Consider the following scenario:  You’re an entrepreneur with a novel concept for development. You were successful in creating a company and gaining funding for your project, and just completed your first proof-of-concept clinical trial, with positive results. Further, you’re in the lucky minority of projects that hits its primary endpoint in the first trial, and now are inspired to start thinking about planning for Phase III. This is, of course, the situation that all new entities hope to be in following their initial trial(s). As you talk with potential pharma partners and investors, depending on the nature of your first trial and the regulatory requirements for your program, you may be considering different pathways for development. Note that there are specific toxicology, manufacturing and regulatory requirements once you start talking about Phase III. In this installment of OPDI, I’ll discuss some general concepts to help frame the key activities you need to prepare for.

The Food and Drug Administration generally looks for replicated data from two well-controlled efficacy studies (with placebo control or appropriate active control with standard of care), with pre-specified endpoints at timepoints meeting FDA expectations, proper statistical analysis and powering (“pivotal” trials) to support the submission of the NDA. What often happens in ophthalmology, particularly with a topical drop formulation, is that an early clinical trial may be a robust Phase II in patients with the condition, with clinical endpoints that match what the FDA requires for submission of the eventual NDA/BLA. In these cases, the trial may already have been powered sufficiently at that stage—given the history and reliability of the clinical endpoint or precision offered with specific, acceptable clinical models—and there’s a possibility that the early trial may actually serve as one of your pivotal trials. Examples may be new drug products for allergic conjunctivitis, postop inflammation, some cases in dry eye or an orphan indication for which the FDA will accept the initial trial as pivotal. Your options for the next steps may be a confirmatory Phase II for further dosing evaluation, investigating other aspects of the drug efficacy; or a Phase III trial. In some cases, your next study may be referred to as Phase II/III, such that it is set up to be a pivotal trial. In your discussions with potential partners, different companies may give you different inputs for planning, which will require you to evaluate the differences in such factors as activities, time and cost between having your next trial be a follow-on Phase II, a pivotal/Phase III, or maybe even the second pivotal trial. There certainly is more complexity than simply repeating the first trial as quickly as possible to move to your NDA filing.

Regulatory

At this juncture, an end-of-phase-II (EOP2) meeting with the FDA will likely be your next step. As we’ve discussed in prior columns, be mindful that you need to time the meeting based on when you will be ready to submit your detailed briefing package with sufficient information to address the specific questions you are looking for input on from the agency. Usually, you may be looking at an approximate three-to-four-month timeframe from the time you request the meeting to the actual meeting. In this scenario, the key topic you’re focused on at this point is confirming the ability of your completed trial(s) to serve as a pivotal trial(s), or firming up plans for your Phase III study designs. 

If this is your first time through this process, be mindful to set expectations for your team, board and potential partners/investors that they can’t expect the FDA to provide a definitive response on final acceptance until the full information is filed in the NDA. But you should be able to get helpful guidance on the potential acceptability of the data for filing the NDA, subject of course to FDA review of the full and complete data package. This is the time to confirm with the FDA your plan for nonclinical toxicology studies, required for initiation of your next trial and for the ultimate NDA submission. Therefore, the EOP2 meeting is often the time to define what’s expected for these activities, so you can map out your funding plans and timelines to support your discussions with partners and investors.

You have to balance your eagerness to have this meeting as soon as possible, to confirm the clinical plan, with your ability to have all the information you need for a good meeting. You may not have all your manufacturing information ready for the meeting, but keep in mind you can have a separate follow-on meeting specific to chemistry, manufacturing and controls (CMC), so that, if it makes sense in your situation, you can move towards your EOP2 meeting to discuss clinical needs as soon as possible.

One item the EOP2 meeting specifically triggers is the need to file your pediatric study plan (or request a waiver for it) within 60 days of the meeting. Though this is generally pretty straightforward, it’s something to keep in mind for your activity and resource planning during the EOP2 meeting stage.

Toxicology

Your toxicology needs to cover length of intended dosing, and with a dose and frequency that meets­—and preferably exceeds—that planned for the clinical trial. If your planned Phase III trial is longer in duration than your Phase II and the toxicology studies from your IND filing, then you’ll need longer-term toxicology data prior to the Phase III. In some cases, for example, an efficacy study may just be one to three months in duration. However, if the indication is chronic dosing, then your NDA will ultimately need longer term chronic dosing. Thus, if your earlier toxicology work was shorter in duration, you’ll need longer chronic toxicology data (typically six to nine months in duration of dosing) prior to this long-term safety clinical trial, but it may not necessarily be needed for your next efficacy trial. Keep in mind that you can design that longer term toxicology to already cover your needs for the NDA. You should also prepare to determine when to start your chronic toxicology work based on the dosing required, reporting time, and when you desire to start that long-term clinical study. Also note that, for biologics, you need to do the toxicology in animal species that have cross-reactivity to your product.

Other requirements that you’ll want to discuss and clarify with the FDA include the remaining studies needed for your program, such as ocular distribution, reproductive toxicology (and any applicable waivers for it based on limited systemic absorption), remaining genotoxicity and any other toxicology with systemic dosing needed to support the chronic dosing. Often, these are more NDA items that may not be rate-limiting for starting your next trial, as long as the original toxicology that supported your IND and prior trial covers the duration of dosing.

Also note that, if you have further formulation optimization work to do as you shift to your scaled-up manufacturing, you may need to repeat the toxicology prior to the next study. This also should be discussed with the FDA at your EOP2 meeting.

CMC

There are a couple of key items related to manufacturing that drive timelines that you’ll need to consider. 

At least one of your planned pivotal trials for filing needs to be conducted with the final formulation, container closure and manufacturing process done at the final facility. Thus, if you’re shifting facilities, consider the timeline for the tech transfer, any scale-up that may require additional initial manufacturing batches and contracting/scheduling issues. Your NDA will also require at least 12 months’ stability on three registration batches at representative commercial scale (there will be scale-up activities to account for this). While your registration batches may not be rate-limiting for your efficacy trial, you also need to take this timeline into account in your early Phase III planning, to account for scale-up and preparation of these batches so you have the required stability for submission. This also becomes part of your discussions with potential pharma partners, and how they may look to plan for scale-up and commercial manufacturing to prepare for launch. In cases where the clinical trials are shorter in duration, such as those that can have patients block enrolled with an acute condition, or in high volume indications such as allergy, post-surgical inflammation, certain cases in dry eye, etc., the rate-limiting step for your submission may be integrating the 12-month stability data from your registration batches. Therefore, early planning is key.

Of course this was not an exhaustive list, and you should conduct development planning and full gap analysis with the appropriate experts that your specific situation calls for, and confirm your plan with the FDA. There are also items, such as commercial activities, that you need to start mapping out if you anticipate quickly transitioning to Phase III. This type of work could be the topic of another column in itself, but just keep in mind the market research and payors analysis for reimbursement that pharma partners and investors may want to see at this point prior to a major deal. Also, be cognizant of where this all fits from a timeline perspective in the context of development activities and a pharma deal or financing. 

In conclusion, I hope this overview helps serve as an initial framework for a few of the considerations surrounding the transition to Phase III.

Mr. Chapin is a senior vice president of the Asset Development & Partnering Group at Ora.  The company offers drug, biologic and device consulting; and preclinical and clinical research execution, regulatory, and development strategy to support its clients and partners. Review and comments on this column were provided by Aron Shapiro, partner in the same group at Ora.

The author welcomes your comments or questions regarding product development. Please send correspondence to mchapin@oraclinical.com or visit www.oraclinical.com.