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December 22, 2020updated 11 Aug 2021 11:34am

Developing a new biologic drug: regulatory challenges and considerations

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 helps prevent headaches later. You need to know when your team is short on regulatory expertise and when to call on a consultant to fill the gap. Your regulatory investigator can also be an excellent resource, able to share 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 Phase 1, you must plan for compliance with a strict level of regulatory requirements.

The Investigational New Drug (IND) process

Prior to initiating human clinical trials, you will need to file an Investigational New Drug (IND) application and get approval. You need someone with chemistry, manufacturing and controls (CMC) regulatory expertise on your team, to guide the development of your IND application, but also to keep an eye on compliance longer-term.

During the development of your IND application, you will have one or more pre-IND meetings with regulatory investigators. Seize this opportunity to learn as much as you can from them. Regulators are not only experts on regulations, they also have knowledge of which regulatory strategies are more likely to succeed and which to fail. The guidance your regulator provides can help you avoid pitfalls that cost you time and money in the long run.

Use the meeting to get guidance on whether your plan, as documented in your IND application, can get approval. Learn where your plan is deficient, and what you need to do to bring it up to par. The regulator will have an ongoing oversight role as your drug moves through clinical trials and commercialization. Establish good cooperation from the outset, and keep in mind they are a valuable knowledge resource.

The IND application

The IND submission describes the substance and activities to date, as well as any plans. The application will cover three key aspects of your drug: your clinical research plan, toxicology, and CMC as it 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?

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 ahead. But unlike a map, it should be general enough to point you in the right direction, but vague enough not to pin you to a specific route.

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 your therapy progresses through clinical trials and to market, 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 you plan to use for commercial manufacturing will reduce potential delays from regulatory compliance later.

Clinical manufacturing: plan for commercial scale

The decision to move to clinical trials will trigger intensive planning, for all aspects of the Phase I trial, but 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.

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 the substance you manufacture at clinical scale is the same substance, with the same critical quality attributes (CQAs), as the reference standard you have manufactured at lab scale for 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.

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. Plans for the next clinical phase, possibly including manufacturing, may 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 INDA and gain approval for your changes. To some extent, you can avoid the need for filing INDAs by carefully crafting your initial application.

The gated approach is iterative, but the one essential at every step is documentation. So you need to plan and document, execute and document, evaluate and document and then repeat.

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 to commercialization, the regulatory requirements 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 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 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.

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