Stuart R. Gallant, MD, PhD
A pharmaceutical company begins development of a new drug by screening dozens or even thousands of molecules to find the one with the most favorable properties: activity in chemical and animal models of disease, indications of safety, ability to deliver the treatment by a convenient route (ideally oral delivery, otherwise parenteral delivery), and chemical stability under the desired conditions.
Once a candidate has been identified, the sprint to file an Investigational New Drug (IND) application can begin in earnest. The subject of this post on PharmaTopoTM is the IND application and a few things to bear in mind during IND preparation.
Non-Clinical Data
Accumulating animal data is an ongoing process throughout drug development. As an example, there are dozens of well recognized animal models of Alzheimer’s disease [1, 2]. Each model has its own advantages, but what all the animal models share in common is that no one model is completely predictive of a drug’s efficacy in human beings. Animal data represents the key to the door of human testing—it should be generated as rapidly as possible, cognizant that both false positive and false negative results may occur. At the same time, the requirements for ADME/PK/Toxicity studies are well established, and a budget and timeline for completion of those studies is important to consider [3].
Chemistry, Manufacturing, and Controls
Chemistry, Manufacturing, and Controls (CMC) constitute a major investment in preparation for filing of an IND. Considerations include:
- Is the active ingredient a small molecule, a protein, a nucleic acid, a virus, or a cell?
- What is the state of the art for characterization of the active ingredient?
- How is the active ingredient manufactured?
- What is the formulation, and how is the drug product manufactured?
During development, investment will be made to transition manufacturing from a research bench to a GMP manufacturing facility; this higher level of control will be documented in the IND. At the same time, as each generation of the manufacturing process is established, it will be critical that the essential qualities of the product have remained unchanged. Banking away both process intermediates and drug product from each generation of the manufacturing process allows side by side comparison in comparability studies—so make sure that an adequate supply of retained samples is held under appropriate storage conditions with each generation of the process.
IND Categories and Structure
The US FDA supports two categories of drug IND. Commercial INDs are submitted by pharmaceutical companies seeking marketing approval for new drugs. Under commercial INDs, drugs like the anti-diabetes medication Ozempic (semaglutide) and the arthritis treatment Humira (adalimumab) are tested for safety and efficacy before being sold to the public. Research INDs are submitted to advance scientific knowledge—a Research IND may test an already approved drug in a new indication or in a new patient population or it may study an unapproved drug.
With a few exceptions, IND applications are submitted in electronic Common Technical Document (eCTD) format. This offers three advantages: 1) Because the individual sections are predefined, FDA reviewers can quickly locate the information they need in order to assess whether the patients in the study will be subject to unreasonable risk. 2) Because the application is submitted electronically, review is efficient and no longer involves multiple paper copies of the IND, as it did in the 2010s and earlier. 3) In most cases, a sponsor will want to submit applications to multiple geographical regions to ensure that a new drug will be available not only in the US, but in Europe, Asia, and other regions; the eCTD allows one application to be submitted to many regions with little editing between the different regional applications. The general structure of the document is shown in this diagram:
Module 3 (Quality) contains information about the manufacturing, testing, and quality controls on the active ingredient and the drug product as delivered to the patients. Modules 4 and 5 contain the nonclinical and clinical study reports. Some comments on preparation of the eCTD include:
- The individual sections are prepared and edited as Microsoft Word documents. Once they are finalized, they are assembled into the full eCTD and submitted.
- Each distinct drug product type is quite similar in its IND flow and contents. For example, preparing a new IND on an antibody pharmaceutical is quite easy, if an earlier submission of an antibody can be followed—cutting out the old information and pasting in the new information for the new product. The new submission is likely to have few reviewer comments if the original submission went through easily.
- Unfortunately, few completed IND applications are available publicly because there is proprietary information throughout the application. Companies are understandably reluctant to release these documents. An example Module 3 is available courtesy of Dr. Marcus Ferrone at the University of California at San Francisco:
GMP Manufacturing
One of the largest expenses in filing an IND application is the manufacture of at least one GMP lot of drug product, as well as release of the lot and initiation of stability testing. Some thoughts on GMP production planning include:
- Investment in a scalable and reproducible manufacturing process is important. Your initial manufacturing lot will power your first clinical evaluations, but you will want additional lots of drug product as your studies proceed. Having a manufacturing process that cannot efficiently supply the clinic is a risk to the program.
- Real time stability data controls when your clinical trial can be initiated. For small molecules, you will need 30 days of real time stability data—which coincides with the 30-day review of your IND. In contrast, for biologics, you will need 6 months of real time stability data, so get your GMP drug product on stability as soon as possible after completing manufacturing.
- There is lore, regarding GLP animal toxicity testing, that using a drug product lot which is too clean (has too few impurities) can be a problem. This very pure lot may box your manufacturing in later if a small amount of impurity appears during scaleup later in your manufacturing history.
Conclusions
Preparation of an IND is a team effort. Team members should have experience with:
- Drug Product: Research scientists doing the early manufacturing and testing work are critical a successful application.
- CMC: Expertise on GMP manufacturing and testing is important during the transition from a research process to a clinical and ultimately commercial process. Your CMC expert(s) will have primary responsibility in production of the GMP clinical supplies required in the IND.
- Preclinical: Efficient in vitro and animal testing evaluation of the product enables the entry to human testing; it is also an expensive and time consuming aspect of preparation to file the IND.
- Clinical: Planning the early clinical program efficiently allows the most rapid dose escalation and enables speedy passage to later stages of evaluation.
- Regulatory: Effectively communicate with regulatory agencies is vital to the success of an IND application. Ensuring that the eCTD is uniformly and accurately drafted, that questions for regulators are designed to elicit the maximum information, and that responses are succinct and timely all requires excellent regulatory knowledge.
In summary, FDA reviewers are always thinking about the safety of the human subjects in any clinical trial, so it is critical that the sponsor create an impression of credibility in each aspect of the IND application to allow FDA reviewers to approve the document.
[1] De Dyne, P.P. and Van Dam, D. Animal Models of Dementia, Humana Press (2011).
[2] Yokoyama, M., Kobayashi, H., Tatsumi, L., and Tomita, T. “Mouse Models of Alzheimer’s Disease,” Front Mol Neurosci, 2022 Jun 21:15:912995. doi: 10.3389/fnmol.2022.912995.
[3] Gallant, S.R. “Nonclinical and CMC,” PharmaTopo, Dec. 27, 2021. pharmatopo.com/index.php/2021/12/27/nonclinical-and-cmc-3-of-3/
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