Regulatory strategies in the field of drug development can be understood as science-driven assessments of a product’s specific development options, key considerations and anticipated regulatory outcomes. A robust regulatory strategy should encompass the whole product lifecycle from initial development through to modifications planned post-marketing.
A product’s regulatory outcome will have a wider impact because it will ultimately link to its potential for patient access, its commercial acceptability and uptake, and any potential business outcomes.
Image Credit: DSI, a PLG Company
A comprehensive regulatory strategy should include a combination of regulatory requirements and business objectives. It will typically be defined by a global regulatory expert, who will seek input from a diverse cross-functional clinical, nonclinical and technical team.
This cross-functional team is an essential part of the regulatory process and should be comprised of experts who are able to:
- Provide information on regional regulatory requirements and up-to-date regulatory intelligence on expectations, precedents, and potential competition
- Liaise with local regulatory authorities
- Facilitate appropriate document management and submission processes
- Provide specific functional expertise around issues such as labeling, nonclinical and clinical trials and CMC
Understanding the CMC component of regulatory strategy
The overall aim of any regulatory strategy is to allow patient access to vital drugs. It is just one element of the new Drug Application marketing application (NDA), and it is within this specific context that a CMC regulatory expert is required to deliver a suitable CMC regulatory strategy.
The strategy must include key CMC milestones and decision points as well as considering regulatory CMC objectives, hurdles, the current regulatory landscape and any relevant precedents. It must also explore and outline any risks to potential success in delivering a specific regulatory outcome.
Drug sponsors should have significant input into the development plan throughout the product’s lifecycle – from the preclinical development phase through to post-marketing activities.
A company’s internal regulatory knowledge is combined with expertise via outside consultants to provide feedback on the likely acceptability of the planned evidence package. This evidence package is compiled for the regulator and subsequent stakeholders and will include information on specific regulatory requirements for product development, product labeling, regulatory submission management, regulatory intelligence, advertising and promotion and post-marketing.
Internal and external business considerations will also feed into a specific CMC regulatory strategy’s development. For example, internal examples may include the product’s intellectual property status or the organization’s financial situation, while external examples may include the drug sponsor’s investor community or business partners.
Establishing the product development strategy
A CMC Drug Development program will be primarily focused on factors such as the drug substance and drug product’s formulation and its process development considerations. It will also consider presentation, process controls and the specifics of manufacturing facility.
In order to be comprehensive, the CMC development program must consider a number of aspects, including the development phase and any specific regional requirements.
The CMC regulatory strategy should ideally be linked and integrated with the wider regulatory strategy to ensure an appropriately formulated product is available that meets the requirements of the development stage.
The three core factors impacting the CMC development program are time, quality and cost. These factors are all related to one another, and the chosen pathway will also be dependent on the risk tolerance of the sponsor.
For example, an organization may initially opt to save time to get the first patient for a given clinical study. This decision may ultimately incur higher costs and additional time, but could potentially result in a target product profile that is less satisfactory to patients; for example, a product may have short storage conditions because of a lack of stability data.
A non-GMP drug substance will be acceptable for nonclinical studies so long as the impurity profile does not lead to a potential toxicity risk in later development stages where limits around impurity are stricter. It is generally the case that only the drug substance is necessary for initial toxicology and pharmacology studies.
It is necessary to evaluate formulation effects. However, nonclinical studies may be required should the product need a complex formulation due to the drug substance’s physicochemical properties, for example, low membrane permeability, solubility, stability, or interactions with formulation excipients.
Recognizing clinical trial product requirements
As the product begins to move into clinical studies, the CMC regulatory strategy must account for clinical trial product requirements in countries where studies are planned. In the majority of countries, comprehensive GMP compliance is required for every clinical study phase. Some countries do permit the use of a non-GMP product for a first-in-human study with healthy volunteers.
Drug product presentation should also be consistent with the clinical development strategy to ensure the dosage dose and form unit meet protocol requirements.
It is typically accepted that early in development, clinical studies may be conducted with a simple formulation, but later clinical studies must be conducted with the actual product planned for marketing.
Should substantial manufacturing or formulation changes be made in the late stages of development, bridging studies may be necessary in order to verify that the changes have not changed the product’s efficacy or safety profile in any way.
A number of other clinical study CMC considerations exist, including requirements around the use of a placebo product identical in appearance to the active product in double-blind studies. Should the active drug substance possess characteristics which are difficult to emulate with an inactive substance (for example, smell or taste), placebo development may be difficult.
The availability of clinical trial supply is a central factor in study start-up times and must be organized in partnership with the clinical development team. While batch records may be necessary for study approval, manufacture timing should strive to ensure that enough stability data is available to avoid any requirement to change batches throughout the study.
Devising the CMC regulatory filing strategy
As a product development program begins to approach marketing approval, it is vital that the CMC team is fully aware of the regulatory filing strategy, desired product profile for patients and priority target countries. These factors are important in ensuring that regulatory dossier CMC sections adhere to the specific format and content requirements for each individual country.
Marketing teams may also be required to accommodate country- or region-specific requirements in order to promote commercial success; for example, in many regions a pack size equivalent to one month’s supply is the maximum quantity permitted to be dispensed or reimbursed on each occasion.
Guidelines from the International Council on Harmonization (ICH) support manufacturers in developing a core CMC dossier, but many countries have specific requirements for the non-CTD format, labeling, packaging and stability studies across temperature zones.
