 38,356 and NDA 21-236 687
5. Reproduction of the Palliative and Preventive Goals Scale 7069
6. Treatment Plan 75
7. Summary Tables from a Review of the Literature 776

I. Introduction and Background

1. Abstract of the Proposed Label

1. Drug Class: Antineoplastic
2. Sponsor’s Proposed Indication: "Recurrent squamous cell carcinoma of the head and neck in patients who are not considered curable with surgery or radiotherapy"
3. Dose: 0.25 – 0.5 mL/cm3 of tumor volume to a maximum of 10 mL
4. Regimen: Weekly administration for 6 weeks with re-measurement and recalculation of the dose at each visit.
5. Age Groups: not specified

1. State of Armamentarium for Indication(s)

1. 19 December 1994 Meeting: several key issues were addressed including treatment goal endpoints, general design of the two studies, importance of capturing local toxicities, control arm, blinding and statistical concerns were discussed.

1. 3 December 1997 Meeting: Issues clarified include photographs (all will be submitted), the primary endpoint and analyses, the primary analysis will be symptom improvement with tumor responses playing a supportive role, "Symptomatic Response" strongly recommended as the primary efficacy endpoint and the association of meeting the treatment goal and the MTT responding will be analyzed.
2. 28 October 1999 Meeting: Clinical benefit and response analyses should be based on the intent to treat (ITT) population with all other analyses playing a supportive role, subset analysis for patients who are considered incurable with surgery should be done, and prior therapies must be extensively described to document refractoriness of disease.
3. 8 May 2000 Response: several statistical issues were clarified. Further details may be found later in this review.

• Written documentation of FDA agreements/expectations/concerns

• Pertinent FDA guidance documents

• Pertinent advisory committee meetings

There have been no recent Oncology Drug Advisory Committee meetings

relevant to this NDA within the last 5 years.

• Prior FDA reviews

• Major issues that arose during clinical trials, for example, study design, safety, or ethical considerations. How were they resolved?

E. Important Issues with Pharmacologically Related Agents

2. Clinically Relevant Findings From Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

• The chemistry reviewers are currently considering the stability of the reconstituted product at room temperature.

• The reconstitution procedure is more involved than standard reconstitution and dilution procedures generally familiar to medical oncologists and oncology pharmacists. The chemistry reviewers have raised questions about the homogeneity of the injected product when the labeled procedure is followed.

1. Pharmacokinetics

1. Pharmacodynamics

There were no specific pharmacodynamic data collected or studies performed in the two pivotal trials. The pharmacokinetic study, 516-99-PK, was submitted in support of this NDA.

IV. Description of Clinical Data and Sources

A. Overall Data

The data submitted from which the two studies have been reviewed include electronic databases ‘Study 414’ and ‘Study 514’ in MS ACCESS which were converted from SAS Transport Files. Several tables within these databases used in the review are identified in the table below. Case report forms (CRF’s) were submitted in .pdf format. ‘Review cards’, which were poster-size pages containing the most relevant clinical data in one place, were also submitted. In addition, serial digitized photographs of most subjects were also submitted.

 

 

Table	Study Information
‘ame’	Adverse medical events/intercurrent illness log
‘conmed’	Concomitant therapy log
‘conthrp’	Concomitant therapy log for any primary or metastatic malig.
‘demog’	Patient demographics
‘disehist’	Screening disease history
‘dosing’	First treatment dosing record
‘goalinv’	Investigator assessment treatment goal questionnaire
‘goalpt’	Patient assessment treatment goal questionnaire
‘inex’	Screening patient eligibility checklist
‘krnfsky’	Karnofsky performance status
‘qol’	FACT-H&N (version 3)
‘rndm’	Randomization of each patient
‘serum’	Local laboratory serum chemistry data
‘tumoreval’	Local tissue conditions
‘tumorscr’	Disease status
‘vital’	Vital signs monitoring

 

 

B. Table Listing of Clinical Trials

Study Number	Clinical Phase	No. Patients	Study Location	Study Dates	Tumor Type	Study Type
414-94-2	III	110	US, Canada Multi-center	6/95 – 3/00	HNSCC	Pivotal
514-94-2	III	115	Multi-center Europe/Israel	6/95 – 3/00	HNSCC	Pivotal
516-99-PK	I	16	US, Europe		HNSCC	Supportive
39-92-P	I	45	US		Breast (13) HNSCC (14) Melanoma (3) Other (14)	Supportive
403-93-2	II	67	US		Breast (13) Esophageal (8) Melanoma (13) Other (30)	Supportive
503-93-2	II	59	Europe S. Africa		Breast (13) Esophageal(16) Melanoma (15) Other (15)	Supportive

 

C. Postmarketing Experience

No postmarketing information exists for IntraDose®.

 

D. Literature Review

A series of tables summarizing the literature describing the active combination drug may be found in Appendix GF.

A review of the relevant literature suggests chemotherapy is active in this disease as single agents, doublets and triplets leading to response rates in the 14 – 58% range with durations of response – when reported – in the 1.5 to 6.8 month range.

V. Clinical Review Methods

A. Describe How the Review was Conducted

The two pivotal trials were reviewed separately although the approach taken was identical because of their similarity in design. The team clinical pharmacologist reviewed Study 516-99-PK. The additional supportive studies were not reviewed.

The clinical and statistical reviewers evaluated and sought to verify the sponsor’s tumor response and clinical benefit claims using the electronic databases and CRF’s. Specific efforts were directed at reviewing the primary tumor dimension data and drug administration data. These efforts identified several issues of concern surrounding data integrity, compliance with the protocol and study conduct. Independent calculations of the tumor volumes, drug administration volumes and durations of responses were compared with the applicant’s findings. Whether the calculations confirmed or failed to verify the applicant’s was noted in tabular format at the appropriate location in this review.

B. Overview of Materials Consulted in Review

The applicant’s IND, #38,356, was originally opened in 1991 and was consulted frequently during the NDA review for specific language regarding AE’s and agreements between the applicant and the Agency.

Descriptions of the sources of data for this review were provided earlier in this

Review and include electronic database information, case report forms, ‘treatment

cards’ and digitized photographs.

References to relevant literature are documented in tables summarizing the

studies’ key findings. The citations are appended to this review.

 

C. Overview of Methods Used to Evaluate Data Quality and Integrity

Concern over the site at UCLA under the direction of Dr. Dan Castro arose during the review and this site has been specifically selected for careful review. The review team has been apprised preliminarily of DSI’s findings by Dr U’s and it is his opinion that the patient data can be used in the review of this NDA.

1. Were Trials Conducted in Accordance with Accepted Ethical Standards?

6. VI. Efficacy Review

1. Integrated Review of Efficacy (Not included in this document; see the Overall Summary in section IX of this review and also refer to FDA efficacy review sections of individual studies)
2. Critical Differences From Sponsor’s Proposed Label Claims

	FDA		Applicant
	Study 414	Study 514	Study 414	Study 514
Benefit Response	0.0%	0.0%	16.1%	10.5%
Objective Response only	4.8%	10.5%	33.8%	24.6%
Clinical Benefit only	1.6%	1.8%	33.8%	19.3%

1. Study 414-92-2

A Randomized Double-Blind, Placebo Controlled Study to Evaluate the Effect of Cisplatin/Epinephrine Injectable Gel (Product MPI 5010) When Administered Intratumorally for Achievement of Treatment Goals in Recurrent or Refractory Squamous Cell Carcinoma of the Head and Neck

1. Location of information reviewed in NDA:

Study Item Volume

Study Report 4.15

Protocol 4.21

CRF’s electronically submitted in .pdf

Database documentation Access database ‘414’

Integrated Summary of Efficacy 4.164, pp. 111-225

2. Important Study Dates

Study Period 15 Jun 95 – 22 Mar 00

First Patient’s First Treatment 15 Jun 95

Last Patient’s First Treatment 06 Jan 00

3. Review of the protocol and amendments

Please see the review of the protocol and amendments appended to the end of this review template.

4. Analysis of Study 414
1. Details of Trial Conduct and Analysis

This was a randomized, blinded 44-center US - Canadian domestic study with 110 patients enrolled. Per protocol, only the 86 patients from stratum 1 and 2 with an MTT (most troublesome tumor) ≤ 20 cm³ were intended for the efficacy analysis. The

data submitted to the FDA are derived from ppatients who were enrolled

between 15 June 1995 and 22 March 2000. (v. 13, p. 23).

