In Drug Development, a Regulatory Strategy can be defined as a science-driven assessment of a product’s development options, key considerations, and likely regulatory outcome. It should span the earliest developmental stages through further modifications planned post-marketing.
This regulatory outcome, in turn, will have broader consideration because it will link to the potential for patient access, commercial acceptability and uptake and, therefore, likely business outcomes.
A regulatory strategy should combine regulatory requirements and business objectives. It often is defined by a global regulatory expert, who must consult with a cross-functional clinical, nonclinical, and technical team.
The cross-functional team should comprise experts who: provide evolving and regional regulatory requirements and regulatory intelligence on expectations, precedents, and competition; correspond with local regulatory authorities; enable document management and submission processes; and provide specific functional expertise such as labeling, nonclinical and clinical, as well as CMC.
The ultimate goal of the Regulatory Plan is to enable patient access, as one piece of the new Drug Application marketing application (NDA), and it is within this context that a CMC regulatory expert must provide a suitable CMC regulatory strategy.
It should encompass key CMC milestones and decision points; consider regulatory CMC objectives, hurdles, the regulatory landscape, and precedents; and characterize risks to potential success in delivering a specific regulatory outcome.
Drug Sponsors must provide comprehensive development plan input throughout the product’s lifecycle. This input starts in the preclinical development phase and continues through post-marketing.
A combination of internal regulatory know-how as well as outside consultants provide input on the likely acceptability of the planned evidence package that will be generated for the regulator and subsequent stakeholders, specific regulatory requirements for product development, post-marketing, regulatory submission management, regulatory intelligence, product labeling, and advertising and promotion.
There also are internal and external business considerations that can drive a specific CMC regulatory strategy’s development. Examples of considerations that influence strategy are the organization’s financial situation or the product’s intellectual property status. External examples include the drug sponsor’s business partner or investor community.
A CMC Drug Development program focuses on the drug substance and drug product’s formulation, process development, and presentation, process controls as well as the manufacturing facility. From a comprehensive perspective, the CMC development program must consider many aspects, including the development phase and regional requirements.
The CMC regulatory strategy should be integrated and linked with the overall regulatory strategy to ensure the suitably formulated product is available to meet a development stage’s requirement. The three key factors influencing the CMC development program are quality, time, and cost. All these factors are related, and the chosen pathway also will depend on the sponsor’s risk tolerance.
For example, an organization initially may choose to save time to get the first patient for a given clinical study. However, in the end, that decision may incur higher costs and additional time or even result in a target product profile that is less acceptable to patients (e.g., short storage conditions due to lack of stability data).
Initially, a non-GMP drug substance is acceptable for nonclinical studies, provided the impurity profile does not increase a toxicity risk that might not occur at later development stages when impurity limits are tighter. Frequently, only the drug substance is required for initial pharmacology and toxicology studies.
However, formulation effects must be evaluated, and the drug product may be required for nonclinical studies if the product required a complex formulation due to the drug substance’s physicochemical properties, e.g., low solubility, membrane permeability, stability, or interactions with formulation excipients.
As the product moves into clinical studies, the CMC regulatory strategy must take clinical trial product requirements into account in the countries where studies are planned. In most countries, full GMP compliance is required for all clinical study phases. However, some countries, allow the use of a non-GMP product for a first-in-human study in healthy volunteers.
The drug product presentation also must be consistent with the clinical development strategy to ensure the dosage form and dose unit meet protocol requirements. Early in development, it is recognized clinical studies may be conducted with a simple formulation, but later clinical studies should be conducted with the product planned for marketing.
If significant manufacturing or formulation changes are made late in development, bridging studies may be required to confirm the changes have not altered the product’s safety or efficacy profile.
Other clinical study CMC considerations include requirements for a placebo product identical in appearance to the active product for use in double-blind studies. Placebo development may be challenging if the active drug substance has characteristics difficult to emulate with an inactive substance, e.g., smell or taste.
