Navigating the complex regulatory landscape poses significant challenges for pharmaceutical companies preparing regulatory submissions for Investigational New Drug (IND) applications, New Drug Applications (NDA), and Biologics License Applications (BLA). In this Q&A, three experts from Cardinal Health Regulatory Sciences — Brenda Schlenk, RPh, Rebecca Wharton, Ph.D., and Mamadou Diallo, PharmD — discuss the critical steps and considerations for building a regulatory roadmap, emphasizing the importance of early and strategic engagement with regulatory bodies, particularly small to midsize companies making their first venture into the complexity of regulatory submissions. In conversation with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D., they highlight the pivotal aspects of regulatory strategy development, from the initial IND through to the final stages of NDA and BLA submissions, including the significance of a target product profile, the impact of regulatory intelligence, and the necessity of clear communication and consistent messaging across all application modules, underscoring the objective to optimize the path to market while ensuring compliance and patient safety.
David Alvaro (DA): To begin, so our audience can understand more about your team, can you describe the scope and the key objectives of Cardinal Health Regulatory Sciences and the kinds of clients you work with?
Rebecca Wharton (RW): Our primary objective is to become a trusted partner and an invaluable extension of our clients’ drug development teams. We offer support as needed to help expedite development and help our clients successfully reach their drug development goals by preparing the best possible regulatory path for their product at every stage of its life cycle.
At Cardinal Health Regulatory Sciences, we have over 150 scientists on staff with diverse expertise, educational backgrounds, and experiences to provide the resources and insights in all regulatory areas. We offer expertise and services for CMC (chemistry, manufacturing, and controls), nonclinical, and clinical, regulatory strategy, medical writing, program management, document formatting and processing, and publishing and submitting eCTD (electronic common technical document) applications to regulatory authorities. We can support drug development from the bench: preparing drug development plans, performing gap analysis, supporting FDA (U.S. Food and Drug Administration) meetings, and preparing designation requests, investigational new drug applications and maintenance, and marketing application submissions, as well as managing the post-marketing requirements after approval. We can come alongside the client at any time in this development timeline.
Additionally, we offer general consulting services to resolve complex problems. If a company needs a sounding board or a second opinion, we are always available for one-off general consulting questions.
We serve over 300 clients, a very diverse mix. I think the companies that stand to benefit the most from a relationship with us are small to midsized startup companies that lack the necessary internal resources. Maybe they have an expert in one field, but they don’t have an expert in CMC. We are very well positioned to serve that type of client. We also support many foreign companies that want to develop their products in the United States but are unfamiliar with the regulatory requirements and need a US agent to support their applications.
Mamadou Diallo (MD): We also have a lot of expertise in the nuances among the different global regulatory agencies, so we can help sponsors develop global regulatory strategies, designed around regional differences or national regulations, submission requirements, and approval procedures. This approach streamlines the regulatory submission process and helps reduce the time needed to bring a product to the market or maintain the life cycle of the product. Centralizing regulatory strategies needs with a company like Cardinal Health Regulatory Sciences can minimize a sponsor’s efforts for a successful submission, saving them a lot of money and helping them stay compliant with constantly changing regulations in the process. We have the capacity and flexibility to quickly regroup and act on unforeseen situations when there is a need.
DA: What are the first steps that you recommend that clients take when building a regulatory roadmap for the first time?
RW: The first step is typically to prepare a target product profile, a document that evolves throughout development but helps to guide and focus the sponsor. This target product profile allows them to identify their patient population, indication, route of administration, dosing regimen, duration of treatment, and formulation, all of which are used to build the regulatory roadmap. This profile eventually becomes the commercial product labeling, and it guides decisions on the nonclinical and clinical studies to be conducted to gain critical answers to questions at the earliest stages of development while also supporting labeling requirements.
Once the sponsor identifies an indication or patient population, the second step is to add specifics to the roadmap by answering a few key questions. Is this a rare disease? Is it serious or life-threatening? Does the product fulfill an unmet medical need? Is it an anti-infective? Depending on the answers, we might recommend a special or expedited program that could utilize an accelerated development pathway.
Third, it’s always good practice to research the FDA website to identify the guidances that are available to support your program. It’s also helpful to gather regulatory intelligence, like reviewing the labeling of FDA-approved products that have similar indications, to anticipate what FDA may expect the sponsor to complete as part of regulatory development.