The sponsor states that the investigators were responsible for ensuring that the study was conducted according to Good Clinical Practices found in 21 CFR 50, 56 and 312, also in accordance with Guidelines for the Monitoring of Clinical Investigations, January 1988, and also under SOP’s of the sponsoring company. All regulatory, institutional, privacy and IRB obligations were the responsibility of the investigators (v. 21, p. 44). In addition, all clinical trials were conducted according to the ethical principles of the Declaration of Helsinki (v. 21, p. 34).

The sponsor also describes in summary form many deviations from the protocol (v. 14, p. 385-396).

2. Baseline Patient Characteristics

One hundred ten patients with a MTT were enrolled, of which 109 received treatment. Breakdown by gender shows that 24 (21.8%) were women and 86 (78.2%) were men.

All Strata	Active CEG	Placebo Gel	Total by Gender
Men	60	26	86
Women	17	7	24
Total by arm	77	33	110

The same table (excluding stratum 3, i.e. patients with volume > 20 cm³) shows the breakdown by gender in the population which form the basis for efficacy claims.

Strata 1 & 2	Active CEG	Placebo Gel	Total by Gender
Men	50	17	67
Women	12	7	19
Total by arm	62	24	86

Reviewer comment: These numbers agree with the sponsor’s analysis. (Table 11-1, v. 15, p. 95)

 

Ethnic representation, described in the electronic database (Access table ‘demog’) included 85 (77.3%) patients identified as "White", 10 (9.1%) as "Hispanic", 8 (7.3%) as "Black", 4 (3.6%) as "Asian" and 3 (2.7%) as "American Indian".

Ethnic Identification	Active CEG n = 62		Placebo Gel n = 25
White	51	82.3%	76.0%	19
Black	4	6.4%	4.0%	1
Hispanic	6	9.7%	4.0%	1
American Indian	1	1.6%	8.0%	2
Asian	0	0.0%	8.0%	2

 

Reviewer comment: The values essentially agree with sponsor’s reported results (Table 11-2, v. 15, p. 95).

The age at enrollment ranged from approximately 34 to approximately 92 years with a median of approximately 63 years. (ACCESS table ‘demog’)

Age	Active CEG		Placebo Gel
	Stratum 1 n=31	Stratum 2 n=31	Stratum 1 n=12	Stratum 2 n=13
Range	33.7 - 84.7	42.8 – 87.8	48.8 – 82.7	40.1 – 85.8
Median	62.7	65.4	61.6	61.5

The values essentially agree with sponsor’s reported results (Table 11-1 and 11-2, v. 15, p. 95).

The Karnofsky Performance Status at enrollment ranged from 50 to 100 with a median of approximately 80 years. (ACCESS table ‘krnfsky’). The following table shows the distribution between arms and strata.

KPS	Active CEG		Placebo Gel
	Stratum 1 n=31	Stratum 2 n=31	Stratum 1 n=12	Stratum 2 n=13
Range	50 – 100	50 – 100	60 – 100	40 – 100
Median	80	80	85	80
Mean	78	79	83	79

The values essentially agree with sponsor’s reported results (Table 11-3, v. 15, p. 97).

Histopathological grade was derived from the submitted electronic database (Access table ‘tumorscr’). The key to the numerical representation of the histopathological grade is shown below the table. Although 62 patients on the active arm and 25 on the placebo arm were randomized, there were only 25 and 17 descriptions histological grade that were included in the table ‘tumorscr’ on each arm respectively.

Histopathology	Active CEG		Placebo Gel
	Stratum 1 N=25	Stratum 2 n=17	Stratum 1 n=9	Stratum 2 n=9
Range	1.0 – 3.0	1.0 - 3.0	1.0 – 3.0	1.0 – 3.0
Median	2.0	2.0	2.0	2.0
Mean	2.3	1.9	2.1	2.0

Key to Histopathology Scores:

Well differentiated 1.0

Moderate to well differentiated 1.5

Moderately differentiated 2.0

Moderate to poorly differentiated 2.5

Poorly differentiated 3.0

Reviewer comment: There does not appear to be appreciable differences in histopathological grade between the arms or strata.

The applicant did not perform this analysis.

1. Prior Therapy

Prior therapy for head and neck cancer in this study included surgery, radiotherapy, chemotherapy and possibly other local therapy such as Nd:YAG or CO2 laser treatments for local ablation.

Prior Therapy	Active CEG
	Stratum 1 n=31			Stratum 2 n=31
MODALITY	S	R	C	S	R	C
Surgery (S)	1	14	0	1	11	1
Radiotherapy (R)	--	1	0	--	0	1
Chemotherapy (C)	--	--	0	--	--	0
All 3 Modalities	15			17

 

Prior Therapy	Placebo Gel
	Stratum 1 n=12			Stratum 2 n=13
MODALITY	S	R	C	S	R	C
Surgery (S)	1	7	0	0	5	0
Radiotherapy (R)	--	1	1	--	2	0
Chemotherapy (C)	--	--	0	--	--	0
All 3 Modalities	2			6

Reviewer comment: By inspection, the arms appear to be balanced with regard to prior therapy.

 

3. Therapy Delivered

The ITT population of all 110 patients in this study is used in the FDA analysis of therapy delivered. Review of the claimed responders and clinical benefitters suggests that compliance after the first few visits drops significantly. The following table describes the drop-off as a function of visit number:

No. of Treatments Received	Active CEG n = 62	Placebo Gel n = 24
1	62 (100.0%)	24 (100.0%)
2	56 (90.3%)	23 (95.8%)
3	42 (67.7%)	17 (70.8%)
4	28 (45.2%)	6 (25.0%)
5	15 (24.2%)	1 (4.2%)
6	10 (16.1%)	0 (0.0%)

 

1. Termination

Review of the table ‘studycomp’ suggests the two predominant reasons for patient termination from the study were systemic disease progression and target tumor progression. The following table below indicates the relative frequencies of the various reasons for termination:

Reason for Termination	Number (%)
Systemic disease progression	28 (25.6)
Progressive disease of the target tumor	22 (20.0)
Patient request, not otherwise specified	18 (16.3)
Unacceptable adverse events/local toxicity	15 (13.6)
Death on study	12 (10.9)
Need for other therapy not per protocol	5 (4.5)
Completed study	1 (0.9)
Other:	9 (8.2)
Admitted to hospice	1
Return home out of state	1
"Treatment Failure"	1
"Company request"	1
Lost to follow-up	1
Non-compliance	1
MTT too close to vital structure	2
"Adequate response"	1
Total	110 (100.0 %)

Reviewer comment: The principal results agree closely with the applicant’s analysis. The Study Report (v. 15, p. 88) states that 44% of patients discontinuing study participation for local or systemic disease progression. Slight differences may be noted in the other reasons for study terminations from Tables 10-3 and 10-2 (v. 15, p.90-91) when compared to this table, but they are not of significant magnitude to affect the overall results of this study.

 

4. Evaluation of Efficacy
1. Sponsor’s Evaluation of the Primary Efficacy Endpoint

The applicant claims an objective MTT response (CR or PR) in the blinded phase of 34% (21/62) of patients randomized to strata 1 and 2 of active CEG (Table 11-9, v. 15, p. 102).

The applicant also claims a clinical benefit in 34% (21/62) of patients randomized to the active CEG arm (strata 1 and 2 only) (Table 11-19, v. 15, p. 112).

The applicant has examined the association between MTT response and clinical benefit and finds that 48% (10/21) of patients who achieved an MTT response (during the blinded phase) also achieved a clinical benefit.

Using the applicant’s claimed rate of blinded phase MTT response and rate of clinical benefit, the following table may be constructed:

Study 414		MTT Blinded Phase Objective Response with Active CEG?		Total with Active CEG
		Yes	No
Clinical Benefit with Active CEG?	Yes	10	11	21
	No	11	30	41
Total with Active CEG		21	41	62

Reviewer comment: The table above suggests that the correlation between a blinded phase MTT objective response and clinical benefit is low. Statistical analysis reveals c 2 = 2.68 (df=1, p=0.10) which suggests non-significance.

