The Not-So-Far-Out Therapeutic Promise of Psychedelics


Throughout history, humans have had a complex relationship with psychedelics. For millennia, ancient indigenous cultures used them for spiritual and healing purposes. For example, in 2007, archaeologists in Spain discovered mushrooms found at a burial site dated more than 7,000 years old. The mushrooms found at the site were identified as psilocybin, a type of psychedelic mushroom. Fast forward to today, and psychedelics are still in use for spiritual and mystical experiences but are also being studied more scientifically as pharmacotherapy for various psychological conditions, including anxiety, depression, posttraumatic stress disorder (PTSD), dependency/addiction, eating disorders, and end-of-life distress. In fact, the FDA even released a draft guidance to industry for designing clinical trials for psychedelic drugs.

What Are Psychedelics?

Psychedelics are derived from plants and fungi, but some are also synthesized in the lab. Psilocybin, the most studied psychedelic comes from fungi, which are unique organisms that are neither plants nor animals. They share some characteristics with plants, such as the ability to photosynthesize, but they also share some characteristics with animals, such as the ability to digest food. Computational phylogenetics have revealed that fungi split from animals about 1.538 billion years ago, whereas plants split from animals about 1.547 billion years ago. This means fungi split from animals 9 million years after plants did, meaning that fungi are actually more closely related to animals/humans than to plants.

LSD, lysergic acid diethylamide; MDMA, 3,4-Methylenedioxymethamphetamine.

Psychedelics modulate brain activity and have been associated with therapeutic effects such as increased neuroplasticity and modulation of reward pathways, not dissimilar to the mechanism of action underlying conventional antidepressants. Psychedelics work by binding to the serotonin 2A receptor on neurons throughout the brain, which causes

  • The neurons to fire more rapidly
  • More effective neuronal communication between different brain regions
  • Disrupted sensory processing leading to changes in sight, hearing, taste, smell, and touch

These changes in the brain lead to alterations in perception, thought, and mood that are characteristic of a psychedelic experience.

The discovery and synthesis of lysergic acid diethylamide (LSD) in 1938 by Albert Hofmann brought about a surge of research into the use of psychedelics in the 1950s and 60s. But this research was largely halted in the 1970s due to unsubstantiated concerns about their safety and potential for abuse. However, in recent years there has been a resurgence of interest concerning the therapeutic potential of psychedelics.

How Are Psychedelics Being Studied?

As of today, psychedelics remain a Schedule 1 drug in the United States, meaning that per the federal government, psychedelics have no medical value and hold high potential for abuse. Despite this designation, the study of psychedelics is acceptable under highly regulated and controlled circumstances. Anyone conducting research with these drugs must obtain approval from the US Food and Drug Administration (FDA) and request a Schedule 1 license from the Drug Enforcement Administration (DEA).

Several recent studies have shown the effectiveness of psychedelics:

LSD, lysergic acid diethylamide; MDMA, 3,4-Methylenedioxymethamphetamine; PTSD, posttraumatic stress disorder.

It is important to note that this field is still in its infancy, with the benefits of psychedelics yet to be proven in large, randomized trials. With psilocybin, the best-characterized psychedelic, several early-phase studies have been conducted. The most notable of these is a phase 1 study (NCT04052568) designed and conducted by Johns Hopkins University, investigating psilocybin in patients with anorexia nervosa.6

There are several explanations for why this field is moving so slowly, including but not limited to

  • Legal and regulatory hurdles
  • Difficulty blinding psychedelic trials because of the obvious effects of the drug
  • Patient expectations of efficacy are often too high and not realistic
  • Social perceptions as well as economic issues make enrollment challenging
  • Requirement of special authorization to study a Schedule 1 drug
  • Limited funding at academic institutions for the large trials needed to produce robust data

FDA Draft Guidance Concerning Psychedelic Clinical Trials

In an effort to highlight fundamental considerations for researchers investigating the therapeutic use of psychedelic drugs, the FDA recently released their first FDA draft guidance to industry for designing clinical trials for psychedelics.7 Key takeaways from the guidance include

  • The FDA recognizes that psychedelic drugs have therapeutic potential for the treatment of a range of medical conditions
  • The FDA is willing to work with sponsors to develop psychedelic drugs for clinical use
  • The FDA has identified challenges that need to be addressed in the development of psychedelic drugs and provides sponsors with recommendations for addressing these challenges

It is important to point out the contradiction between the federal status of psychedelics as Schedule 1 drugs and the simultaneous FDA acknowledgement that these agents do in fact hold therapeutic potential. This will need to be remedied through federal law, opening the door to more pharmaceutical industry investment in clinical trials.


