10 Critical Components Of A Successful Global Drug Development Plan
By Albert Yehaskel, President and CEO, Refuah Global Pharmaceutical Development
We use plans every day to help us arrive at our desired destinations. Pilots utilize flight plans prior to take off — although they have flown to their destination perhaps hundreds of times before, they nevertheless reviews and follows a flight plan. Likewise, ship’s captains also file plans and chart courses. Road maps provide guidance on how to drive from point A to point B, though today most people rely on electronic global positioning systems (GPS) to assist with navigation.
In the pharmaceutical world, the global development plan (GDP) is a company’s GPS to successfully navigate the various disciplines that ultimately culminate in a desired regulatory submission. The GDP is a pharmaceutical roadmap that provides clear direction to your program’s destination. It’s a cogent plan that identifies critical paths and issues, it’s a carefully thought-out plan that identifies and mitigates risk, and it’s a lucid plan that can potentially reduce the overall time to a new drug approval (NDA) filing. A drug development program without a GDP is like a ship without a rudder.
A global development plan is for internal use only and should not be shared with FDA (only in the broadest terms) or other regulatory body. It is also a living document that needs to be updated as soon as new information is available. In this article, we will review the 10 critical components of a drug GDP:
- Summary of the development strategy
- Target product profile
- Market assessment
- Nonclinical overview
- Clinical development strategy
- Regulatory strategy
- Intellectual property (IP)
- Manufacturing strategy
- Lifecycle management plan
- Back-up and follow-up compounds
To make the GDP a successful document, input is required from functional units on each of the above areas, along with a timeline from each discipline that identifies risks in its particular area(s).
1. Summary of the Development Strategy
You can start a GDP at almost any point during the development program, but ideally it is begun very early in the drug development process — but looks all the way ahead to your final goal.
The early development portion of the development strategy identifies the disease state and discusses the methods used to identify the potential molecules/compounds that have been reviewed and researched. It provides background information on each of these molecules and indicates the active site(s) on the molecule that will target the disease. It also answers the question as to whether a lead compound has been identified.
Early stage development in the GDP considers the following:
- Supply, manufacturing, and scale-up activities of the active pharmaceutical ingredient (API)
- Assessment of IP to avoid any patent infringement issues
- Stability
- Impurities and degradation products
- Specifications
- Supply, manufacturing, and scale-up activities of the drug product
- Analytical methods
- Quality control methods for API and drug product
- Quality parameters
- Reference standards
- Metabolism and metabolite determination
During the lead optimization stage, the compounds from initial screening are identified. The objective of this final drug discovery phase is to maintain favorable properties in lead compounds while improving on deficiencies in the lead structure. The plan should identify potential targets (i.e., those the molecule acts upon), discuss the relevance of the disease, and indicate whether the compound can alter the course of the disease. The plan should also focus on target validation (does the drug/molecule act on the target?) and discuss the validation techniques that will be used.
We now arrive at the preformulation stage, or formulation development, for your lead compound.
Exploring the following preformulation properties in your GDP will lead to a formulation that is suitable for clinical trial:
- Dissolution properties and solubility
- Stability to light exposure, acid, base, and oxidants
- Compressibility
- Friability (how readily the substance crumbles)
- Wettability
- Hygroscopicity
- Compatibility with various excipients
- Proposed route of administration
- Large-scale manufacture
The specifics of these studies depend on the projected route of administration and the physicochemical properties of the API.
It is important to consider back-up molecules in the event your lead compound does not make it. The GDP should clearly discuss this.
2. Target Product Profile (TPP)
The next key item in your global development plan should be a profile of the proposed product, better known as the target product profile (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) meetings to investigational new drug (IND) applications through to post-marketing programs — e.g., to pursue new indications or other substantial changes in labeling.
The TPP should be organized according to key sections in the drug’s labeling:
- Indications and usage
- Dosage and administration
- Dosage forms and strengths
- Contraindications
- Warnings and precautions
- Adverse reactions
- Drug interactions
- Use in specific populations
- Drug abuse and dependence
- Overdosage
- Description
- Clinical pharmacology
- Nonclinical toxicology
- Clinical studies
- References
- How supplied / storage and handling
- Patient counseling information
3. Market Assessment
The next section of the GDP is a marketing overview. It is incumbent upon the marketing department to discuss and provide a market assessment overview, which summarizes the vision and marketing strategy, disease demographics for each expected indication, marketing dynamics and expected market tendency, competitive analysis, unmet needs, commercial potential, expected net present value (NPV), publication strategy overview (domestic and global), and marketing risks and issues (e.g., positioning in the market, launch timing, and expiry date of patents).