1. Medical Officer’s Evaluation of the Primary Efficacy Endpoints

The regulatory history of this NDA and the reviewer's summary of and thethe study protocol (with a summary of each amendment) was reviewed and may be found in Appendices A and D.

SSection 9.5.5 of the study protocol states, "Primary efficacy analysis of tumor response of the MTT will be performed excluding the third stratum." (that is in patients with tumors less than 20 cm³.

A review of the past discussions between the applicant and the division reveals that clinical benefit in the form of "symptom improvement" is was to be the primary efficacy endpoint and that tumor responses are intended were to be supportive (meeting minutes 12/3/97). Indeed, a strong correlation between patient benefit and tumor shrinkage is requiredwas to be required (response to applicant 5/8/00).

The Following this overview of the study protocol and regulatory history, thefollowing is the medical reviewer evaluation of response and clinical benefit. Efficacy data from of the each of the objective or clinical benefit responses claimed by the applicant were medical reviewer focused next on the nature of the clinical benefit and responses claimed. The applicant submitted a list of 15 patients who (by the applicant’s analysis) achieved clinical benefit and a clinical response at some time during enrollment in the study. Each of these patients’ data, independent of randomization, stratification, or protocol period in which responses or benefit occurred, was carefully reviewed to analyze evaluate adherence to the protocol and, data integrity and study qualityquality.

 

1. Medical Officer’s Evaluation of the Claimed Responses

A summary of the findings of the FDA review of efficacy are found in the table below. Detailed findings may be found in Appendix E at the end of this review.

 

 

FDA Evaluation of Response and Clinical Benefit Claims by Applicant

Study 414

Patient No.

Blinded Period OR?

Correct Dose?

Duration ³ 28 days

Response Comment

Reviewer Response Analysis1

Patient Palliative Goal 2

P.I. Palliative Goal 2

Preventive Goal Met?

Reviewer Benefit Assessment

PATIENTS WITH BOTH CLINICAL BENEFIT AND OBJECTIVE RESPONSE PER APPLICANT'S ANALYSIS

1797

Yes

See dosing table

Yes

Many incorrect doses

R*

None selected

None selected

Achieved

No Clinical Benefit

1825

Yes

Yes

25 d

Small lesions+measurement error+high gel/tumor ratios

No valid response

3 – no D

1 – 1 pt. D

None Selected

One point

1993

Yes

See dosing table

27 d

Missing tumor dimensions; early PD; photos incorrect

R**

1 – 1 pt. worse

None Selected

Achieved

No Clinical Benefit

1995

Yes

See dosing table

Yes

Incorrect doses (reflux)

R*

None Selected

None Selected

Achieved

No Clinical Benefit

1998

No

See dosing table

Yes

Missing tumor dimensions; DOR outside blinded phase

R **

1 – no D

None Selected

Achieved

No Clinical Benefit

2136

Yes

See dosing table

Yes

Both doses incorrect; many additional tumors

R*

5 – no D

1 – no D

Achieved

No Clinical Benefit

5036

Yes

See dosing table

Yes

Dosing logic unclear

R*

1 – no D 1 – 1 pt. worse

1 – no D 1 – 1 pt. worse

Achieved

No Clinical Benefit

5134

No

See dosing table

No

One dose significantly incorrect; Missing tumor dimensions

R**

1 – 3 pt. D 1 – 2 pt. D 2 – no D

1 – 3 pt. D 2 – 1 pt. D

Achieved@censoring

Apparent Clinical Benefit

5301

Yes

Yes

Yes

Valid Response

2 – no D

1 – no D

Achieved@censoring

No Clinical Benefit

5303

Yes

See dosing table

Yes

2 small dosing error + 1 significant small measurement error; high gel/tumor ratios

R**

1 – 2 pt. D (?PEG) 3 – no D

5 – no D

Achieved@censoring

ApparentPossible3 Clinical Benefit

1 R* = response with errors in dosing

R** = possible response, with questions regarding tumor measurement irregularity (under discussion between FDA and Applicant)

 

2 The conventions used in these columns are as follows. The first numeral refers to the number of treatment goals chosen by the patient or investigator. The next characters following the dash refer to how many points change there is in the positive direction. Thus, ‘5 – no D ’ indicates that there were five treatment goals chosen and there were no changes in any of them at during the study. ‘1 – 3 pt. D ’ indicates that there was one treatment goal chosen which revealed a three point improvement based on the scale referred to earlier in this review.

3 The validity of these data are under discussion with the Applicant.

 

Patient No.

Blinded Period OR?

Correct Dose?

Duration ³ 28 days

Response Comment

Reviewer Response Analysis1

Patient Palliative Goal

P.I. Palliative Goal

Preventive Goal Met?

Reviewer Benefit Assessment

PATIENTS WITH OBJECTIVE RESPONSE ONLY PER APPLICANT'S ANALYSIS

1772

Yes

See dosing table

No

Many incorrect doses

R*

No Claim

--

--

--

1992

Yes

Yes

No

No valid response

No Claim

--

--

--

2000

Yes

See dosing table

Yes

Many incorrect doses

R*

No Claim

--

--

--

2110

Yes

Mostly

Yes

Valid Response

No Claim

--

--

--

4964

Yes

See dosing table

Biologically unusual behavior

R **

No Claim

--

--

--

5110

Yes

Yes

No

No valid response

No Claim

--

--

--

5111

Yes

See dosing table

Yes

R*

No Claim

--

--

--

5133

Yes

See dosing table

Yes

R*

No Claim

--

--

--

5151

Yes

See dosing table

Yes

R*

No Claim

--

--

--

5348

No

See dosing table

No

No measurements after d41

R**

No Claim

--

--

--

5372

Yes

Close

Yes

Valid Response

No Claim

--

--

--

1 R* = response with errors in dosing

R** = possible response, with questions regarding tumor measurement irregularity (under discussion between FDA and Applicant)

Patient No.	Blinded Period OR?	Correct Dose?	DOR ³ 28 days	Response Comment	Reviewer Response Analysis1	Patient Palliative Goal	P.I. Palliative Goal	Preventive Goal Met?**	Reviewer Benefit Assessment
CLINICAL BENEFIT CLAIM ONLY
1795	No Claim	--	--	--	--	None selected	None selected	Yes	No Clinical Benefit
1871	No Claim	--	--	--	--	5 – no D	None selected	Yes	No Clinical Benefit
1944	No Claim	--	--	--	--	1 – no D	None selected	Yes	No Clinical Benefit
1996	No Claim	--	--	--	--	None selected	None selected	Yes	No Clinical Benefit
2015	No Claim	--	--	--	--	3 – no D	None selected	Yes	No Clinical Benefit
2157	No Claim	--	--	--	--	1 – 1 pt. D	2 – no D 1 – 1 pt. D	Yes	One Point
2183	No Claim	--	--	--	--	1 – no D	1 – 1 pt. worse 1 – 2 pt. worse	Yes	No Clinical Benefit
5253	No Claim	--	--	--	--	None selected	None selected	Yes	No Clinical Benefit
5278	No Claim	--	--	--	--	None selected	None selected	Yes	No Clinical Benefit
5396	No Claim	--	--	--	--	3 - no D 2 – 1 pt. worse	3 - no D 1 – 1 pt. worse 1 – 1 pt. better	Yes @ censoring	One point

1 R* = response with errors in dosing

R(**) = possible response, with questions regarding tumor measurement irregularity (under discussion between FDA and Applicant

2 The conventions used in these columns are as follows. The first numeral refers to the number of treatment goals chosen by the patient or investigator. The next characters following the dash refer to how many points change there is in the positive direction. Thus, ‘5 – no D ’ indicates that there were five treatment goals chosen and there were no changes in any of them at during the study. ‘1 – 3 pt. D ’ indicates that there was one treatment goal chosen which revealed a three point improvement based on the scale referred to earlier in this review.