Our current knowledge of psychedelics owes much to our ancient ancestors’ wisdom in exploring these substances. Today, despite being classified as Schedule 1 drugs at the federal level, psychedelics are being studied more seriously for their potential to treat psychological conditions. The recent release of the FDA’s draft guidance for designing clinical trials on psychedelics demonstrates a growing recognition of their therapeutic potential. As we move forward, rigorous research will be essential to fully understand the advantages and risks of psychedelics, potentially leading to groundbreaking medical treatments in the future.


  1. Griffiths RR, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.
    J Psychopharmacol. 2016;30(12):1181-1197.
  2. Noller GE, et al. Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. Am J Drug Alcohol Abuse. 2018;44(1):37-46.
  3. Davis AK, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489.
  4. Mitchell JM, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033.
  5. Holze F, et al. Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness: a randomized, double-blind, placebo-controlled phase II study.
    Biol Psychiatry. 2023;93(3):215-223.
  6. Effects of psilocybin in anorexia nervosa. identifier: NCT04052568. Updated: May 6, 2023. Accessed: July 21, 2023.
  7. US Food and Drug Administration, Center for Drug Evaluation and Research. Psychedelic Drugs: Considerations for Clinical Investigations. Guidance for Industry. US Food and Drug Administration; June 2023. Accessed July 28, 2023.

Aaron Csicseri, PharmD
Aaron Csicseri, PharmD
Senior Scientific Director

Dr. Csicseri joined the ProEd team in November 2017 as a scientific director, responsible for scientific leadership, content development, strategic input, and effective moderation of team meetings. Aaron has extensive experience guiding Sponsor teams through the AdCom preparation process. He received his PharmD at the University of Buffalo, where he studied the clinical curriculum. Aaron has 10+ years of experience as a medical director/clinical strategist in the accredited medical education field (CME), as well as in the non-accredited PromoEd sphere. Over the past 6 years, he has been supporting Sponsors in their preparations for FDA and EMA regulatory meetings in a wide variety of therapeutic areas. Aaron is based in Grand Island, NY, just outside Buffalo.

Connect with Aaron on LinkedIn.


FDA Decision for Sarepta’s Gene Therapy for DMD Sets New Regulatory Precedent

Historic Regulatory Decision for First FDA-Approved Gene Therapy for DMD

On June 22, 2023, in a-much anticipated decision, the United States Food and Drug Administration (FDA) granted accelerated approval for Elevidys (also known as SRP-9001), Sarepta’s one-time gene therapy for ambulatory children with Duchenne’s muscular dystrophy (DMD). However, the accelerated approval was limited to the subset of boys between 4 and 5 years of age who had the debilitating disease but were still able to walk. Sarepta had originally sought accelerated approval in ambulatory children aged 4 to 7 years of age, but the FDA pushed back, citing no evidence of benefit in the older patient subgroup (ages 6 to 7). Exploratory subgroup analyses are generally considered to be prone to statistical bias and/or misinterpretation; however, the FDA has used such analyses to limit indications to patients who are most likely to benefit (see our recent blog post to learn more).

While this approval is a symbol of hope for patients and families dealing with this devastating condition, the accelerated approval means that clinical benefit for SRP-9001 has not yet been established. As a condition of approval, Sarepta will be required to generate confirmatory data showing clinical benefit, including an improvement in motor function, compared with placebo. This confirmatory data will likely be forthcoming soon from the Phase 3 EMBARK trial. The FDA has promised to rapidly review these data as soon as they are available and, if necessary, adjust the indication further or recommend withdrawal of accelerated approval if clinical benefit is not confirmed.

Regardless of the ultimate outcome, this historic decision paves the way for future accelerated approvals of a rapidly growing class of gene therapies for rare diseases.

FDA sought expert advice on accelerated approval from their Cellular Tissue and Gene Therapies Advisory Committee (CTGTAC)

The FDA decision follows a May 12, 2023, meeting of the FDA’s CTGTAC where the topic of accelerated approval based on a surrogate biomarker, namely expression of micro-dystrophin (the transgene product of SRP-9001), was hotly debated. The FDA asked the committee to vote on whether the data generated from Part 2 of Study 102 were sufficient to support accelerated approval while “taking into account the existing uncertainties.”

The vote landed slightly in favor of accelerated approval, with 8 yes votes, 6 no votes, and no abstentions. However, the discussion revealed a dramatically split committee with considerable nuance associated with individual votes.

FDA commissioner, Robert Califf, has indicated that advisory committees should prioritize discussion and feedback over the strict, “thumbs-up, thumbs-down” results of the voting questions, which often receive the most media coverage. While the FDA usually makes decisions in line with the committee’s vote, it is not required to do so.

