# Presentation: 245695

## Regulatory Considerations

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

## Outline

-   FDA Requirements for Drug Approval
-   ICH Regional Variations
-   Cancer Approval Endpoints

## FDA Requirements for Drug Approval

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

## FDA Accelerated Approval

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

## Regular Approval (~Clinical Benefit)
Longer life
Better life, i.e. a favorable effect on 
Valid measure of how patient feels or functions
Accepted surrogate

Accelerated Approval (~Surrogate) 
Surrogate of better life
Reasonably likely to predict clinical benefit

- Longer life
- Better life, *i.e.* a favorable effect on
- Valid measure of how patient feels or functions
- Accepted surrogate
- Accelerated Approval (~Surrogate)
- Surrogate of better life
*Reasonably likely* to predict clinical benefit

- Endpoints Supporting FDA Approval

## Oncology Surrogates at FDA

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

## ICH Regional Considerations: EU

- New Medicines Legislation, 11/05
- Conditional Marketing Authorization, 3/06
- Approval Mechanisms

## The New Medicines Legislation

- 11/05, Modifies EMEA Role
- Mandates Centralized Procedure for new treatments of cancer, AIDS, neurodegenerative diseases, diabetes, *etc.*
- Access to 27 countries in Europe (25 EU + Norway and Iceland)
- EMEA Marketing Authorisation
- Objective criteria of quality, safety efficacy
- Economic considerations, comparative efficacy remain excluded (Member State responsibility)
- Approval mechanisms
- Normal
- Exceptional circumstances
- Conditional (new)

## Conditional Marketing Authorization

- Scope and conditions
- Orphan drugs, emergency threats, serious, chronic, life-threatening conditions
- Public health interest; to fulfill an unmet medical need
- Applicant must demonstrate “presumed positive benefit/risk” of the product based on scientific evidence and pending completion of further studies (“specific obligations”)
- Quality and non-clinical safety data should be complete

## Conditional Marketing Authorization Obligations and Compliance

- Obligations and timeframes publicly available
- Clear information to patients and health professionals on conditional nature of authorization
- Authorisation valid for 1 year, renewable
- Assess compliance with timeframe for obligations
- Retain, modify obligations, or consider benefit-risk established
- If holder does not apply for renewal, authorization expires
- Suspend, revoke, withdraw or vary authorisation if a product viewed as harmful or lacking therapeutic efficacy

## Models for conditional authorization

| Basis for approval | Confirmation |
| --- | --- |
| Short-term
“Soft endpoint” | Long-term
“Hard endpoint” |
| Interim analysis of RCT | Further analysis |
| “Selective approval” (small effect in broad indication) | Identify responders (restrict indication) |
| Biomarker
Exploratory (Phase II single-arm or randomized) | Clinical outcome
Randomized controlled trial (Phase III in the same or related indication) |

## Approval Mechanisms

- Normal
- Comprehensive data to assess risk-benefit balance
- In general, randomized active and placebo-controlled trials required
- Phase IV: “Follow-up” studies of (dose-response), therapeutic use
- Exceptional circumstances
- Comprehensive data cannot be provided (because of specific circumstances: rarity, medical ethics, state of scientific knowledge)
- Phase IV: “Specific obligations” to inform about the safe and effective use (normally not possible to assemble full data package)
- Conditional Marketing Authorization
- Can demonstrate positive benefit risk balance, based on preliminary evidence from an ultimately comprehensive development
- Phase IV: “Specific obligations” to provide missing data (intended to become a “normal” marketing authorisation)

## Conditional vs. Exceptional

| Conditional MA | Exceptional circumstances |
| --- | --- |
| Granted before all data are available | Comprehensive data cannot be provided (e.g., too rare) |
| Authorization valid for one year  (renewable) | Annual reassessment of the risk-benefit balance |
| Obligations: Further clinical studies to verify benefit/risk balance | Obligations: Specific procedures in particular concerning safety |
| Data package: 
Initial + Obligations = Normal | Data package: 
Initial + Obligations < Normal |

- Approved under exceptional circumstances: MabCampath (alemtuzumab), Foscan (temoporfin), Glivec (imatinib), Onsenal (celecoxib), Taxotere (docetaxel), Trisenox (arsenic trioxide), Velcade (bortezomib), Zevalin (ibritumomab tiuxetan)

## Patient Focused Drug Development

|  | EU | US |
| --- | --- | --- |
| Early Access | Named Patient Basis | Single patient IND |
| Early Evaluation | Accelerated Assessment | Fast Track |
| Early Distribution | Conditional Authorization | Treatment IND |
| Early Approval | Conditional Authorization | Subpart H & E |

## Regulatory Considerations: Japan 

- Figure: Schwartsmann, G., *et al*.  2002.  *Journal of Clinical Oncology* **20** (18S): 47s-59s
-  Local Phase 1 for PK/PD mandatory
-  Bridging to western studies feasible

## FDA Cancer Approval Endpoints

| Historical Order | When Introduced | Effect Measured | Benefit Measured | Need for Blinding |
| --- | --- | --- | --- | --- |
| Tumor Shrinkage | 1950s | Drug | Surrogate | No |
| Overall Survival | 1980s | Drug plus 
natural history | Direct | No |
| Symptom Palliation | 1980s | Drug in 
disease setting | Direct | Yes |
| Time to Event 
(PFS, TTP) | 1990s | Drug plus 
natural history | Surrogate | Yes |

## 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 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
- Not *necessarily* reflective of clinical benefit
*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 as 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; direct measure of clincal benefit
*Limitations*
- 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

## Patient Reported Outcomes in FDA Anticancer Product Approvals

| Drug | Year | Domains | # |
| --- | --- | --- | --- |
| Photofrin | 1995 | Dysphagia | 1 |
| Gemzar | 1996 | Pain / PS / weight | 2 |
| Novantrone | 1996 | Pain | 1 |
| Hycamtin | 1998 | SCLC symptoms (9) | 1 |
| Amifostine | 1999 | Xerostomia | 1 |
| Palifermin | 2004 | Mucositis | 1 |

## Trial Design Considerations

*Randomization*
- Enables convincing demonstration of effect
- Allows concomitant safety assessment
*Blinding*
- Addresses measurement bias
- Incorporated at each step subject to bias
*Instrument characteristics*
- Measured change should be clinically relevant
- Prospective statistical analysis plan

## Cancer Approval Endpoints

| Historical Order | When Introduced | Effect Measured | Benefit Measured | Need for Blinding |
| --- | --- | --- | --- | --- |
| Tumor Shrinkage | 1950s | Drug | Surrogate | No |
| Overall Survival | 1980s | Drug plus 
natural history | Direct | No |
| Symptom Palliation | 1980s | Drug in 
disease setting | Direct | Yes |
| Time to Event 
(PFS, TTP) | 1990s | Drug plus 
natural history | Surrogate | Yes |

## Common reasons for rejection

- Negative trials
- Claims based on exploratory subgroup analysis
- Non-inferiority without established control arm effect
*A posteriori* defined non-inferiority margins
- Marginal activity with safety issues
- Lack of randomized control trial
- No appropriate historical control
- No dramatic activity

## Outline

-   FDA Requirements for Drug Approval
-   ICH Regional Variations
-   Cancer Approval Endpoints