The applicant determined that 21 of the 62 patients (34%) on the CEG arm had an objective tumor response. The final FDA analysis of response rate will be performed after further discussions with the applicant, and prior to the ODAC meeting on September 10. The tables above list some of the problems that FDA found in review of the data. Dosing irregularities were observed with most patients, usually because of errors in recalculating the dose after change in tumor size. In several patients, duration of response was not well documented or was only documented after the blinded phase of study. Some tumor measurement data were not recorded, perhaps because the investigator could not measure the tumor due to local tissue changes from CEG. From the data in the tables above, it seems likely that the final FDA analysis of objective response will be at least 19% (12/62) and perhaps as high as 27% (17/62) after the Applicant clarifies issues related to tumor measurements and response duration. Another issue that should be considered is how the dosing errors affect the conclusions one can draw from the study -- can we assume that when patients are given CEG according to dosing in the proposed drug labeling they will get similar results?A summary of the findings of the detailed medical review are found in the table below. Detailed findings may be found in Appendix E at the end of this review.

Of the 15 patients listed by the sponsor as benefitters and responders, three were randomized to the placebo arm and received placebo during the blinded phase. Two additional patients (both of whom were randomized to the active CEG arm) did not achieve an MTT response during the blinded period. One was non-evaluable and one showed progressive disease. These two patients, in addition to the three above who were randomized to the placebo arm are not included in the table below.

 

Patient No.	Blinded Period OR?	Correct Dose?	DOR > 28 days	Response Comment	Reviewer Response Analysis
1797	Yes	See dosing table	Yes	Many incorrect doses	???
1825	Yes	Yes	25 d	Small lesions+measurement error+high gel/tumor ratios	No valid response
1993	Yes	See dosing table	27 d	Missing tumor dimensions; early PD; photos incorrect	???
1995	Yes	See dosing table	Yes	Incorrect doses (reflux)	???
1998	No	See dosing table	Yes	Missing tumor dimensions; DOR outside blinded phase	???
2136	Yes	See dosing table	Yes	Both doses incorrect; many additional tumors	???
5036	Yes	See dosing table	Yes	Dosing logic unclear	???
5134	No	See dosing table	No	One dose significantly incorrect; Missing tumor dimensions	???
5301	Yes	Yes	Yes		Valid response
5303	Yes	See dosing table	Yes	2 small dosing error + 1 significant small measurement error; high gel/tumor ratios	???

From this table, it can be seen that the medical reviewer could not confirm most responses claimed by the applicant. Specifically, 1 of the 10 responses in the applicant’s claimed 'benefit response' category can be confirmed.

The sponsor claims that there were 11 subjects randomized to the active CEG arm that attained a clinical response although they did not achieve any clinical benefit. The following table summarizes the medical officer’s review of these 11 patients.

 

Patient No.	Blinded Period OR?	Correct Dose?	DOR > 28 days	Response Comment	Reviewer Response Analysis
1772	Yes	See dosing table	No	Many incorrect doses	???
1992	Yes	Yes	No		No valid response
2000	Yes	See dosing table	Yes	Many incorrect doses	???
2110	Yes	Mostly	Yes		Valid response
4964	Yes	See dosing table		Biologically unusual behavior	No valid response
5110	Yes	Yes	No		No valid response
5111	Yes	See dosing table	Yes		???
5133	Yes	See dosing table	Yes		???
5151	Yes	See dosing table	Yes		???
5348	No	See dosing table	No	No measurements after d41	???
5372	Yes	Close	Yes		Valid response

From the above table, 2 of the 11 claimed responders in the response-only group could be confirmed by the medical reviewer.

Combining the results of these two tables, 3 of the 21 claimed responses could be confirmed. These 21 claimed responses arise from the population randomized to active CEG which was 62 and from which the sponsor claims a response rate of 34% (Table 11-9, v. 15, p. 102). Based on the medical reviewer’s confirmed responses, the FDA-determined response rate is approximately 4.8%.

 

1. Medical Officer’s Evaluation of the Clinical Benefit Claim

• During protocol development, FDA expressed reservations about use of preventive goals, and emphasized that it was the sponsor's responsibility to assure that specific goals were legitimate, e.g., that in the absence of effective treatment, the event that one was attempting to prevent would almost certainly occur within 28 days. FDA reviewers are not convinced that the preventive goals outlined in the NDA fulfill this requirement.
• Even more significant, FDA statistical analysis (Table 14 in FDA statistical review) suggests that the results in favor of CEG on preventive goals are artifacts of bias. Patients on the placebo arm dropped out of the study earlier (probably due to progression or lack of response) and therefore were not on study for the requisite 28 days to be declared a "success." The analysis was not driven by actual failures (e.g., skin breakthough) on the placebo arm, but rather by the tendency for patients on the placebo arm to drop out sooner. (Actually, 4 patients on CEG and 0 patients on placebo failed by having the event that was to be prevented). One should also consider the effect of these data on the sponsor's analyses of the correlation between clinical benefit and objective response. These preventive data should be excluded from such analyses.

Study 414		MTT Blinded Phase Objective Response with Active CEG?		Total with Active CEG
		Yes	No
Clinical Benefit with Active CEG?	Yes	0	1	1
	No	3	58	61
Total with Active CEG		3	59	62

1. Evaluation of Safety
1. Deaths

Of the 110 patients who were enrolled on this study, 12 (10.9%) expired while on protocol. Analysis of the cases in which a detailed review was conducted by the medical reviewer indicated systemic disease progression to be responsible in most cases.

The applicant notes that the majority of deaths, which occurred after the patients terminated the study, were due to disease progression. The applicant also states that no deaths were related to therapy.

The medical reviewer confirms that there were no cases of immediate death directly related to injection of active or placebo CEG.

 

2. Serious Adverse Events

Serious adverse events include systemic AE’s, organ-specific AE’s and ‘severe’ local toxicity (unique for this application).

One of the most serious adverse events, stroke, was experienced by six patients on this study in the early phase of accrual. The underlying mechanism was not positively identified by the sponsor and its consultants at the time the problem initially emerged. Factors potentially predisposing patients to stroke were incorporated into the protocol as exclusion criterion. Since institution of such exclusions, there was one additional recorded case of stroke.

The applicant briefly described its experience with this serious finding. Careful analysis of the ACCESS table ‘ame’ was performed and confirm there were no additional cases of stroke beyond the additional one which may have been encoded using different terminology.

3. Analysis of Local Toxicity

Local toxicity data represented a significant component of this study and detailed information was collected by the applicant. A grading scale was used based on numbers ranging from zero to three; zero being no toxicity and three being ‘severe’.

Numerical data grading the toxicity were collected at each visit for the various manifestations of the local toxicity. These manifestations included bleeding/hemorrhage, erosion, erythema, eschar/scabbing, necrosis, swelling and ulceration. The objective criteria by which each form of toxicity was graded were not described in the protocol.

The blinded phase of the study consisted of a minimum of three and a maximum of six administrations of study agent.

Charts showing the frequency of each of the local toxicities and their severity with each administration are appended to this review.

 

4. Analysis of Systemic Toxicity

Table ‘ame’ lists approximately 2200 adverse events reported by investigators. Although the applicant had agreed to use the NCCOG/NCI scale of toxicity (1991 edition), the majority of data collected was neither organized graded by this scale. Instead, a more subjective scale, categorized by COSTART terminology and using ‘mild’, ‘moderate’, and ‘severe’ to grade severity and ‘not related’, ‘possibly related’, ‘probably related’ and ‘related’ to describe attribution was employed. Objective criteria by which the reviewer could confirm the nature, severity and attribution of the AE were not provided. Therefore, the investigator’s judgement at each clinical site was the primary determinant of the severity and attribution of each AE.

The medical reviewer briefly reviewed the electronic data tables pertaining to serum chemistry and hematology (Access tables ‘serum’ and ‘hema’). There were no obvious effects on serum chemistry or hematological parameters referable to platinum administration. Neutropenia, thrombocytopenia, elevated creatinine or BUN appear to be absent. These findings suggest that IntraDose®, as administered in this study, has marginal effects on the bone marrow and kidneys.

A number of confounding variables render a quantitative analysis of the toxicities arising from active CEG (versus the placebo gel) extremely difficult. These factors include the disparity of treatment compliance and drop-off across arms, incorrect dosing (numerous examples provided), investigator differences in recording, and lack of use of standardized toxicity tables.

Brief and exploratory analysis of the relative number of AE’s between arms suggests there were approximately two-fold more AE’s of all types and attributions in the CEG arm. This same ratio was similar in the most important subsets, which were ‘severe’, and ‘moderate’ AE’s which were ‘related’ and ‘probably related’.