Notably, several panelists who voted “yes” revealed that they might have voted “no” on the basis of insufficient data to meet regulatory requirements but were swayed by the extremely high unmet need and the emotional testimonies of parents whose children appeared to have benefitted from SRP-9001 in videos shown during the open public hearing. Those statements, and the overwhelming unmet need likely factored heavily into the FDA’s ultimate decision to grant accelerated approval, despite major reservations on the part of FDA reviewers..

Surrogate endpoints and substantial evidence of efficacy called into question

In briefing documents released prior to the CTGTAC meeting, the FDA raised several concerns regarding Sarepta’s proposed surrogate endpoint, noting that expression of the micro-dystrophin transgene product (a purely synthetic protein not naturally expressed in skeletal muscle) does not necessarily translate into an improvement in muscle function. In other words, it is not known if expression of the transgene is “reasonably likely to result in clinical benefit” (an essential requirement for accelerated approval). This question likely cannot be answered without further placebo-controlled clinical study data. 

Importantly, the only randomized, double-blind, placebo-controlled clinical study (Part 1 of Study 102) failed to demonstrate a statistically significant treatment effect on muscle function versus placebo, as measured by the North Star Ambulatory Assessment (NSAA) Total Score. While an apparent effect could be discerned in the small subgroup of children aged 4 to 5 years, the study was not powered to detect a change in this group.

Slide 31 from the FDA’s CTGTAC meeting presentation (show below) illustrates these data. In the 4- to 5-year-old subgroup there was a 2.5 point difference in the change from baseline on the NSAA in patients treated with SRP-9001 versus placebo at Week 48 (P = .0172), indicating a possible clinical improvement. The 6- to 7-year-old subgroup treated with SRP-9001 had a decline in their NSAA score of -0.7 compared with placebo, indicating no apparent difference between the treatment groups. Sarepta’s scientists pointed out that an imbalance in the NSAA score at baseline may have affected the results in the 6- to 7-year-old subgroup, further confounding interpretation of the results.

The FDA concluded that

“the clinical studies conducted to date do not provide unambiguous evidence that SRP-9001 is likely beneficial for ambulatory patients with DMD. It is challenging to conclude with reasonable certainty from the data provided by the Applicant either that SRP-9001 is likely effective for younger patients, or that it is likely ineffective for older patients or those with somewhat poorer functional status. Additionally, FDA has safety concerns related to the possibility of administering an ineffective gene therapy.”

During the discussion, the CTGTAC panelists agreed that expression of the micro-dystrophin transgene speaks to the biological plausibility of SRP-9001; however, there was disagreement as to whether this expression could serve as a surrogate endpoint. Dr. Rajiv Ratan indicated, “I was not convinced, either by the nonclinical or the clinical data, that an effect on the primary functional endpoints really provided plausibility that expression of micro-dystrophin would predict clinical outcome,” and later voted “no.”

Dr. Caleb Alexander, a temporary panelist at the CTGTAC meeting and veteran of the Peripheral and Central Nervous System (PCNS) advisory committee, noted that nothing changes the fact that there was no significant effect on the primary endpoint, making it difficult to attribute any predictive power to expression of the transgene. He stated that

“…the threshold of substantial evidence has to be met whether or not a product is being approved under the standard pathway or accelerated pathways…the totality of evidence that we’ve reviewed today simply doesn’t rise to the threshold of substantial evidence that’s required for accelerated approval.”

It should be noted that the FDA has previously granted accelerated approval to 4 other therapies for DMD, three of which were developed by Sarepta – eteplirsen (Sarepta, exon 51 skipping), viltolarsen (NS pharma, exon 53), golodirsen (Sarepta, exon 53), and casimersen (Sarepta, exon 45).. These 4 therapies are all antisense oligonucleotides targeting specific mutational subtypes of DMD and use exon-skipping technology to remove a specific mutated region of the dystrophin protein to render it more functional. To date, however, none of those therapies have successfully confirmed clinical benefit, raising concerns about the feasibility of confirmatory trials in DMD.

The surrogate endpoint used in those prior approvals was expression of the “edited” dystrophin protein. The shortened versions of endogenous dystrophin produced by exon-skipping technology mimic the shortened forms of dystrophin protein found in patients who have Becker Muscular Dystrophy (a much milder form of DMD). In contrast, the expression of the SRP-9001 transgene lacks the type of empirical evidence that has been previously used to support a determination that a surrogate endpoint is reasonably likely to predict clinical benefit in DMD.

Difficulties in confirming clinical benefit following accelerated approval in DMD

Sarepta will be required to generate confirmatory data from the Phase 3 EMBARK trial to ensure that the expression of the micro-dystrophin transgene translates into significant improvement on clinical outcomes, including slowing of progression on the NSAA.

