The Small Biotech's Checklist For FIH Trials

By Jon Strauss, FASTFORWARDBIO

Once a biologic drug has shown sufficient promise in early in-vitro and in-vivo studies, it’s time for the drug sponsor to initiate first-in-human (FIH) trials.

For a small biotech company, managing the multitude of tasks requiring completion to get medicine to its first patients can be daunting. Mistakes are expensive and time-consuming at their best and they may harm patients at their worst.  This article aims to provide best practices for managing the completion of these tasks efficiently, with less rework, and to the required level of compliance.

The critical steps the sponsor must commonly complete are listed below. While a pre-IND meeting with the relevant regulatory agency is not mandatory, it is highly recommended to obtain their guidance regarding the sponsor’s proposed clinical and nonclinical studies, as well as any concerns they may have with regard to chemistry, manufacturing, and controls (CMC).

These are the steps between selecting a promising candidate and FIH:

• Schedule pre-IND meeting with the regulatory agency.
• Develop a comprehensive drug development plan for FIH study and for any remaining required nonclinical studies, along with CMC strategy.
• Conduct pre-IND meeting and follow up on agency questions and comments.
• Complete required nonclinical studies.
• Produce and release clinical trial material (CTM).
• Develop clinical protocol.
• Prepare investigator's brochure.
• Prepare regulatory documentation.
• Prepare informed consent documents.
• Submit IND application to the FDA.
• Respond to FDA inquiries.
• Obtain institutional review board (IRB) approval.
• Open clinical sites.
• Recruit patients.

Smaller biotech companies outsource the manufacturing of CTM and may also outsource drug product material for nonclinical studies to one or more CDMOs. Only a select number of CDMOs have the capability to produce the drug substance (DS) and fill, label, package, store, and distribute drug product (DP) to clinical trial sites.

For complex manufacturing processes like protein conjugates that require custom-made, small molecules, which can be highly potent, additional manufacturing contractors are required and may be managed either as subcontractors by a CDMO or as independent contractors by the sponsor.

A smaller biotech company will also typically outsource a large portion of the necessary nonclinical studies and clinical trial preparations to one or more CROs. Only select CROs may be experienced in the handling, testing, or administration of drugs with highly potent components or complex modes of action. However, the same CROs may not have experience executing FIH studies in a particular country or may not have experience with a certain patient population or disease state the drug is being used to treat.

Who’s Responsible For What?

Each contractor typically manages scope, timelines, and resources for the tasks they are responsible for. The sponsor is responsible for providing oversight of the entire FIH project and coordination with each of the contractors to ensure deliverables are met. It is common for the sponsor and one or more contractors reside in other countries, posing communication and logistical challenges in shipping and testing materials.

While managing multiple CDMOs and CROs, the sponsor must also manage communications, documentation, meetings, and responses with the relevant regulatory agency.

How Does A Small Biotech Effectively Manage All These Moving Parts?

The following are best practices that a drug sponsor can follow to minimize the risk of delay in initiating FIH studies.

Drug development plan and CMC strategy

• Ensure the plan is comprehensive, covering all tasks, milestones, deadlines, and responsibilities of both internal and external stakeholders.
• Use Gantt charts to visualize the project timeline and track progress.
• Ensure each stakeholder understands their responsibilities along with any interdependencies with other tasks and stakeholders.
• List all key assumptions and revisit frequently to ensure they are still valid.
• Perform risk assessments with risk mitigation strategies for high-risk items.
• Reassess risk upon completion of pre-IND meeting and each time there is a change in project scope, resources, or assumptions.

Selecting contractors

• Perform thorough due diligence when selecting contractors. Check their track record, expertise, and references.
• Minimize the number of contractors needed where possible. An example is hiring a single CDMO that can manufacture DS and DP and perform all release testing and most of the product characterization if possible.
• Ensure contracts are clear, covering the scope of work, deliverables, timelines, and payment terms.
• Require the contractor to perform a risk assessment on the state of the current process and analytical documentation, material sourcing, and the fit of their facility and personnel.
• Build in buffers for added cost and time for tasks identified as high risk.

Managing contractors

• Assign a single point of contact within your company for each contractor to streamline communication.
• Provide necessary training to contractors on your company’s processes, systems, and expectations.

Define key performance indicators (KPIs) to measure contractor performance and project progress.

• Conduct regular performance reviews with contractors, providing feedback and addressing any issues promptly.
• Maintain an open feedback loop with contractors to continuously improve processes and outcomes.

Managing the entire project

• Schedule regular meetings with external and internal stakeholders to review progress, discuss issues, and align on next steps.
• Use project management and communication tools (e.g., Slack, Trello, Asana) to keep everyone informed and engaged.
• Implement SOP to govern internal and external parties for documentation, data handling, and reporting.
• Use a centralized repository for all project documentation and data, ensuring easy access and version control.
  • Use widely available document management platforms like SharePoint or Google Workspace, if possible, for document storage and collaboration.

Be prepared to adapt plans and strategies as the project evolves and new challenges arise.

Quality and regulatory considerations

• Ensure the correct agency center and office are engaged for discussions and approval of the IND.
  • For new gene or cell therapies, the IND application is submitted to the Office of Tissues and Advanced Therapies (OTAT), which is part of the Center for Biologics Evaluation and Research (CBER) at the FDA.
  • For vaccines, the IND application is submitted to the Office of Vaccines Research and Review (OVRR), which is part CBER at the FDA.
  • For monoclonal antibodies (mAbs), bispecific antibodies, and antibody-drug conjugates (ADCs), the IND application is submitted to the Office of Oncologic Diseases (OOD) or the Office of Immunology and Inflammation (OII), depending on the therapeutic area, within the Center for Drug Evaluation and Research (CDER) at the FDA.
  • For a peptide or a recombinant protein, the IND application is submitted to the CDER at the FDA. The specific office within CDER depends on the therapeutic area of the recombinant protein.
    • Office of Oncologic Diseases (OOD)
    • Office of Immunology and Inflammation (OII)
    • Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (ORPURM)
    • Office of Neuroscience (ON)
• Schedule the pre-IND meeting and prepare questions for the agency along with anticipated responses to questions or comments from the agency.
  • Monitor progress made by the company for each agency comment or question.
• Implement QA processes to ensure all work meets regulatory standards and project requirements.
• Regularly monitor compliance with regulatory requirements and guidelines.
• Implement a QMS like MasterControl, Trackwise, or Veeva for managing quality processes.
• Prior to submitting an IND, set up a response plan for possible agency questions, including responsible persons for each module with backups if possible.

Conclusion

Hiring and managing several contractors for manufacturing the drug, nonclinical testing, and setup for the FIH study is a common reality for a small biotech company. At the same time, the company must manage its relationship with the primary investigator (if applicable) and manage communications and obligations with the relevant regulatory agency.

With so many moving parts, it is vital that best practices for selection and management of each contractor are implemented along with those for management of the overall project, to ensure timely completion and that quality and regulatory compliance are met.

About The Author:

Jon Strauss is an industry consultant and founder of FASTFORWARDBIO LLC. Previously, he was the director of CMC operations at 89bio and before that the CMC director at Calibr-Skaggs Institute for Innovative Medicines, a division of Scripps Research. He’s held positions of increasing responsibility at Ambrx, Abzena, and Genentech. He’s also worked for CMC Biologics, now a division of AGC Biologics; Momenta Pharmaceuticals; and Bayer. He received his bachelor’s degree in chemistry from James Madison University and a master’s degree in biochemistry at Johns Hopkins University. Contact him at www.fastforwardbio.com or connect with him on LinkedIn.