FDA’s drug development tool-focused ISTAND pilot accepts its first submission

Nearly two years after the creation of a pilot program intended to assist with the development of novel drug development tools, the FDA has announced that the first-ever submission has been accepted to the program, known as ISTAND. But even as the tool is the first through the gates, it’s likely to be years before the tool is ready for full qualification.


Regulatory Background

  • Drug Development Tools (DDTs) are generally used to evaluate or create clinical endpoints and can include things like clinical outcome assessments, biomarkers and animal models. In short, they demonstrate that a method, material or measure is meaningful and can be relied upon during the drug development process.
  • To expand the use of DDTs, the FDA maintains a qualification process. According to the FDA, which published a guidance on the subject in November 2020, “qualification means that a DDT and its proposed context of use can be relied upon to have a specific interpretation and application in drug development and regulatory review.” The qualification process itself is a relatively recent addition to FDA’s regulatory toolbox. The 21st Century Cures Act established a “statutory process for qualifying DDTs.” Prior to the Act, the FDA had already started providing recommendations on DDTs, but the recommendations were limited in scope compared to those required under the Cures Act.
  • Qualification of a DDT is important in two ways. First, it signals to a sponsor that its proposed use of a tool for a trial or other development program is proper, which adds predictability to the review process. Second, because the qualification is public, it signals to other developers that a DDT may be used in the development of drugs for the same (or similar) conditions.
  • DDTs are qualified for a specific context of use (COU). The FDA explains the COU “defines the boundaries within which the available data adequately justify use of the DDT.” As new data become available, developers may also request to “expand upon a qualified COU.” The statutory process under Cures provides for “transparency provisions that includes information in the qualification submissions and FDA’s Determination Letters in response to such submissions” to foster collaboration and the broader use of such tools. Thus, the FDA publishes information on qualification programs on its DDT Qualification Programs webpage.
  • There are currently three types of DDT qualification programs: biomarkers, clinical outcome assessments (COA) and animal models (although it notes other programs can be added if needed). Biomarkers can be defined using the BEST glossary, a “taxonomy for classifying and developing biomarkers and other DDT-related scientific topics.” COA qualification programs (COAQPs) currently have four different type of measures: patient-reported outcomes (PROs), observer-reported outcomes (ObsRo), clinical reported outcomes (ClinRO) and performance outcomes (PerfO). Lastly, the animal model qualification program (AMQP) can only be used for animal models that are used to support applications that rely on the Animal Rule. Animal models used to inform clinical studies are not eligible under this program. [ For more information on DDTs and the qualification process, read AgencyIQ’s analysis here.]

In December 2020, the FDA launched a pilot program called ISTAND, focused on novel DDTs

  • The ISTAND pilot program, which stands for Innovative Science and Technology Approaches for New Drugs, aims to “provide scientific and logistical support to DDT developers and to FDA’s clinical divisions for timely incorporation of novel technologies and scientific approaches in drug development and regulatory review,” with the ultimate goal of getting new therapeutics to patients faster.
  • The intent of the program is to provide greater collaboration and flexibility, the FDA explained. Unlike the typical DDT qualification process, the ISTAND program allows for a wider variety of submission types and creates more opportunities for developers to work with the FDA. “We wanted to give these newest-of-the-new tools a regulatory home,” said Steve Berman, the FDA’s lead for ISTAND, in a blog post. He explained that new types of DDTs like data collection or analysis methods, “tissue chips,” and certain digital health technologies (such as artificial intelligence or sensor-based technologies used in clinical trials) were exemplary of the types of novel products the FDA hoped to review under ISTAND.
  • However most notably, the ISTAND pilot program does not require the tool seek qualification. While some applicants of novel programs may be considered eligible and will go through the qualification process, programs that are not fit for qualification but may provide value to drug development can instead benefit from meetings with FDA staff, the development of white papers, or FDA guidance, all in order to gain FDA input and further the DDT’s long-term development.
  • Another key benefit to developers is assistance. The program provides benefits including the receipt of FDA feedback early in the development process. That’s key for novel development tools like that those are AI-based and might require a more hands-on approach.
  • At the time the program was announced, FDA indicated that another key feature of the program would be its transparency. “Submissions to the ISTAND Pilot Program that are admitted for review and deemed appropriate for qualification as an outcome are subject to the transparency provisions of the 21st Century Cures Act,” FDA wrote. This transparency was intended to allow all drug developers to benefit from the qualification process, thereby accelerating development for multiple therapies in a given therapeutic area.
  • However, since launch the FDA has said relatively little about the program, leaving regulatory analysts to speculate about the fate of the program.