During the CTGTAC meeting, the committee emphasized the importance of the confirmatory trials to confirm clinical benefit, regardless of whether they voted yes or no, with Dr. Raymond Roos indicating that his yes vote “included the results of the [EMBARK] study that’s going to end in September 2023.”

The committee members who voted in favor of accelerated approval frequently cited the dire unmet need for treatments as their reason for voting “yes,” rather than the strength of the data package. With the added confidence that confirmatory results will be available soon, they argued that it is important not to delay treatment any longer. The dissenting committee members came to the opposite conclusion. They expressed concern that, given the uncertainty around the surrogate endpoint and the fact that a definitive answer would be available so soon, approval should only follow evidence of clinical benefit on muscle function.

Two additional considerations include the impact of accelerated approval on completing EMBARK while maintaining study integrity and what will happen if the confirmatory trial fails to generate conclusive data. Historically, withdrawal of accelerated approval after a confirmatory trial has failed has been a lengthy and complicated process resulting in potentially ineffective drugs remaining on the market for far longer than intended. We have previously written about the difficulties with confirmatory trials after accelerated approval on this blog.

Mitigating much of the concern around the confirmatory trial is the fact that the results are expected soon. The last patient, last clinical visit for EMBARK is expected to be completed by September 2023, which is very soon by accelerated approval standards. In addition, in September all patients who were on placebo are scheduled to switch over to SRP-9001. However, this does not mean that the accelerated approval will have no effect on completion of EMBARK. Patients currently in the placebo group of the EMBARK trial may demand to receive SRP-9001, rather than waiting an additional 3 to 4 months. If enough patients drop out of the study, it could reduce the ability to generate conclusive data.

In any case, the results of the confirmatory EMBARK study are highly anticipated and will determine the next steps for Elevidys. Positive results could lead to a potential conversion to full approval, along with a potential expansion of the label to include older children (6 to 7 years of age). Negative or inconclusive results, however, may result in the withdrawal of the accelerated approval.

New regulatory precedent may affect future approvals

There are currently more than 1,745 gene therapies in development, including several gene therapies for DMD (Pfizer’s gene therapy may be next in line). Indeed, gene therapy approvals seem to be gaining steam in the first half of 2023. The newest approval is Biomarin’s gene therapy for hemophilia A, Roctavian, which gained full FDA-approval on June 29. This new wave of gene therapies is promising but brings questions regarding multimillion-dollar price tags, safety of the gene delivery vectors, and longevity of transgene expression. Ultimately, many unknowns remain.

With so little precedence for gene therapy approvals, the accelerated approval of Elevidys is likely to have a major effect on future approvals for gene therapies in rare diseases. The approval establishes a regulatory precedent indicating that simply demonstrating that the transgene is expressed in the target tissue may be sufficient to use as a “reasonably likely surrogate endpoint” for accelerated approval. This indicates a willingness on the part of FDA leadership to expand the definition of what will be accepted as surrogate endpoints for gene therapies, especially when dealing with diseases of high unmet need.

Angela W. Corona, PhD
Senior Scientific Director, Scientific Services
Angela is responsible for helping sponsors navigate complex regulatory communications, such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University. Connect with Angela on LinkedIn.

Kathryn M. Madalena, PhD
Scientific Associate, Scientific Services
Kathryn provides scientific support for content development and FDA advisory committee meeting preparation across a broad range of therapeutic areas. A neuroscientist by training, with specializations in neuroendocrinology and neuroimmunology, she received her PhD in Neuroscience at The Ohio State University. Connect with Kathryn on LinkedIn.

Communicating the Complexities of Subgroup Analyses at an AdCom

Within clinical trials, exploratory or post-hoc subgroup analyses are widely recognized as only “hypothesis generating” due to their high potential for bias and/or misleading interpretation. This is the main reason why Sponsors cannot make efficacy claims or seek regulatory approval based on evidence of efficacy in a certain subgroup unless that benefit is consistent with the broader trial population and unless the trial is positive overall for the intention-to-treat (ITT) population. This begs the question, “Is it acceptable to use an exploratory subgroup analysis to restrict an indicated population when the data suggest less benefit in a particular subgroup?”

That is exactly what FDA asked the Oncologic Drugs Advisory Committee (ODAC) to consider in the case of the PROpel data, based on their conclusion that the combination of olaparib plus abiraterone has a favorable benefit/risk only in the subgroup of patients with advanced prostate cancer who test positive for a mutation in the BReast CAncer (BRCA) gene, which regulates homologous recombination repair of DNA. However, one might argue that the exploratory/post-hoc analysis on which FDA based their conclusion remains, by its very nature, fraught with potential for bias and/or misleading interpretation and is thus only hypothesis generating.

“Is it acceptable to use an exploratory subgroup analysis to restrict an indicated population when the data suggest less benefit in a particular subgroup?”

