Executing A Smooth IND Submission (And Avoiding Clinical Holds)
By Life Science Connect Editorial Staff
The pharmaceutical industry has seen an unprecedented uptick in IND submissions in recent years, spurred, in part, by increasing research interest in novel and innovative advanced therapeutic modalities. But the route to a successful IND is riddled with potential setbacks, and establishing and executing a successful submission strategy hinges on identifying and fulfilling regulators’ expectations for a given drug across a range of variables.
In a recent live panel discussion hosted by Bioprocess Online, Daniela Drago, Ph.D., of NDA Partners, and Helen Kim, from Umoja Biopharma, regulatory affairs experts whose longstanding experience in the biopharmaceutical space has afforded them insights into the IND process, explored risk-proofing IND submissions. In “IND Success: Navigate Through the Regulatory Gray,” the pair explained some of the intricacies of pre-IND prep, detailed resources for crafting a submission, and explored some of the most common reasons for agencies to issue a clinical hold, as well as how to avoid them.
Pre-IND Planning For Successful IND Execution: A Primer
The most common mistake a biopharmaceutical company preparing an IND submission can make, according to Drago, is skipping a pre-IND meeting with a regulatory agency. The pre-IND meeting is an opportunity to interact with the FDA or other regulator before launching a clinical study; as such, it can represent a crucial opportunity for a company to gain insight and feedback regarding potential critical issues. While companies are not required to hold a pre-IND meeting, it is a strongly recommended component of a solid preclinical development strategy. This is because, in addition to serving as an opportunity to de-risk a potential IND application, it can also help to reduce time-to-market. It can help developers identify and avoid unnecessary studies, ensure that any proposed studies are well-defined, and foster a proposed strategy that has the nominal approval of the participating agency. Likewise, a pre-IND meeting may serve as a jumping-off point for a stronger relationship between a company and the FDA or EMA or may help nascent companies uncover knowledge gaps in their existing strategy critical to future success.
Another common mistake that can plague a biopharmaceutical company is failing to construct a well-written IND that is organized and easy to understand. Leaving out pertinent data, for example, can make it difficult for the agency to recognize the true value of a proposed study. Conversely, including massive amounts of data without adequately contextualizing it can significantly slow the review process. While the time required to develop an IND can vary greatly based on the modality, the sponsor, or the product itself, it can typically take about a year to craft the proposal, Drago said. Companies can often underestimate the amount of time it takes to provide a quality pre-IND briefing package, according to Kim, and some organizations may determine that the six months or so needed to craft one would be better spent on the IND itself – something she characterizes as “a big mistake.”
For cell and gene therapies in particular, prioritizing a pre-IND meeting can be crucial, as many of these modalities have far fewer historical successes to reference when compared to products like small molecule drugs. Neglecting a pre-IND meeting can result in scenarios where a company submits their IND only for the FDA to inform them that the animal model they selected for a study cannot adequately measure safety for the product in question, for example. In light of legislation passed in late 2022 rolling back animal testing requirements for new drugs, many drug developers may be on the lookout for significant shifts in the FDA’s requirements surrounding GLP tox studies, but any changes to protocol are likely to take time. Moreover, GLP studies are not always a requirement, Kim says, and determining whether they represent a necessary investment is another good reason to pursue a pre-IND meeting.
The Causes Of – And Cures For – Clinical Holds
Many developers have noted an uptick in recent months regarding the number of clinical holds issued by the FDA. A clinical hold, an order to delay a proposed clinical investigation or to suspend an ongoing one, can come in many different forms and for many different reasons. According to the agency’s own numbers, between 2017 and 2021 it halted clinical activity an average of 664 times per year, up from an average of 557 holds per year between 2001 and 2016. The agency may choose to enact either a complete clinical hold or a partial one, Kim explained, adding that for an initial IND a complete hold barring a sponsor from commencing clinical studies is more likely, often due to concerns surrounding quality or CMC. A partial hold is more likely for an active IND with studies up and running, where one study is flagged by the agency and consequently put on hold.
