Operation Warp Speed for Rare Diseases: Expected Boom in Drug Development and Approval

Rapid growth in gene therapy is expected to receive additional support as the Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER) prepares to launch Operation Warp Speed for Rare Diseases.

Gene therapy has achieved notable successes, particularly in treating resistant or refractory B cell leukemias (achieving overall response rates around 90% or greater) and the speed with which COVID-19 vaccines were developed under the original Operation Warp Speed.

Now, FDA’s CBER is setting its sights on making ambitious strides toward tackling rare diseases.

Why Warp Speed for Rare Diseases?

The 1983 Orphan Drug Act defines a rare disease as a disease or condition affecting less than 200,000 people in the United States. There are over 7,000 rare diseases affecting more than 30 million people in the U.S., many of which are life-threatening. Most rare diseases do not have treatments. The Orphan Drug Act creates incentives for developing orphan drugs to treat such diseases.

Given the relatively small populations affected by any one rare disease or condition, a pharmaceutical company developing an orphan drug may reasonably expect the final approved drug to generate relatively small sales (when compared with the drug development costs) and consequently incur a financial loss.

However, recent advancements in the clinical use of recombinant DNA (rDNA) technology creates opportunities for changing this calculation and addressing a great, unmet medical need.

“I am very excited for the field because I feel like we’re beginning to get to a critical mass, where a single method or product can be deemed safe and then adapted for many uses,” said Dr. Peter Marks, head of FDA’s CBER – the organization responsible for regulating gene therapies.

Many rare diseases, like cystic fibrosis and sickle cell anemia, are monogenic in nature, caused by mutations to single genes. From a technical standpoint, such diseases should be easier to treat with current gene therapy technology. (More common diseases caused by multiple genes, like cardiovascular disease or diabetes, are less ideal targets, as they pose greater challenges with current capabilities.)

FDA CBER began issuing approvals for gene therapies in 2015 and issued the first approval for a rare disease gene therapy in 2017, with the second rare disease approval issued in 2019. The pace has since increased: 2022 and 2023 each saw three approvals issued. Operation Warp Speed for Rare Diseases looks to accelerate both drug development and approval.

According to Dr. Marks, “…[I]t would be a shame if all we manage to do, every year in the next few years, is approve another two or three gene therapies—that’s a failure,” he said. “Success would be…, if not exponential, at least some logarithmic progression here toward more and more gene therapies being approved.”

What is the FDA Proposing to do?

The FDA plans to launch Operation Warp Speed for Rare Diseases in 2023 with a focus on increased communication between the agency and drug and biotech companies. This will aid clinical development and preparation for investigational new drug (IND) and biologics license application (BLA) submissions.

The project should also help clinical research sponsors take advantage of various FDA pathways for accelerated review and approval. The enhanced guidance could involve a discussion regarding the use of surrogate endpoints thought to predict clinical benefit. To simplify the regulatory submission process, regulators could rely on what’s known about one gene therapy to inform the regulatory review of another investigational product utilizing similar gene delivery mechanisms.

The FDA has already taken steps to increase efficiency and bandwidth for the review of gene therapies. The agency’s Office of Tissues and Advanced Therapies (OTAT), which reviews gene therapies, has been elevated and is reorganized as the Office of Therapeutic Products.

This project seeks “to improve functional alignment, increase review capabilities, and enhance expertise on new cell and gene therapies… to further accelerate the pace of development of therapeutics for very small populations with very high medical need.”

How Can Research Professionals Mitigate Risks with Engineered Genetic Materials?

Gene therapy products may pose unknown risks, and Dr. Marks said there is much to learn about the field.

“We still have much to learn about how gene therapy products work, how to administer them safely, and whether they will continue to work properly in the body without causing adverse side effects over long periods of time,” Dr. Marks said. “[W]e may need to accept some level of uncertainty around these questions at the time of approval.”

The risks associated with the research of engineered genetic materials are why the National Institutes of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) provide the standard for oversight of research involving genetic engineering and gene therapy.

NIH Guidelines are promulgated by the NIH Office of Science Policy (OSP), and call for local oversight at the research site by an institutional biosafety committee (IBC) reporting to the NIH OSP.

IBCs are charged with protecting study personnel, the community, and the environment from exposure to engineered genetic material. An IBC may also advise the IRB to aid in assessing risks to the study participants.

The IBC review requirement applies to gene therapy research at sites that receive funding from the NIH or that have ever participated in NIH-funded research. Sponsors or sites that have received any NIH funding are obligated to comply with IBC review regardless of whether the funding is associated with the gene therapy study.

In cases where the agency did not provide monetary support, IBC review may still be necessary if the NIH collaborated in the research of the study agent or provided materials for its development (NIH Guidelines Section I-C-1-a-(2)).

Even if there are truly zero NIH funds or collaboration involved, IBC review is considered a best practice.

What Should Sites do to Prepare for Operation Warp Speed for Rare Diseases?

The best way a site can prepare to participate in gene therapy studies is to register an IBC with the NIH and become familiar with the basic requirements for IBC review.

Each site’s IBC must first register with the NIH OSP before convening a meeting or issuing an approval. The NIH OSP will review the proposed committee members’ qualifications to confirm the IBC meets the NIH Guidelines’ requirements.

The NIH OSP review of a site’s IBC registration may take four to six weeks. Sites can compress timelines by registering their IBCs well before having a new study for IBC review. This way sites are ready to start the IBC review process immediately, staying one step ahead of their less proactive colleagues.

Furthermore, sites with registered IBCs already in place may choose to position themselves as “gene therapy ready” to be more attractive to sponsors and contract research organizations (CROs) during the site selection process.

Keep in mind, there is no cost to register an IBC with the NIH. Research sites without access to an IBC may consider relying on a commercial IBC. Additionally, pharmaceutical companies and CROs conducting multisite clinical trials may benefit from efficiencies provided by centrally administered IBC reviews, utilizing a model similar to central IRB reviews.

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