Bioethics with Biotechnology, Bioengineering, and Genetic Engineering

Biotechnology and bioengineering are advancing at an unprecedented pace. Through genetic engineering, possibilities once considered unthinkable are now within reach. While it is widely accepted—both morally and ethically—to use genetic engineering for treating diseases and addressing organ transplant shortages, its application for human enhancement remains highly controversial.

Recently, I watched a YouTube video titled "Rewriting Genomes to Eradicate Disease and Aging" featuring Dr. George Church. In the discussion, Dr. Church covered topics like synthetic genomics, germline editing, and more. When speaking about xenotransplantation, he stated:

“…to have something that’s enhanced is immunologically superior—that is less rejected, resistant to pathogens, resistant to cancerous senescence, and capable of cryopreservation. All of these things have been demonstrated in animals, and now we want to either get them into humans via cell or organ transplants.”

This statement highlights the transformative potential of genetic engineering in medicine, particularly in creating organs that are less prone to rejection and more resilient to diseases. However, it also raises important ethical questions about how far these advancements should be pursued.

I am a fan of the Harvard philosopher Michael Sandel. I thoroughly enjoyed watching his online course, "Justice: What's the Right Thing to Do?" and reading his book, "What Money Can't Buy: The Moral Limits of Markets." Sandel has also weighed in on the ethical issues surrounding genetic engineering.

In a lecture held in the Netherlands, Sandel engaged with the audience to explore these ethical dilemmas in depth. I have included the video below for those interested.

The Perfect Human Being

In the video, Michael Sandel posed several thought-provoking questions to the audience:

• Should biotechnology aim to create the "perfect" human being? And perhaps an even harder question—what would "perfection" mean?
• Should parents be able to choose the sex of their child? This is already possible through embryo screening and other methods. Imagining yourself as a parent, would you find it morally permissible or objectionable to select whether to have a boy or a girl?
• What about selecting a child’s sexual orientation? If technology existed to predetermine whether a child would be straight or gay, should parents have the freedom to make that choice?
• What about enhancing traits like intelligence, appearance, or talents? Suppose it became possible (and safe) to select for a smarter, more attractive, athletically gifted, or musically talented child. Would parents have a responsibility to use these technologies to give their children the best possible advantages?
• Should genetic engineering be used for self-enhancement? For instance, could interventions—genetic, pharmacological, or surgical—be morally justified if they were used to make oneself smarter, improve memory, or enhance cognition? Should individuals have the freedom to do whatever they want with their own brains?
• If biotechnology enabled us to live far longer—perhaps even forever—would that be desirable? How many people would want to live to 1,000 years old, for example?
• Should humanity evolve without limits? What would be the implications of such limitless evolution? Could it lead to a genetic arms race?

Sandel ended by encouraging the audience to reflect on these questions: What would the world look like if everyone could use biotechnology to become the smartest or if people no longer died?

Sandel wrote a book "The Case against Perfection: Ethics in the Age of Genetic Engineering" to explore the ethical implications of genetic engineering and other forms of human enhancement. Sandel argues that the pursuit of perfection through biotechnology undermines core human values and raises profound moral concerns.

• Ethical Limits of Enhancement

Sandel critiques the drive to enhance human traits—such as intelligence, physical abilities, or appearance—through genetic engineering. He contends that this pursuit reflects a problematic desire for mastery over life, rather than an acceptance of human imperfections.

• The Giftedness of Life

A central argument is the importance of appreciating the "giftedness" of human life. Sandel suggests that genetic enhancement erodes this appreciation, replacing humility with hubris and diminishing our capacity to accept the unbidden aspects of existence.

• Moral and Social Implications

Genetic engineering risks exacerbating social inequalities by creating a divide between the "enhanced" and the "unenhanced." Sandel also highlights how it could lead to a commodification of human traits, treating them as products to be optimized.

• Parenthood and the Drive for Perfection

The book explores how the desire for "designer babies" transforms the relationship between parents and children, shifting the focus from unconditional acceptance to a mindset of control and customization.

• The Ethical Boundary

While Sandel acknowledges the benefits of genetic engineering for therapeutic purposes (e.g., curing diseases), he argues that enhancement for non-medical reasons crosses a crucial ethical boundary.

