Quick Snips: CRISPR

CRISPR is a powerful gene-editing tool that enables targeted therapeutic gene editing, with clinical applications for improving treatment of inherited and/or rare genetic diseases, viral infections, and arresting the progression of cancer. CRISPR gene-editing technology has the potential to revolutionize the treatment of rare genetic disorders, with the first product poised for FDA approval in December 2023.

In early 2023, Vertex and CRISPR Therapeutics submitted the first CRISPR-based therapy in the US, UK, and Europe for the treatment for sickle cell disease (SCD) and beta thalassemia using a CRISPR-based ex vivotherapy called exagamglogene autotemcel (exa-cel). Priority review was granted to the SCD whereas standard review was granted for transfusion-dependent beta thalassemia. If all goes well, this will be a landmark approval, markedly changing the regulatory environment and expanding the possibilities for precision-based medicine.

CRISPR: Revolutionizing Science

Emmanuelle Charpentier and Jennifer A. Doudna discovered the CRISPR method of genome editing, described as “genetic scissors: a tool for rewriting the code of life,” and were awarded the Nobel Prize in Chemistry in 2020. CRISPR has been described as a “revolution in progress” and it has been used in a multitude of basic science and clinical applications, ranging from agricultural (modification of crops) to animal models to therapies for rare diseases. More than 200 people have now been treated with CRISPR-based therapies in clinical trials.

Expanding the Applications of CRISPR

Traditionally, CRISPR had been used to genetically modify cells ex vivo followed by re-infusion of the cells into the patient. Recently, the first in vivo study, which directly edited genes in the body, occurred in 6 patients with transthyretin amyloidosis, was successful, and the company now has clearance to start clinical trials in hereditary angioedema using a new delivery method for in vivo treatment (lipid nanoparticles). Trials have begun in several therapeutic areas such as diabetes, HIV/AIDS, cancer, cardiovascular disorders, and genetic blindness. In the future, CRISPR-based methods may even have the potential to reduce the spread of antimicrobial resistance or to serve as a rapid diagnostic for early diagnosis of COVID-19 or pancreatic cancer. Additional applications include serving as a screening tool for identification of new drug targets and biomarkers with the potential to identify mechanisms of underlying disease.

As CRISPR Technology Continues to Evolve, Concerns Remain

Basic science research is accelerating, and process innovations are making CRISPR-based gene editing more efficient and reducing off-target effects. However, any gene-editing technology has the potential to cause adverse downstream effects, and ethical and safety concerns are still being hotly debated. In the scientific community, that debate centers around treating heritable diseases with gene-editing therapies, especially since the 2018 announcement that He Jiankui had used CRISPR-based technology to create genetically modified embryos. Clinical trials have not been without their stumbling blocks, as evidenced by the October 2022 death of a volunteer who had entered a study for Duchenne muscular dystrophy. Recently, it has been reported that his death was linked to the virus used to deliver the therapy, not CRISPR itself (note: this study has not yet been peer reviewed).

The Bottom Line

CRISPR-based therapies can treat diseases by fixing the root cause: the underlying genetics. This, in addition to their potential as a drug screening tool and use in various diagnostics, has wide (and mostly positive) implications for public health. Stay tuned for updates as we get closer to a potential approval.

Jackie Orabone, PhD, helps clients prepare for FDA Advisory Committee meetings by combining her scientific expertise and research knowledge in immunology with medical communications agency experience. Connect with Jackie on LinkedIn.


Introduction to the Accelerated Approval Pathway

The FDA has developed several mechanisms to speed drugs to market when a compelling medical need exists including Accelerated Approval (AA), Priority Review, Fast Track, and Breakthrough Therapy Designation. Accelerated Approval is an important regulatory pathway that provides patients with earlier access to treatments for serious medical conditions when there is an unmet medical need. This is the first post in a 3‑part series on the AA Pathway. Herein, I’ll focus on how this pathway is used to bring drugs to market and highlight some of the key issues surrounding it.

The AA Pathway was created in 1992 in response to the AIDS crisis and was codified in 2012 under the Food and Drug Administration Safety Innovations Act (FDASIA) in an effort to bring potentially life-saving drugs to market more quickly. The majority of drugs granted AA have been for AIDS, rare diseases, and cancer. Over the past 10 years, there has been a steady increase in the number of New Drug Applications (NDAs) seeking AA (Figure1,2); this increase has been driven largely by immune checkpoint inhibitors, which have transformed the treatment of many types of cancer.

