Drug development can be described as the process of obtaining the relevant information necessary to be included in your drug prescribing information. Development Plan (DP) is the strategic document that guides the lifecycle of a new product from the pre-clinical lead compound stage through Lifecycle Management (LCM). LCM starts with the first approval of BLA/NDA (first Marketing Authorization) and encompasses development of new indications. In mature pharma organization, DP is approved by the governance bodies. Once approved, it can be regarded as the agreement between executive leadership/board of directors and the program team involved in the discovery, development & commercialization of the product. The DP is a living document and should be amended when the development strategy changes.
Before diving into the recommended DP chapters, it is essential to understand the drug development process complexities. The 2016 analysis by the Tufts Center for the Study of Drug Development of the average cost to develop and gain marketing approval for a new drug—is $2.87 billion. Drug development is not only costly; it is a lengthy, laborious and usually, sequential process. The latter may change in some extent for the USA, pending the appointment of new FDA commissioner. Future changes in regulations may potentially revolutionize and accelerate the drug development process and lower the drug prices. However, as of today, one can safely rely on the typical stages described below.
- Discovery Phase can take 2-10 years. Compounds are created either in pharma discovery labs or collaborating universities and biotech labs. The major goal of discovery teams is lead compound. Lead compound is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful (change the course of the targeted disease), but may still have a suboptimal structure that requires modification to fit better to the target.
- Non-Clinical & Pre-Clinical Development can last 2-6 years. Studies are performed in vivo and in animal models to establish drug candidate safety before the drug is given to humans in clinical studies. The goal of both preclinical and nonclinical research is to support the clinical trials that lead to product approval. While the strategic plan should include the “must have” studies in this area, it also wise to consider the “good to have” studies as part of product differentiation strategy.
- Clinical Development is the process where drug candidates are tested on humans in phase I, II and phase III clinical studies. In the USA, clinical development starts with the submission of IND. Once the one IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.
- Phase I typically takes 1-2 years; it is 1st in a human test with 12 to 40 subjects or healthy volunteers. The primary purpose is to establish profile & dosing regimens, assess safety & tolerability.
- Phase II can take 2-3 years, requires 20 to 400 subjects with the target disease. The goal is to establish proof-of-concept, test safety and preliminary efficacy in disease-affected patients.
- Phase III duration is 3-4 years; study recruitment is anywhere from 300 to 1,500 subjects with the target disease. Phase III is conducted to prove safety & efficacy and establish long-term safety of the tested compound.
A clinical development strategy should include detailed plans for study designs, identification of investigators, statistical analyses, and timelines with contingency planning and risk management. Also, one should consider adding risk management plan (RMP). In the USA, Risk Evaluation and Mitigation Strategy (REMS) is developed to help ensure that the benefits of a medicine outweigh its risks. REMS may be required by the FDA as part of the approval process for a new product, or for an approved product when new safety information emerges. An applicant may also voluntarily submit a REMS. REMS is a strategy to manage a known or potential serious risk associated with medicine. Its purpose is to allow patients continued access to certain drugs for which there are safety concerns that may be managed through appropriate use.
- After the sponsor of a new drug determines that enough evidence on the drug’s safety and effectiveness has been obtained to meet FDA’s requirements for marketing approval, it proceeds with NDA/BLA submission. NDA/BLA median standard approval time of 12 months and 8 months for priority review (2015).
- Drug development activities that come after first NDA/BLA approval are considered part of product Life Cycle Management (LCM).
When the discovery and development teams consider writing a DP, they should answer several of essential questions that will form a backbone of the well-integrated DP:
- What is the end business goal: getting your drug to market or licensing your compound?
- What are the desired product attributes: indication/usage & dosage, administration & pharmacology, adverse reactions & toxicology, clinical data?
- Where will the drug be marketed, in what countries?
After those key questions are answered, the teams have to prepare detailed strategic and operational plans for regulatory, manufacturing & quality, preclinical & nonclinical development, clinical development, intellectual property, market access & pricing, and marketing.
What are core sections of the Development Plan and what should they include?
General Product Strategy
General Strategy chapter defines what drives the product value and why the company should develop the product. Provides medical and scientific arguments which will translate potentially to commercial success. Define what are the unique characteristics of the drug candidate (examples: novel MoA, superiority to existing therapies, unmet medical needs). Evaluate medical value and sales potential and define key target markets. In most cases, it is recommended to plan the global development program to meet the most stringent criteria among all intended markets. It is important to keep in mind that planning on a first product launch in the USA, followed by launches in the unspecified “rest of markets,” is not recommended. Missing clear upfront list of countries and launch sequence plan can lead to expensive and frustrating drug development process at the end. The sponsor may be facing unplanned changes to the manufacturing quality controls, be requested to ran additional country/region specific clinical studies, etc.
Product Strategy for Selected Indication(s)
The presently desired attribute of the candidate drug in Target Product Profile. Include the summary of the Target Product Profile (TPP) and an assessment of the probability of achieving the TPP based on the collected data. Summarize translational medicine strategy. Describe targeted commercial formulation, dose, and route of administration. Provide commercial and medical rationale for each option. Consider development of companion diagnostic or other solutions (medical devices such as injector device etc.) Plan for Asian development or/and pediatric population strategies. Consider additional lifecycle management options such as other indications, differentiation vs. competitors, etc.
