I. INTRODUCTIONThe purpose of this guidance is to provide sponsors and the review staff in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA) with information regarding target product profiles (TPPs). A TPP is a format for a summary of a drug development program 2 described in terms of labeling concepts. A TPP can be prepared by a sponsor and then shared with the appropriate FDA review staff to facilitate communication regarding a particular drug development program. Submission of a TPP is voluntary. This guidance describes the purpose of a TPP, its advantages, and its optimal use. It also provides guidance on how to complete a TPP and relates case studies that demonstrate a TPP’s usefulness. FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. Although guidance documents do not legally bind FDA, review staff may depart from guidance documents only with appropriate justification and supervisory concurrence. II. BACKGROUNDIn 1997, a Clinical Development Working Group composed of representatives from the FDA and pharmaceutical sponsors began discussions on ways to improve sponsor and FDA interactions in the drug development process. The working group recommended use of a template that provides a summary of drug labeling concepts to focus discussions and aid in the understanding between sponsors and the FDA. The name given to this template was the target product profile. Experience with TPP-focused meetings with sponsors at the FDA has indicated that such documents can be useful (see Appendix A). An efficient dialogue between a sponsor and the FDA during the drug development process can minimize the risk of late-stage drug development failures, increase the probability that optimal safety and efficacy data are available in a timely manner, improve labeling content, and possibly decrease the total time involved with drug development.
III. DESCRIPTION AND BENEFITS OF A TPP
The purpose of a TPP is to provide a format for discussions between a sponsor and the FDA that can be used throughout the drug development process, from pre-investigational new drug application (pre-IND) or investigational new drug application (IND) phases of drug development through postmarketing programs to pursue new indications or other substantial changes in labeling. The TPP embodies the notion of beginning with the goal in mind. That is, the sponsor specifies the labeling concepts that are the goals of the drug development program, documents the specific studies intended to support the labeling concepts, and then uses the TPP to assist in a constructive dialogue with the FDA. The ideal version of what the sponsor would like to claim in labeling guides the design, conduct, and analysis of clinical trials to maximize the efficiency of the development program. Ideally, the final version of the TPP will be similar to the annotated draft labeling submitted with a new drug application (NDA) or biologics license application (BLA).
Ideally, the TPP provides a statement of the overall intent of the drug development program, and gives information about the drug at a particular time in development. Usually, the TPP is organized according to the key sections in the drug labeling and links drug development activities to specific concepts intended for inclusion in the drug labeling. The sponsor can draft and update pertinent sections of the template that are intended to support the specific statements in labeling. The sponsor can also use these updated versions of the TPP in preparation for discussions with FDA review staff to identify the most important development goals for the drug. The TPP is a dynamic summary that changes as knowledge of the drug increases. For optimal use, we recommend that the TPP be updated regularly to reflect new information about the drug and changes in the clinical development program. Generally, the final TPP is shorter than the ultimate annotated draft labeling since it captures only a summary of the drug development activities and concepts. Early TPPs can be brief depending on the status of the sponsor’s development process.
A well-organized TPP can save meeting time for discussion of issues by eliminating the need for a sponsor’s introduction to the history of the drug development program. Sponsors can also use a TPP to streamline their interactions with FDA review staff by distinguishing TPP entries and sections that have been previously discussed from entries that are the current or future focus of a discussion. This process can eliminate the need to revisit the established entries, unless the development goals change or new scientific issues emerge. The use of a TPP is especially important at pre-new drug application (pre-NDA) and pre-biologics license application (pre-BLA) meetings, when it can help the review staff focus on a sponsor’s goals and make sure previously discussed items have not changed when the sponsor submits an NDA or BLA. In a Briefing Document, a sponsor can use a TPP to quickly update new FDA or sponsor personnel who join the program. A TPP enables a sponsor to pursue the desired outcome (i.e., approval and optimal labeling of a safe and effective drug) in the most efficient manner with respect to FDA interaction because all such interaction is focused on the explicitly stated goals of the development program.
Submission of a TPP is voluntary and is not required for granting an end-of-phase 2 (EOP2) or other meeting with sponsors. A TPP does not represent an implicit or explicit obligation on the sponsor’s part to pursue all stated goals. Providing a TPP summary does not constrain the sponsor to submit draft labeling in an NDA or BLA that is identical to the TPP. The TPP does not represent a commitment or an obligation on the FDA’s part to consider the resultant evidence as adequate to attain approval. FDA concordance with part or all of the TPP does not represent a commitment to approve the identical language in the final label.