4. Nonclinical Overview
The nonclinical (or preclinical) overview discusses the nonclinical studies that will be planned, their timelines and development costs, and associated risks and issues. Delineate the suite of studies that will need to be conducted to open an investigational new drug (IND) application — i.e., IND-enabling studies — and subsequent studies to support the clinical program and ultimately the NDA.
5. Clinical Development Strategy
Sufficient time and detail should be spent on the clinical program, identifying the Phase 1 through Phase 3 studies that will be conducted, end points, and patient population. This section should present a high-level executive summary of the proposed clinical program. Emphasis is on achieving the next developmental milestone and ultimately demonstrating safety, tolerability, and efficacy. Key areas for discussion in the GDP should include an approach to dose selection, regional information on development, clinical development timelines, and development costs. As the GDP is being developed over time, the appropriate clinical protocols with respective investigator brochures should be discussed.
6. Regulatory Strategy
The regulatory strategy section of the GDP will need to provide a flow chart of key dates for all disciplines that captures the important nonclinical studies (and reports), anticipated regulatory meetings with FDA, planned regulatory submissions, drug substance and drug product campaign manufacturing dates, and commitments relating to go/no-go decisions
Key areas of discussion include chemistry, manufacturing, and controls (CMC); CMC issues common across regions; CMC region-specific issues; global regulatory requirements, laws, and/or guidelines/guidance; significant regional regulatory differences; and regulatory issues common across major regions. Discussions of global filing activities and strategies by clinical phase provide food for thought on issues and strategies with potential impact on approvability.
The package insert is also discussed in this section and should provide a high-level outline of the anticipated label based on the target product profile that was discussed earlier.
Another facet of regulatory strategy is risk management strategy. At this juncture, risks of intended and anticipated use and ways to minimize risk are addressed.
7. Intellectual Property (IP)
The next major item for discussion in the GDP is intellectual property. This topic will address the company’s proprietary position by indicating the IP case number, subject matter, filing date, priority date(s), patentee(s), major filing countries, and other filing countries.
8. Manufacturing Strategy
We now come to a discussion of manufacturing strategy. The following topics should be discussed in as much detail as possible: overview of CMC strategies, clinical trial material manufacturing flow, commercial production flow, clinical-to-commercial transition, cost of goods (COGS) estimate, resource allocation plan, manufacturing timeline, and manufacturing contract cost.
9. Lifecycle Management Plan
An examination of the company’s life cycle management plan is also analyzed. These plans may comprise one or more of the following topics:
- New indications
- New patient populations
- New formulations
- New packaging
- Regulatory requirements and safety commitments
- Over-the-counter (OTC) switches
- Publication planning
- Scientific symposia
- Launch preparations
10. Back-up and Follow-up Compounds
Finally, a back-up plan for alternate compounds or in-licensing of a compound within the therapeutic realm should be discussed, along with how these will fit in the program in the event your lead compound does not make at any stage of your development.
Conclusion
Building a GDP is not an easy task, but once it has been completed — and maintained throughout the lifetime of your new product — it will bear fruit in the form of on-time submissions, eliminating or dealing with risk early on, and establishing a cash flow once the product has been approved. Ensure that you have someone who is capable and will take ownership of the GDP, to ensure that all the different disciplines, at the appropriate time (when new data/information becomes available), will be able to feed into the GDP.
About The Author
Albert Yehaskel is president and CEO of the consulting firm Refuah Global Pharmaceutical Development. He has been in the pharmaceutical industry for over 40 years, working for companies including Schering-Plough, Lederle Laboratories (part of American Cyanamid, now known as Wyeth), Block Drug, Sanofi, Purdue Pharma, Daiichi-Sankyo, Shionogi USA, and Indigo Pharmaceuticals. Over 25 years of his career has been devoted to regulatory affairs, managing and directing domestic and international regulatory submissions, orchestrating key FDA meetings, and conducting pharmaceutical research and development. He has two master’s degrees — an MBA in economics and finance from Fairleigh Dickinson University and an M.S. in organic chemistry from Queens College, City University of New York — as well as a B.S. in chemistry from the Polytechnic Institute of Brooklyn.