Sandel urges society to resist the temptation to pursue perfection through biotechnology and instead embrace the inherent imperfections that define humanity. He advocates for humility and a respect for the natural limits of human life, warning that unchecked enhancement technologies could compromise the moral fabric of society.

Known knowns and Unknown Unknowns

On several occasions during scientific presentations, I have come across citations of Donald Rumsfeld's statement. Donald Rumsfeld was one of the most famous US Secretary of Defense.

"There are known knowns; there are things we know that we know. 

There are known unknowns; that is to say, there are things we now know we don't know.

But there are also unknown unknowns - there are things we do not know we don't know."

Wikipedia includes an entry on the phrase 'there are unknown unknowns,' a term popularized by Donald Rumsfeld. He famously used it in response to a question about the absence of evidence linking the Iraqi government to the supply of weapons of mass destruction to terrorist groups.

With respect to awareness and understanding, unknown unknowns can be compared to other types of problems in the following matrix:

In clinical trials, comparing an experimental therapy to a control group is often complicated by confounding factors—both known and unknown. Randomization is a key method for addressing these challenges, as it helps balance these factors across treatment groups. By randomly assigning participants to different groups, randomization ensures that potential confounders are evenly distributed, enabling a more accurate comparison of treatment effects.

For known confounding factors, stratified randomization can be employed. This approach involves dividing participants into strata based on specific factors and then randomizing them within each stratum, ensuring an equal probability of assignment to either treatment group within each category. For unknown known or unknown unknown confounding factors, the only way to minimize the impact is to utilize the randomization. 

Randomization is regarded as the cornerstone of causal inference in randomized controlled trials (RCTs). It enables researchers to attribute differences in outcomes between groups to the treatment under investigation, rather than to pre-existing differences among participants, thereby strengthening the validity of the findings.

The awareness-understanding matrix, which includes concepts like 'known unknowns' and 'unknown unknowns,' can be applied to scenarios such as xenotransplantation—for instance, the transplantation of porcine organs into humans. In the context of xenotransplantation, there is always a potential risk of zoonotic infections, where pathogens may be transmitted from animals to humans. There are known pathogens (viruses) and there are unknown pathogens. As Dr Jay Fisherman discussed the issue in his paper "Xenotransplantation-associated infectious risk: a WHO consultation":

"In xenotransplantation, there is the unique potential risk for the transmission of both known and unknown zoonotic infectious agents of animal origin into human recipients and into the wider human population."

"Xenotransplantation will necessitate the development of surveillance programs to detect known infectious agents as well as previously unknown or unexpected pathogens in the absence of recognizable clinical syndromes. This may include assays for known infectious agents, probes for classes of infectious agents (e.g., common genes or antigens of herpesviruses), and assays for unknown pathogens in a variety of tissues."

 "Unknown pathogens: Organisms not known to be human pathogens, not known to be present in the source animals, or for which clinical syndromes and microbiologic assays are poorly described or unknown"

The awareness-understanding matrix is dynamic. With advancements in science, today's unknown unknowns may eventually evolve into known unknowns or even known knowns.

Real world data (RWD) and Real world evidence (RWE) in Drug Development

The 21st Century Cures Act (Cures Act), signed into law on December 13, 2016, is designed to accelerate medical product development and bring new innovations and advances faster and more efficiently to the patients who need them. Following the passing of the Cures Act, the Food and Drug Administration (FDA) has created a framework for evaluating the potential use of real-world evidence (RWE) to help support the approval of a new indication for a drug already approved or to help support or satisfy drug postapproval study requirements.

In December, 2018, FDA issued "Framework for FDA’s Real-World Evidence Program" and FDA's CDER and CBER divisions (now also including the oncology center of excellence) created the RWE program. A series of guidance documents were released. 

