Small molecule drug development is experiencing increasing numbers of molecules in the pipeline on expedited regulatory pathways being developed by small and emerging pharma companies and a trend towards greater complexity of chemical structures and enabling technologies. Given these trends, understanding the potential regulatory pitfalls is critical to a successful drug approval.

How is the pharmaceutical development pipeline evolving?

Hall: I would say it’s evolving well; however, this evolution brings with it certain challenges. What we see is that the number of molecules in the pipeline is increasing at an approximate growth rate of 6% per year. In 2022, we could count 7,500 new chemical entities in development, which is really an impressive number. I believe it provides us all with a great opportunity to improve the lives of the patients by the contributions made as a pharmaceutical development company or as a CDMO like Lonza.

An analysis of the pipeline shows that a growing proportion of drugs in development are starting out life inside small and emerging pharma companies. Historically, discovery and development were made by big pharma businesses. The transition is very dramatic, to the point at which nearly 80% of new molecules are now coming from these small and emerging companies, rather than big pharma. Additionally, in the past, smaller companies would license or sell their programs to big pharma relatively early on in development and usually would not continue development beyond clinical phase 2 or Proof of Concept. However, recent data shows that smaller pharma companies are now much more likely to carry out late-stage clinical trials themselves and even take the drugs to market. The most recent new drug application (NDA) filing data from the FDA, from last year, shows more than half of applications for new drugs come from companies with less than 1,000 employees. This means small emerging pharma companies are certainly taking on much more risk. However, they have a greater chance of reaping the rewards that may result.

Are there technical challenges experienced when new molecules enter development?

Hall: Yes, it is very noticeable looking at molecules coming through the pipeline in recent years that they are becoming increasingly complex. Chemical structures are growing in complexity, which can make them more difficult and take longer to manufacture. We also notice that the molecules are increasingly likely to be highly potent, which means that special facilities are needed to develop, handle, and ultimately, manufacture them. This may be attributed to the increased push to develop new cancer treatments.

Another challenge is that many new molecules need help with solubility, which is an important property for new drugs. In fact, around 80% of all small molecule drugs in the development pipeline are described as having minimal aqueous solubility. This compares with approximately 60% of molecules currently on the market. Therefore, you can see that the issue of solubility is growing.

It is not only challenges relating to producing drugs that are adding complexity to the development. We also notice a much greater proportion of drugs in development are part of an expedited regulatory approval pathway. Indeed, in the US, 75% of the drugs approved in 2021 made use of one or more expedited pathways, and that compares with only 61% in 2017. Expedited pathways require companies to develop treatments faster and produce more data at an earlier stage than normal. When increased technical challenges are combined with the use of expedited pathways and put together with smaller companies taking drugs later into development, you have some increase in risk.

What are some other pitfalls that may impact likelihood of getting this approved?

Hall: If the company makes a regulatory submission to a regulator, it does not mean that the new drug will be approved. If we look at the US FDA, it may not even accept a filing of an NDA. It can sometimes send out a Refusal-to-File notice to the applicant if the NDA is found to be incomplete. Whilst this is clearly not a positive response, it does allow the recipient of the Refusal-to-File to relatively quickly add the missing information and resubmit the NDA before the FDA starts the process of a full review of the data.

Once the FDA accepts the filing and makes a more detailed review of the data, it may refuse to approve the application and issue what is known as a Complete Response Letter. Generally, this is very bad news for the small biotech companies and emerging pharmaceutical companies receiving it. It can take the FDA up to 10 months after the original NDA filing was accepted to come to this conclusion. Refusal-to-File notification and Complete-Response-Letters are usually not made public. Sometimes the pharma company receiving the Refusal-to-File notification and Complete-Response-Letters will make a press release themselves. However, when they do this, they often don’t provide the full details of the deficiencies that the FDA has identified. This can make it very difficult to work out what the problems were with the filing.

