Regulatory Oversight in Gene Therapy: How far have we come?

21st May 2020

Christine Piscitelli and Jessica Kokosinski, G&L Scientific


What was once viewed as a theoretical concept over 50 years ago, gene therapy has finally emerged as a therapeutic reality delivering meaningful benefits to human health. The U.S. Food and Drug Administration (FDA) defines gene therapy as a technique that “seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use”. To date, there are only four FDA-approved gene therapy products that insert new genetic material into a patient’s cells. However, FDA reports that there are more than 900 active investigational new drug (IND) applications in this area, studying treatments for diseases such as cancer, genetic diseases, and infectious diseases [1].

The regulatory framework for the development and manufacturing of gene therapy products comprises regulations and guidance documents, including the interpretation of these governing documents by regulators and sponsors as experience is gained in practice. Today, gene therapy products are regulated by FDA’s Center for Biologics Evaluation and Research (CBER). FDA requires submission of an IND prior to initiating clinical studies, and an approved biologics license application (BLA) to market the product in the United States. However, this regulatory framework did not exist when the potential to alter human genes first emerged in the 1960s. Since that time, regulators have ensured that the regulatory framework and oversight continually evolve to keep pace with each new scientific breakthrough and advancement in the field. Yet, it has not always been a smooth journey to get to where we are today – advancing science and human health while accelerating the availability of safe and effective gene therapy products is a fine balance and can be fraught with obstacles.


Brief History of Gene Therapy and U.S. Regulatory Oversight

Although gene therapy is a seemingly new frontier for biotherapeutic products, its history dates to the earlier part of the last century. The field evolved out of two significant discoveries in the first half of the 1900s: Frederick Griffith’s discovery of the “transforming principle” while studying pneumococcal bacteria in 1928, followed by the Avery et al. discovery in 1944 that bacterial transformation occurred through DNA [2]. By 1961, the first DNA-mediated heritable genetic transformation was successfully demonstrated in mammalian cells by Waclaw Szybalski [3]. This study ultimately laid the groundwork for gene therapy as a potential strategy to correct defective DNA in human cells. Soon after, research into gene transfer and its potential for clinical application began to flourish.

The early 1970s brought the first direct human gene therapy study which unsuccessfully attempted to treat two pediatric subjects suffering from the genetic disorder hyperargininemia [2]. At the time, there was little regulatory oversight for human gene therapy studies. Members of the scientific community began expressing growing concern over safety, scientific, social, and ethical issues raised by human gene therapy. Most notable was a 1972 opinion piece written by Theodore Friedmann and Richard Roblin. While Friedmann and Roblin believed in the potential of gene therapy to treat human genetic diseases and encouraged continued research in this field, they also advised the need for additional scientific understanding and regulation before allowing further clinical trials in humans [4].

By 1974, a gene therapy regulatory framework began to take shape in the United States. The National Institutes of Health (NIH) established the Recombinant DNA Advisory Committee (RAC) to bolster oversight of basic and clinical research involving recombinant DNA and later expanded its scope to include human gene transfer research. Regulators and the scientific community continued to make significant strides in addressing ethical, legal, and social implications of gene therapy and improving patient protections over the next 25 years. Several layers of federal and local oversight and regulations were established during this time. Namely, the Institutional Review Board (IRB) system was established, RAC developed biosafety guidelines, NIH published research guidelines for recombinant DNA molecules and established Institutional Biosafety Committees (IBC), and the FDA began regulating gene therapy products and issued its first guidance document on cell and gene therapy [5]. FDA and NIH continued to foster innovations in the development of gene therapy products while also eliminating overlaps in oversight efforts. By 1997, the FDA assumed sole authority to approve gene transfer protocols and gene therapy products, while NIH eliminated director approval of individual protocols and shifted the responsibilities of the RAC to an advisory role [5,6].

The first U.S. gene therapy trial with a therapeutic attempt in humans occurred in September 1990 at the NIH Clinical Center [2]. This marked the first gene therapy trial with FDA oversight. Throughout the 1990s the number of trials increased over time, although not steadily. By the end of the decade, a total of 484 gene therapy clinical trials had been approved, were ongoing or completed worldwide with the peak occurring in 1999 (117 trials) [7]. While the outcome of many of these trials were unsuccessful, the research looked promising as no major safety concerns had been raised. The potential for gene therapy to treat and cure some of the most debilitating diseases remained encouraging.

