Get Your Development Program Started on the Right Foot
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The document outlines the importance of a Target Product Profile (TPP) in drug development, which serves as a strategic document detailing product expectations and guiding the development process. It emphasizes interdisciplinary collaboration and the need for constant updates throughout the drug's life cycle, integrating regulatory considerations and market needs. Additionally, it highlights common pitfalls and offers a comprehensive flowchart of the integrated product development plans necessary for successful market approval.
Get Your Development Program Started on the Right Foot
- 1. A Full-Service CRO Get Your Development Program Started on the Right Foot…
- 2. Presenter Introduction Senior Vice President, R&D David Shoemaker, PhD Senior Medical Officer Jack Modell, MD Senior Research Scientist Dana Minnick, PhD Senior Research Scientist Scott Burian, PhD
- 3. Overview • Overview • Content • Example Target Product Profile • Overview • Clinical Development Plans • Nonclinical Development Plans • CMC • Regulatory Strategy Integrated Product Development Plans
- 4. What is a TPP? • Key strategic planning document that: – Provides a clear understanding of requirements and expectations of the ultimate outcome of product development – Is driven by unmet patient, physician and payer needs at time of launch • Roadmap of key Go/No-Go decision points • Statement of the overall intent of the product development program – and much more than just a draft product label
- 5. What is a TPP? A differentiated value proposition Snapshot in time Summary of studies that justify labeling claims Dynamic & multidisciplinary document Communication tool Starting point for annotated package insert (label)
- 6. Link to FDA Guidance The purpose of a TPP is to provide a format for discussions that can be used throughout the drug development process. The TPP embodies the notion of beginning with the goal in mind. 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. The TPP is a dynamic summary that changes as knowledge of the drug increases.
- 7. Road Map for Development • Focuses development • Required studies – no more, no less – become apparent • Requires comparison with similar products • Constant updating of indication required – With new information from your studies & market – Go/No-Go decision points are forced
- 8. When is the TPP Needed? • As early in development as possible – Pre-IND Meeting – IND – End-of-Phase 1 Meeting – End-of-Phase 2 Meeting – Annotated Package Insert Template – Pre-NDA or -BLA Meeting
- 9. Establish the Targets Early • Begin with the end in mind – “If you don’t know where you’re going, you’ll be lost when you get there.” Yogi Berra • Interdisciplinary activity – Project teams (Clinical/Nonclinical/CMC/Regulatory) – Labeling and marketing teams • Initial interdisciplinary and senior management input and buy-in • Decision log – Conflict resolution system – Go/No-Go rationale
- 10. Typical TPP Checklist Includes: • Scientific rationale • Preclinical support • Toxicology/ADME/PK • Acute vs. chronic indication • Unmet need • Clear diagnostic criteria • Target population or subpopulation • Clinical plan • Anticipated safety profile, drug interactions • Contraindications • Regulatory plan • Endpoints (with estimate of needed benefit) • Manufacturing/stability issues • Route of administration • Anticipated storage conditions • Desired shelf life • FDA guidelines available • International objectives • Competition • Patents
- 11. Indications and Usage Target • What is the drug product? • Is it for treatment or prevention? • What disease/condition and unmet needs does it target? • Who are the target patients? Annotations in TPP • Completed/planned studies supporting the target Comments • Summarize the drugs currently used for treatment or prevention in your target indication and write a brief statement on their competitive positioning
- 12. Dosage and Administration Target • How much drug is required? • How is it administered? • How often is the treatment? • What is the duration of treatment? Annotation • Summarize completed & planned studies that support the safety and effectiveness of the proposed dosage and route of administration Comments • Summarize the positioning of the dosage and administration relative to current treatments
- 13. Adverse Reactions Target • What adverse effects might be anticipated based on results of nonclinical studies? • What adverse effects might be expected due to the drug class? • What adverse effects have been observed in clinical studies? • What adverse effects are acceptable based on product risk-benefit and positioning? Annotation • Summarize completed/planned studies that support the target (include references to reported class-related drug effects)
