Development of advanced analytical methods for the characterization of complex generics | RFA FD 22 013

FAQs: FDA Grant RFA-FD-22-013 (Complex Generic Drugs: PS Oligonucleotides)

What is the focus of FDA grant opportunity RFA-FD-22-013?

This funding opportunity focuses on strengthening scientific and analytical tools needed to evaluate and develop generic versions of complex drug products, specifically synthetic oligonucleotide medicines that cannot be fully characterized using routine testing.

Why is the FDA emphasizing better analytical methods for these products?

The goal is to create clearer links between measurable product attributes and real-world performance factors such as quality, safety, and efficacy. More capable analytical methods can reduce uncertainty in generic development and support more reliable assessments of whether a proposed generic is truly comparable to its reference product.

Which type of oligonucleotides are at the center of the research objective?

The opportunity centers on phosphorothioate (PS) oligonucleotides, which are modified nucleic acid drugs where a non-bridging oxygen in the phosphate backbone is replaced with sulfur.

What makes phosphorothioate (PS) oligonucleotides challenging to characterize?

The sulfur substitution creates chiral centers at each PS linkage, resulting in mixtures of diastereomers. These diastereomeric patterns can be subtle and difficult to resolve using basic identity or purity testing, yet they may influence how the drug performs.

What are diastereomers in the context of PS oligonucleotides?

Because each phosphorothioate linkage becomes chiral, multiple stereochemical variants (diastereomers) are possible across the oligonucleotide backbone. A final PS oligonucleotide drug product therefore contains a distribution (pattern) of diastereomeric forms rather than a single stereochemical species.

Why does the diastereomer composition matter?

The opportunity notes that diastereomeric patterns may influence properties such as stability, binding behavior, pharmacokinetics, and potentially biological activity. Understanding and measuring these patterns can therefore be relevant to quality and comparability assessments.

What does the FDA want applicants to develop under this grant?

Applicants are expected to develop advanced analytical methods capable of analyzing and understanding the diastereomer composition of PS oligonucleotides. The methods should go beyond basic tests and be able to resolve, measure, and compare stereochemical distributions that could be important to product performance.

Which reference (model) drug products should be used in the proposed research?

The grant calls for using either TEGSEDI (inotersen) or SPINRAZA (nusinersen) as the model (reference) product for method development and analysis.

Do applicants have to choose between inotersen and nusinersen?

Based on the summary provided, the work is expected to use either TEGSEDI (inotersen) or SPINRAZA (nusinersen) as the model product, meaning applicants should select one of the two as their reference for the proposed studies.

What are the two main research questions the proposed studies should address?

The studies are organized around two core questions: (1) characterize and better understand the diastereomer composition present in the selected model product, and (2) examine whether, and in what ways, manufacturing processes can shift or shape diastereomeric distributions in the final drug product.

What does it mean to "characterize and better understand" the model product's diastereomer composition?

It means building a detailed analytical picture of how the reference product is distributed across diastereomeric forms, potentially including how reproducible that profile is and what molecular or sequence features may drive the observed distribution.

Why is the manufacturing process part of the research objective?

The opportunity specifically calls for evaluating whether manufacturing processes can change diastereomeric distributions. This is intended to identify process-related sources of variability and determine how sensitive the diastereomer profile is to process choices, which is directly relevant to assessing sameness or meaningful differences.

How does this research support generic drug development?

By improving the ability to characterize and compare complex PS oligonucleotide products, the work can reduce uncertainty in demonstrating comparability between a proposed generic and its reference product, supporting more reliable regulatory assessments.

Is the work expected to be useful beyond the selected model product?

Yes. A key emphasis of the opportunity is transferability. Methods developed for the model PS oligonucleotides should be broadly applicable to other synthetic oligonucleotide drugs.

Does the FDA expect the outputs to support quality control?

Yes. The opportunity highlights that the knowledge gained could support quality control, implying the outputs should be useful not only for research comparisons but also for routine or semi-routine assessment frameworks that improve confidence in product consistency over time.

What agency is offering this funding opportunity?

The funding opportunity is offered by the U.S. Food and Drug Administration (FDA).

What type of funding mechanism is used?

The opportunity uses a cooperative agreement mechanism. This typically indicates substantial programmatic involvement from the agency compared with a standard grant.

What is the CFDA/Assistance Listing number for this opportunity?

The CFDA/Assistance Listing number is 93.103.

What is the award ceiling listed in the opportunity summary?

The listed award ceiling is $300,000.

When was the opportunity created and when did it close?

The opportunity was created on 2022-01-12 and originally closed on 2022-03-07.

Is the number of awards specified in the provided summary?

No. The summary states that expected awards information was provided in the source listing, but it does not specify the number of awards in a clear way.

Who is eligible to apply?

Eligibility is broad and includes public and private institutions of higher education; nonprofit organizations with or without 501(c)(3) status (as long as they are not higher education institutions in the categories noted); for-profit organizations (including small businesses and other than small businesses); and many government entities such as state, county, city or township governments, special districts, independent school districts, public housing authorities/Indian housing authorities, and federally recognized or other tribal governments and tribal organizations.

Are minority-serving institutions specifically encouraged to apply?

Yes. The FDA notes that institutions such as Hispanic-serving institutions, HBCUs, tribally controlled colleges and universities, Alaska Native and Native Hawaiian serving institutions, and AANAPISIs are encouraged to apply.

Are foreign (non-U.S.) entities eligible?

Yes. The opportunity allows participation by non-U.S. entities: foreign institutions are eligible, non-domestic components of U.S. organizations may apply, and foreign components are allowed as defined by HHS grants policy.

What types of government entities are listed as eligible?

The opportunity lists state governments, county governments, city or township governments, special district governments, independent school districts, public housing authorities/Indian housing authorities, and federally recognized or other tribal governments and tribal organizations as eligible applicants.

What is the overall purpose or intended impact of the grant?

The grant is designed to catalyze advanced measurement science for stereochemical characterization in PS oligonucleotides, with a clear line of sight to improving generic oligonucleotide development and strengthening regulatory-grade quality control approaches.