 

5. Safety Summary

1. Efficacy Conclusions

1. Study 514-92-2

A Randomized Double-Blind, Placebo Controlled Study to Evaluate the Effect of Cisplatin/Epinephrine Injectable Gel (Product MPI 5010) When Administered Intratumorally for Achievement of Treatment Goals in Recurrent or Refractory Squamous Cell Carcinoma of the Head and Neck

1. Location of information reviewed in NDA:

Study Item Volume

Study Report 4.42, 4.193

Protocol 4.21

CRF’s electronically submitted in .pdf

Database documentation Access database ‘514’

Integrated Summary of Efficacy 4.164, pp. 111-225

2. Important Study Dates

Study Period 21 Jun 95 – 22 Mar 00

First Patient’s First Treatment 28 Jun 95

Last Patient’s First Treatment 11 Jan 00

3. Review of the protocol and amendments

Please see Appendix A for medical officer summary and comments on study protocols and amendments. the review and comments of the study protocol and

amendments for details.

4. Analysis of Study 514
1. Details of Trial Conduct and Analysis

This was a 28-center study conducted in Europe and Israel with 115

patients randomized. The data submitted to the FDA are derived from patients who were enrolled between 21 June 1995 and 22 March 2000.

The sponsor states that the investigators were responsible for ensuring that the study was conducted according to Good Clinical Practices found in 21 CFR 50, 56 and 312; in accordance with Guidelines for the Monitoring of Clinical Investigations, January 1988; and also under the SOP’s of the sponsoring company. All regulatory, institutional, privacy and IRB obligations were the responsibility of the investigators (v. 21, p. 44). In addition, all clinical trials were conducted according to the ethical principles of the Declaration of Helsinki (v. 21, p. 34).

The sponsor also describes in summary form many deviations from the protocol (v. 42, pp. 91-92).

2. Baseline Patient Characteristics

The following table shows the number of patients enrolled on to each stratum and arm of study 514.

	Active CEG	Placebo Gel
Stratum 1 (n=48)	31	17
Stratum 2 (n=44)	26	18
Stratum 3 (n=23)	17	6
Strata 1 & 2 only (n=92)	57	35
Total (by arm)	74	41
Study Total (both arms)	115

One hundred fifteen patients were enrolled by 27 investigators (v. 42, p. 87). All patients received treatment with either active or placebo gel. Baseline demographics reveal that 24 (21.8%) were women and 91 (79.1%) were men. The distribution by gender is shown below.

Stratum 1 (n=48)

	Active CEG n=31	Placebo Gel n=17
Men	21	13
Women	10	4

Stratum 2 (n=44)

	Active CEG n=26	Placebo Gel n=18
Men	24	17
Women	2	1

Stratum 3 (n=23)

	Active CEG n=17	Placebo Gel n=6
Men	13	3
Women	4	3

Ethnic representation, submitted in the electronic database (Access table ‘demog’), described all patients in study 514 as ‘white’.

 

Ethnic Identification	Active CEG n = 74		Placebo Gel n = 41
White	74	100.0%	100.0%	41
Black	0	0%	0%	0
Hispanic	0	0%	0%	0
American Indian	0	0%	0%	0
Asian	0	0%	0%	0

These values agree with the sponsor (Section 11.2.1.1, p. 92 and Tables 11-1 and 11-2, p. 93, v. 42).

The age at enrollment ranged from approximately 37 to approximately 84 years of age with a median of approximately 59 years (Access table ‘demog’).

Age	Active CEG		Placebo Gel
	Stratum 1 n=31	Stratum 2 n=26	Stratum 1 n=17	Stratum 2 n=18
Range	37 - 82	41 - 81	46 – 84	43 - 81
Median	54	62.5	60	64

The values essentially agree with sponsor’s reported results (Section 11.2.1.1, p. 92 and Tables 11-1 and 11-2, v. 42, p. 93).

The Karnofsky Performance Status at enrollment ranged from 50 to 100 with a median of approximately 80 years. (Access table ‘krnfsky’). The following table shows the distribution between arms and strata.

KPS	Active CEG		Placebo Gel
	Stratum 1 n=31	Stratum 2 n=26	Stratum 1 n=17	Stratum 2 n=18
Range	50 – 100	50 – 100	60 – 100	40 – 100
Median	90	80	90	80
Mean	85	70	81	75

The values essentially agree with sponsor’s reported results (Table 11-3, p. 95, v. 42).

Histopathological data was derived from the submitted electronic database (ACCESS table ‘tumorscr’). The key to the numerical representation of the histopathological grade is shown below the table. Although 92 patients assigned to strata 1 and 2 were randomized between active CEG and placebo, there were only 38 and 28 (total of 66) descriptions of histological grade included in the table ‘tumorscr’ respectively.

 

Histopathology	Active CEG		Placebo Gel
	Stratum 1 n=21	Stratum 2 n=17	Stratum 1 n=12	Stratum 2 n=16
Range	1.0 - 3.0	1.0 - 3.0	1.0 - 3.0	1.0 - 3.0
Median	2.0	2.0	2.0	2.0
Mean	2.0	2.1	2.2	2.2

Key to Histopathology Scores:

Well differentiated 1.0

Moderate to well differentiated 1.5

Moderately differentiated 2.0

Moderate to poorly differentiated 2.5

Poorly differentiated 3.0

Reviewer comment: There do not appear to be appreciable differences in histopathological grade that were reported between the arms or strata. The applicant did not perform this analysis.

1. Prior Therapy

Prior therapy for head and neck cancer in this study included surgery, radiotherapy, chemotherapy and possibly other local therapy such as Nd:YAG or CO2 laser treatments for local ablation.

Prior Therapy	Active CEG
	Stratum 1 n=31			Stratum 2 n=26
MODALITY	S	R	C	S	R	C
Surgery (S)	1	13	0	0	8	0
Radiotherapy (R)	--	4	7	--	4	3
Chemotherapy (C)	--	--	1	--	--	0
All 3 Modalities	4			7
UNCLEAR	0			2

Reviewer comment: These values vary from those found in the sponsor’s analysis (v. 42, p. 96). The sponsor states that 10 patients in stratum 1 of the active arm received all three modalities compared to 4 in the FDA analysis. This difference could influence the study results, but caution about any over-emphasis of this point must remain great.

 

 

 

 

 

Prior Therapy	Placebo Gel
	Stratum 1 n=17			Stratum 2 n=18
MODALITY	S	R	C	S	R	C
Surgery (S)	0	3	0	0	8	0
Radiotherapy (R)	--	4	2	--	3	4
Chemotherapy (C)	--	--	0	--	--	0
All 3 Modalities	7			6
UNCLEAR	1			0

 

The following table, for Stratum 3 only, is included to document the integrity of the accounting for each of the 115 patients enrolled. It will not be included in the analysis of efficacy as specified in the protocol.

Prior Therapy	STRATUM 3
	Active CEG N=17			Placebo Gel n=6
MODALITY	S	R	C	S	R	C
Surgery (S)	0	7	0	0	1	0
Radiotherapy (R)	--	0	1	--	0	0
Chemotherapy (C)	--	--	0	--	--	0
All 3 Modalities	8			3
UNCLEAR	0			1
Arm Total	16 (should be 17)			5 (should be 6)
Stratum Total	21 (should be 23)

 

3. Therapy Delivered

The ITT population of all 115 patients in this study is used in the FDA analysis of therapy delivered. Detailed review of the claimed responders and clinical benefitters suggests that compliance after the first few visits drops significantly.