Specific product type guidelines in place in a number of jurisdictions require different or additional product specifications.
Building the regulatory modules
ICH provides structure and content guidelines for Modules 2–5. Module 2 - Quality Overall Summary (QOS) includes summaries of the organization’s position on available data. It also includes summaries of quality (QOS), safety (CSS) and efficacy (CSE).
In this section, regulators will ask the sponsor to provide its own assessment of the product’s overall benefit-risk balance, alongside any unaddressed uncertainties in terms of either risk or benefit from the initial regulatory review.
Module 3 includes information on the product’s development and manufacturing processes and evidence of product stability under storage conditions (standard and stressed). Data is also required to confirm that the product can be manufactured reproducibly and analyzed to generate a reproducible product.
The Quality Overall Summary (QOS) is also a good place to note things that may be absent or potentially not necessary or the reasons why certain guidelines were not followed.
In Modules 2 and 3, sponsors have a degree of autonomy in terms of how data is presented and how key messages are formatted during the compilation of a CTD application.
Knowing the regulatory authority
Organizations must be aware of written regulatory requirements, but it is also important to have a good understanding of any unwritten requirements, such as the personal preferences of agency reviewers reviewing their dossiers.
Regulatory agencies expect companies to be honest, transparent, collaborative, science-based and patient-focused in every interaction.
It is advisable for regulatory personnel to interact with regulators during new product development, although it may not be possible or practical to meet with all relevant agencies.
These interactions can assist an organization in developing relationships with an agency review team, helping that team become more familiar with the product’s innovative aspects while gaining input on any proposed strategies.
The manufacturing development program has evolved for many drugs, so much so that notable differences may exist between a drug substance or product in the early stages of development versus that which is proposed for marketing.
One common challenge in the construction of a cohesive and coherent Module 3 is the issue of generated CMC data coming from a variety of sources.
In some circumstances, all CMC development is undertaken in-house, but it is commonplace that the module relies on a mix of data contributions from in-house and external parties.
As drug development accelerates, there is an increased pressure to generate batches of drug substances and drug products for nonclinical and clinical trials. GMP standards remain strict and documentation on the analytical and stability programs supporting manufacturing must be robust and comprehensive.
Technical experts in manufacturing will continue to explore more efficient process schemes, often prompting them to look to alternate contractors to reduce costs and avoid being constrained within a single-sourced strategy.
All of these process changes necessitate the maintenance of detailed documentation and evidence of control. This should ideally commence at the initiation of the project and be proactively planned as far ahead as possible.
When compiling Module 3, it is especially important to get it right from the beginning. It is extremely difficult to go back in time to a primary source and try to reconstruct data after the fact. This is even more difficult if the people responsible are no longer available, or other links are missing.
The challenge in the description of manufacturing development data and changes is persuading FDA reviewers that it is appropriate to consider and integrate nonclinical and clinical data obtained at different points during development, having studied drugs that may have been notably different at these points.
It is important to tell a story - a much easier task when the history of changes has led to improved purity and tightening of release specifications, for example.
Where this is not the case, a degree of creativity may be necessary. Pharmaceutical development reports must incorporate drug substance (active ingredient), drug product and analytical reports. These reports need to detail the story of the evolution of these three development aspects as a product has continued to develop.
Should these development reports be unconvincing or poorly prepared, this may lead to an ongoing cycle of agency queries and sponsor responses, extending the review cycle and delaying approval times.
Acknowledgments
Produced from materials originally authored by Ed Narke at Design Space InPharmatics.
About DS InPharmatics 
DS InPharmatics (DSI) provides regulatory, technical, and project management consulting services to healthcare product companies that manufacture and/or market pharmaceuticals, biopharmaceuticals, and cellular and gene therapy products.
Since 2007 we have provided our clients with innovative strategies and exceptional quality work products intended to enhance product development, approval, and marketing presence. Whether advocating CMC strategy, directing CMC operations or developing CMC submission content that represent the best interests of emerging biotech, we focus on the critical CMC issues and build programs that enhance development.
In April 2021 we were thrilled to announce that DSI has just become part of ProductLife Group.
French-headquartered ProductLife Group (PLG) is well-known in the Life Sciences market. It has a track record of successfully managing global outsourcing programs and insourcing services for its international client base. The company is on a mission to help transform human health outcomes by optimizing regulatory affairs, safety & vigilance, and quality compliance for life sciences organizations worldwide.
The fit between our two organizations could not be more perfect. We will complement PLG's growing biotech services portfolio. US biotech sponsors recognize DSI as a leader in consulting for go-to-market strategies and RA pre-market consulting. At the same time, PLG has a strong reputation for managing end-to-end outsourcing of regulatory affairs and pharmacovigilance activities worldwide.
Our merger with PLG will harness our combined strengths, offering our clients on both sides of the Atlantic support with their developed drugs approvals and post-approvals compliance, plus advisory services on the best market strategies to deliver a rapid ROI on their development. Together we will offer our clients increased pharmacovigilance capabilities - including a QPPV; pharmacovigilance consulting; and a fully validated safety database - as well as complementary toxicology-related services; RIM/electronic document management services; and support for medical device regulatory requirements.
We see enormous potential in this new chapter for DSI and you, our clients. As a PLG company, we have the opportunity to become part of a global force in life sciences regulatory and compliance solutions and services, and we're incredibly excited to add our momentum to that effort.
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