Part 312 of Title 21 of the FDA’s Code of Federal Regulations outlines that the agency may put all or part of an IND on a clinical hold if “human subjects are or would be exposed to an unreasonable and significant risk of illness or injury; clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND; the investigator brochure is misleading, erroneous, or materially incomplete; [or] IND does not contain sufficient information required under § 312.23 to assess the risks to subjects of the proposed studies.” The agency outlines additional rationale for placing a hold for drugs found to introduce the potential for “reproductive or developmental toxicity” in patients with reproductive potential. Phase 2 or 3 studies under an IND are likewise subject to these standards and may be placed on hold if the agency identifies deficiencies in studies or approach that may preclude an IND from meeting its stated objectives.
Whatever the flagged issue, whether the need for additional manufacturing steps or revised animal studies, a clinical hold has the potential to significantly delay an IND, Kim said. According to research published in the Journal of Investigative Medicine in 2016, issues with CMC strategy were the most cited reason for a hold, followed by clinical issues and problems with the toxicology approach. In another paper published in Regulatory Toxicology and Pharmacology in 2020, investigators performed a systematic analysis of oncology INDs and found that the most common reasons for holds placed on these modalities were clinical, followed by concerns related to pharmaceutical quality and nonclinical development. Far from a minor obstacle, clinical holds represent a highly disruptive roadblock for INDs, as no clinical activity can move forward until all the deficiencies outlined by the agency are addressed. This process can take a minimum of 60 days, Drago explained, or it can drag on for years, and may, in either scenario, signal to stakeholders and investors that there are potential issues with the product itself. Depending on the reason for a clinical hold, such a scenario could also impact the reputation or credibility of the sponsor, she added.
A clinical hold often results in a heavy lift for sponsors, who must notify health authorities in other countries where applicable, as well as stakeholders, Institutional Review Boards (IRBs), and sites. Often a clinical hold serves to halt a program, delaying the necessary data for a marketing application and creating a wide-ranging impact, particularly for companies with a single product, Kim said. The clinical hold process can be very back-and-forth: the FDA may issue an explanation within 30 days of the hold, which a sponsor must then respond to in writing, which the agency then has another 30 days to review. This can greatly impact timelines, ultimately delaying commercialization, Kim added.
An Ounce Of Prevention: How To Avoid A Clinical Hold
The potential ramifications of a clinical hold on a program can be disastrous. So, what are the best ways to avoid one and keep clinical development on track? According to Drago, selecting the right (or wrong) animal model for toxicology testing can represent one of the most important early decisions a sponsor can make. Likewise, affording special attention to the CMC section of an IND package is critical, she noted, as proving the manufacturing process is controlled adequately and does not introduce impurities is a facet of a proposal FDA reviewers evaluate very carefully. Drago also recommends documenting a reasonable expectation of safety in the program’s informed consent documentation; although the FDA does not routinely require this documentation, it may request it for certain high-risk patient populations or specific therapeutic areas, she said. Finally, engaging the right experts in order to understand every potential pain point is crucial to circumventing the issues that result in clinical holds.
Another big mistake sponsors can make is to have a pre-IND meeting only to decide not to pursue certain recommendations that emanate from that meeting, Kim said. She recommended laying out any concerns resulting from that pre-IND meeting and where they have been addressed within the IND in order to demonstrate that their guidance is taken seriously. Drago added that if a sponsor is notified of a clinical hold, it is beneficial to try to glean as much information from that initial contact as possible to begin to formulate a strategy even before formal reasoning is issued. By learning as much as possible, even during this brief interaction, a company can begin aligning internally to prepare solutions. Asking whether the hold is full or partial, for example, can help inform next steps and prevent interruptions for existing participants, Drago said. While it is possible to follow up with the FDA, any delay in response can affect dosing timelines, making it critical to collect pertinent information on that first call.
The probability of encountering a clinical hold is not insignificant. Sponsors should therefore familiarize themselves with the FDA’s guidance document, “Submitting and Reviewing Complete Responses to Clinical Holds,” which provides details on how to adequately respond to a hold. For those pursuing cell and gene therapies, another document that can offer critical insight into how the FDA handles clinical holds is its own standard operating policy and procedure (SOPP), SOPP 8201: Administrative Processing of Clinical Holds for Investigational New Drug Applications. By familiarizing themselves with FDA procedure, convening internal stakeholders, and launching a thorough review of any and all agency feedback, sponsors can help minimize the time lost to a clinical hold and strengthen their IND package for subsequent review.