The value-driven, precision-based drug development boom now underway introduces new complexity and competitive dynamics for drug development including clinical trials. Traditional small molecule-based biotech therapies focus on addressing symptoms of disease while Advanced Therapy products restore or establish normal function through the modification of human cells (cell therapy), or of DNA or RNA (gene therapy).

Advanced Therapies

The drug development world moves from volume to value as targeted, precision-driven gene and cell therapy product pipeline grows to nearly 700 in both clinical and preclinical programs. Known as “Advanced Therapies” or “ATs” the Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research (CBER) regulates ATs and certain devices associated to ATs. These pipelines are growing at a fast rate with significant numbers of products advancing to clinical development.

Cellular-based ATs may include a number of specialized therapeutic targets from cellular immunotherapies and cancer vaccines to both  autologous and allogeneic cells for various therapeutic indications, such as hematopoetic stem cells and adult and embryonic stem cells. Gene therapy-based ATs are designed and engineered to modify or manipulate the expression of a gene or actually change the biological properties of living cells for therapeutic use.

FDA Approved AT Products

The FDA’s Office of Tissues and Advanced Therapies (OTAT) reports a list of AT-based products have been approved in the United States—the world’s largest single national drug market.  TrialSite News includes this list below.

Approved Advanced Therapy-based ProductSponsor/OwnerAT Type
ALLOCORD (HPC, Cord Blood)SSM Cardinal Glennon Children’s Medical CenterCell
CLEVECORD (HPC Cord Blood)Cleveland Corp Blood CenterCell
Ductord, HPC Cord BloodDuke University School of MedicineCell
GINTUIT (Allogeneic Cultured Keratinocytes & Fibroblasts in Bovine Collagen)Organogenesis IncorporatedCell
HEMACORD (HPC, cord blood)New York Blood CenterCell
HPC Cord BloodClinimmune Labs, University of Colorado Cord Blood BankCell
HPC, Cord Blood—MD Anderson Cord Blood BankMD Anderson Cord Blood BankCell
HPC, Cord Blood–Life SouthLifeSouth Community Blood Centers Inc.Cell
HPC, Cord Blood—BloodworksBloodworksCell
IMLYGIC (talimogene laherparepvec)BioVex, Inc. (Amgen)Gene
KYMRIAH (tisagenlecleucel)*NovartisGene
LAVIV (Azficel-T)Fibrocell TechnologiesCell
LUXTURNASpark Therapeutics Inc.Gene
MACI (Autologous Cultured Chondrocytes on a Porcupine Collagen Membrane)Vericel CorpCell
PROVENGE (sipuleucel-T)Dendreon CorpCell
YESCARTA (axicabtagene ciloleucel)Kite Pharma Incorp (acquired by Gilead)Gene
ZOLGENSMA (onasemnogene abeparvovec-xioi)AveXis, Inc. (Novartis acquired)Gene

*first approved gene-based therapy in the USA

Gene Therapies

For a sample review of studies, sites and investigators, TrialSite News focuses on gene therapies approved by the FDA. It should be noted that China has produced the word’s first commercial gene therapy products. A list of commercialized gene therapies reveals that although China got a first start, possibly due to more “liberalized’ regulatory oversight, the U.S. and Europe are rapidly advancing commercial candidates.

Clinical Investigator Site Overview

TrialSite News research selected a sampling of approved gene therapy-based ATs and surveyed1) what institution invented or created the product; 2) what company owns the treatment 3) include some key research sites involved at trials used by regulators for basis for approach. Three gene-based therapies approved in the United States include KYMRIAH (Novartis), YESCARTA (Gilead) and ZOLGENSMA (Novartis).


Designed for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia, was the first gene-based therapy to be approved by the FDA.  As then FDA Commissioner Scott Gottlieb commented “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.” 

Initially developed by a team in the University of Pennsylvania headed by Carl H. June, the asset was licensed to Switzerland-based Novartis. The Swiss giant completed development, obtained approval and markets the treatment. It was the first FDA-approved treatment involving a gene therapy step in America. It was approved in Europe shortly thereafter.

According to the FDA, the safety and efficacy of Kymriah resulted from the pivotal Phase 2 JULIET study, enrolling patient with relapsed or refractory diffuse large B cell lymphoma from 27 site in 10 countries. Tisagenlecleucel evidenced an overall response rate of 50% with 32% of patients achieving a complete response and 18% of patients achieving a partial response.

The Study

The JULIET study commenced in 2015 and runs ongoing till 2023.  A global study, Novartis only disclosed site names within America. They included Mayo Clinic, University of California, San Francisco, Emory University Winship Cancer Center, University of Chicago Medical Center, Hematology & Oncology, University Kansas Cancer Center, Sidney Kimmel Cancer Center Johns Hopkins, University of Michigan, University of Minnesota, Weill Cornell Medical College, Duke University, Ohio State University James Cancer Hospital, Oregon Health & Science University, University of Pennsylvania and MD Anderson Cancer Center.

