Clinical trials are complicated.
And when embarking on a new clinical program, the regulatory requirements and logistical planning can often seem daunting, if not completely overwhelming. Depending on the product and indication, there may be existing guidance or precedence to support the proposed development pathway and study designs for the clinical program.
But keep in mind: if the product or proposed pathway is innovative or controversial, the sponsor may need to rely on internal experts and consultants to outline the clinical development program, with often limited input from regulatory authorities. Not to mention, if the initial clinical study involves investigational treatment for a US product not yet approved for marketing, it will likely require an Investigational New Drug application (IND) submission to the Food and Drug Administration (FDA) before enrollment can begin.
The IND Timeline
Following initial IND submission, the FDA review period is 30 days before either A) granting IND clearance, giving the study the green light to proceed; or B) placing the study in complete or partial clinical hold, delaying or completely suspending all clinical activity until the clinical hold issues are addressed by the sponsor. If FDA reviewers have questions or requests regarding particular aspects of the IND, these may be provided to the sponsor during the 30-day review period by the assigned FDA Regulatory Project Manager (RPM), with a prompt deadline for the sponsor’s responses to be sent back to FDA for consideration.
However, if there are extensive issues with the IND, or if the reviewers don’t complete their review and provide questions in advance of the 30-day review clock running out, FDA’s findings may be provided to the sponsor at the end of the review period, along with FDA’s intention to place the study on clinical hold, which may delay the start of the clinical study and then prolong the overall development program.
Note once the IND is cleared by FDA, subsequent IND amendments (including submissions of new protocols) don’t require a 30-day waiting period before initiating the respective clinical study. However, the study is still subject to a clinical hold order from FDA at any time if the study or program is deemed too risky or if the IND is found to have a major deficiency.
Avoiding the Impulse to Start Your Trial Too Soon
Careful planning and management of start-up activities are critical to shortening the time between IND submission and First Patient In (FPI). So, taking a sequential approach to regulatory and ethics board submissions is recommended whenever possible, with ethics board submissions ideally occurring after IND submission and clearance.
Although clinical study documents may be provided to sites and submitted to institutional review board (IRBs)/independent ethics committees (IECs) before IND submission, some ethics boards request documentation showing the IND for the proposed study is active prior to reviewing and approving the study. Thus, submitting to ethics boards before the IND is cleared may not save any time in the downstream approval process.
Since FDA may request modifications to the protocol design prior to study start, it’s often preferred to wait until after the IND is submitted and the initial 30-day review period is completed to then implement any changes to the protocol or study documents required by the Agency prior to ethics board submission(s). Waiting until after the IND is cleared to submit to the ethics boards can then prevent unnecessary re-work, saving time and money in the process.
Ideal Model vs. Real-world Priorities
The goals of study start-up should focus on high-quality deliverables on time and within budget. But that isn’t always the case. Timelines are often the primary focus of study start-up targets, with the objective to complete start-up activities as quickly as possible to reduce time to FPI and hopefully reduce time to study completion.
It’s important to evaluate and adjust the submission strategy to accommodate the program’s overall goals and sponsor preferences, taking into account business needs and any existing commitments associated with study conduct (e.g., milestone payment from investment partner contingent on IND clearance or initiating enrollment), so these items should be considered when planning the study start-up strategy.
Learn to Walk, Then Run
Despite the complexities of product development, it’s still possible to design and implement a clinical program that is scientifically sound, clinically responsible, and operationally efficient. Taking the time to fully plan the submission strategy upfront before diving into the start-up pool will set your study up for success from day one.
by Lauren Neighbours, PhD, RAC
US Head Regulatory, PSI CRO