DEFINITION of RWD and RWE:

FDA GUIDANCE DOCUMENTS on RWD and RWE (as of November 2024):

Topic	Title	Category	Current Status
EHRs and claims data	Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products	Data considerations	Final, July 2024
Registry data	Real-World Data Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products	Data considerations	Final, December 2023
Data standards	Data Standards for Drug and Biological Product Submissions Containing Real-World Data	Data submission	Final, December 2023
Regulatory considerations	Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products	Applicability of regulations	Final , August  2023
Submitting RWE	Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products	Procedural	Final, September 2022
Externally controlled trials	Considerations for Design and Conduct of Externally Controlled Trials for Drug and Biological Products	Design considerations	Draft, February 2023
Non-interventional studies	Considerations Regarding Non-Interventional Studies for Drug and Biological Products	Design considerations	Draft, March 2024
RCTs in clinical practice settings	Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice	Design considerations	Draft, September 2024

WEBINARS for RWD/RWE:

FDA officials have given various webinars to explain these RWD/RWE guidance documents and encourage the sponsors to apply the RWE to the drug approval process. A non-profit organization, the Reagan-Udall Foundation for the FDA, in collaboration with the Food and Drug Administration (FDA), hosted a series of free, public webinars to discuss FDA-issued guidance in the RWD/RWE. 

Title	Webinar Series	Date
Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products	https://reaganudall.org/news-and-events/events/public-webinar-series-fda-issued-guidance-real-world-evidence	November 4, 2021
Data Standards for Drug and Biological Product Submissions Containing Real-World Data	https://reaganudall.org/news-and-events/events/real-world-data-webinar-series-data-standards	December 3, 2021
Real-World Data Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products	https://reaganudall.org/news-and-events/events/real-world-data-webinar-series-registries	January 28, 2022
Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products	https://reaganudall.org/news-and-events/events/real-world-data-webinar-series-considerations-use-rwd-and-rwe	February 11, 2022
Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products	No webinar was conducted
Considerations for Design and Conduct of Externally Controlled Trials for Drug and Biological Products	https://www.youtube.com/watch?v=5rfInDy7osw&t=1s	April 13, 2023
Considerations Regarding Non-Interventional Studies for Drug and Biological Products	https://reaganudall.org/news-and-events/events/real-world-evidence-webinar-series-considerations-regarding-non	May 30, 2024
Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice	https://reaganudall.org/news-and-events/events/real-world-evidence-webinar-series-integrating-randomized-controlled-trials https://youtu.be/VRaQyOvn3AM?si=YrM9pY6JhL3LBr_o	November 22, 2024

Duke Margolis Center for Health Policy, in collaboration with the FDA, also conducted a series of free, public webinars to discuss the application of RWD/RWE: 

Webinar Title/Link	Date
Optimizing the Use of Real-World Evidence in Regulatory Decision-Making for Drugs and Biological Products – Looking Forward	December 12, 2024
2024 State of Real-World Evidence Policy	July 25, 2024
The State of Real-World Evidence Policy 2023	September 28, 2023
Understanding the Use of Negative Controls to Assess the Validity of Non-Interventional Studies of Treatment Using Real-World Evidence	March 8, 2023
Workshop on Draft Guidance on Real-World Data: Electronic Health Records/Medical Claims Data and Data Standards	February 27, 2023
The State of Real-World Evidence Policy	May 12, 2022
An Introduction to Real-World Data & Real-World Evidence: A Virtual Training Series for the Patient Community	March 12, 2021

SUMMARY:

RWD / RWE play an increasingly vital role in drug development by complementing traditional clinical trial data. Derived from sources such as electronic health records, insurance claims, registries, and patient-reported outcomes, RWD provides insights into how drugs perform in diverse, routine care settings. RWE, generated by analyzing RWD, helps assess the safety, efficacy, and value of treatments in real-world populations, addressing gaps that controlled clinical trials may leave. These insights are particularly valuable in identifying long-term outcomes, supporting regulatory decisions, designing pragmatic trials and comparative effectiveness researches, and informing post-market safety surveillance. Regulatory agencies like the FDA and EMA are encouraging the integration of RWE to enhance decision-making, optimize study designs, and support label expansions or accelerated approvals.

Comparing "In Vitro," "In Vivo," "Clinical Trial," and "In Silico": Understanding Research Approaches in Science

Scientific research relies on diverse methods to study complex biological systems, test hypotheses, and develop treatments. Four commonly used terms you might come across are "in vitro," "in vivo," "clinical trial," and "in silico." Each of these approaches plays a unique role in understanding how living systems function and how interventions—like new drugs or treatments—might affect them. Let’s break down these terms and see how they differ in purpose, application, and benefits.