Unfortunately, the boom experienced in the 1990s would be marred by several tragic events that underscored the many uncertainties that existed at the time regarding safety, efficacy, and long-term effects of human gene therapy. The death of 18-year-old Jesse Gelsinger, who died of a massive immune response during a gene therapy safety trial in September 1999, accentuated the risks associated with viral vectors [2]. The risk of insertional mutagenesis was later observed in the early 2000s when five out of 20 pediatric subjects in a European trial developed gene transfer-related leukemia 2 to 5.5 years after gene therapy, resulting in the death of one child [8]. These events exemplified the potential for serious adverse events associated with gene therapy and highlighted the need for increased regulatory oversight and safety precautions. They led to the FDA and NIH taking additional individual and cooperative actions to strengthen protections for trial participants. Among these initiatives were the establishment of the Gene Therapy Clinical Trial Monitoring Plan and the Gene Transfer Safety Symposia [9]. was also launched which provided a high level of transparency for gene therapy trials conducted by both public and private sponsors [6]. Additionally, the NIH and FDA jointly launched the Genetic Modification Clinical Research Information System (GeMCRIS), an information resource and analytical tool to coordinate adverse event reporting and expand public access to reports of serious events [5]. Unfortunately, despite these efforts, confidence in gene therapy appeared to falter. After hitting a new peak in 2008, the number of completed, ongoing or approved clinical trials worldwide declined between 2009 and 2012 [7].


A New Era in Gene Therapy and U.S. Regulatory Oversight

Within the last 7 years, the gene therapy field appears to have finally hit a major turning point in the United States. There has been a quantum leap forward with the discovery of new technologies and advancements in safer gene delivery systems. In 2017, the first three gene therapy products were approved for use in the U.S. market: Kymriah (Novartis), Yescarta (Gilead), and Luxturna (Spark Therapeutics). Kymriah and Yescarta are cell-based gene therapies for the treatment of cancer (ex vivo treatments), whereas Luxturna is an adeno-associated virus (AAV) vector-based gene therapy indicated for treatment of an inherited form of blindness. Luxturna was regarded as a landmark approval as it was the first approved gene therapy product to be administered in vivo and the first to target a specific genetic condition [6]. Another milestone was achieved in 2019 when FDA approved Zolgensma (AveXis), the second AAV vector-based gene therapy for a hereditary disease. Zolgensma is the first approved gene therapy for spinal muscular atrophy and for any chronic neurologic disease. The U.S. has also not been alone in sharing such momentous achievements. Gene therapies have previously been approved in Europe and China (Glybera, Stremelis, Gendicine).

With such recent historical successes, as well as significant advancements in gene therapy technologies, interest in the gene therapy sector has exploded and development of gene therapy products is now moving at an accelerated pace. Today, there are many active gene therapy clinical trials underway to treat various diseases such as cancer, HIV/AIDS, and blood disorders. The FDA anticipates to be approving 10 to 20 cell and gene therapy products a year by 2025, and is working to expand its review group by about 50 additional reviewers dedicated to evaluation of gene therapy INDs [10].

The regulatory framework and oversight have also continued to evolve with rapidly advancing innovations in the development of gene therapy products. As the field matures and the risks are better understood, regulators continue to streamline duplicative and burdensome oversight efforts. In 2019, the NIH and FDA jointly announced they were eliminating RAC review and reporting requirements. At the same time, NIH also announced it was renaming and refocusing the RAC into a role closer to its original mandate [11]. In January 2020, FDA announced the release of six final guidance documents on gene therapy manufacturing and clinical development of products and a draft guidance on interpreting sameness of gene therapy products under the orphan drug regulations. This suite of documents not only signifies FDA’s contribution towards helping shape the modern era of gene therapy regulation and oversight, but also their commitment to help ensure such innovative products meet FDA’s standards for quality, safety, and effectiveness.

The FDA also continues to encourage sponsors of new gene therapy products to make full use of the expedited programs and other novel regulatory pathways available for products intended to address unmet medical needs in the treatment of serious or life-threatening conditions. There are currently five expedited approval designations available for gene therapy products: Fast Track; Breakthrough Therapy; Priority Review; Accelerated Approval; and Regenerative Medicine Advanced Therapy (RMAT). While a gene therapy product may qualify for one or more of the five expedited approval designations, the RMAT designation is the only accelerated pathway focused specifically on regenerative medicine products inclusive of gene therapy. It carries all of benefits of Breakthrough and Fast Track designations, including early intensive interactions with the FDA, organizational commitment involving senior managers from the FDA, and actions to expedite product development and review as well as rolling review [12].


The Path Forward

Where do we go from here? While we cannot predict what will happen tomorrow in the field of gene therapy, it is exciting to imagine what is on the horizon. The field is rapidly expanding with many promising new approaches being developed and studied. Already, there have been discoveries and advancements in new and existing gene editing systems that have opened the door for treating diseases that might be a challenge to address with gene transfer technologies. Significant improvements in viral vectors have also driven the recent resurgence in gene therapy efforts. Table 1, for example, provides a snapshot of the numerous gene therapies being pursued in 2020 that are using viral vectors to address a missing or mutated endogenous gene [13].


