By Michael Cooper, Clinical and Regulatory Affairs, Pharmatech Associates
Most regulatory professionals could sketch a map of the pharmaceutical product development life cycle in short order, starting with the investigational new drug (IND) application as the first milestone, followed by Phase 1, 2, and 3 clinical trials, then new drug application (NDA) or biologic drug application (BLA) submission, followed by post-approval life cycle maintenance or Phase 4 clinical trials. These stepwise diagrams usually do not show the pre-IND meeting because it is an optional step. The pre-IND meeting takes place when the sponsor presents its planned Phase 1 study design, including the proposed patient population, inclusion or exclusion criteria to participate, and the primary, secondary, and exploratory objectives and endpoints. Later, the IND will include the Phase 1 protocol, and it is likely that it has been revised in response to agency feedback.
Sponsors should consider the pre-IND meeting as a necessary milestone. It is during this meeting that the sponsor presents their proposed product development plan and regulatory strategy to FDA and supports it with available safety and efficacy data. By asking a series of well-crafted questions, the sponsor requests agency feedback to move their product development forward. The responses can guide the rest of the regulatory strategy up to NDA/BLA submission in the fastest, most cost-effective manner.
Preparing For The Pre-IND Consultation
The purpose of the meeting is to present the FDA with safety and efficacy data, predominantly from animal studies, to obtain an opinion on readiness to start first-in-human (FIH) clinical trials. It is also an opportunity to identify any agency concerns about the proposed regulatory strategy. Appearing ill informed about the therapeutic indication being pursued could bias the FDA against the sponsor in future reviews and interactions. Similarly, if the sponsor does not present a well-thought-out clinical protocol, the agency could specify elements that then become binding. The key to avoiding these negative outcomes is to prepare.
Since the FDA allows pre-IND meetings for all investigational products — not just new molecular entities (NMEs) — it behooves all sponsors to request one. Should a sponsor skip this preliminary step and submit an IND, it is fine if the program development information is sufficient for the regulator to support FIH Phase 1 trials. However, such an approach leaves the FDA with limited options should it have a significant concern: it may respond by placing the program on partial or full clinical hold. This consultation is an opportunity to flush out any concerns that could lead to a clinical hold and subsequent program delay. It is important for sponsors to remember that regulators who have reviewed similar molecules can share useful advice concerning safety parameters to evaluate and submit in the IND and NDA or BLA.
A pre-IND meeting carries no cost for the sponsor beyond that associated with preparation, the meeting itself, and follow-up communications that include meeting minutes and responses or clarifications to agency questions. Avoiding unnecessary studies and obtaining FDA alignment with the regulatory strategy earlier means faster time to market and equates to lower program cost. Sponsors want to minimize the number of rounds of investor capital they request, as the funding often has strings attached.
Foremost, the pre-IND meeting offers an opportunity for the sponsor and the FDA project manager to get to know each other and start off the working relationship on the right footing. This meeting also allows the sponsor to educate the FDA on the molecule, particularly useful for an NME that has never been tested in humans before. This type of information exchange builds the foundation for a collaborative sponsor-agency relationship.
Accelerated Development Timelines
We’ve discussed that the information exchange focus can accelerate the timeline to approval because it could eliminate unneeded studies, ensure that proposed studies will satisfy the FDA, and minimize the potential for program delays during the drug development process.
A sponsor can use this time to discuss programs or strategies that expedite time-to-approval, such as the priority review designation, accelerated approval pathway, Fast Track designation, and breakthrough therapy designation.
Drugs that treat rare diseases — defined as affecting fewer than 200,000 people in the U.S. population — can apply for orphan drug designation (ODD). ODD brings its own set of incentives for the sponsor. Patent exclusivity is extended to seven years and the sponsor is exempted from user fees, which are currently $3,117,218.1 Sponsors can receive tax credits for expenses associated with clinical research conducted in the U.S.
Sponsors who obtain approval of an orphan drug for a pediatric rare disease also receive a rare pediatric disease priority review voucher. The voucher entitles the holder to a priority review for a marketing application (NDA or BLA). Because a priority review results in an FDA decision in six months instead of 10, they are worth a lot of money. Several recipients have sold their vouchers to larger multinational companies, fetching about $100 million.
3 Steps To Request A Pre-IND Meeting
For the sponsor, the first step is to identify the reviewing office and division within the FDA. For example, a therapy for multiple sclerosis will be reviewed by CDER’s Office of Neuroscience (ON), Division of Neurology II (DN II); whereas a therapy for breast cancer will be reviewed by the Office of Oncologic Diseases (OOD), Division of Oncology 1 (DO1). The reader may locate the applicable CDER review division on the FDA’s website.2 For biologic products, CBER performs application reviews in one of its three offices: the Office of Vaccines Research and Review (OVRR), the Office of Tissues and Advanced Therapies (OTAT), or the Office of Blood Research and Review (OBRR). Since the sponsor can request specific FDA attendees, knowing the FDA review office helps identify the appropriate personnel to invite.
