Stuart R. Gallant, MD, PhD

In the earliest stages of drug research, scientists conduct bench experiments at a university or in a corporate pharmaceutical research lab.  As some point, the pharmaceutical technology becomes ready to be developed into a drug to treat human disease.  Today’s post discusses the 4 axes which determine readiness to advance from research to development.  They are:

• Drug Product
• Manufacturing Process
• Team
• Funding

Drug Product

Data about the drug product is the juiciest aspect of the research data.  A researcher may point to rodent data that says that a new chemical entity has effect on disease X.  Epidemiologic data is brought in to estimate market size, and current cost of treatment data is brought in to calculate a market value for the new treatment.  Here are some simple questions to ask before the discussion advances to stock option sizes:

• How good is the animal model?  Is it the best available, and what would be the cost of generating additional data in a better model? 
• How good is the research?  Is more than one researcher involved?  Who has audited the data?
• Have the correct controls been included, such as comparison with the current state-of-the-art treatment?
• How difficult will it be to deliver the treatment to a human?  Often, certain routes of administration in rodents are not practical in humans.  Can the expected route of administration in humans be validated (if it has not already been validated)?
• Document important drug product properties:  dosage form, formulation, and storage conditions—these will be a starting point and may change during development.
• What is the state of intellectual property?  Have patents been filed?  Is there a clear path to commercialization?

Manufacturing Process

Manufacturing processes in research and in development look very different.  Take the case of gene therapy.  A patient-based gene therapy starts with cells from the patient’s body and with a gene therapeutic agent, often a virus.  Making a small batch of virus in the research lab may be quite easy for a graduate research student, and many separate batches of virus may be used over the course of a research project.  For development purposes, the goal will be to use a smaller number of well-controlled virus lots which have been extensively characterized.  An important discussion for the project team is which aspects of the manufacturing process will need to be altered or more tightly controlled.  Here are some things to look at:

• How much data is available on the manufacturing process?  Generating a report on the key parameters and how the product has been manufactured to date is good information to capture.
• Triage what is standard versus what is special about the process.  Standard materials and conditions include:  material which can be purchased from vendors like Millipore Sigma and Avantor and common unit operations like mixing and filtration.  Special materials and conditions include:  custom chemicals, unusually long process times, steps with poor yields, hazardous synthetic conditions, steps requiring specialized equipment available at only a few locations, and steps which require a “green thumb.”  (A green thumb step is one which only one technician can get to work—he or she is the one with the green thumb.  Green thumb steps are the hallmark of a manufacturing process which is poorly understood.)
• What is the plan for clinical manufacturing?  Will the manufacturing occur at a contract manufacturer or at a university facility?  Are there any nonstarters for clinical manufacturing that would make the product too difficult or expensive to manufacture—how can those roadblocks be removed?

Team

With each step along the drug development path, the team gets larger.  In the transition from research, several team members are added:

• Business team:  This includes initial investors who may purchase the patents, as well as a leadership team (a CEO and CFO).
• Non-clinical and clinical team:  The non-clinical and clinical personnel will write their respective sections of the IND.  Management of animal testing data is a critical task during development; data must be both robust and rapidly obtained.
• Manufacturing team:  The manufacturing team writes the CMC section of the IND.  The manufacturing team faces many challenges:  developing a formulation suitable for humans, preparing GMP manufacturing process for the active ingredient and for the drug product.  So, CMC flexibility is important to success.
• Regulatory team:  The regulatory person will manage the relationships with regulatory agencies and assemble and submit the IND.

It is not essential to bring on all these people at once, but there should be a clear plan for how to staff the project prior to making a decision to advance to development from research.

Funding

Development, like research, requires money to move forward.  Paths to funding vary depending on perceived risk and likely reward:

• Government programs (SBIR/STTR) and patient advocacy groups:  Is there access to subsidized facilities such as university labs or incubators which can reduce costs?  What will the end point of this work be—will completion of the work allow further funding through angels or other early investors?
• Angels or other early investors:  What fraction of the value of the project will the investors seek?  What is the path to an exit?
• Series A has already been completed:  A detailed timeline and budget have already been prepared—do those documents still agree with the current state of knowledge about the project?  The team will need to move the project forward as fast as possible, even as they manage investor expectations.

The critical insight regarding funding is that available funds should extend to the next “fundable event” or to an exit.

Conclusion

Previous PharmaTopo posts have addressed detailed topics like the drug development plan, the raw materials assessment, the design process, and decision making and fund raising [1, 2, 3, 4]—readers seeking more detailed advice regarding early development are advised to scroll through previous PharmaTopo posts.  Developing a short list of must-haves in order to advance from research to development has two main advantages.  First, if a project meets the necessary qualities for advancement, the team can be confident that they have reduced project risk and maximized the chance of success on the path to filing an IND.  Second, if a project is not ready to advance, the team has established a to-do list for the coming months of research in order to prepare the project to advance to the development stage.

[1] Gallant, S. R.  “Nonclinical and CMC,” PharmaTopo, Dec. 27, 2021.  pharmatopo.com/index.php/2021/12/27/nonclinical-and-cmc-3-of-3/

[2] Gallant, S. R.  “Risk Assessment of Raw Materials and Contact Materials,” PharmaTopo, Part 1 and 2, Jan. 17, 2022.  pharmatopo.com/index.php/2022/01/17/risk-assessment-of-raw-materials-and-contact-materials-1-of-2/

[3] Gallant, S. R.  “The Design Process,” PharmaTopo, Jun. 22, 2022.  pharmatopo.com/index.php/2022/06/22/the-design-process/

[4] Gallant, S. R.  “Pharmaceutical Decision Making and Fundraising,” PharmaTopo, Aug. 6, 2022.  pharmatopo.com/index.php/2022/08/06/pharmaceutical-decision-making-and-fundraising/

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