In the era of precision medicine, we expect that treatment choices are driven by biomarkers that can predict clinical benefit. In the case of poly ADP-ribose polymerase (PARP) inhibitors, like olaparib, BRCA mutations or deficiencies in homologous recombination repair (HRR) can predict clinical benefit. But there may be clinical situations where biomarker testing is limited or where patients without BRCA mutations might benefit from treatment with a PARP inhibitor. Indeed, the science suggests that patients with metastatic castration-resistant prostate cancer (mCRPC) may benefit from the combination of a PARP inhibitor with an antiandrogen, like abiraterone, regardless of BRCA mutation status, based on the synergistic activity of these 2 drug classes. In addition, the majority of patients with mCRPC (especially in disadvantaged communities) do not have definitive biomarker testing for BRCA mutations, usually due to cost and/or lack of available tumor tissue. That is the context for the PROpel study investigating the combination of the PARP inhibitor olaparib (Lynparza) plus abiraterone (Zytiga) as first-line treatment of mCRPC.

The PROpel trial was designed to assess the activity of this combination in the broad, unselected, ITT population, and data on BRCA mutation status by ctDNA and tissue tests were collected for the purpose of exploratory subgroup analysis. The trial met its primary endpoint in the ITT population, demonstrating a statistically significant 40% improvement in radiologic progression-free survival (rPFS). Therefore, AstraZeneca was seeking a broad indication that includes BRCA mutant, BRCA wild-type, and BRCA unknown patients. The Sponsor also presented evidence that patients without BRCA mutations or with unknown BRCA status benefited from the combination of olaparib plus abiraterone. However, on April 28, 2023, the ODAC voted 11 to 1 (with 1 abstention) to limit use of the combination to men whose tumors tested positive for a BRCA mutation, which represents only about 10% of patients with mCRPC. This was based on post-hoc subgroup analyses that created the perception of a less favorable benefit/risk in the BRCA wildtype or unknown patients.

On April 28, 2023, the ODAC voted 11 to 1 (with 1 abstention) to limit use of the combination to men whose tumors tested positive for a BRCA mutation

Dr. Chana Weinstock articulated the FDA’s position on this issue at the April 28 ODAC meeting. She said that the Agency discourages using subgroup analysis to try to argue for efficacy in a specific group, particularly in a failed trial (although PROpel was a positive study). However, she highlighted historical precedent for limiting indications based on post-hoc subgroup analysis suggesting that certain subgroups might have compromised safety or a potential overall survival detriment. Finally, she cited the FDA guidance that states that if a trial only shows benefit in a selected subgroup, the indication may be limited to a narrower population, especially if that same signal is observed in other comparable trials. (Figure 1)

Figure 1


Jorge Nieva, section head of solid tumors at the University of Southern California, objected to restricting the indication to only those patients with known BRCA mutations, saying “I worry that the approach used in this application can justify removing any subgroup from any application where that subgroup has an OS curve that crosses one. FDA seems to be looking at these OS curves in a vacuum and is ignoring the corroborating evidence that some non-BRCA patients could benefit significantly.”

“I worry that the approach used in this application can justify removing any subgroup from any application where that subgroup has an OS curve that crosses one.”

It is common for Sponsors to find themselves in this situation at ODAC where the data are somewhat ambiguous and the arguments/counter arguments are highly statistical in nature. This is especially true for subgroup analyses. The key communication goal when addressing an advisory committee is to make your position as easy to understand as possible by breaking down your argument into digestible bites. If your messages are too complex, statistical or philosophical, the committee may not fully appreciate your position. When this occurs at ODAC, the committee typically defers to the FDA’s position.

Aaron Csicseri, PharmD
Aaron Csicseri, PharmD
Senior Scientific Director

Dr. Csicseri joined the ProEd team in November 2017 as a scientific director, responsible for scientific leadership, content development, strategic input, and effective moderation of team meetings. Aaron received his PharmD at the University of Buffalo, where he studied the clinical curriculum. He has 10+ years of experience as a medical director/clinical strategist in the accredited medical education field (CME), as well as in the non-accredited PromoEd sphere. Over the past 5 years, he has been guiding Sponsor teams in their preparations for FDA and EMA regulatory meetings in a wide variety of therapeutic areas. Aaron is based in Grand Island, NY, just outside of Buffalo, New York.

Connect with Aaron on LinkedIn.


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.


Pitfalls of Accelerated Approval: What Happens When Confirmatory Trials Fail?