 

 

 

# of Treatments Received	Active CEG n = 57	Placebo n = 35
1	57 (100.0%)	35 (100.0%)
2	55 (96.5%)	30 (85.7%)
3	49 (86.0%)	24 (68.6%)
4	34 (59.6%)	15 (42.9%)
5	24 (42.1%)	8 (22.9%)
6	24 (42.1%)	6 (17.1%)

 

 

 

1. Termination

Review of the table ‘studycomp’ indicates the reasons patients were terminated from the study. The following table below indicates the relative frequencies of the various reasons for termination:

Reason for Termination	Number (%)
Systemic disease progression	22 (19.1)
Progressive disease of the target tumor	44 (38.2)
Patient request, not otherwise specified	9 (7.8)
Unacceptable adverse events/local toxicity	9 (7.8)
Death on study	13 (11.3)
Need for other therapy not per protocol	2 (1.7)
Completed study	6 (5.2)
Other:	10 (8.7)
"Re-treatment with open label"	1
"No convincing response"	2
"Investigator decision"	1
"Deterioration of Karnofsky status"	1
"Incomplete regression"	1
"Pharmacy error"	1
Lost to follow-up	1
"Responsive of treated tumor [sic] tumor 1"	1
"Changed to open label at treatment #5"	1
Total	115 (100.0)

The principal results agree closely with the applicant’s analysis. The Study Report (v. 15, p. 88) states that 44% of patients discontinuing study participation for local or systemic disease progression. Slight differences may be noted in the other reasons for study terminations from Tables 10-3 and 10-2 (v. 15, p.90-91) when compared to this table, but they are not of significant magnitude to affect the overall results of this study.

 

4. Evaluation of Efficacy
1. Sponsor’s Evaluation of the Primary Efficacy Endpoint

The applicant claims an objective MTT response (CR or PR) in the blinded phase of 25% (14/57) patients randomized to strata 1 and 2 of active CEG (Table 11-10, v. 42, pp. 100-101). The sponsor also claims one MTT objective response (1/35) in the placebo arm.

The applicant also claims a clinical benefit in 19% (11/57) of patients randomized to the active CEG arm (including both strata 1 and 2) (Section 11.4.1.2.2 and Table 11-20, v. 42, p. 110-111).

The applicant has examined the association between MTT response and clinical benefit and finds that 43% (6/14) of patients who achieved an MTT response (during the blinded phase) also achieved a clinical benefit.

Using the applicant’s claimed rate of blinded phase MTT response and rate of clinical benefit, the following table may be constructed:

Study 514		MTT Blinded Phase Objective Response with Active CEG?		Total with Active CEG
		Yes	No
Clinical Benefit with Active CEG?	Yes	6	5	11
	No	8	38	46
Total with Active CEG		14	43	57


Reviewer comment: The table above suggests that there may be a correlation between a blinded phase MTT objective response and clinical benefit. This table is similar to one produced by the sponsor (Table 11-23, p. 117). By FDA analysis, chi-square analysis reveals c 2 = 6.14 (df=1, p=0.010) which suggests statistical significance.

 

1. Medical Officer’s Evaluation of the Primary Efficacy Endpoints

 

See the FDA review of efficacy of Trial 414 for a detailed discussion of the FDA approach to review of efficacy. The following is the medical reviewer evaluation of response and clinical benefit. Efficacy data from each of the objective or clinical benefit responses claimed by the applicant were carefully reviewed to evaluate adherence to the protocol and data quality. A summary of the findings of the FDA review of efficacy are found in the tables below. Detailed findings may be found in Appendix E at the end of this review.

FDA Evaluation of Response and Clinical Benefit Claims by Applicant

Study 514

Patient No.	Blinded Period OR?	Correct Dose?	DOR ³ 28 days	Response Comment	Reviewer Response Analysis1	Patient Palliative Goal2	P.I. Palliative Goal2	Preventive Goal Met?	Reviewer Benefit Assessment
CLINICAL BENEFIT AND RESPONSE CLAIM
2687	Yes	Yes	Yes	Biologically unusual; SD x 63d, then unexpected CR at d103-132 Substantial weight loss	Response valid	1 – 1 pt. D	1 – 1 pt. D	None Selected	One point
2688	Yes	Yes	No		No valid response	1 – 1 pt. D	1 – 1 pt. D	None Selected	One point
2732	Yes	See dosing table	Yes	All three doses incorrect; Missing tumor dimensions	R**	None Selected	1 – 3 pt. D 1 – 2 pt. D	None Selected	Apparent Clinical Benefit
2735	No	See dosing table	Yes	Missing tumor dimensions; Inevaluable dosing regimen	R**	1 – 1 pt. D	1 – 1 pt. D	None Selected	One point
2736	Yes	See dosing table	Yes	Missing tumor dimensions; Substantial weight loss	R**	1 – 1 pt. D	1 – 1 pt. D	None Selected	One point
5854	Yes	Yes	Yes		Response valid	1 – 2 pt. better 4 – no D 1 – 1 pt. worse	1 – 1 pt. worse	Achieved @ censoring	No Clinical Benefit

1 R* = response with errors in dosing

R** = possible response, with questions regarding tumor measurement irregularity (under discussion between FDA and Applicant)

2 The conventions used in these columns are as follows. The first numeral refers to the number of treatment goals chosen by the patient or investigator. The next characters following the dash refer to how many points change there is in the positive direction. Thus, ‘5 – no D ’ indicates that there were five treatment goals chosen and there were no changes in any of them at during the study. ‘1 – 3 pt. D ’ indicates that there was one treatment goal chosen which revealed a three point improvement based on the scale referred to earlier in this review.

 

Patient No.	Blinded Period OR?	Correct Dose?	DOR ³ 28 days	Response Comment	Reviewer Response Analysis1	Patient Palliative Goal	P.I. Palliative Goal	Preventive Goal Met?	Reviewer Benefit Assessment
RESPONSE CLAIM ONLY
2541	No	Yes	No	Only one dose administered	No valid response	No Claim	--	--	--
2681	Yes	Yes	Yes	Many incorrect doses < 10% off	Response valid	No Claim	--	--	--
2686	Yes	Yes	Yes	One incorrect dose	Response valid	No Claim	--	--	--
2731	Yes	See dosing table	Yes	Many incorrect doses	R*	No Claim	--	--	--
2753	Yes	Yes	Yes	Close; within 12%	Response valid	No Claim	--	--	--
5494	Yes	See dosing table	27d	Many incorrect doses	R*	No Claim	--	--	--
5496	Yes	See dosing table	Yes	Many incorrect doses	R*	No Claim	--	--	--
5565	Yes	Yes	Yes		Response valid	No Claim	--	--	--

1 R* = response with errors in dosing

R** = possible response, with questions regarding tumor measurement irregularity (under discussion between FDA and Applicant)

 

 

Patient No.	Blinded Period OR?	Correct Dose?	DOR ³ 28 days	Response Comment	Reviewer Response Analysis1	Patient Palliative Goal2	P.I. Palliative Goal2	Preventive Goal Met?	Reviewer Benefit Assessment
CLINICAL BENEFIT CLAIM ONLY
2366	No Claim	--	--	--	--	2 – 1 pt. D	1 – no D 1 – 1 pt. D	None Selected	One point
2421	No Claim	--	--	--	--	1 – 1 pt. D 1 – no D	1 – no D	None Selected	One point
2564	No Claim	--	--	--	--	1 – 1 pt. D	1 – 1 pt. D	None Selected	One point
5421	No Claim	--	--	--	--	1 – 1 pt. D 1 – no D	2 – 1 pt. D	None Selected	One point
5588	No Claim	--	--	--	--	1 – 1 pt. D worse	None Selected	Failed	No Clinical Benefit

1 R* = response with errors in dosing

R** = possible response, with questions regarding tumor measurement irregularity (under discussion between FDA and Applicant)

2 The conventions used in these columns are as follows. The first numeral refers to the number of treatment goals chosen by the patient or investigator. The next characters following the dash refer to how many points change there is in the positive direction. Thus, ‘5 – no D ’ indicates that there were five treatment goals chosen and there were no changes in any of them at during the study. ‘1 – 3 pt. D ’ indicates that there was one treatment goal chosen which revealed a three point improvement based on the scale referred to earlier in this review.

The applicant determined that 14 of the 57 patients (25%) on the CEG arm had an objective tumor response. The final FDA analysis of response rate will be performed after further discussions with the applicant, and prior to the ODAC meeting on September 10. The tables above list some of the problems that FDA found in review of the data. Dosing irregularities were observed with most patients, usually because of errors in recalculating the dose after change in tumor size. FDA rejects two of the responses as having inadequate documenation of the required 28-day response duration. In three additional cases, the reason for lack of recorded tumor measurements at some visits needs to be clarified. From the data in the tables above, it seems likely that the final FDA analysis of objective response will be at least 16% (9/57) and perhaps as high as 1921% (12/6257) after the Applicant clarifies issues related to tumor measurements.