I cannot stress the fourth step enough — to frequently meet with FDA to discuss the development plan and the roadmap. If you are submitting an application, discuss its contents. Those milestone meetings at various stages in development can be critical: the pre-IND (Investigational New Drug application) meeting, the end of phase II meeting, and the pre-NDA (New Drug Application) or pre-BLA (Biologics License Application) meeting.
A drug development company should tackle those four steps upfront to develop a roadmap and position themselves for success in submitting these large applications to the FDA.
MD: Maintaining communication between the sponsor and the FDA at every stage of drug development may ultimately facilitate early patient access to safe and effective drugs. From my experience, a well-written CMC section is a key success factor that helps to ensure a smooth regulatory approval process and to prevent delays or rejection because the objective of this section is to assure the quality of the finished product during all phases of development.
DA: Particularly for young companies that are preparing for their first submissions, are there a few unique considerations or tips that you could share for each of these applications: IND, NDA, and BLA?
RW: One of the keys to a successful IND submission is having the INTERACT meeting and the pre-IND meeting — both excellent opportunities to receive key scientific and regulatory advice early on the development plan, regulatory strategy, and content of IND.
When preparing the IND, review your data from the FDA’s perspective knowing their expectations. Generally, safety is a big concern for the FDA at the IND stage. They will focus on safety relative to the quality of the product, whether the animal studies support the design of the clinical study, and whether any toxicity was noted in animal studies. It’s important to describe how safety will be monitored in the clinical protocol to minimize any risk to human subjects.
Aim to anticipate any risk that the FDA might identify during the review so that the sponsor is prepared to respond quickly to an information request. Since FDA usually only gives the sponsor 24 to 72 hours to respond to their request, it’s critical to know what FDA is likely to ask and have the team ready to respond just in case. Success means that there is no clinical hold when the IND is submitted, and the clinical study can be initiated in 30 days.
Remember that the IND sets the tone for all future interactions with the FDA review division because the sponsor will be working with FDA probably for the next 5 to 10 years, so it’s important to start things on the right foot.
Brenda Schlenk (BS): I would emphasize a few additional considerations during IND preparation. The first is to identify, review, understand, and address relevant regulations and guidances that apply to your program. If there are any gray areas, make sure that you have a strong scientific rationale supporting your position.
Number two: prepare for the pre-IND meeting well in advance. Keep in mind that this meeting is the first glimpse that FDA will have of the proposed product, and the meeting will set the tone for future interactions — the importance of making a good first impression cannot be overstated. It is imperative to anticipate questions that FDA may ask and designate someone to respond to each, ensuring that the message is consistent.
That leads to my third point: the importance of consistent messaging throughout the application, whether it be an IND, NDA, or BLA. The goal is to weave texts together into the final application to provide the reviewer with a cohesive and clear understanding of the product’s journey. Tools, templates, style guides, and an experienced medical writing team can help with that consistent messaging.
In the context of marketing applications, the benefits of advance preparation also apply. For example, for a marketing application where authoring of clinical modules may be delayed due to data availability, downstream bottlenecks may be alleviated by early population of the nonclinical sections (which should have final data available).
MD: The guidelines and processes for the BLA are designed to help patients access safe and effective products, but navigating them can be quite complicated, especially for the first time. The FDA has several guidelines for approving a biological product, which could be a monoclonal antibody, tissue, gene therapy, protein therapy, or stem cell therapy. Since passage of the Biologics Price Competition and Innovation Act (BPCI) in 2009, most biological products have been approved through the BLA pathway, primarily following the CBER path with the FDA. Today, a lot of biosimilars are being approved through abbreviated FDA pathways.
RW: The NDA is fundamentally similar to the BLA, but some requirements differ for small molecules versus large molecules, and there are nuances between CDER and CBER. There are five modules, each of which calls upon different expertise. Module 1 covers the fundamental administrative information, as well as the prescribing information and product labeling, while Module 2 provides an overview of the whole application, including summaries of the drug substance and drug product and the nonclinical and clinical studies, and Module 3 contains detailed information about quality and CMC. Nonclinical and clinical studies are addressed in Modules 4 and 5, respectively, which can be very complex.
A team with expertise in all these different modules can streamline processes. Document specialists can format the documents, so they appear uniform across the NDA application, which is helpful for reviewers. Experts in eCTD can ensure that the reference documents can be easily located and navigated via hyperlinks to make the marketing application as reviewer-friendly as possible. Otherwise, the applicant is likely to receive information requests, each asking for an individual document. Ensure that the application is concise and consistent with ample navigation so that FDA can find everything easily.