The second step is to review all FDA guidance documents applicable to the targeted class of therapeutic products. Asking the agency a question it has already answered in a guidance document demonstrates a lack of preparedness.
The third step is for the sponsor to submit a formal meeting request and meeting package for a Type B meeting to the FDA. The FDA’s guidance document, Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,3 provides clear instructions on requirements and timelines.
Questions should be grouped by discipline (e.g., nonclinical, CMC, clinical) and provide sufficient background information for the reviewers. If travel for a face-to-face meeting is not possible due to the COVID pandemic, time, or cost constraints, then the sponsor may request video- or teleconference meetings or written response only (WRO) feedback. Note that if the agency deems a meeting unnecessary, they may elect to provide WRO feedback.
The Meeting Scope
For pre-IND meetings, the sponsor can expect preliminary responses not later than two calendar days before the meeting date. The sponsor should review these immediately for any insights offered, so that they can adjust their discussion in the actual meeting.
The format of the meeting is for the sponsor and agency to discuss the already submitted and reviewed questions and background information. Therefore, the sponsor is not expected to present any information unless asked to do so. An FDA representative will chair the meeting, which typically lasts one hour.
While there are no defined limits on how many sponsor participants may attend, a regulatory affairs representative should be the designated point of contact for all communications. Subject matter experts should be present to answer agency questions on manufacturing and process development aspects of CMC, analytical method aspects of CMC, nonclinical (including toxicology), and clinical (e.g., proposed study design, proposed study endpoints, inclusion/exclusion criteria, start/stop criteria, etc.). We highly recommend that the sponsor bring someone to take minutes. The FDA will also take minutes that will be considered the official record once they are finalized and agreed to by the sponsor. Most companies choose to take their own minutes and submit them to the agency.
The sponsor will have gained some knowledge of its molecule’s safety and efficacy through testing on animals by the time of the pre-IND meeting. Most programs will run in vivo tests in two mammalian species, one of which is non-rodent and most closely mimics humans. In vitro tests on liver cell lines can be used to identify the most relevant non-rodent species. In terms of safety, a no-observed-adverse-effect level (NOAEL) will be established in the relevant species, and this can be translated into a safe starting dose for humans by multiplying it with a species-dependent safety coefficient.
Safety pharmacology studies conducted on animals will have determined any adverse effects on the cardiovascular, central nervous, and respiratory systems. Genotoxicity studies will flag any potential for genetic damage, and carcinogenicity studies will assess the risk of inducing cancer.
Acute toxicity studies identify how high a single dose will cause toxicity, whereas repeated-dose toxicity studies determine dose limiting toxicity (DLT) from repeated (chronic) dosing. This knowledge should be provided as background information when asking the FDA if they agree with the proposed FIH dose.
Pharmacokinetics (PK) should be established at this point. Data will characterize how the drug is absorbed, distributed, metabolized, and excreted or if there is a particular organ that the drug or its metabolites accumulate in. Because test animals can be sacrificed to obtain drug-specific data, there should be a clear story to tell here. Provide this PK as background information to justify the proposed starting dose.
The previous paragraphs discuss safety; data from animal studies will demonstrate efficacy. Primary pharmacodynamic (PD) studies should have been performed in vivo (in test animals) and in vitro (in human cell lines) to confirm that the drug binds to the appropriate target. Present this data as justification for the starting dose.
CMC: Chemistry, Manufacturing, and Controls
First-in-human studies proposed by the sponsor should demonstrate a controlled process for manufacturing and testing drug substance/drug product to the expected level of quality, purity, and strength. The sponsor should have a strong understanding of the drug’s mechanism of action, of impurities in the process, and of potential impurities that develop over time through the performance of forced degradation and stability studies.
The agency wants assurance that the materials for Phase 1 studies are manufactured, tested, and released in the same way as they were for the nonclinical studies that justify testing in humans. The sponsor should also be thinking ahead to Phase 3 clinical studies and commercialization, where larger quantities of drug product will be needed. It is not unusual at a later step to move to a contract manufacturing organization (CMO) to produce at a larger scale. The sponsor will need to demonstrate comparability between manufacturing sites. Comparability studies are also required when making process changes (e.g., to increase manufacturing efficiency, to optimize an analytical method, etc.).
Early engagement with the FDA during a pre-IND meeting is valuable on many levels. The major advantage is dialogue, and any feedback that the agency provides could reduce the cost and time to approval. For this reason, all sponsors should consider the pre-IND meeting a necessary milestone along the product development life cycle.
About The Author:
Michael Cooper is associate director, clinical and regulatory affairs, at Pharmatech Associates. He has over 20 years of experience in the biopharmaceutical industry, with expertise in regulatory affairs chemistry, manufacturing, and controls (CMC) submissions; GMP inspections for biologics and vaccines; QA lot release of drug substance and drug product; deviation and CAPA resolution; and facilities, utilities, and equipment validation.