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1. In Vitro: "In the Glass"

• Definition: In vitro research refers to experiments conducted outside a living organism using isolated cells, organs, or tissues, typically in a controlled lab environment. The term literally means "in the glass," as many early studies were done in glass dishes or test tubes.

• Examples: Cell culture studies, molecular biology experiments, and biochemical tests are common examples of in vitro research. For instance, researchers may expose human cancer cells in a petri dish to a potential new drug to observe its effect on cell survival.

• Applications: This approach allows scientists to isolate specific variables and study biological processes or drug effects in a highly controlled way. It’s useful for preliminary testing of how compounds interact with specific cell types, enzymes, or receptors.

• Advantages:

  • Allows precise control of the experimental environment
  • Reduces complexity by focusing on specific cells or molecules
  • Often faster and more cost-effective than in vivo or clinical trials

• Limitations:

  • Lacks the complexity of whole-organism interactions
  • Results may not fully translate to living organisms, limiting their predictive power for real-life scenarios

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2. In Vivo: "In the Living"

• Definition: In vivo studies are performed within a living organism. This can involve testing in animals (like mice or zebrafish) or humans under controlled research conditions. Theoretically, in vivo tests consist of both pre-clinical (animal) tests and clinical trials (in human). 

• Examples: Animal studies that assess drug absorption, metabolism, and toxicity are examples of in vivo research. Researchers might administer a potential new medication to lab mice to monitor its effects on health and behavior over time.

• Applications: In vivo research is critical for understanding how treatments work within the complexity of a whole organism. It provides insights into drug absorption, distribution, metabolism, and excretion (ADME), and can help identify possible side effects before testing in humans.

• Advantages:

  • Captures interactions within a whole, living system
  • Helps predict how a treatment might work in humans
  • Essential for assessing safety and efficacy before clinical trials

• Limitations:

  • Often more expensive and time-consuming than in vitro studies
  • Ethical considerations, especially in animal testing
  • Results may not fully translate to humans due to species differences

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3. Clinical Trials: Testing in Humans

• Definition: Clinical trials are research studies conducted in human volunteers to evaluate the safety and effectiveness of medical, surgical, or behavioral interventions. They are typically divided into phases (Phase I-IV) to assess safety, dosage, efficacy, and long-term effects.

• Examples: A Phase I trial might test a new drug’s safety in a small group of healthy volunteers, while a Phase III trial could assess its efficacy in a larger group of patients with the target disease.

• Applications: Clinical trials are the gold standard for determining if a treatment is safe and effective in humans. They provide the final step before a new drug, therapy, or medical device can gain regulatory approval and reach the public.

• Advantages:

  • Directly measures effectiveness and safety in humans
  • Provides data necessary for regulatory approval
  • Helps identify real-world effectiveness and adverse effects

• Limitations:

  • High cost and time commitment
  • Ethical considerations, including informed consent and participant safety
  • Risk of unforeseen adverse effects or low efficacy in broader patient populations

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4. In Silico: "In the Computer"

• Definition: In silico research refers to studies conducted via computer simulations or computational models. This approach has grown with advances in bioinformatics, machine learning, and artificial intelligence.

• Examples: Using software to model how a drug might interact with a target protein or predict side effects based on chemical structure is an in silico approach. It can also include simulations to predict disease progression or drug outcomes.

• Applications: In silico methods allow researchers to screen vast numbers of compounds, optimize drug design, and predict potential outcomes with minimal laboratory resources. It’s particularly valuable for preliminary drug discovery and disease modeling.

• Advantages:

  • Reduces the need for animal or human testing in early stages
  • Cost-effective and can analyze vast amounts of data quickly
  • Enables virtual experiments that may not be feasible in the lab

• Limitations:

  • Models rely on available data, which may not be complete or entirely accurate
  • Predictions may not always match real-world biological systems
  • Still requires validation in in vitro, in vivo, or clinical settings to confirm results

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Summary Table

Final Thoughts

Each of these research methods—in vitro, in vivo, clinical trials, and in silico—serves a distinct role in scientific research. They are complementary and often used together, with insights from each approach informing the others. For example, in silico models may predict which compounds are worth testing in vitro, which, in turn, helps decide which treatments should move to in vivo studies and eventually to clinical trials.

By understanding these approaches, we gain a clearer view of the journey from basic research to new treatments that reach the public, illustrating how complex and collaborative scientific advancement truly is.