Table 1: 2020 Gene Therapies Pursued

DiseaseGene of interestCompany pursuing gene therapy
AADC deficiency (CNS)AADCPTC Therapeutics (GT-AADC)
ADA-SCIDadenosine deaminaseOrchard Therapeutics
(Strimvelis, EMA approved)
Alpha-1 antitrypsin deficiencyA1ATAdverum
β-thalassemia (severe sickle cell)Hemoglobin (β-chain)Bluebird Bio (LentiGlobin, EMA approved)
Cancer (head and neck squamous cell)p53SiBiono (Gendicine approved, China, CDFA)
Cerebral ALDABCD1Bluebird Bio (Lenti-D)
ChoroideremiaCHMBiogen/Nightstar, Spark
Congestive heart failureAdenyl cyclase 6Renova (RT-100)
Cystic FibrosisCTFRVertex, Boehringer Ingelheim
Duchenne muscular dystrophy (DMD)DystrophinSarepta, Pfizer, Audentes, Solid
GlaucomaBDNF pathwayAstellas
Glioma (cancer)RRVs deliver cytosine deaminaseTocagen (Toca511 & TocaFC)
Hemophilia AFactor VIIIBioMarin, Spark, Shire, Sangamo
Hemophilia BFactor IXSpark, UniQure, Sangamo, Freeline
HoFH (hypercholesterolemia)LDLRRegenxBio
Huntington’s DiseasehuntingtinUniQure
Lipoprotein lipase deficiencyLipoprotein lipaseUniQure (Glybera, EMA approval)
Leber hereditary optic neuropathy (LHON)ND4GenSight Biologics
Metachromatic leukodystrophyARSAGlaxoSmithKline (GSK)
MPS I (Hurler syndrome)IDUASangamo1
MPS II (Hunter’s syndrome)IDSSangamo, RegenexBio
MPS III (Sanfilippo Syndrome)SGSHAbeona
Parkinson’s diseaseAADCVoyager
Pompe Diseaseacid alpha-glucosidaseSarepta, Audentes
Recessive Dystrophic Epidermolysis BullosaColagen C7Abeona (EB-101)
RPE65 deficiency (vision loss)RPE65Spark (Luxturna, FDA approved)
Spinal Muscular Atrophy (SMA I)SMN1Novartis (Zolgensma, FDA approved)
Wet AMD (retinal disease)anti-VEGFRegenexBio
Wiskott Aldrich syndrome (WAS)WASGlaxoSmithKline (GSK)
X-linked myotubular myopathyMTM1Audentes
X-linked retinitis pigmentosaRPGRBiogen/Nightstar

Note: Developmental pipelines can change quickly and the above represents a list as of the date of this article.

1These trials rely on viral vectors to deliver genome editing technology (i.e., ZFN, CRISPR).

With such incredible and complex science and technology behind these gene therapy products, regulators must continue adapting and tailoring the regulatory framework and oversight to meet the unique challenges created by this technology. Some key considerations and challenges that regulators must still address include:

  • Continued efforts to standardize safety,
  • Facilitating reimbursement and patient access, and
  • Developing a practical approach for post-approval product lifecycle management.

These items lead to crucial questions that must be considered, such as:

  • To what degree must critical quality attributes be understood for regulators to have confidence in the safety and clinical benefits of the product?
  • How can regulators help ensure access to gene therapy products, especially when many come with a hefty price tag?
  • Given that gene therapy can offer such personalized treatment, how can regulators offer a pathway to reasonably manage post-approval changes without creating significant burden on industry?


Concluding Remarks

What is clear is that there are no shortage of questions surrounding gene therapy products and regulatory oversight. From the technical aspects of developing such products to the cost and everything in between, we are at a precipice. The promise of gene therapy, inclusive of cures and one-time treatments for serious and life-threatening diseases, looms ahead of us. Will the regulatory constructs be able to keep pace with these scientific and clinical breakthroughs so as not to inhibit the staggering potential of gene therapy products? Only time will tell.


G&L Scientific

G&L Scientific is a market-leading, multi-national consultancy firm with over 25 years’ experience in Regulatory Affairs and Quality Assurance. G&L is recognized as a leader in Pharmaceutical and Biologics CMC serving clients globally from offices in North America, Europe, and Asia. We combine a unique and dynamic approach to providing collaborative Regulatory Affairs support to your organization ensuring success first time, every time. Client-focused. Industry Experts.

At G&L Scientific, we understand the changing pharmaceutical landscape – as new technologies are ushered in, global regulations and guidelines morph and adapt to ensure the quality, efficacy and safety of medications manufactured under these new modalities. And the pressure to do more with less is an ever-present reality of our industry. It would be our pleasure to explore potential Regulatory Affairs solutions to the challenges faced within your organization. Please feel free to contact Christine Piscitelli or Jessica Kokosinski with your thoughts on this article or how we can help address your regulatory affairs challenge.



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