Even though the refusal to file notices and complete response letters are normally not made public, some research has been published in recent years. When assessing this research, one of the major deficiencies that the FDA often cites in their Refusal-to-File notices or Complete Response Letters is insufficient data relating to what is known as chemistry, manufacturing, and controls, or CMC for short. Research also highlights that it can take a company many months, or even a year or two, to assemble the additional data and resubmit an NDA to the FDA. Sadly, this may cause significant delays to patients receiving critical treatments. It also causes additional costs and delayed revenue for the company developing the drug.

If it’s small biotech companies and emerging pharmaceutical companies with only one drug in their pipeline, such a rejection by the FDA can even put the company, itself, at risk. For example, their cash might run out before they can resubmit the application, especially if additional clinical trials or production is required.

Can you explain CMC and its challenges?

Hall: CMC is a complicated topic and, as mentioned, is an area often cited as a deficiency by the FDA in regulatory applications. It is the collection of information that describes the manufacturing process of the new drug. It covers a wide range of areas, such as how the drug is made, the quality control, and information about everything from its specifications to stability. It also includes details of the manufacturing facility where the drug is made and all support utilities. It details the design and qualifications, as well as how to operate and maintain the facility. If the FDA decides that CMC data is missing or insufficient in a regulatory filing, it does not matter how safe and efficacious the drug was in clinical trials. The regulator will still not approve the application.

Failures and omissions in CMC data may have a direct impact on how soon a medicine is approved for patients. As part of the approval process, Regulators will normally physically inspect the drug production facility, which adds another layer of risk. This is particularly relevant when the development and manufacture of a new drug is outsourced to a CDMO. This is often the case for small biotech companies and emerging pharmaceutical companies that do not have a development or manufacturing facility of their own.

Can you guarantee that your CDMO will be ready and available for inspection whenever the FDA demands it? Is it vital to select the right CDMO in the first place?

Hall: Yes, it is really one of the critical decisions, particularly for small and emerging pharma companies, in terms of who they should partner with for support of their chemistry, manufacturing, and controls needs. There is no substitute for having a rigorous and careful selection process when you’re looking for a CDMO to develop and manufacture your precious, highly valuable potential new drug.

To help save time and money, it is important to understand whether a particular CDMO is able to support the entire needs of your program. For example, are they able to develop and manufacture both drug substance and the drug product? If so, how integrated are the different parts of the business that will need to work together to make that happen efficiently? This will have a big impact on how fast the development process may be.

When we consider technical complexity, another important thing to consider is the enabling technologies that a CDMO may offer. If your drug is highly potent, you’ll need someone with experience in handling these types of molecules. If it is poorly soluble, you will want a CDMO with technology needed to enhance the solubility of the molecule. It is important to consider a CDMO partner that has necessary capabilities for late-phase development and commercial supply. If you choose a partner who can support both early and late-phase development, this will give continuity throughout the process and allow you to avoid technology transfers between companies, again saving time and money.

It is important to elect a CDMO that is able to offer significant support in regulatory filings and will be able to help you avoid those problems associated with incomplete CMC data. All these considerations are really at the forefront of our thinking here at Lonza. Our goal is to support small and emerging pharma companies, overcome complexity, and meet aggressive timelines demanded by expedited regulatory pathways. We want to offer customers a full range of integrated development and manufacturing services, for both drug substances and drug products. This includes specialist technology, such as making and handling highly potent drugs and bioavailability enhancement services, which can help overcome problems with solubility.

Our regulatory affairs experts are a vital part of the project team, and they are important when working towards submitting an NDA that will be approved at first attempt. Our aim is to help avoid some of the pitfalls with incomplete or inaccurate CMC data. The sooner a new medicine can be launched, the better it is for the innovator and ultimately, the patients who receive the treatment.

Want to stay up-to-date in the small molecule space?

Join our community to receive regular updates, content and insights.

Latest content
Latest briefing from the Knowledge Center