Some References:

• Emili & Rizk (2024) in Silico Technologies: Leading the Future of Drug Development Breakthroughs
• Marshall et al (2024) In Silico Lung Deposition Profiles of Three Single-inhaler Triple Therapy Combinations Assessed With Functional Respiratory Imaging (FRI) at a Low Inspiratory Flow Rate
• Khani et al (2022) Human in silico trials for parametric computational fluid dynamics investigation of cerebrospinal fluid drug delivery: impact of injection location, injection protocol, and physiology
• Crate et al (2022) Lung deposition of inhaled once-daily longacting muscarinic antagonists via standard jet nebulizer or dry powder inhaler, measured using functional respiratory imaging, in patients with chronic obstructive pulmonary disease 

US Approved Gene Therapies and Summary Basis for Approvals

The FDA presentation by Dr Gopa Raychaudhuri, "Facilitating Development of Gene Therapies for Rare Diseases," summarized all Gene Therapies approved by the US FDA. There were 19 approved gene therapies: 6 stem cell therapies, 6 T cell therapies, and 7 directly administered therapies.  

Gene therapy therapies are reviewed and approved by FDA Center for Biologicals Evaluation and Research (CBER), especially the Office of Therapeutic Products (OTP) - Approved Cellular and Gene Therapy Products are listed here. 

For each approved gene therapy, FDA publishes the product approval and review information on their website by year. The clinical evidence of effectiveness is provided to the public for transparency. For those 19 approved gene therapies, "Summary Basis for Regulatory Action" documents were reviewed and some basic information was summarized in the table below. 