Prominent clinical investigators associated with JULIET included the following:

Stephen J. Schuster, MDUniversity of Pennsylvania
Michael R. Bishop, MDUniversity of Chicago
Constantine S. Tam, MDPeter MacCallum Cancer Centre
Edmund K Waller, MD, PhDWinship Cancer Center
Peter Borchmann, MDUniversity Hospital of Cologne
Joseph P McGuirk, DOUniversity of Kansas
Ulrich Jäger, MDMedical University of Vienna
Samantha Jaglowski, MDOhio State University, the James
Charalambos Andreadis, MDUniversity of California, San Francisco
Jason R. Westin, MDMD Anderson
Isabelle Fleury, MDHospital Maisonneuve-Rosemont
Veronika Bachnova, MD, PhDUniversity of Minnesota


Yescarta (axicabtagene ciloleucel), developed by Kite Pharma, Inc. (acquired by Gilead for $11.9 billion), a treatment for large B-cell lymphoma that has failed conventional treatment, was in late 2017 representing the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL)

Due to the risk of  cytokine release syndrome (CRS) and neurologic toxicities, Yescarta was approved with a risk evaluation and mitigation strategy (REMS), including elements to assure safe use. For example, the FDA requires that hospitals and their associated clinics that dispense Yescarta be specifically certified. As part of that certification, any staff involved in the prescribing, dispensing or administering of the gene therapy are required to be trained to recognize and manage CRS and nervous system toxicities.


Yescarta’s approval was based on data from the ZUMA-1 pivotal trial. This single-arm, open-label, multicenter study evaluated the efficacy of a single infusion of Yescarta in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. 72% of the patients receiving a single infusion (n-101) responded to the therapy including 51% of patients who had no detectable cancer remaining (complete remission; 95% Cl; 41, 62). During median follow-up at 7.9 months, those who had met complete remission hadn’t achieved the median duration of response (95% Cl: 8.1 months, not estimable [NE]). Again CRS represented risk as 13% of the study’s patients experienced grade 3 or higher CRS and 31% experienced neurologic toxicities.

Study Centers and Investigators/Coordinators

The pivotal study leading to the approval was global but not all institutions and principal investigators (PIs) were named. TrialSite News includes a list of named PIs.

InvestigatorContacts (either PI or Study Coordinator)
Banner MD AndersonAmanda Stanford
City of HopeHormoz Mirshkarlo
UCSDDimitrios Tzachanis , PI
UCLAShenetra Walker  
Stanford University 
Sarah Cannon Karen Morris 
University of MiamiKirenia Correa, CCRP
Moffitt Cancer CenterJeffrey Edelman , Matthew Scott   
Loyola University Med CenterKaren Pilman, Anna Adjar    
University of Iowa 
Dana Farber Cancer Inst.Michael Rocchio    
Karmanos Cancer CenterCharlotte Brown, CCRP
Mayo ClinicYi Lin, MD    
Washington UniversityFay Hwang 
University of NebraskaSusan Blumel, RN, BSN, OCN
Hackensack University Med CenterKara Yannott  
Montefiore Medical CenterAmbar Baez 
University of Rochester Patrick Reagan, PI
Cleveland ClinicAyesha Khan 
Sarah Cannon 
Vanderbilt UniversityDelia Darst
MD Anderson 
Sarah Cannon-Methodist Healthcare SystemPaul Shaughnessy , PI
Vancouver General HospitalKevin Song, MD, FRCPC, PI
Princess Margaret Hospital, TorontoJohn Kuruvilla, MD, PI


Married researchers Jean Bennett and Albert Maguire, among others, studied congenital blindness for years, which culminated in the approval of Luxturna. Known as voretigene neparvovec is a novel gene therapy for the treatment of Leber’s congenital amaurosis. It was developed by Spark Therapeutics and Children’s Hospital of Philadelphia. An AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence, tt represents the first gene therapy approved by the FDA. Leber’s congenital amaurosis, or biallelic RPE65-mediated inherited retinal disease, is an inherited disorder causing progressive blindness. Voretigene is the first treatment available for this condition. The gene therapy is not a cure for the condition, but substantially improves vision in those treated. It is administrated as an subretinal injection.


Luxturna’s approval was based on two open-label Phase I trials, which continue to follow participants who received the treatments between 2007 and 2012 and one open-label, randomized, controlled Phase III trial. The clinical program included up to four years of efficacy data from a single dose. The overall safety profile remained stable. The Phase I studies involved Children’s Hospital of Philadelphia and University of Pennsylvania based on the initial work of Bennett and Maguire.

A Phase III trial started in 2012 and runs ongoing till 2029.  The study sites included Children’s Hospital of Philadelphia (Albert M. Maguire, MD) and University of Iowa (Stephen R. Russell, MD). 


Known as the $2 million dollar drug, this gene-based therapy represents an example of the volume to value model Novartis has embraced. Swiss global drug maker acquired it via the AveXis Inc. acquisition for $8.7 billion

Developed for spinal muscular atrophy (SMA), it is used with corticosteroids as a one-time injection into the vein. It was approved in 2019 by the FDA for use with children less than 2 years old. The therapy works by providing a new copy of the gene that makes the human SMN protein.

The Study

The approval was in part based on safety and effectiveness established in an ongoing clinical trial and a completed trial involving a total of 36 pediatric patients with infant-onset SMA between the ages of approximately 2 weeks and 8 months at study entry. Primary evidence for approval is based on the results from 21 patients treated with the gene therapy in the ongoing clinical trial. There was some controversy associated with this approval—from the price tag of the drug to Novartis withholding information that certain data was manipulated (from AveXis) until after approval. The FDA declared that the information didn’t represent any material risk to patients hence they upheld the approval. AveXis didn’t list all clinical investigator names however their study includes dozens of major academic medical centers in the United States. The lead principal investigator was Jerry Mendell, MD, Center for Gene Therapy at the Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio.

Further Surveys

TrialSite News will continue to review gene therapy approvals and candidate in late-stage trials for additional information about participating clinical research sites and principal investigators.


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