The accelerated approval (AA) pathway was introduced in 1992 (in response to the AIDS epidemic) to shorten the FDA approval process for drugs to treat serious or life-threatening diseases or rare diseases where there is a high unmet medical need. AA allows for drugs to be approved on the basis of surrogate endpoints that are “reasonably likely to predict clinical benefit.”1 Please see Part 1 of this blog series for an introduction to the accelerated approval pathway and Part 2 for more information on how surrogate endpoints for accelerated approval are identified and validated.

Although AA can speed access to potentially lifesaving drugs years earlier than traditional approvals, the tradeoff for this quicker access is a period of uncertainty regarding the true efficacy and safety while confirmatory evidence is gathered. Confirmation of clinical benefit is often achieved but is not guaranteed.

In Part 3 of our blog series on AA, we will dive into a controversial aspect of the accelerated approval pathway: confirmatory studies.

What is a confirmatory study?

The FDA requires that drugs initially approved under AA are subject to postmarketing confirmatory trials that can directly confirm the clinical benefit predicted by the surrogate endpoint. Confirmatory studies are typically agreed on between the sponsor and FDA ahead of time and formally established as a postmarketing requirement (PMR) for continued approval.2 Usually PMRs for AA indications include large, phase 3 randomized studies with primary endpoints that assess direct clinical benefit. Overall survival, for example, is often used in oncology studies as a direct measure of clinical benefit.2

While straightforward in principle, designing confirmatory trials presents many practical challenges that can impede the completion of the trial and/or complicate the interpretation of the results. Most importantly, it is not always feasible to enroll patients in confirmatory trials once the drug is already on the market, particularly for very rare diseases. For this reason, sponsors may need to consider a randomized confirmatory trial in a clinical setting that differs from the approved indication, such as an earlier line of therapy or, for rare diseases, a less rigorous single-arm approach may be used. The nature of what evidence constitutes a confirmation of benefit remains a heavily debated topic that is outside of the scope of this article; however, some of these challenges were presented at a Friends of Cancer Research Annual Meeting in 2020.3

When a confirmatory study reaches its primary endpoints, this fulfills the PMR, and the clinical benefit is considered to be verified; at which point the AA is generally converted to a full approval. On the other hand, in cases where a confirmatory study fails to confirm clinical benefit, or an appropriate confirmatory study could not be conducted, the AA may be withdrawn by the FDA. The FDA is not required to withdraw the AA; however, there is no time limit for completion of confirmatory trails defined in legislation or regulatory guidance.

Conversion of AAs to full approvals: Is the glass half-full or half-empty?

Two separate studies found that approximately 50% of all AAs have successfully converted to full approval.

  • An investigation published in the British Medical Journal studied all 253 AAs granted by the FDA in the 28 years since the inception of the program in 1992, through 2020. Of these, 125 (49%) successfully confirmed clinical benefit, 44% had not yet completed confirmatory trials, and 6% had been withdrawn.4
  • In a study focusing only on oncology AAs, the record is slightly better. Out of 93 oncology indications granted AA between 1992 to 2017, 51 (55%) had fulfilled their PMR within a median of 3.4 years. Forty percent of oncology indications had not yet completed confirmatory trials, and 5% had been withdrawn from the market.5

From a “glass half-full” perspective, half of all drugs approved under the AA pathway are successful—delivering promising, life-saving drugs to patients years sooner than traditional approval pathways, with verification of clinical benefit confirmed in a timely manner. In this context, the 5-6% of AAs that were withdrawn demonstrate a commitment to removing AAs that fail to confirm benefit.

However, from the “glass half-empty” perspective, nearly half of AAs had not yet confirmed clinical benefit. In the case of more recent AAs, confirmatory trials may still be ongoing. However, a small number of AAs had not yet started a confirmatory trial or had  a failed confirmatory trial, yet they remained on the market. For critics, this is evidence that the FDA is allowing some AAs to “languish” in the pathway, without appropriate efforts to confirm clinical benefit. These critics believe that the number of AAs withdrawn should be much higher.

The most controversial situation with the AA pathway is the very small subset of AA drugs that have completed one or more confirmatory trials that failed to confirm clinical benefit, but the approval for that indication has not been withdrawn. These so-called “dangling approvals” often fall into a regulatory gray area, are a target of fierce criticism, and have been the subject of several FDA advisory committee meetings.

“Dangling” accelerated approvals: FDA advisory committee meetings

In April 2021, the FDA held a multi-day, multi-sponsor meeting of the Oncologic Drugs Advisory Committee (ODAC) to get expert advice on several immune-checkpoint inhibitors (“ICIs”) with dangling AAs. All the ICIs in question were PD-1/PD-L1 monoclonal antibodies. Each of these dangling AAs had failed to reach statistical significance on the endpoint of overall survival in one or more confirmatory trials. The FDA chose to use this meeting to publicly reevaluate these approvals. In the weeks leading up to the meeting, 4 of the indications were voluntarily withdrawn by the sponsors. Out of the 6 indications that were publicly reevaluated at the ODAC meeting, the panel voted against continued AA for 2 indications and voted in favor of maintaining AA for 4 indications. 

