The United States is one of the largest and most influential markets for pharmaceuticals, making it an important destination for many global clinical development programs. Bringing a clinical development program to the U.S. is a multifaceted process that requires careful planning and adherence to regulatory requirements. Receiving U.S. Food and Drug Administration (FDA) clearance for the first clinical trial under a new IND requires a level of planning and paperwork that surpasses the process of many other national agencies.
Understanding how to successfully transition a clinical development program to the U.S. is crucial to advance your product toward the market and requires a thorough understanding of FDA regulations, documentation requirements, and strategic considerations. Read on to explore what it takes to navigate these challenges and how KreaMedica can help you successfully conduct clinical trials in one of the world’s most important markets.
Making the Transition to the U.S. between Program Phases
Two common circumstances might lead a pharmaceutical organization to transition its development program to the U.S. after the clinical program has already initiated:
- A U.S.-based company executes Phase 1 overseas, then brings Phase 2 back to the States
- An international client initiates their program locally, then wants to bring their program to the U.S.
Many programs are conducted entirely outside the U.S.. Once complete, they seek FDA approval. Sometimes, the program satisfies the FDA, and other times, the FDA doesn’t approve and the work to bring the clinical program to the U.S. is in vain.
Regardless of when you transition your program to the U.S., there are several factors to consider to successfully begin clinical trials in the U.S.
Risk Factors for Programs Developed Outside the U.S.
Clinical development programs always have risks, and those risks increase for projects that begin outside the U.S. Below are some common obstacles in obtaining agency approval for these programs.
- Nonclinical Data Submission
Meeting the agency’s nonclinical requirements to demonstrate the drug’s safety and efficacy is the first hurdle. Many Clinical Trial Application (CTA) processes in other regions (e.g. Europe, Canada, Australia) rely on the Investigator’s Brochure (IB) and nonclinical reports that are typically provided only when requested. In contrast, the FDA mandates that all nonclinical study reports be included in the IND, along with SEND datasets for toxicology, carcinogenicity, CV and Respiratory Safety Pharmacology and Embryo-Fetal Development studies. They will use the SEND data to conduct their own analyses, examining each toxicological finding to assess the benefit-risk profile for the proposed clinical trial. Regulators often take different stances or require different monitoring or restrictions on inclusion/exclusion criteria in a clinical trial based on potential risks identified in nonclinical studies.
Clinical data can help you overcome a nonclinical issue–– but it’s not a given. You must understand the potential risks of your nonclinical program and acknowledge that the FDA will do a detailed review. The FDA is meticulous and will leave no stone unturned when evaluating the risks associated with your program.
- Justification for Clinical Trial Design in IND Documents
You must ensure that your program presents adequate justification for clinical trial design in its IND documents.
When you’ve conducted studies outside the U.S., you must present all available clinical data to the FDA so they can thoroughly review and evaluate your program. A completed Clinical Study Report (CSR) should be included in the IND submission. The Investigator’s Brochure will provide a summary of available data and guidance to the investigator. The protocol itself should include appropriate justification for the study design. However, other documents can be provided in the IND to share more detailed justifications for the proposed clinical trial.
You want to present all available data to the FDA in the most thorough, transparent way possible as they consider your design. For example, suppose you have a patient population in Phases 1 or 2, you need to show how the efficacy and patient population you’ve studied outside the U.S. relates to the U.S. patient population within which you’ll conduct the study and eventually seek approval in the U.S. Are treatment guidelines and the standard of care the same across regions? Are there known differences in disease pathology or potential differences expected on pharmacokinetics of your product based on ethnicity? These are clinical data questions that you must answer with appropriate justifications.
- Data and Report Translations
All documentation including nonclinical study reports and clinical study reports must be submitted to the FDA in English. This means that a report written in a foreign language will need to have a certified translation for submission to the IND. Report translations are often forgotten or overlooked until just before submission. Plan ahead to ensure that resources are available for certified translation of reports stress during the final stages of IND submission.
- CMC Manufacturing Documentation
CMC data are a vital component of your submissions to the FDA. Some regions such as Australia are highly sought after for Phase 1 development because the requirements for the CTA are more streamlined and there may be cost savings in the form of tax credits. In Australia, the CTA is primarily a submission to the Human Research Ethics Committee (HREC). Typically, the Sponsor follows the Clinical Trial Notification process, which requires notifying the Therapeutic Goods Administration (TGA) of the trial but does not involve a formal review of study documents by the regulator. In this case, companies executing their Phase 1 in Australia don’t have to submit detailed CMC documents, such as Module 3, but can supply a high-level manufacturing summary.
When pharmaceutical organizations choose to bring their molecule stateside, the FDA requires CMC documentation in the eCTD format. You’ll need a full Module 3 included in the IND with all appropriate data to ensure that manufacturing is stage appropriate. In early development, you will not have a lot of manufacturing experience, but as the volume of data and experience in manufacturing grows, Module 3 will be updated to meet the stage of development. If you’re preparing to move the development program to the U.S. for a Phase 3 trial, you must provide a clear CMC manufacturing plan. This plan should demonstrate your ability to support compound supply for both the Phase 3 trial and the anticipated marketing application.
The Importance of Having a Pre-IND Meeting and the Right Team of Advisors
Regardless of why you’re considering bringing a clinical development program to the U.S., you need a pre-IND meeting to ensure the process goes smoothly.
Your first meeting for an indication always qualifies as a pre-IND meeting. When organizations plan to begin development outside the U.S. before bringing it in for Phase 2, having a pre-IND meeting before or while conducting your Phase 1 study can be helpful, especially if you already have a planned synopsis of the Phase 2 study. You can discuss nonclinical findings, seek advice on CMC and the acceptability of the proposed Phase 1 study to be adequate for a Phase 2 design. This can help identify risks or data gaps early and minimize the time between Phase 1 and Phase 2. Furthermore, if there are questions that arise in Phase 1, a second meeting as a Type C or Type D may be feasible prior to the IND filing.
Submitting an IND later in development means you will be providing a more extensive package, and the FDA only has 30 days to review and decide to clear the IND or place the IND on clinical hold. This can lead to receiving a lot of questions that you need to negotiate quickly. A pre-IND meeting allows you to receive helpful feedback before your IND submission, giving you more time and insight to prepare. The pre-IND meeting may also be considered a necessary milestone meeting such as an End-of-Phase 2 meeting.
Holding a pre-IND meeting gives your team more time to address potential concerns raised about the program or your data. If you want to counter the FDA’s concerns or evaluation of your program, you have that opportunity. When you file the IND, you can include additional justification or potential information that the agency raises as concerns, and you can address them when you file the IND.
As you prepare your IND, you want the right team –– clinical, CMC, and regulatory experts –– to assess your program. You need people in your corner to lead your pre-IND process and strategy who will:
- Craft the right questions
- Provide strategic guidance and risk assessments
- Collaborate with the team to understand key development issues to ensure questions are worded appropriately and your project has adequate justification.
At KreaMedica, we bring together the industry leaders in regulatory consulting to guide Sponsors through their pharmaceutical development journeys. We know what it takes to get your clinical development program to the U.S. and how to ensure a successful IND submission so you can continue your project on American soil.
Contact our team today to meet with a regulatory specialist who can help you successfully bring your program to the U.S. so that you can carry it to trial.