Figure: Novel Drugs Approved Using the Accelerated Approval Pathway.

Data sources: Darrow JJ, et al. JAMA. 2020 (through 2017);1 FDA CDER reports 2017-20212

How does Accelerated Approval work?

Under normal or traditional FDA approval pathways, a drug must show evidence of clinical benefit based on endpoints that measure how a patient feels, functions, or survives. In contrast, AA allows FDA to grant a drug a “conditional” approval based on its effect on a surrogate or an intermediate clinical endpoint that is reasonably likely to predict clinical benefit.3 (We’ll share more on this in part 2 of this series.) In some cases, AA can shave years off the clinical development timeline. Under the same law, the FDA requires sponsors to conduct a confirmatory clinical trial in the postmarketing setting to confirm that the drug does provide meaningful clinical benefit, and FDA can withdraw approval if further trials fail to verify the predicted clinical benefit.

Pros of the Accelerated Approval Pathway

The majority of drugs granted AA are for rare diseases, where the unmet need is great (90% of rare diseases have no approved therapy),4 and for oncologic indications where the disease is often life-threatening. In the case of rare diseases where patients are few and far between, it can be extremely challenging to conduct controlled clinical trials of sufficient size to demonstrate clinical benefit using traditional endpoints. The use of surrogate endpoints under an AA may be the only feasible path to approval; however, it can often be difficult subsequently to confirm clinical benefit in the postmarketing setting. In the case of oncology drugs, clinicians want to have access to promising new therapies for patients who have limited time to wait for the latest, potentially life-saving innovation, so speed to market becomes paramount.

Cons of the Accelerated Approval Pathway

The nature of the AA Pathway allows drugs to be marketed for a given indication before clinical benefit has actually been demonstrated using validated clinical endpoints. Although a surrogate endpoint must be reasonably likely to predict clinical benefit, this anticipated benefit must be verified in a confirmatory trial.

FDA prefers that a well-designed confirmatory trial be planned or underway at the time of AA, but there is no action enforceable by the FDA to require completion of confirmatory trials. According to a recent investigation in the British Medical Journal, nearly half of the drugs granted AA have not confirmed clinical benefit,5 and only 16 AAs have been withdrawn. This calls into question whether some of the drugs approved through the AA pathway are actually providing the promised clinical benefit to patients. That being said, there are many situations, particularly in rare diseases, where it can be difficult to complete confirmatory trials.

Finally, even more problematic, is what to do when confirmatory trials fail. In some cases, FDA will convene an advisory committee meeting to discuss whether the unmet need still exists and whether additional ongoing trials may confirm clinical benefit. (We’ll share more on this in part 3 of this series.)


While confirmatory trials can be difficult to complete, the AA pathway has been used to approve an increasing number of novel drugs in the past 10 years and remains an important regulatory pathway that provides patients with earlier access to treatments for serious medical conditions. Stay tuned for our next installment, which will explore the use of surrogate endpoints in Accelerated Approvals.

Jackie Orabone, PhD, helps clients prepare for FDA Advisory Committee meetings by combining her scientific expertise and research knowledge in immunology with over 2 years of medical communications agency experience. Connect with Jackie on LinkedIn.



  1. Darrow JJ, Avorn J, Kesselheim, AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA. 2020;323(2):164-176.
  2. US FDA. New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products. Current as of January 27, 2022. Accessed March 3, 2022. https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products
  3. US FDA. Accelerated Approval. Current as of January 4, 2018. Accessed March 3, 2022. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval
  4. Huron J. New report finds medical treatments for rare diseases account for only 11% of US drug spending; nearly 80% of orphan products treat rare diseases exclusively. March 4, 2021; National Organization for Rare Disorders. Accessed March 3, 2022. https://rarediseases.org/new-report-finds-medical-treatments-for-rare-diseases-account-for-only-11-of-us-drug-spending-nearly-80-of-orphan-products-treat-rare-diseases-exclusively/#:~:text=Approximately%207%2C000%20known%20rare%20diseases,rare%20diseases%20have%20no%20treatment
  5. Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898.