Importantly, in the cases where the AA indication was withdrawn, it wasn’t because of a lack of benefit, or even a failed confirmatory trial, but rather that the treatment landscape had evolved, so that other treatment options were available. In short, the urgent unmet need that had originally justified the AA in these cases, no longer existed.

FDA advisory committee meetings are often a clue as to how the FDA is thinking about regulatory policy and how they may make decisions in the future.

What does it mean when a confirmatory trial fails? The FDA weighs in…

When a confirmatory trial fails to meet its endpoints, these data cannot be used to confirm clinical benefit or fulfill the PMR. However, a failed trial is not necessarily evidence that the drug is ineffective. In a perspective article published in The New England Journal of Medicine shortly before the April 2021 ODAC meeting, Dr. Julia Beaver and Dr. Richard Pazdur, from the FDA’s Oncology Center of Excellence, wrote:

“The fact that a clinical trial did not meet its endpoints does not necessarily mean that the drug is ineffective. A failure to demonstrate efficacy might be attributable to the selection of the primary endpoint, the power calculation, hierarchical statistical testing procedures, biomarker selection, trial design, or an inability to select the patients most likely to have a response. If there are clear reasons why a trial may not have achieved its primary endpoint and an unmet medical need still exists, the FDA works with sponsors to identify subsequent clinical trials that could satisfy the accelerated approval requirement.”6 [emphasis added]

This perspective from the FDA provides an important clue into their thinking: unmet need is paramount. In many cases, drugs receive AA because there is an urgent unmet need. In these cases, the immediate removal of AA after a failed confirmatory trial could leave patients with severe or life-threatening diseases with no treatment options. So, while strict statistical requirements for fulfilling a PMR must be met, it is just as important for the FDA to weigh those criteria against the unmet medical need.


The AA pathway legislation allows for flexibility and discretion on the part of the FDA when enforcing PMRs for confirmatory studies. Proponents of AA, including the FDA itself, point out that this flexibility is necessary, given the complexity of these decisions and the need to balance benefit/risk with unmet need. Quoting the FDA, “the small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with severe or life-threatening diseases.”6

However, critics believe there is too much flexibility in the pathway, resulting in arbitrary decisions that lack appropriate transparency, inappropriate use, and patients with serious diseases potentially being exposed to drugs that lack confirmed clinical benefit. Recently, these critics have called for reform of the AA pathway, and legislation is now being considered in Congress.

Coming next: Proposed reforms to the AA pathway

The AA pathway has far-reaching implications for patient access, coverage for new drugs under insurance plans and Medicare, and decisions made by sponsors in their clinical development strategy. In a future blog post, we will look in detail at proposed reforms that could impact the AA pathway and the surrounding regulatory landscape.  

Angela W. Corona, PhD
Scientific Director, ProEd Regulatory

Angela is a Scientific Director for ProEd Regulatory. She is responsible for helping sponsors navigate complex regulatory communications, such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University.



  1. US Food and Drug Administration. Expedited programs for serious conditions – drugs and biologics. May 2014.
  2. For more information on the details of Postmarket Requirements (PMRs) for drugs approved under AA – an interested reader may wish to review the public PMR database maintained by the US Food and Drug Administration.
  3. Friends of Cancer Research Working Group. Optimizing the use of accelerated approval. 2020.
  4. Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374:n1898.
  5. Beaver JA, Howie LJ, Pelosof L, et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4(6):849-856. doi:10.1001/jamaoncol.2017.5618.
  6. Beaver JA and Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med. 2021;384:e68.

Surrogate Endpoints for Accelerated Approval

Surrogate endpoints have been used for accelerated approval (AA) since the early 1990s, playing a vital role in getting therapies for serious conditions to patients sooner. The AA pathway was first created in 1992 to accelerate the approval of drugs intended to treat “serious conditions that fill an unmet medical need.” In the intervening 30+ years, surrogate endpoints have played a major role in oncology and rare disease clinical trials, but their appropriate use is still being debated in the literature. Most often that debate centers around whether an endpoint is a true surrogate that predicts clinical benefit in the clinical context in which it is being used.

What is a “surrogate”endpoint? How is it different from “clinical outcome”endpoint?

A “surrogate” endpoint is a biomarker, lab measurement, radiographic image, physical sign, or other measure that is “reasonably likely to predict clinical benefit” whereas a “clinical outcome” endpoint is one that “directly measures clinical benefit.” Importantly, the FDA definition of clinical benefit is how a patient feels, functions, or survives.