With all these converging activities, it can be very helpful to engage external consultants like Cardinal Health Regulatory Sciences to provide comprehensive program management to coordinate the applicant’s team and consultants, vendors, or contract resource organizations to meet NDA timelines. Clear and effective communication are key to keeping the program on track and aligning the messaging. A consistent story needs to be told across your application to convince FDA that the product is safe and effective with a good benefit-to-risk profile, as well as providing a scientific rationale for why the product should be approved.
Another best practice is to create a detailed submission map that ensures that every document in the NDA is tracked to monitor when it’s coming, the status, who the responsible author is, as well as which sections are impacted by a rate-limiting step with backup plans to address any delays in the process.
DA: When do you think is the ideal time to begin developing regulatory strategies and/or engaging with external consultants like Cardinal Health Regulatory Sciences? And do you typically see clients doing that at the right time?
BS: That very much depends on the type of client. A client with their own regulatory group who only requires support for medical writing or publishing would likely engage us much later in the process compared to a client who may be delving into pharmaceutical development for the first time. We have publishing-only clients where we support the end process, so they wouldn’t engage us until that point.
However, other clients will benefit from engaging us relatively early in the process; and for clients with limited or no regulatory experience — the earlier, the better. For clients that are unfamiliar with regulations, we can help save them quite a bit of time leveraging our in-house expertise. Additionally, a real pitfall that many companies encounter is not understanding the massive amount of information that goes into IND, BLA, and NDA submissions and the collective effort that it takes to put them together.
RW: We may also have clients that feel comfortable at the IND stage and just come to us for their marketing application, which is also important to get right the first time, in part because of the huge associated PDUFA (Prescription Drug User Fee Act) fee. Sponsors need people onboard that know the required content of marketing applications and could perform a gap analysis to identify if any critical information is missing. Their needs and the timing depend on their comfort level and the resources and expertise that they have in-house.
DA: Every program is obviously unique, but how would you characterize the impact of a robust regulatory strategy?
BS: Building a solid regulatory strategy early and implementing that strategy correctly the first time can enable a product to reach the market faster than it would otherwise. It is vital to be efficient so that products get into the hands of patients as soon as possible. A difference of only a few weeks may not seem like much in everyday life, but that lost time can be critical to a patient waiting for a lifesaving or life-changing therapy. Every day that a product is not on the market can also represent a loss in potential revenue. Having the right plan of action and the right team onboard to execute that strategy can make a real difference.
DA: How does your team stay up to date on regulatory changes, including what is coming over the horizon?
MD: We stay abreast and adapt to changes in regulatory policies and guidelines through constant training, participating in webinars, studying literature from regulators and other sources, and many other activities. Many of us are members of regulatory affairs professional or clinical societies, which typically share weekly regulatory intelligence newsletters.
We provide drug development services for new drugs in all major therapeutic areas and across many countries. Consequently, we can typically find someone within the team with the relevant expertise to address any need.
One space in which our expertise is actively growing is our dedicated advanced therapy consulting team. CMC is very different for products like cell and gene therapies, and navigating the clinical and regulatory hurdles that they present — from early stages all the way through life cycle management — is challenging.
DA: Beyond the depth and breadth of your expertise, what most differentiates Cardinal Health Regulatory Sciences from your peers and competitors?
MD: We have a partner-based, milestone-driven business model for initial submissions and life cycle management. The model is highly flexible and easily customized to any sponsor’s specific needs. Our experts can work independently or at the direction of the sponsor’s management team and can interact with manufacturing groups to evaluate deviation or change control for global regulatory impact. With our deep bench of experts, we can quickly mobilize to resolve an issue as soon as possible without the client needing to be involved.
BS: Most of our consultants have been in this business for decades. Our consultants have expertise in regulatory strategies, CMC, nonclinical programs, clinical programs, medical writing, project management, document formatting and processing, as well as in submission publishing. Each of these areas are important, and our ability to offer expertise across all these disciplines is a truly unique feature of our regulatory consulting group that sets us apart from others in this space.
This information is provided for educational purposes only. Cardinal Health is not responsible for any use of the information contained herein, or any implemented recommendations or results therefrom. The opinions and recommendations expressed are solely those of the author and not necessarily those of Cardinal Health, or its subsidiaries or affiliates.
Our expert team at Cardinal Health Regulatory Sciences is ready to accelerate your path to market. Learn more at cardinalhealth.com/regulatory or email us directly at: biopharmarservices@cardinalhealth.com