Regulatory procedures and Agency recommendations introduced in recent years provide sponsors with standardized mechanisms to prepare sound drug development proposals, submit them to the FDA for review, and engage in a structured dialogue to reach an understanding of the FDA’s thinking on various aspects of a drug development program. Specifically, regulations related to EOP2 meetings (21 CFR 312.47(b)), the guidance for industry Formal Meetings With Sponsors and Applicants for PDUFA Products, 3 and the guidance for industry Special Protocol Assessment all contribute to fostering an environment that encourages proactive dialogue between sponsors and FDA review staff on drug development programs. FDA regulations and guidances such as those relating to drugs and biologics with a fast track designation, 4 drugs for severely debilitating or life-threatening diseases (21 CFR 312.82), and drugs and biologics pursuing accelerated approval (21 CFR part 314, subpart H) further recognize and reinforce structured, proactive dialogue. The TPP summary goes a step further in the recognition of the value of proactive dialogue. The TPP enhances a sponsor’s effort in preparing a Briefing Document that will provide the basis for a constructive milestone meeting with review staff. With respect to meetings between a sponsor and the review staff, the guidance for industry Formal Meetings With Sponsors and Applicants for PDUFA Products states the following key points:
A TPP can provide the structure to such a Briefing Document and help ensure the sponsor presents all relevant medical and scientific information in the context of the overall drug development goals. The TPP itself can assist in the achievement and maintenance of constructive feedback and understanding between the FDA and sponsor, which is critical for successful drug development. The FDA official meeting minutes should reflect when the sponsor submitted a TPP and the review staff and the sponsor discussed its contents. For the meetings, the TPP should be attached as an appendix to the official meeting minutes. IV. COMPLETING A TPP
The TPP can include information from each discipline. Usually, the TPP briefly summarizes the specific studies (both planned and completed) that will supply the evidence for each conclusion that is a labeling concept. The TPP should be organized according to key sections in the drug’s labeling. Typical key sections from which a sponsor can choose, depending on the nature of the meeting, include:
The Target Product Profile Template, shown in Appendix C, details the information (in italics) that we suggest sponsors include in each section. 5 In general, we recommend sponsors use the following steps to complete a TPP:
B. Proposed Promotional ClaimsA TPP can assist in a constructive dialogue with FDA review staff regarding proposed promotional claims and/or presentations for use in product promotional materials and the documentation of specific studies intended to support these claims. The TPP can link drug development activities to specific concepts intended for proposed promotional claims. In general, we recommend sponsors use the following steps to complete the Target, Annotations, and Comments areas of a TPP for proposed promotional claims:
V. LINKAGES WITH OTHER INITIATIVESThe TPP initiative complements other initiatives in which the FDA and pharmaceutical sponsors are participating. The FDA is sponsoring the Critical Path Initiative following the March 16, 2004, release of the report entitled “Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.” 6 In this report, the FDA suggests that there is a substantial opportunity to increase the pace of discovery and development of new medical products. The report stresses the need for new tools from discovery or the pre-IND phase through approval of the medical product. Since a TPP can facilitate constructive discussion and understanding between a sponsor and the FDA, the TPP represents a potential critical path tool. VI. CONCLUSIONBoth the FDA and sponsors have seen the advantages of using a TPP at meetings early in the drug development process. Use of a TPP can facilitate the efficiency of sponsor-FDA interactions and communications. A TPP helps focus a sponsor’s drug development team and FDA review staff on the drug development goals in terms of drug labeling. If used properly, a TPP can help address issues early on in the drug development process thereby preventing late-stage drug development failures and decreasing the total time involved with drug development. Appendix A:
|
Milestone(meeting or submission) |
Date |
*TPP Submitted? Y/N |
TPP Version Date |
TPP Discussed?Y/N |
Pre-IND |
02FEB2005 |
N |
N |
|
IND Submission |
17JAN2006 |
Y |
Y |
|
EOP1 |
09NOV2006 |
Y |
Y |
|
EOP2A |
N/A |
|||
EOP2/Pre-Phase 3 |
12DEC2007 |
Y |
Y |
|
Pre-NDA/BLA |
||||
Other (specify) |
1 Indications and Usage
Target |
Annotations |
Postmenopausal Osteoporosis Drug name is indicated for the treatment and prevention of osteoporosis in postmenopausal women. Treatment of Osteoporosis: In postmenopausal women with osteoporosis, drug name reduces the incidence of vertebral fractures and increases bone mineral density (BMD). Prevention of Osteoporosis: Drug name may be used in postmenopausal women at risk of developing osteoporosis and for whom the desired clinical outcome is to increase or maintain BMD and to reduce the risk of fractures. |
Protocol-XXX-001: completed dose range finding study to support phase 3 registration trials
Protocol-XXX-002 planned study: protocol not yet submitted
Protocol-XXX-003: protocol to be submitted FEB 2008
