Regulatory challenges and considerations when bringing a new biologic to market

The journey from research lab to market is a long one, and most drug candidates do not make it. For those that do progress to market, there are many regulatory milestones and hurdles. As in other aspects of drug development, up-front planning can prevent headaches down the road. One of the key decisions is knowing when your team is short on regulatory experience and expertise, and when to call on a consultant or hire an expert to fill the gap. Your regulatory investigator can also be an excellent resource, who can share valuable knowledge and advice. Meet with them early, and cultivate a good relationship.

Phase I clinical trials are first-in-human trials on healthy subjects to determine drug safety. As you complete pre-clinical trials and plan to move to clinical Phase 1 trials, you must plan for compliance with a strict level of regulatory requirements as part of these efforts.

The Investigational New Drug (IND) process

Prior to initiating human clinical trials, you will need to file your Investigational New Drug (IND) application and get approval. Be sure you have a resource with chemistry, manufacturing and controls (CMC) regulatory expertise and experience on your team, not only to guide the development of your IND process and application, but also to keep an eye on the longer-term compliance view.

The pre-IND meeting

During the development of your IND application, you will have one or more pre-IND meetings with regulatory investigators. Seize on this opportunity to learn as much as you can from their knowledge and experience. The regulator is not only an expert on the regulatory aspects, he/she also has knowledge of which regulatory strategies are more likely to succeed and which are more likely to fail. The guidance your regulator provides can be invaluable in helping you avoid pitfalls that can cost you time and money in the long run. What will the regulator want to know?

Use the meeting to get guidance on whether your plan, as documented in your IND application, can get approval to begin Phase I clinical trials. Learn where your plan is deficient, and what you need to do to bring it up to par.

▻TIP: Your regulator will have an ongoing oversight role as your drug moves through clinical trials and commercialization. Establish good communications and cooperation from the outset, and always keep in mind that they are also a valuable knowledge resource.

Infographic: Be prepared for your pre-IND meeting

The IND application

The IND submission describes the substance and activities to date, and plans for going forward. The IND application will cover three key aspects of your drug: your clinical research plan, toxicology, and CMC as relates to manufacturing the bulk drug substance (BDS) and drug product (DP).

  • The clinical plan describes the indication, the mechanism of action (MOA), the type of drug, the anticipated effect on the patient and the disease.
  • The toxicology section will describe the pre-clinical animal studies and their results, and the plan for Phase I clinical trials. How will safety be established and validated? What are the planned dosing amounts, intervals and duration?
  • The CMC, or chemicals, manufacturing and control section, will describe your plan for manufacturing the drug for your clinical trials. What analytical methods will be used, and how will you ensure the consistency and purity of your drug?

Crafting a successful IND submission requires that you have all your ducks in a row, so in addition to regulatory knowledge, intensive planning is a prerequisite. The two go hand-in-hand. The IND submission is much more than a description of the substance and activities to date and plans for going forward. It is also the regulatory roadmap, laying out the path for milestones and approvals down the road. Unlike a Google™ map, however, it should be general enough to point you in the right direction, but vague enough not to pin you down to a specific route without allowance for changes.

This is the time not only to plan for a manufacturing process using current good manufacturing practices (cGMP), but to think about future scale-up milestones as well. As your therapy progresses along the path of clinical trials and to market, any significant changes to the manufacturing process will entail further validation work for regulatory compliance, and potentially an IND amendment (INDA). Therefore, initiating clinical manufacturing with the same type of equipment and materials that you envision for commercial manufacturing will reduce the work and potential delays of regulatory compliance in the long run.

▻TIP: Your IND lays out and documents your plan for moving forward with your drug both clinically and in manufacturing. Establish and maintain alignment within the regulatory framework, as well.

Clinical manufacturing: plan for commercial scale

The decision to move to clinical trials will trigger intensive planning, both for all aspects of the Phase I trial, and also for manufacturing your drug substance at clinical scale. All of the activities involved in planning and executing Phase I trials, including manufacturing at scale, have regulatory implications. But your manufacturing choices have significant long-term regulatory (and business) implications, as well. Regulators will want to know how you will produce your bulk drug substance and product, and guarantee purity, as well as your analytical plan to demonstrate that the substance you manufacture at clinical scale is the same substance, with the same critical quality attributes (CQAs), as the reference standard that you have manufactured at lab scale for your pre-clinical trials. Similarly, when you scale up to commercial production, you must demonstrate that your process yields the same product. If your drug is targeting a rare disease with an unmet medical need, it may be accelerated from Phase I to Phase III clinical trials, in which case you will need to accelerate your scale-up to commercial manufacturing, as well.

▻TIP: Utilizing processes, materials, and equipment that can be validated for commercial manufacture can save a lot of time and effort, and facilitate regulatory approvals down the road.

A gated approach

As you move through clinical trials, you will evaluate results at each milestone. Every check-point includes a go/no-go decision, depending on the results. Additional factors, such as a new competitive therapy, may also influence your decision. If moving forward, plans for the next clinical phase, possibly including manufacturing, will need to be revisited, and potentially modified. And here, some regulatory caution is required. Depending on the scope of the changes, you may need to file an IND amendment (INDA) and gain approval for your changes. To some extent, you can avoid the need for filing INDAs by carefully crafting your IND application.

▻TIP: Be as general as possible in your IND document. Leave yourself room, if possible, for variations in your manufacturing process and modifications to your clinical plan that need not entail an INDA.

Documentation: an essential tool for regulatory compliance

The gated approach is iterative, but the one essential at every step is—document, document, document, document. Let’s break that down:

Plan and document > execute and document > evaluate and document > repeat

▻TIP: The more thoroughly you document, the better prepared you will be to work with regulators.

Data collected throughout manufacturing, including process parameters and analytical results, is a critical component of your documentation. This data is part of the feedback loop for process control and optimization, and is also an important record from a regulatory perspective, demonstrating process reliability, robustness and repeatability.

Biologics require strict oversight

As you progress through clinical trials and to commercialization, the regulatory requirements will become increasingly stringent. Approval of biologics in the US requires a Biologics License Application (BLA). Due to the nature of biologics, which are produced by living cells, the process as well as the product must be validated and strictly monitored against CQAs throughout the manufacturing process, not just at the end as for chemistry-based drugs.

The core objective of the BLA is to ensure patient safety and drug efficacy when used as directed. The BLA provides the (US) FDA reviewers information on the complete history of the drug, from clinical trials design, results, and conclusions through proposed labeling, including patent and manufacturing information. To gain approval, the regulatory bodies must approve not only the end product, but also the CQAs, process, equipment, consumables and cell lines that went into the production.

Regulatory compliance is an ongoing process

As your drug or therapy moves through clinical studies and commercialization, expect to be in close communications with your regulator. Plan on sharing and discussing reporting and results at milestones and at regular intervals. All aspects, including clinical plan, manufacturing, analytical methods and results will be reviewed, as the regulator builds familiarity and deep understanding of your drug and processes. They will also conduct a pre-approval inspection (PAI) of your commercial manufacturing facilities. Continue to look to them for insights and guidance regarding the regulatory process, but remember, they don’t replace having your own expert on your team.

▻TIP: Utilize the abundant resources that are available to educate yourself about regulatory requirements, but nothing replaces experience. Bring a consultant or hire on board who has the experience of working with regulators to bring a biologic to market.

Read this article to learn more about realizing your therapeutic vision when bringing your drug to clinic, here are some questions to consider.

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