Now the FDA has indicated the program has reached a critical milestone: The acceptance of its first submission

  • On September 7, 2022 FDA announced that its Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) had accepted the program’s first submission under its qualification pathway.
  • The prospective tool, accepted by the FDA into ISTAND in July 2022, is being developed by Integral Molecular and is intended to improve the safety profiling of investigational biotherapeutic products using something called the Membrane Proteome Array (MPA). At present, the company’s context of use is quite broad, applying to nearly every biotherapeutic modality including CAR-T cells, bispecifics, peptides and immunoglobulin products.
  • According to the company, the tool’s principal use is to assess antibody specificity “to assess unintended binding of monoclinal antibodies that can result in safety and toxicity issues.” MPA includes a collection of thousands of proteins “encompassing nearly the entire human membrane proteome,” helping it to detect issues that may affect the safety of monoclonal antibodies, bispecifics and CAR-T products, among others.
  • The FDA has told the company it should consider “prioritizing and limiting the modalities in your initial COU to those for which data can be submitted” to support its use. The implication gleaned from the FDA’s determination letter is that the FDA may otherwise not be able to qualify the tool without a substantial sum of supporting data, or that a more expansive proposed use would require considerably more time to review.
  • FDA offered an extensive list of other constructive critiques as well, asking for data to support various statements, including that the MPA “has now been used to test the specificity of hundreds of biotherapeutics from different biotech and pharmaceutical companies as a commercial research service,” and that many companies already support their clinical filings using MPA data. It also offers various analytical considerations regarding validation of the company’s assumptions and testing.

What’s Next

  • The acceptance of the Letter of Intent (LOI) into the program is likely to be helpful for a variety of different reasons. First, it shows what FDA regulators are most likely to be focused on during their ISTAND tool reviews and offers a roadmap for companies wishing to participate in the ISTAND process to avoid likely concerns. Second, the prospect of a validated tool may benefit developers of advanced cell-based therapies and bispecifics, which must currently undertake such work on a case-by-case basis (i.e., proving the approach is suitable for their specific product). A qualified tool helps to de-risk part of the assessment process and potentially improve the likelihood of clinical success.
  • That being said, it’s far from clear if the program will be the success that FDA clearly thinks it could be. It’s been nearly two years since the launch of the program, and this is the first accepted LOI. It’s not clear how many other companies have submitted LOIs, or how many the FDA is prepared to accept each year, although it has said it expects to accept being two and four submissions “each year, with a triage and selection process that focuses on public health impact and feasibility of implementation.” Based on the reference number given to Integral Molecular, DDTIST00006, we can estimate there are at least five other applications under review. Notably, the ISTAND pilot is not mentioned in the latest Commitment Letter for the PDUFA VII agreement even though DDTs and qualification are mentioned extensively.
  • It’s also not clear how long the qualification process will take. As compared to FDA’s traditional DDT qualification process, ISTAND’s emphasis on novel products is likely to make qualification even more difficult. FDA’s emphasis on asking Integral Molecular to focus on a narrowed COU is perhaps a reflection of the difficulties ahead for this first ISTAND qualification. FDA has indicated that the qualification process involves three steps: The acceptance of a Letter of Intent, the development of a Qualification Plan, and the publication of a Full Qualification Package. Based on data from qualified DDTs contained within FDA’s DDT database, the full qualification process is likely to take several years at least – if it’s successful at all.

Featuring prior research by Kedest Tadesse and former AgencyIQ analyst Lily Rosenfield.
To contact the author of this piece, please email Alec Gaffney ( [email protected])

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