|
Comments: The proposed biomarkers included in Protocol-XXX-02 and Protocol-XXX-03 are acceptable to the DMEP. Protocol XXX-003 will be submitted for special protocol assessment. The sponsor intends to submit an NDA supported by a clinical pharmacology package (Section 3 and Appendix D of the Briefing Document) and data from the proposed 2-year osteoporosis prevention trial and the 3-year osteoporosis treatment trial (Section 2; Appendix A). Does the FDA agree that the proposed clinical pharmacology package and phase 3 registration trials are sufficient for registration of drug name for the proposed osteoporosis indications in postmenopausal women? At the pre-IND meeting, the FDA stated that 3 years of fracture data were required to obtain an osteoporosis indication. Would the FDA consider an NDA submission if the analyses of the osteoporosis treatment trial data demonstrated robust vertebral fracture risk reduction at a 2-year interim analysis? |
Target Product Profile: Drug Name
Milestone(meeting or submission) |
Date |
*TPP Submitted? Y/N |
TPP Version Date |
TPP Discussed?Y/N |
Pre-IND |
||||
IND Submission |
||||
EOP1 |
||||
EOP2A |
||||
EOP2/Pre-Phase 3 |
||||
Pre-NDA/BLA |
||||
Other (specify) |
* The TPP can be submitted to the FDA as part of a Briefing Document or as a stand-alone document.
1 Indications and Usage
Target |
Annotations |
|
Summary information regarding completed or planned studies to support the target:
When listing studies, consider:
|
Comments: |
2 Dosage and Administration
Target |
Annotations |
For each indication, state the following:
|
Summary information regarding completed or planned studies to support the safety and effectiveness of the proposed dosage and route of administration:
|
Comments: |
3 Dosage Forms and Strengths
Target |
Annotations |
Include information on the available dosage forms, including strength or potency of dosage form in metric system and a description of identifying characteristics of dosage forms |
Summary information regarding completed or planned studies to support the dosage forms and strengths:
|
Comments: |
4 Contraindications
Target |
Annotations |
List situations in which the drug might be contraindicated, including:
|
Summary information regarding completed or planned studies to support the target:
Or, literature references describing contraindication for drug class. |
Comments: |
5 Warnings and Precautions
Target |
Annotations |
Include a description of clinically significant adverse reactions and potential safety hazards and limitations of use because of safety considerations, as reasonable evidence of these issues is established or suspected during the drug development program. A causal relationship need not be demonstrated. Include information regarding any special care to be exercised for safe use, including precautions that are not required under any other section of the label. Identify any laboratory tests helpful in following the patient’s response or in identifying possible adverse reactions. |
Summary information regarding completed or planned studies to support the target:
Or, literature references describing significant adverse reactions shared by the drug class of the new drug. |
Comments: |
6 Adverse Reactions
Target |
Annotations |
Describe overall adverse reaction profile of the drug based on entire safety database. List adverse reactions that occur with the drug and with drugs in the same pharmacologically active and chemically related class, if applicable. Within a listing, adverse reactions should be categorized by body system, severity of the reaction, or in order of decreasing frequency, or by a combination of these, as appropriate. Within a category, adverse reactions should be listed in decreasing order of frequency. Include the studies in the development program that will address adverse reactions associated with a particular drug class. |
Summary information regarding completed or planned studies to support the target:
|
Comments: |
7 Drug Interactions
Target |
Annotations |
Describe clinically significant interactions, either observed or predicted (i.e., other prescription drugs or over-the-counter drugs, class of drugs, or foods such as grapefruit juice or dietary supplements); practical advice on how to prevent drug-drug interactions; (description of results from studies conducted or observations from the integrated safety summary); drug-laboratory test interactions (known interference of drug with lab test outcome). |
Summary information regarding completed or planned studies to support the target:
|
Comments: |
8 Use in Specific Populations
Target |
Annotations |
Consider the following:
|
Summary information regarding completed or planned studies to support the target:
If there are no plans to study the drug in a specific population, include rationale. |
Comments: |
8.1 Pregnancy (This subsection can be omitted if the drug is not absorbed systemically):
8.2 Labor and Delivery: Use during labor or delivery, effects on mother, fetus, duration of labor, delivery, and effects on later growth of newborn.
8.3 Nursing Mothers: If the drug is absorbed systemically, information about excretion of drug in human milk and effects on the nursing infant. Describe pertinent adverse events in animal offspring or tumorigenicity potential if it is detected or suspected.
8.4 Pediatric Use: Statements relevant to the use of the drug product in the pediatric population (birth to 16 years of age). Cite any limitations, need for monitoring, specific hazards, differences in response, or other information pertinent to the pediatric population.