To illustrate the difference between surrogate and clinical endpoints, below are some oncology-specific examples:

Surrogate Endpoints Clinical Outcome Endpoint
Progression-Free Survival (PFS) Overall Survival (OS)
Objective Response Rate (ORR)
Duration of Response (DoR)

The FDA publishes a Surrogate Endpoint Table updated every 6 months and listing surrogate endpoints that can support approval of a drug or a biological product under both accelerated and traditional approval pathways.1 The FDA encourages development of “novel” surrogate endpoints; a novel endpoint can become established as a surrogate based on persuasive evidence that it predicts clinical benefit in the context of a specific disease and patient population. The FDA determines the acceptability of a surrogate endpoint on a case-by-case basis, dependent on context and influenced by the disease, patient population, therapeutic mechanism of action, and currently available treatments (ie, unmet need for new treatments). If a surrogate endpoint was previously used to support AA, but subsequent confirmatory trials consistently fail to demonstrate the expected clinical benefit, that surrogate endpoint should no longer be accepted for that use.

When is it appropriate to use a surrogate endpoint?

The main purpose for using a surrogate endpoint is to shorten clinical development timelines or improve the feasibility of clinical studies in rare diseases where the number of patients is limited and large, controlled studies are challenging. In many cases, a surrogate endpoint can be reached much sooner and with fewer patients than a clinical outcome endpoint such as overall survival (OS), which is a direct measure of clinical benefit. Sponsors must think about this in the context of the specific disease and indication for which they are developing the drug.

For example, in cancer patients with a long life expectancy, a surrogate endpoint such as progression-free survival (PFS) can provide a much earlier readout than a clinical outcome endpoint such as overall survival (OS). If PFS has been shown to correlate with OS in that specific disease and indication, there is a good chance that the confirmatory trial would be able to show an OS benefit. However, in some cases this can be challenging.

In the context of rare genetic diseases, for example, the surrogate endpoint is often a biomarker that can be easily measured with precision and that is reasonably likely to predict how patients feel or function. Because clinical measures of how patients function over time can be difficult to assess with precision, they often require much larger studies to demonstrate a clinically meaningful effect. For example, in Duchenne muscular dystrophy, rather than measuring functional outcomes such as ability to walk, which can vary from one day to the next, researchers will often use a surrogate endpoint such as quantitative measurements of dystrophin protein expression.

In severe respiratory diseases, measures of lung function are often used as a surrogate to predict how well the patient can perform activities of daily living, which can often be difficult to measure with precision. These few examples illustrate how surrogate endpoints can be used to facilitate clinical research.

How much time is saved by using these endpoints?

The amount of time saved by using a surrogate endpoint is disease dependent. For example, use of PFS rather than OS in breast cancer can save almost a full year, whereas the use of response rate (RR) versus OS can save 19 months.2 It all depends on the natural history of the disease and the nature of the endpoint being studied. So, while the use of surrogate endpoints can save time on the front end, and while patients will benefit sooner, the tradeoff is that the sponsor must invest in the development of an additional post-approval confirmatory trial—and there is no guarantee that a direct clinical benefit will be confirmed. Thus, there is a chance that the patient might be taking a drug that turns out not to help them in the long run.

What are “validated” surrogate endpoints?

A “validated” surrogate endpoint meets a higher standard and can be used to support full approval. This requires that the endpoint be “supported by a clear mechanistic rationale and clinical data providing strong evidence that an effect on the surrogate endpoint predicts a specific clinical benefit.”3

Two examples include:

  • HbA1c predicting improvements in long-term complications of type 2 diabetes mellitus
  • Virologic suppression of HIV as a proxy for preventing progression to AIDS

More than 75% of approvals that used a surrogate endpoint came through the traditional pathway using a validated surrogate endpoint.3 The AA pathway does not require the use of validated surrogate endpoints.

Aaron Csicseri, PharmD, Aaron has 10+ years’ experience as a Senior Scientific Director, Medical Director, or Clinical Strategist within the medical communication field. He is responsible for overseeing and developing high-quality scientific and medical content that incorporates key communication objectives and accurate representation of data. Aaron is experienced in the development of strategic scientific communication platforms, strategic publication planning and implementation, medical expert outreach and engagement, guiding and executing medical education programs, and support for medical affairs. He received his PharmD from the University of Buffalo.



  1. US FDA. Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. Updated February 28, 2022. Accessed March 8, 2022.
  2. Chen EY, Joshi SK, Tan A, Prasad V. Estimation of study time reduction using surrogate end points rather than overall survival in oncology clinical trials. JAMA Intern Med. 2019;179(5):642-647.
  3. US FDA. Surrogate Endpoint Resources for Drug and Biologic Development. Updated July 24, 2018. Accessed March 8, 2022.