# Presentation: 512378

## Oncology Pediatric Initiatives

- Richard Pazdur, MD
- Director, Division of Oncology Drug Products

## Food and Drug Modernization Act of 1997- An incentive Program

- Provision for 6 month extension to existing marketing exclusivity or patent protection can be granted to an entire product line of an active moiety for providing new pediatric information that will benefit the public health.
- Submissions must come in response to an FDA Written Request.

**Notes:**
	I would like to present information regarding a recent pediatric initiative underway in the Division. In order to initiate this discussion, I would like to review the existing pediatric regulations and contrast the Food and Drug Modernization Act of 1997 from the 1998 Pediatric Rule.

	The 1997 FDAMA provides a VOLUNTARY incentive program to encourage sponsors to develop agents in pediatric indications. The Act provides for a 6 month patent extension to an entire product line provided that new pediatric information is provided. This can be done twice--each time for a different pediatric indication. Submissions from sponsors must come in response to an FDA written request. The exclusivity extension is granted on the basis of completion of written request rather than the results of a trial.

## Pediatric Rule of 1998- A Mandate

- A product under review must provide pediatric information if the indication under review is a disease found in children. If the disease is not found in children, a waiver may be granted.

**Notes:**
In contrast to the Pediatric Section of FDAMA, the Pediatric Rule of 1998 is a mandate providing that a product under review must provide pediatric information if the indication under review is a disease also found in children. If the disease is not found in children , a waiver may be granted

## Comparison of FDAMA vs. 1998 Rule

- Voluntary
- Applies to entire product line
- No restriction on eligible pediatric diseases
- Only applies when there is underlying patent or exclusivity protection
- Biologicals  and some products excluded
- Orphan products included

- Mandatory
- Only applies to the product and indication under review
- Only applies if the pediatric disease is similar to the adult disease
- Applies to biologicals
- Orphan products excluded

**Notes:**
This slide compares these regulations.

	As stated previously, the FDAMA regulation is voluntary; whereas, the Pediatric Rule is Mandatory. The FDAMA  exclusivity applies to an entire product line without an restrictions on eligible pediatric diseases. However, the Pediatric Rule applies only to the product and indication under review and applies only if the pediatric disease is similar to the adult indication under review.

Because FDAMA deals with exclusivity extensions the provision only applies when there is underlying patent protection or marketing exclusivity.

FDAMA extensions do not apply to biologicals; orphan products are included in consideration for exclusivity extensions under FDAMA.

The Pediatric Rule applies to biologicals however,  orphan products are excluded. 

## Pediatric Exclusivity

**Written Request**
**From FDA**

**Submission of **
**Study Reports**

**FDA **
**Determination**

**Proposed Pediatric**
**Study Request**

**Notes:**
Pediatric Exclusivity extensions are usually granted by the following mechanism. A proposal for study request are generated by sponsors or investigators. In response to the proposal, a written request is generated from the FDA stipulating the conditions--such as details of the proposed clinical trials. After completion of the conditions, the sponsor is required to submit study reports. The FDA subsequently determines whether the sponsor complied with the details outlined in the written request. Note that exclusivity extensions are granted on the completion of the plans outlined in the written request--NOT on the results of the trial. Hence, a sponsor may obtain an exclusivity extension by meeting the plan outlined in the written request even if the results of the trials fail to demonstrate clinical efficacy.     

## FDA experience with FDAMA incentive

- _Overall_
- Proposals received: 163
- Written Requests issued: 127

- _Oncology_
- Proposals received: 5
- Written Requests issued: 1

**Notes:**
The FDA has demonstrated that the FDAMA incentive has worked in diseases outside of pediatric oncology. In general, overall 163 proposals were obtained for all pediatric indications and 127 written requests were issued as of 
March 1, 2000.  In Oncology we have only received 5 proposals and have issued 1 written request.

We believe that the discrepancy between the peds oncology experience and the pediatric at large experience points to distinctly  different situations that face the pediatric oncology community. First, the pediatric oncology market is small in comparison to adult oncology markets. Secondly,  participation in pediatric oncology trials is high--in fact, participation in phase III trials represents the “standard of care” of ped oncology patients. Thirdly, the perception by sponsors that unexpected toxicity encountered in the pediatric patient population may adversely effect the regulatory development of their agents  may deter development of agents in pediatric oncology until the agent has been approved for an adult indication.