Clinical trial supply availability is a key factor in study start-up times and should be coordinated with the clinical development team. Batch records may be required for study approval, but manufacture timing should ensure, as far as possible, sufficient stability data are available to avoid the need to change batches during the study.
As the product development program moves closer to marketing approval, it is important the CMC team understands the regulatory filing strategy, desired product profile for patients, and priority target countries to ensure regulatory dossier CMC sections meet both the format and content requirements for each country.
Marketing teams also may have a country- or region-specific requirements that must be accommodated to support commercial success, e.g., a pack size equivalent to one month’s supply is the maximum quantity permitted to be dispensed or reimbursed on each occasion.
International Council on Harmonization (ICH) guidelines assist and enable manufacturers to develop a core CMC dossier, but many individual country requirements exist for the non-CTD format, stability studies across temperature zones, labeling, and packaging.
In addition, specific product type guidelines developed by many jurisdictions may require additional or different product specifications.
ICH publishes structure and content guidelines for Modules 2–5. Module 2 Quality Overall Summary (QOS) contains summaries of the organization’s position on available data and summaries of quality (QOS), alongside safety (CSS) and efficacy (CSE).
Regulators require the sponsor to provide its assessment of the product’s overall benefit-risk balance in this section, including any outstanding uncertainty in either risk or benefit at the time of initial regulatory review.
Module 3 provides information related to how the product was developed, how it is manufactured, evidence of product stability under standard and stressed storage conditions, and data ensuring it can be manufactured reproducibly and analyzed to generate a reproducible product.
The Quality Overall Summary (QOS) is a good place to explain the things that are missing, likely not necessary, and why certain guidelines were not followed. In Modules 2 and 3, sponsors have latitude in how data are presented, and how important messages are formatted in the compilation of a CTD application.
Organizations need to know not only the written regulatory requirements; they also should have a good understanding of unwritten requirements and the personal preferences of any agency reviewers who may review their dossiers.
All regulatory agencies expect companies to be truthful, transparent, collaborative, science-based, and patient-focused in all interactions.
If possible, regulatory personnel should be encouraged or advised to interact with the regulators during new product development, although it is not possible or efficient to meet with all agencies.
These interactions can help the organization get to know the future agency review team, help that team become familiar with the product’s innovative aspects, and gain input on the proposed strategy.
For many drugs, the manufacturing development program has truly evolved, often such that substantial differences can exist between a drug substance or product early in development versus that which is proposed for marketing. Part of the difficulty in constructing a cohesive and coherent Module 3 is the common situation where the generation of CMC data comes from a variety of sources.
Although sometimes all CMC development is undertaken in-house, it is more common that the module must rely on the data contributions of both in-house and outside parties. As drug development accelerates, the pressure to generate batches of drug substances and drug products for nonclinical and clinical trials increases greatly.
GMP standards are high, including documentation requirements for the analytical and stability programs supporting manufacturing.
At the same time, technical experts in manufacturing are investigating more efficient process schemes and, frequently, look to alternate contractors to shave costs and prevent being boxed into a single-sourced strategy, if possible.
All of these changes require documentation and evidence of control, if possible, beginning at the initiation of the project and planned proactively as far out in time as possible. For purposes of putting together Module 3, it is particularly important to get it right from the start.
It is extraordinarily difficult to have to go back in time to some primary source and try to reconstruct after the fact, particularly if the people responsible are no longer available or if other links are missing.
The challenge inherent in describing manufacturing development data and changes is to convince FDA reviewers that it is appropriate to consider and to integrate nonclinical and clinical data obtained at various points during development, having studied drugs that might have been considerably different at these points.
When the history of changes has led to improved purity and tightening of release specifications the story is easy to tell; if this is not the case, considerable creativity may be necessary. Pharmaceutical development reports include drug substance (active ingredient), drug product, and analytical reports and need to tell the story of the evolution of these three development aspects throughout a product’s development. If development reports are poorly prepared or unconvincing, the result can easily be an almost endless cycle of agency queries and sponsor responses, prolonging the review cycle and delaying approval times.