Another issue that should be considered is how the dosing errors affect the conclusions one can draw from the study -- can we assume that when patients are given CEG according to dosing in the proposed drug labeling they will get similar results?.

As noted in discussion of the efficacy results in Study 414, FDA did not accept preventive goals as evidence of clinical benefit. However, this had no effect on analysis of Study 514, as none of the claimed clinical benefit successes were based on preventive goals. On the other hand, the issue of whether 1-point changes on the palliative scale constitute clinical benefit does affect this analysis. If one point-changes are included as clinical benefit, the clinical benefit rate is 16% (9/57); if only 2-point and greater changes are accepted, the clinical benefit rate is only 2% (1/57).

Section 9.5.5 of the study protocol states, "Primary efficacy analysis of tumor response of the MTT will be performed excluding the third stratum."

A review of the discussions between the applicant and the division reveals that clinical benefit in the form of "symptom improvement" is the primary efficacy endpoint and that tumor responses are intended to be supportive (meeting minutes 12/3/97). Indeed, a strong correlation between patient benefit and tumor shrinkage is required (response to applicant 5/8/00).

The applicant submitted a list of 10 patients who (by the applicant’s analysis) achieved clinical benefit and a clinical response at some time during enrollment in the study. Each of these patients’ data, independent of randomization, stratification, or protocol period in which responses or benefit occurred, was carefully reviewed to analyze adherence to the protocol, data integrity and study quality.

1. Medical Officer’s Evaluation of the Claimed Responses

A summary of the findings of the detailed medical review are found in the table below. Of the 10 patients listed by the sponsor as benefitters and responders, three were randomized to the placebo arm and received placebo during the blinded phase. One additional patient who was randomized to the active CEG arm did not achieve an MTT response during the blinded period according to the applicant’s analysis. These four patients are not analyzed further. These remaining six patients’ response data are summarized in the table below.

Patient No.	Blinded Period OR?	Correct Dose?	DOR > 28 days	Response Comment	Reviewer Response Analysis
2687	Yes	Yes	Yes	Biologically unusual; SD x 63d, then unexpected CR at d103-132 Substantial weight loss	Response valid
2688	Yes	Yes	No		No valid response
2732	Yes	See dosing table	Yes	All three doses incorrect; Missing tumor dimensions	No valid response
2735	No	See dosing table	Yes	Missing tumor dimensions; Inevaluable dosing regimen	No valid response
2736	Yes	See dosing table	Yes	Missing tumor dimensions; Substantial weight loss	?
5854	Yes	Yes	Yes		Response valid

This tables shows that most responses claimed by the applicant cannot be confirmed by the medical reviewer. However, 2 of the 6 responses in the applicant’s claimed ‘benefit response’ category could be confirmed.

The sponsor claims that there were 8 subjects randomized to the active CEG arm that attained a clinical response but did not receive clinical benefit. The following table summarizes the medical officer’s review of these 8 patients.

 

 

Patient No.	Blinded Period OR?	Correct Dose?	DOR > 28 days	Response Comment	Reviewer Response Analysis
2541	No	Yes	No	Only one dose administered	No valid response
2681	Yes	Yes	Yes	Many incorrect doses < 10% off	Response valid
2686	Yes	Yes	Yes	One incorrect dose	Response valid
2731	Yes	See dosing table	Yes	Many incorrect doses	No valid response
2753	Yes	Yes	Yes	Close; within 12%	Response valid
5494	Yes	See dosing table	27d	Many incorrect doses	No valid response
5496	Yes	See dosing table	Yes	Many incorrect doses	No valid response
5565	Yes	Yes	Yes		Response valid

The table shows that 4 of the 8 claimed responders in the response-only group could be confirmed by the medical reviewer.

Combining the results of these two tables, 6 of the 14 claimed responses could be confirmed. These 14 claimed responses arise from a subpopulation of 57 patients randomized to active CEG and from which the applicant claims a response rate of 24.5% (Table 11-10, v. 42, pp. 100-101). Based on the medical reviewer’s confirmed responses, the FDA-determined response rate is 6/57 or approximately 10.5%.

 

1. Medical Officer’s Evaluation of the Clinical Benefit Claim

In study 514, clinical benefit was assessed by the use of a palliative scale and a preventive question. The palliative scale, appended to this review, was used by both the patient and the investigator. Each participant could choose one or more palliative "treatment goals" which they seek to improve over the course of the study by the administration of the study drug.

The patient and investigator could choose one or more palliative treatment goals, but were obligated to designate one as the "primary" treatment goal. This primary treatment goal would comprise the primary clinical benefit data upon which the results of this goal that would be correlated with the tumor response leading to the claim of a "symptomatic response".

The preventive goal provided the opportunity for the PI -- the only study participant to choose such -- to observe for prevention of events associated with head and neck squamous cell cancer. For example, the investigator could choose to prevent skin breakthrough of the tumor or invasion into the carotid artery by the tumor.

The following table summarizes the results of the medical officer’s review of the clinical benefit endpoint in the 6 patients in which the sponsor claims both clinical benefit and response.

Patient No.	Patient Palliative Goal(s)	P.I. Palliative Goal(s)	Preventive Goal Met?**	Reviewer Benefit Assessment
2687	1 – 1 pt. D	1 – 1 pt. D	None Selected	No Clinical Benefit
2688	1 – 1 pt. D	1 – 1 pt. D	None Selected	No Clinical Benefit
2732	None Selected	1 – 3 pt. D 1 – 2 pt. D	None Selected	Apparent Clinical Benefit
2735	1 – 1 pt. D	1 – 1 pt. D	None Selected	No Clinical Benefit
2736	1 – 1 pt. D	1 – 1 pt. D	None Selected	No Clinical Benefit
5854	1 – 2 pt. better 4 – no D 1 – 1 pt. worse	1 – 1 pt. worse	Achieved @ censoring	No Clinical Benefit

The conventions used in this table are as follows. The first numeral refers to the number of treatment goals chosen by the patient or investigator. The next characters following the dash refer to how many points change there is in the positive direction. Thus, ‘5 – no D ’ indicates that there were five treatment goals chosen and there were no changes in any of them at during the study. ‘1 – 3 pt. D ’ indicates that there was one treatment goal chosen which revealed a three point improvement based on the scale referred to earlier in this review.

This tables shows that the medical reviewer could confirm 1 of the 6 clinical benefit claims of the applicant in the ‘benefit response’ category.

A similar review of the 5 patients in which there is claimed clinical benefit only (no claimed response) is shown below.

 

Patient No.	Patient Palliative Goal(s)	P.I. Palliative Goal(s)	Preventive Goal Met?**	Reviewer Benefit Assessment
2366	2 – 1 pt. D	1 – no D 1 – 1 pt. D	None Selected	No Clinical Benefit
2421	1 – 1 pt. D 1 – no D	1 – no D	None Selected	No Clinical Benefit
2564	1 – 1 pt. D	1 – 1 pt. D	None Selected	No Clinical Benefit
5421	1 – 1 pt. D 1 – no D	2 – 1 pt. D	None Selected	No Clinical Benefit
5588	1 – 1 pt. D worse	None Selected	Failed	No Clinical Benefit

No clinical benefit claim could be confirmed by the reviewing medical officer arising from the 5 patients in whom the applicant claims clinical benefit only.

Combining the results from the two tables, the medical officer could confirm 1 of the 11 applicant-claimed clinically benefiting patients for a clinical benefit rate of 1/57 or approximately 1.8%. It should be noted that there were no simultaneously confirmed responses and confirmed clinical benefit in any individual patient.

Based on the medical reviewer’s confirmation of the applicant’s claims, a table may be constructed as follows:

Study 514		MTT Blinded Phase Objective Response with Active CEG?		Active CEG
		Yes	No
Clinical Benefit with Active CEG?	Yes	0	1	1
	No	6	50	56
Active CEG		6	51	57

 

These findings suggest limited anti-tumor activity and clinical benefit of active CEG.

Reviewer comment: These findings also imply that, although a lesion may shrink or even completely disappear, clinical benefit from such cannot be assumed. This has implications for future trials of this and other agents in this clinical setting.