Sponsor	Product & Indication	Study Design	Sample Size	FDA approval date/Brand Drug Name
Pfizer	Adeno-associated virus vector-based gene therapy.   Adults with moderate to severe hemophilia B.	Phase 1/2a Study C0371005 (Safety)  - open-label, single-dose, single-arm, multi-center.   Phase 3 Study C0371002 (Efficacy and Safety), open label, single-dose, multi-national study .   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/beqvez	15 subjects     45 subjects	April 2024 Beqvez
Orchard Therapeutics	Stem cell-based gene therapy.   Children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile, metachromatic leukodystrophy.	Data from an adequate and well-controlled investigation comprised of two single arm, single-center, open-label studies, a European Union Expanded Access Program (EAP), and one ongoing long-term follow-up study and a natural history study. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy	Study OTL-200-201222 (n=18) and Study 205756 (n=10)	March 2024 Lenmeldy
Vertex	Stem cell-based gene therapy-genome editing using CRISPR/Cas9 and SPY101. Patients aged 12 years and older with transfusion-dependent β-thalassemia (TDT).	Multinational, single-arm, open-label, phase 1/2/3 study. https://www.fda.gov/vaccines-blood-biologics/casgevy	52 dosed, 35 evaluable.	Jan 2024 Casgevy
Vertex	Stem cell-based gene therapy -genome editing using CRISPR/Cas9/SPY101 technology. Sickle cell disease in patients aged 12 years or older with recurrent vaso-occlusive crises.	Multinational, single-arm, phase 1/2/3 study.     https://www.fda.gov/vaccines-blood-biologics/casgevy	44 treated, 31 evaluable.	Dec 2023 Casgevy
Bluebird Bio	LVV gene therapy. Sickle cell disease in patients aged12 years or older with a history of vaso-occlusive events.	Study Hgb 206, an ongoing Phase 1/2, open label, multicenter. https://www.fda.gov/vaccines-blood-biologics/lyfgenia	Safety: 54 subjects.   Efficacy: 32 subjects.	Dec 2023 Lyfgenia
BioMarin	Adeno-associated virus vector-based gene therapy.   Adults with severe hemophilia A.	Open-label, single-dose, single-arm, multinational phase 3 study.   https://www.fda.gov/vaccines-blood-biologics/roctavian	112 subjects dosed and constituted the rollover population evaluated.	June 2023 Roctavian
Sarepta	Adeno-associated virus vector-based gene therapy. Ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.	Open-label study 101. Randomized, double-blind, placebo-controlled study 102. Open label study 103.  https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/elevidys	Safety: 85 subjects. 73 subjects received intended dose and 12 received lower doses.	June 2023 Elevidys
Krystal Biotech	Vector-based gene therapy.   Wounds in patients 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.	First-in-human, single-center, open-label, randomized, intra-subject, placebo (vehicle) controlled phase 1/2 study (KB103-001). Multicenter, intra-subject randomized, placebo-controlled, double-blind open-label phase 3 study (B-VEC-03). https://www.fda.gov/vaccines-blood-biologics/vyjuvek	9 subjects.           Safety: 31 subjects.	May 2023 Vyjuvek
Ferring Pharmaceuticals A/S	Vector-based gene therapy. Adult patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.	Single-arm trial study (CS-003).   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/adstiladrin	107 subjects enrolled. 98 subjects evaluable. Efficacy: 55 subjects.	Dec 2022 Adstiladrin
CSL Behring	Adeno-associated virus vector-based gene therapy.   Adults with Hemophilia B (congenital Factor IX deficiency).	Open-label, single-dose, single-arm, multi-center phase 2b study. Open-label, single-dose, multi-center, multinational phase 3 study. https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix	3 subjects.     54 subjects.	Nov 2022 Hemgenix
Bluebird bio	Stem cell-based gene therapy. Slowing the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy.	Open-label, multicenter, single-arm phase 2/3 study. Open-label, multicenter, single-arm phase 3 study.   https://www.fda.gov/vaccines-blood-biologics/skysona	Safety: 67 subjects. Efficacy: 61 subjects.	Sept 2022 Skysona
Bluebird Bio	LVV Gene Therapy Beta-thalassemia. B cell maturation antigen-directed genetically modified. Adult and pediatric patients with ß-thalassemia who require regular red blood cell (RBC) transfusions.	Two open-label, multicenter, single-arm phase 3 studies. https://www.fda.gov/vaccines-blood-biologics/zynteglo	18 in HGB-212 study and 23 in HGB 207 study.	Aug 2022 Zynteglo
Janssen Biotech	Autologous T cell immunotherapy. Adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy.	Single-arm, phase 1b-2 multicenter study.   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/carvykti	Efficacy: 97 subjects.	Feb 2022 Carvykti
Celgene Corporation	B cell maturation antigen-directed genetically modified autologous T cell immunotherapy. Adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody	Single-arm, multicenter phase 2 study.   https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel	Safety: 127 subjects. Efficacy: 100 subjects.	March 2021 Abecma
Juno Therapeutics	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.	Single-arm, multicenter phase 1 study.   https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel	Safety: 268 subjects. Efficacy: 256 subjects.	Feb 2021 Breyanzi
Kite Pharma	CD19-directed genetically modified autologous T cell Immunotherapy.   Adult patients with relapsed or refractory Mantle Cell Lymphoma.	Single-arm, multicenter, phase 2 study.   https://public4.pagefreezer.com/browse/FDA/27-12-2021T03:59/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel	68 subjects treated. Efficacy: 60 subjects.	July 2020 Tecartus
AveXis	Adeno-associated virus vector-based gene therapy.  Pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 gene.	Open-label, single-arm, ascending-dose, phase 1 study. Open-label, single-arm, phase 3 study. https://public4.pagefreezer.com/browse/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/zolgensma	15  subjects.     44 subjects.	May 2019 Zolgensma
Spark Therapeutics	Adeno-associated virus serotype 2 vector gene therapy.  Confirmed biallelic RPE65 mutation-associated retinal dystrophy.	Open-label, dose-escalation, phase 1 study. Open-label, randomized, controlled, cross-over, phase 3 study. https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna	12 subjects.   29 subjects.	Dec 2017 Luxturna
Kite Pharma	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy	Single-arm, open-label, multicenter phase 1/2 study.   https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel	Safety: 108 subjects. Efficacy: 101 subjects.	Oct 2017 Yescarta
Novartis Pharmaceuticals	CD19-directed genetically modified autologous T cell immunotherapy. Adult patients with relapsed or refractory follicular lymphoma after two or more lines of therapy.	Multicenter, open-label, single-arm, trial.   https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel	63 subjects.	Aug 2017 Kymriah

The clinical evidence for the effectiveness of gene therapies often comes from multi-center, open-label, single-arm studies with relatively small sample sizes, as shown in the table above. In some cases, phases of clinical development are combined.