Development Timeline & Project Management Resource Plan
Provide program summary timeline with functional activities to milestones and critical events. Include the timing of reaching preclinical & clinical proof of concept (POC), submissions, approvals and launches in the major markets. Include stage-gate decision timelines you’re your company governance framework. Provide project resourcing plan for each indication (FTEs and budgets).
Product Commercial Value & Competitive Environment
Provide expected return-on-investment for the product, probability of success, cumulative worldwide sales forecast per year per indication, eNPV calculations.
Intellectual Property and Exclusivity Strategies
Summarize the strategy for protecting the intellectual property, including patents, regulatory exclusivity, orphan drug status and any issues for selected markets.
Product Market Access, Pricing and Evidence Generation Strategy
The section should describe core value messages that will be shared with payers and if there is a suspected superiority of the investigational treatment over a standard of care and existing alternative therapies. Analyze what evidence needs to be developed to justify the core value messages for HTA. Summarize marketing strategy plan.
- Evidence Generation Strategy
Include gathering of evidence and development of appropriate models to present the relevant clinical and economic evidence to Health Technology Assessment (HTA) agencies. Explain the intends to demonstrate the relative effectiveness needed to inform coverage and payment decisions in all targeted key markets. Include plans for seeking early advice from national HTA bodies and how any feedback has been or will be incorporated.
- Pricing Strategy
Identify possible pricing and reimbursement issues across the key target markets and mitigation plans. Include which pricing strategy to pursue and the reference points, specifying prices currently known and how these may evolve over time. Include the summary of the launch profile.
- Key Activities
Summarize the key events planned for market access, HTA, pricing, and reimbursement.
Overall Regulatory Development Strategy
The product regulatory strategy document with relevant timeline serves as a tracking tool for overall program status and can help identify risks to the program (e.g., cost overruns, delays, and competitor activities). This section should include the summary of proposed filing strategy and health authority interactions, including analysis of the regulatory risks and potential mitigations.
Regulatory strategy at indication level should contain:
- Overview of proposed filing strategy and health authority interactions
- Proposed filing strategy for the indication with opportunities for accelerated or conditional approval, priority/accelerated reviews, plans for relevant regulatory filings for medical device (e.g., companion diagnostic)
- Post-approval commitments: Include strategies for meeting requirements for US-REMS and EU-RMPs, PSURs, renewals, annual re-assessment, etc.
Clinical Pharmacology Strategy
Summarize the clinical pharmacology approach to support the overall development of the drug product across indications. List the main issues and considerations and how these will be addressed. Include indication specific clinical pharmacology studies and PK/PD Modeling & Simulation strategy.
Overview the key issues or non-standard considerations required for this candidate drug.
- Preclinical Pharmacology
Describe the strategy to establish the preclinical Proof of Concept with relevant biomarker strategy included.
- Pharmacokinetics & Drug Metabolism
Outline plans for bio-analytical methods and critical implications from Drug Metabolism and Pharmacokinetics data.
- Non-Clinical Safety
Summarize the non-clinical safety aspects relevant to the program and appropriate regulatory path plus safety biomarker strategy.
Summarize the objectives, biomarker, endpoints of clinical studies until launch to deliver clinical proof of concept for the project. List key operational issues (recruitment, biomarker, operational issues). Include a summary of the data pooling (including key biostatistics, modeling & simulation components) planned for studies in a particular indication and how it supports data pooling strategy across indications.
Summary Benefit / Risk Assessment
Include a summary of the current benefit/risk assessment in a particular indication. Specify the risk mitigations plans.
The manufacturing and quality aspects of strategic drug development include all activities related to the production of the final dosage form, including sourcing the active pharmaceutical ingredient (API), creating a viable formulation, assessing and maintaining quality, packaging, and shipping. A failure to integrate all of the disciplines in drug development from the beginning can cause the manufacturing/quality group make wrong decisions with costly implications.
Describe CMC development strategy to support clinical testing quality TPP and supply to meet the clinical and commercial forecast. Provide the summary of the tactics how to avoid putting manufacturing activities on the critical path. List required interactions with regulatory authorities specific to CMC topic and inputs needed for various functions. Identify significant risks associated with the development and manufacturing and summarize the mitigation plan.
Critical Risks and Contingency Planning
List the top known, internal and external risks up to post-launch with accompanying contingency plans.
Communication is developed at product level first. When the program matures, communication strategy should also be created for specific indications. There are two types of the communication strategies that have to be defined:
- Medical publications & communication
- Commercial communication
Summarize medical publications & communication strategy across all clinical studies for the indication and across activities within a program. Do same for a commercial strategy for pre-launch and post-launch. Define the strategic and tactical goals to be achieved by the relevant communication groups, which target audiences are to be reached and what communication channels and formats will be used, etc.
- CDER Approval Times for Priority and Standard NDAs and BLAs Calendar Years 1993 – 2015
- 5 Key Areas for Strategic Drug Development Planning
- 3 Foundational Questions for a Comprehensive Drug Development Strategy
- FDA Types of Applications
- Tufts CSDD Assessment of Cost to Develop and Win Marketing Approval for a New Drug Now Published
- Peter Thiel vs. the FDA
- Diving into Best Practices for Pooling Clinical Trial Data