- 14. Adverse Reactions Comments • Identify AEs associated with current drug treatments that might be mitigated by your new drug candidate Considerations • Similar product monographs • Acceptable thresholds for incidence of AEs • Opportunities to demonstrate superior safety profile
- 15. Clinical Studies Target: Statements regarding efficacy & safety benefits • Clinical evidence to support the indication claims • Strength of evidence • The safety profile • Endpoints in the clinical studies to support the competitive positioning and marketing strategy for the new drug Annotation • Summarize completed/planned studies that will develop evidence in support of treatment Comments • Identify key areas of competitive advantage
- 16. Additional Considerations Nonclinical requirements Enrollment challenges Time to market Groundwork for subsequent indications Biomarkers Companion diagnostics
- 17. Common Pitfalls • Interdisciplinary input not sought • Late stakeholder buy-in • “Interest group”-driven targets • Lack regulatory intelligence • No prospective key decision points • Failure to revisit when new data obtained • Failure to use it as a tool for planning, development, communication
- 18. Example Starting Point: Novel antidepressant • Currently marketed AD’s are only effective in about 50% of patients because of problems with tolerability and/or lack of efficacy • Currently marketed AD’s have relatively few significant drug interactions • Currently marked AD’s are generally given once-daily • Currently marketed AD’s, when they do work, may require a few weeks for significant effect • The world doesn’t need another expensive variation of a currently marketed antidepressant What’s known
- 19. Example: Novel antidepressant • A once-daily antidepressant, with no significant drug interactions, and one or more of the following: • Rapid onset (placebo separation by the end of the first week) • Good tolerability, including no sexual dysfunction, weight gain, or sedation • Robust efficacy greater than that of currently marketed AD’s (and not less than) What’s needed
- 20. General Development Flowchart Diagram source: http://qb3.org/sites/qb3.org/files/QB3Podcast20120316_2_0.pdf
- 21. Integrated Product Development Plan (IPDP) A strategic plan covering all components of the drug development spectrum for a product
- 22. IPDP Transformation to Label Integrated Product Development Plan Target Product Profile Product Label (prescriber’s Information) Collect data, revisit, refine
- 23. IPDP Label Claim Nonclinical Clinical CMC Strategic & dynamic tool Unique & integrated Goals, activities, contingencies ‘Go/no go’ decision points Competitive landscape Target Markets
- 24. Begin with the End in Mind •Label claims •Efficacy •Safety Market Approval •Intended indication & population •Efficacy •Safety Phase III •Target indication & population •Proof of concept •First in humans Phase I-II •Preclinical & quality (CMC) data to support human exposure •GLP safety and toxicology testing •Stability of IP File IND/CTA “The End” Now expand on this to include all activities required to enable each other to occur…
- 25. Comprehensive & Evolving End Goal Plan Evaluate Go/No Go Decision Revise From TPP!!! New Data
- 26. A Full-Service CRO Production Chemistry Pharmaceutics Pharmacology and Pharmacokinetics Toxicology Regulatory Clinical Drug Selection 18+ Mo.18 Mo. 6 Mo. 18 Mo.12 Mo. 12 Mo.24 Mo. Phase I Phase II Phase III Data Analysis ISS/ISE/ERs Phase IV Safety in healthy volunteers Efficacy & safety small group patients Pivotal large group patients NDA Prepare Submit FDA Review NDA Approval Post-market Surveillance IND Prepare Submit Pilot Plant GMP Plant Stability, Validation Production Formulation, Dose & Administration Stability, Tech Transfer, Validation Healthy humans Human patients ADME (animal) Mutagenicity Acute Toxicity Sub-acute Toxicity Long-term Feeding Studies (chronic toxicity and carcinogenicity) Reproductive Toxicology 8 Years PRODUCT DEVELOPMENT Pop PK DISCOVERY 1O Pharm 2O Pharm 1 Year +
- 27. IPDP Basic Content Regulatory history and strategy Chemistry, manufacturing, & controls (CMC) plan Nonclinical (pre-clinical) development plan Clinical development plan Elements of the target label (target product profile) Introduction
- 28. Mapping TPP to IPDP for Novel Antidepressant TPP • Global market • Once daily oral dosing, rapid onset, chronic • Multiple dose strengths • Adults and elderly with major depression • Efficacy superior to placebo, similar/better versus gold standard IPDP • Phase 3 studies (US, non- US) • Phase 2 studies • Clinical pharmacology • Nonclinical studies • Chemistry, Manufacturing and Controls • Regulatory • Marketing
- 29. Mapping TPP to IPDP for Novel Antidepressant TPP • Global market • Once daily oral dosing, rapid onset, chronic • Multiple dose strengths • Adults and elderly with major depression • Efficacy superior to placebo, similar/better versus gold standard IPDP • Phase 3 studies (US, non- US) • Phase 2 studies • Clinical pharmacology • Nonclinical studies • Chemistry, Manufacturing and Controls • Regulatory • Marketing