8.5 Geriatric Use: Statements relevant to the use of the drug product in the geriatric population (age 65 and older). Cite any limitations, need for monitoring, specific hazards, differences in response, or other information pertinent to the referenced population.
8.6 Additional Subsections: Use of drug in other specified populations (e.g., those with renal or hepatic impairment).
9 Drug Abuse and Dependence
Target |
Annotations |
Include the following subsections, as appropriate for the drug: |
Summary information regarding completed or planned studies to support the target:
|
Comments: |
9.1 Controlled Substance:Anticipated DEA schedule.
9.2 Abuse:Identify types of abuse and adverse reactions pertinent to them. Identify particularly susceptible patient populations.
9.3 Dependence:Discuss potential for dependence and describe the characteristic effects resulting from psychological or physical dependence.
10 Overdosage
Target |
Annotations |
Provide specific information about:
|
Summary information regarding completed or planned studies to support the target:
Update with human data, if available. |
Comments: |
11 Description
Target |
Annotations |
Include the proprietary name and established name, dosage form and route of administration, qualitative and quantitative ingredients, pharmacologic or therapeutic class, and any other important physical and chemical characteristics. |
Summary information regarding completed or planned studies to support the target:
|
Comments: |
12 Clinical Pharmacology
Target |
Annotations |
Include a concise factual summary of the clinical pharmacology and actions of the drug in humans. Data that describe the drug’s pharmacologic activity can be included in this section, including biochemical or physiological mechanism of action, pharmacokinetic information, degree of absorption, pathway for biotransformation, percent dose unchanged, metabolites, rate of half-lives including elimination concentration in body fluids at therapeutic and toxic levels, degree of binding to plasma, degree of uptake by a particular organ or fetus, and passage across the blood-brain barrier. Include the following subsections: |
Summary information regarding completed or planned studies to support the target:
If applicable, a subsection (e.g., 12.4 Microbiology) can be created under this section heading and all of the microbiology information for antimicrobial products consolidated into that subsection. |
Comments:
|
12.1 Mechanism of Action:Summarize established mechanisms of action in humans at various levels (e.g., receptor membrane, tissue, organ, whole body). Do not include theorized mechanisms of action.
12.2 Pharmacodynamics:Include a description of any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drug’s clinical effect or those related to adverse effects or toxicity. Include data on exposure-response relationship and time course of pharmacodynamic response.
12.3 Pharmacokinetics:Describe clinically significant pharmacokinetics of a drug or active metabolites (i.e., pertinent absorption, distribution, metabolism, and excretion parameters). Include results of pharmacokinetic studies that establish the absence of an effect, including pertinent human studies and in vitro data.
13 Nonclinical Toxicology
Target |
Annotations |
Include the following subsections, as appropriate: |
Summary information regarding completed or planned studies to support the target:
|
Comments: |
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility:
13.2 Animal Toxicology and/or Pharmacology: Ordinarily, significant animal data necessary for safe and effective use of the drug in humans should be included in other sections of the labeling, as appropriate. If the pertinent animal data cannot be appropriately incorporated into other sections of the labeling, this subsection can be used.
14 Clinical Studies
Target |
Annotations |
Provide a description of studies that support statements about the efficacy or safety benefits. Consider including a description of supporting tables and graphs. |
Summary information about completed or planned studies regarding the intent to develop evidence to support benefits of treatment (i.e., safety or efficacy benefits of primary or secondary endpoints in the selected population):
Also consider including where the studies will be (or have been) run (i.e., geographical area).
|
Comments: |
15 References — Can include when labeling must summarize or otherwise rely on recommendation by authoritative scientific body, or a standardized methodology, scale, or technique, because information is necessary for safe and effective use.
16 How Supplied/Storage and Handling
Target |
Annotations |
Include information about the available dosage forms to which the labeling will apply and for which the manufacturer or distributor will be responsible. For example:
|
Summary information regarding completed or planned studies to support the target:
|
Comments: |
17 Patient Counseling Information
Target |
Annotations |
Include information for prescribers to convey to patients to use the drug safely and effectively. For example:
Indicate whether a Patient Package Insert or MedGuide are planned. |
Summary information regarding completed or planned studies to support the target:
|
Comments: |
2. For the purposes of this guidance, all references to drug include both human drugs and therapeutic biological products unless otherwise noted.
3. We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance Web page at http://www.fda.gov/cder/guidance/index.htm.
4. See the guidance for industry Fast Track Drug Development Programs — Designation, Development, and Application Review (http://www.fda.gov/cder/guidance/index.htm).
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Date created: March 29, 2007