 

 

5. Evaluation of Safety
1. Deaths

Of the 115 patients who were enrolled on this study, 13 (11.3%) expired while on protocol. Analysis of the cases in which a detailed review was conducted by the medical reviewer indicated systemic disease progression to be responsible in the majority of cases.

The applicant notes that the majority of deaths, which occurred after the patients terminated the study, were due to disease progression. The applicant also states that no deaths were related to therapy.

The medical reviewer confirms that there were no cases of death directly related to injection of active or placebo CEG.

 

2. Serious Adverse Events

Serious adverse events (SAE’s) include severe systemic AE’s and severe organ-specific AE’s. Unique to this application local toxicity data that was systematically collected. Local toxicity was occasionally to frequently found to be "severe" in nature.

One of the most serious adverse events, acute stroke, was observed in six early patients in Study 414. This finding was not observed in study 514. The underlying mechanism was not positively identified by the sponsor and its consultants at the time the problem initially emerged, although factors potentially predisposing patients to stroke were incorporated into the protocol as exclusion criterion. Since the institution of such exclusions, there was only on additional recorded case of stroke in study 414.

 

3. Analysis of Local Toxicity

Local toxicity data represented a significant component of this study and detailed information was collected by the sponsor. A grading scale was used based on numbers ranging from zero to three; zero being no toxicity and three being ‘severe’.

Numerical data describing the toxicity were collected at each visit based on the several factors comprising the local toxicity. These components include bleeding/hemorrhage, erosion, erythema, eschar/scabbing, necrosis, swelling and ulceration. The objective criteria by which each toxicity was graded were not described in the protocol.

The blinded phase of the study consisted of a minimum of three treatments and a maximum of six administrations of study agent. The comparison of active CEG to placebo will only be performed up to study visit 4.

 

4. Analysis of Systemic Toxicity

The electronic database contains Access table ‘ame’ which lists approximately 900 adverse events reported by investigators. Although the applicant had agreed to use the NCCOG/NCI scale of toxicity (1991 edition), the majority of data collected were not graded by this scale. Instead, a less useful scale, categorized by COSTART terminology was employed. This grading system uses more subjective terms such as mild, moderate, and severe to grade severity and not related, possibly related, probably related and related to describe attribution. Objective criteria by which an independent and uninterested reviewer could reconstruct the nature, severity and attribution of the AE were not provided thereby disallowing independent confirmation of the investigators’ grading and attribution selections. Essentially, the subjective opinion of the evaluator at each clinical site was the primary determinant of the severity and attribution of each AE.

Review of the tables relevant to serum chemistry and hematological toxicity by the medical officer (Access tables ‘serum’ and ‘hema’) indicates the anticipated effects of CEG on the bone marrow and kidneys (from the active moiety cisplatin) is minimal and possibly not detectable.

There are a number factors confounding a quantitative analysis of the toxicity of active CEG as it compares to placebo. These factors include the disparity of treatment compliance and drop-off across arms, incorrect dosing (numerous examples provided), investigator differences in recording, and lack of use of standardized toxicity tables.

Brief and exploratory analysis of the relative number of AE’s between arms suggests there were approximately two-fold more AE’s of all types and attributions in the CEG arm. This same ratio was similar in the most important subsets, which were ‘severe’, and ‘moderate’ AE’s which were ‘related’ and ‘probably related’.

 

5. Safety Summary

VII. Integrated Review of Safety

1. Additional Safety Studies or Specific Findings in the Safety Review

Studies 414 and 514 comprised the vast majority of the clinically relevant safety database and are the principal data sources for the toxicity analyses performed for this NDA review. Studies 39-93-P, 403-93-2 and 503-93-2 were small phase 1 or II studies in substantially different patient populations. The sites of injection, volume of injected material, toxicity data collection methods and natural history of the various solid tumors represented in this studies renders their safety data substantially incomparable to the safety databases represented by studies 414 and 514.

2. Adequacy of Safety Testing

8. Dosing, Regimen, and Administration Issues

IX. Conclusions and RecommendationsOverall Summary

• The sponsor proposed using preventive goals as a component of clinical benefit. FDA emphasized that it was the sponsor's responsibility to assure that specific goals were legitimate, e.g., that in the absence of effective treatment, the event that one was attempting to prevent would almost certainly occur within 28 days. FDA reviewers are not convinced that the preventive goals outlined in the NDA fulfill this requirement.
• The sponsor proposed that using the proposed 4-point symptom evaluation scale (see appendix E), an increase of 1-point or greater would constitute clinical benefit. The FDA noted that it was unclear whether a 1-point change would be sufficient to define significant clinical benefit for each category on the scale and that the Applicant would need to support this position. (The view of ODAC on this point would be instructive.)

Applicant ORR FDA ORR

Trial 414 34% (21/62) 19% (12/62) to 27% (17/62)

Trial 514 25% (14/57) 16% (9/57) to 1921% (12/6257)

Applicant CB FDA CB

(Excluding 1-PC) (Including 1-PC)

Trial 414 34% (21/62) 3% (2/62) 8% (5/62)

A. Conclusions

1. Description and Review of Study Protocol Including Amendments
2. Table of Adverse Events (not included in the ODAC briefing document)
3. Narratives of Selected Toxicities (not included in the ODAC briefing document)
4. Regulatory History
5. Reproduction of the Palliative Treatment Goal Scale
6. Summary Tables from a Review of the Literature
7. Reproductions of the Most Relevant Publications (not included in the ODAC

XII. Relevant Additional Information

1. Studies 414-94-2 and 514-94-2

A Randomized Double-Blind, Placebo Controlled Study to Evaluate the Effect of Cisplatin/Epinephrine Injectable Gel (Product MPI 5010) When Administered Intratumorally for Achievement of Treatment Goals in Recurrent or Refractory Squamous Cell Carcinoma of the Head and Neck (inclusive of amendments I-V)

1. Location of information Relevant to the Protocol for both studies:

Study Item Volume

Protocol 4.21

CRF’s Electronically submitted

Database documentation Electronically submitted

 

2. Review of the protocol and amendments

Amendment #1 Volume 4.21 (p.80) 03 Feb 1995 # Patients before amendment: 0

This amendment clarified a number if issues which are listed below. No patients were entered on the protocol until Amendment #3. The following trial design features were clarified:

• Study design changed to a randomized, double-blind, placebo controlled trial
• Added treatment goals as a primary study objective and primary efficacy endpoint
• Added the requirement for an identifiable treatment goal as an entry criterion
• Clarified restrictions of concomitant therapy
• Clarified Treatment Plan for patients who are treatment failures
• Added minimum tumor volumes and minimum does per tumor required for inclusion in the efficacy analysis
• Specified minimum dose for tumors that may be treated but will not be included in the efficacy analysis
• Clarified Visit Schedule and Study Visit Requirements
• Replaced FACT-H&N version 2 with version 3
• Clarified primary and secondary efficacy parameters
• Revised Statistical Methods section
• Added Appendix G, Treatment Goal Questionnaire

Amendment #2 Volume 4.21 (p.80) 05 May 1995 # Patients before amendment: 0

This amendment clarified a number if issues which are listed below. No patients were entered on the protocol until Amendment #3. The following trial design features were clarified:

• Clarified the need for the local Investigator to identify the patient’s MTT and a primary treatment goal related to that tumor prior to the enrollment of the patient
• Clarified that the primary efficacy endpoint will be an objective response to treatment as measured by change in tumor volume for the MTT
• Clarified that all the laboratory studies will be conducted by a designated central laboratory
• Clarified that the decision to enter a patient into open-label treatment at treatment visit 4 or beyond will be determined by disease progression (>25% increase in tumor volume) of the MTT (as identified by the investigator)
• Clarified the objective response criteria
• Add tumors involving a major artery or any visceral organ as an exclusion criterion and clarify that systemic disease in tissues such as the liver, lung, or pancreas will not receive treatment with the gel.
• Revised the Statistical Methods section of the protocol.

Amendment #3 Volume 4.21 (p.74) 25 Sep 1995 # Patients before amendment: 6

This amendment clarified a number of issues that are listed below:

• Allowed up to 30 patients with >20cm3 tumors to be enrolled. If the MTT was >20, the maximum dose of 10 mL of gel would be distributed evenly throughout the tumor. If the assigned dose for the MTT was <10mL the remaining dose volume may be distributed to additional target tumors.