- 30. Mapping TPP to IPDP for Novel Antidepressant TPP • Global market • Once daily oral dosing, rapid onset, chronic • Multiple dose strengths • Adults and elderly with major depression • Efficacy superior to placebo, similar/better versus gold standard IPDP • Phase 3 studies (US, non- US) • Phase 2 studies • Clinical pharmacology • Nonclinical studies • Chemistry, Manufacturing and Controls • Regulatory • Marketing
- 31. Mapping TPP to IPDP for Novel Antidepressant TPP • Global market • Once daily oral dosing, rapid onset, chronic • Multiple dose strengths • Adults and elderly with major depression • Efficacy superior to placebo, similar/better versus gold standard IPDP • Phase 3 studies (US, non- US) • Phase 2 studies • Clinical pharmacology • Nonclinical studies • Chemistry, Manufacturing and Controls • Regulatory • Marketing
- 32. TPP IPDP • Favorable side effect profile versus gold standard (sedation, weight gain, sexual dysfunction) • Minimal/no drug interactions • No cardiovascular safety issues • Phase 3 studies (US, non- US) • Phase 2 studies • Clinical pharmacology • Nonclinical studies • Chemistry, Manufacturing and Controls • Regulatory • Marketing Mapping TPP to IPDP for Novel Antidepressant
- 33. TPP IPDP • Favorable side effect profile versus gold standard (sedation, weight gain, sexual dysfunction) • Minimal/no drug interactions • No cardiovascular safety issues • Phase 3 studies (US, non- US) • Phase 2 studies • Clinical pharmacology • Nonclinical studies • Chemistry, Manufacturing and Controls • Regulatory • Marketing Mapping TPP to IPDP for Novel Antidepressant
- 34. Clinical Development Plan • Phase 3 – Focus on efficacy and safety – Pivotal or confirmatory if adequate, well-controlled and agreed with FDA – Target population & regimen for market – Generally at least 2 studies required – Major basis for marketing approval decisions and label • Phase 2 – Focus on efficacy and safety, proof-of-concept – Population - patients with target disease – Dose range finding, dose selection for phase 3 – Further define outcomes/endpoints, population • Phase 1 – Focus on safety, pharmacokinetics, pharmacodynamics – First in human, SAD, MAD – Drug interactions, Thorough QT, food effect, bioavailability
- 35. Nonclinical Development Plan • Comprehensive assessment of the pharmacology, pharmacokinetics, and toxicity of the drug substance and product • How are data used? – Dose selection for initial clinical trials – Pharmacodynamics, MOA, biomarker development – Therapeutic index – Specific safety monitoring, use in specific populations – Labeling • GLP requirement for some studies • Dose selection is critical for safety studies
- 36. Chemistry, Manufacturing, & Controls (CMC) Plan • Assure proper identification, quality, purity and strength • Manufacture active pharmaceutical ingredient (API) • Analytical assay development & validation • Pre-formulation/formulation development • Manufacture of Clinical trial material – Release testing – Packaging and labeling – Comparators (active or placebo) • Stability
- 37. Regulatory Strategy • Filing Pathway – 505(b)(1), 505(b)(2), 505(j), drug-device combination – What data are required for each pathway – Pertinent regulatory hurdles • Understand competition – Review labels, SBAs, EPARs, financial reports • Awareness of region specific regulations – ICH – FDA – EMA
- 38. Regulatory Strategy • Orphan Drug Designation • Qualify for acceleration mechanisms? – Breakthrough Therapy – Accelerated Approval – Priority Review Know your drug to take advantage of these programs!
- 39. Type B Development Meetings with FDA • Pre-IND Meeting • End of Phase 1 Meeting • End of Phase 2 Meeting • Pre-NDA Meeting
- 40. Initial Agency Interactions • Pre-IND – Obtain Agency buy-in on: • Clinical protocol • Nonclinical safety studies • CMC program • What is required: – IPDP in Briefing Document – Well-written questions • No open-ended questions When is the right time to schedule meeting???
- 41. Avoiding Delays (e.g., Clinical Hold) • Unfocused development plans are doomed to lead to delays • CDER receives approx. 1500 IND submissions per year • Lapteva and Pariser (Journal of Investigative Medicine, 2016) – In 2013, 9.0% were placed on clinical hold – Most commonly cited reasons • CMC • Clinical • Toxicology
- 42. Common Reasons for Clinical Hold • Poorly organized submission and/or insufficient information • Inadequate information to assess safety • Clinical study design too aggressive, lacks needed safety monitoring, dose limiting toxicity is not well defined and/or stopping rules inadequate, inadequate inclusion/exclusion criteria • Unqualified impurities, excipients in clinical batch or poorly defined impurity profile • Drug product not stable throughout the testing program • NOAEL not determined in toxicity study(ies)