## Pediatric Development Plan

- _Overview_
- Dosing and pharmacokinetics in Phase 1
- Phase 2 or pilot studies in a range of potential indications
- Not a supplemental NDA since efficacy need not be demonstrated
- Applies to both new agents and approved agents that have not been adequately investigated in pediatric oncology

**Notes:**
We realized that to promote the development of pediatric oncology drugs that a DEVELOPMENT PLAN be established to encourage sponsors to provide a commitment to drug development. We are looking for a good faith effort--an effort of shared risk--which provides the incentives provided under FUDAMA to encourage drug development. We also realize that to develop drugs one must commit to phase I and phase II trials. The plan which we will explain applies to both new agents and approved agents which have not been adequately investigated in pediatric oncology. In contrast to a supplemental NDA, efficacy is not required to obtain exclusivity extensions.

We also understand that for any plan to be effectively implemented  there needs to be a collaborative effort between pediatric patients and families, pediatric oncology groups, NCI, FDA, and sponsors. This collaboration can not be mandated by the FDA, neverthless the unique aspects of pediatric oncology--with a limited patient popultion treated by specialists--certainly would favor a unified plan for the pediatric oncology discipline.   

## Pediatric Development Plan

- _First Stage_
- Phase 1 studies to determine dose, pharmacokinetics, and toxicities
- Planned for about 25 patients
- If unacceptable toxicity occurs, the development would stop and an exclusivity extension could be granted
- If toxicity is acceptable, proceed to second stage (anticipated general case)

**Notes:**
The first stage of the plan provides for phase I trials to determine the dose, pharmacokinetics, and toxicities of pediatric patients. As stated before, we are looking for a good faith effort to develop drugs beyond dose and toxicity and examine efficacy. Nevertheless, if unacceptable toxicity occurs following appropriate dose finding studies, the development of the agent would stop and an exclusivity extension could be granted. We believe this would be an unusual situation, but does provide the incentive of exclusivity extension for an unpredictable situation.

In the vast majority of cases, if the toxicity was acceptable, a second stage would be conducted to examine efficacy.

## Pediatric Development Plan

- _Second Stage_
- Phase 2 studies (single agent or add on comparative design) and/or pilot studies (combinations) to demonstrate an agent’s characteristics and contribution to
- efficacy, perhaps using surrogate endpoints such as response rate
- justification for further development to examine clinical benefit

**Notes:**
This stage would require the demonstration of efficacy and the outline of this stage is dependent on the agent. This stage could include single agent studies in refractory settings  (several classic phase II trials ) or add on the agent to a known regimen in a comparative design.

Efficacy probably would be assessed by examining surrogate endpoints such as response rates.

These preliminary trials would provided --if positive--a justication for further development to examine clinical benefit.    

## Possible Outcomes

- _At the completion of the second stage_
- If efficacy is demonstrated, approval for the indication under subpart H or full approval
- If no beneficial effect is observed, development is stopped
- If results are promising but not sufficient to support approval, a commitment to further development
- _ALL THREE CASES CAN RESULT IN GRANTING OF EXCLUSIVITY EXTENSION_

**Notes:**
At the completion of the second stage, there are several outcomes.

If efficacy is demonstrated using a surrogate endpoint in a specific setting, accelerated approval under subpart H could be granted and exclusivity extension is granted.

If no beneficial  effect is observed, development is stopped and exclusivity extension is granted.

If results are promising but not sufficient to support approval, a commitment to further develop is agent is made and, again, exclusivity extension is granted.

As previously stated, under all cases granting of the exclusivity extension is granted corroborating our efforts to encourage a drug development program in a good faith effort irrespective of the demonstration of benefit.

## Results of Completion  of a Pediatric Development Plan

- The results are summarized in a study report and submitted to the FDA
- Upon review, if the conditions of the initial Written Request are met, _*REGARDLESS OF OUTCOME*_*, *a 6 month exclusivity extension may be granted
- Well designed, well executed studies with a negative result can qualify
- Intent is a prospective plan to produce new information of importance to pediatric oncology

**Notes:**
To obtain exclusivity the results of the plan must be reported to the FDA.
Upon review,  if the conditions of the initial written request are met, irrespective of outcome, a  6 month extension to the entire product line may be granted.
Although negative results can qualify, we are interested in well designed and well executed trials and will evaluate the quality of trials in assessing the granting of exclusivity.
The intent of the plan is prospective. It is risk sharing to promote the development of oncology agents in pediatrics with the intent of providing new information.
Although the FDA cannot mandate to sponsors which institutions or cooperative groups to use, we strongly urge sponsors to  be aware of the unique aspects of current pediatric oncology care and research and consider cooperating with the  existing pediatric clinical trials structure to ensure quality care, quality research, and prevent splintering of patient resources.
The Division of Oncology Drug Products will be convening a subcommittee of ODAC --the Pediatric Oncology Subcommittee--in September. In addition, we are presently writing a Guidance regarding the described plan, and will be providing a template for a pediatric oncology written request on the FDA website. We are also in the process of  recruiting additional pediatric oncologists to the Division to support this commitment.