James Riddle, Senior Vice President, Global Review Operations, Advarra05.13.24
Gene therapy research is booming. Since the U.S. Food and Drug Administration (FDA) issued its first approval for a gene therapy in 2017,1 oncology researchers have been breaking barriers in gene therapy trials, followed by an explosion in mRNA research during the COVID pandemic. Today, this trailblazing science is providing new ways to approach rare diseases and new hope when other investigational interventions have failed. In fact, the majority2 of approved gene therapies are for rare diseases—14 are currently in Phase III trials for 10 rare diseases and 45 gene therapies are in early stages of development to treat 30 rare diseases.
“We see great potential for gene therapies,” said Leslie Johnston, senior vice president of biotech delivery for Parexel. “As more products are approved, it will gain traction and more companies will look to expand their therapies into other therapeutic indications. This progress presents tremendous potential to change more patients’ lives across many different diseases.”
This could be gene therapy’s moment. But to fully seize it, the industry must clear some complex hurdles. Gene therapies pose several unique challenges for clinical research, including ethical and safety considerations, regulatory hurdles, precarious logistics, and potentially staggering costs. These challenges may already be having ramifications: New U.S. patients treated with gene therapies approved or in development are expected to fall by one-third from 2025 to 2034.3
The key to clearing these hurdles? Cooperation between sponsors, sites, regulators, patients, and other stakeholders is essential to expediting the advancement of life-saving gene therapies.
However, obtaining regulatory approval under these conditions is time consuming and resource intensive. To avoid hampering scientific progress, regulators should aim to ensure that requirements are appropriately rigorous without being unmanageably onerous.
Thankfully, the FDA is paying close attention to gene therapy and has demonstrated a desire to work with drug developers toward the success and approval of these treatments. Dr. Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER) at the FDA, has expressed his hope for an exponential, if not logarithmic, increase in gene therapy approvals.
“There is a lot of excitement that this could potentially make a big difference for the treatment of human disease,” said Dr. Marks in his remarks to the National Press Forum last November.4
The FDA is going beyond mere rhapsodizing and taking action to accelerate gene therapy. Last year, the agency launched a pilot program called Support for Clinical Trials Advancing Rare Disease Therapeutics, or START.5 This program is designed to accelerate the development and approval process for treatments targeting rare diseases by providing regulatory guidance, assistance, and incentives to sponsors conducting clinical trials in this field. The program represents an important step forward in fostering innovation and collaboration between regulatory bodies and sponsors.
In addition, the FDA is working to harmonize global requirements for the review of gene therapies.6 Encouraging and facilitating international cooperation and harmonization of regulatory standards—including mutual recognition agreements and shared regulatory pathways for multinational clinical trials—can help streamline gene therapy development globally and help bring innovations to patients faster.
Even with this progress, regulators should continue to help accelerate gene therapy research by streamlining regulatory pathways specifically tailored to gene therapies. This means providing clear guidance on requirements for preclinical and clinical development, fostering collaboration between stakeholders to share knowledge and best practices, and offering expedited review processes for gene therapy products aimed at treating serious or life-threatening diseases.
With a staggering 2,500 cell and gene therapy investigational new drug applications (INDs) on file, the FDA approved just five cell and gene therapies in 2023. Dr. Marks has suggested that accelerated approval, which has successfully advanced cancer and HIV/AIDS treatments, may be the most appropriate path for this new category of treatments. But regulators also need to commit to proactively partner with developers to understand the patient population and the risks and benefits of each new therapy.
Likewise, researchers, industry stakeholders, and patient advocacy groups should engage with regulators to help them understand the unique challenges and opportunities in the field of gene therapy. This can help regulators adapt regulatory frameworks to ensure patient safety while expediting the development and approval of promising treatments.
By working closely with clinicians and regulators, sponsors can ensure that the trial development process aligns with clinical needs and regulatory standards. Sponsors should have a thorough understanding of FDA requirements pertaining to design, preclinical testing, and long-term follow-up. Better alignment from the outset will lead to more efficient trial designs, faster regulatory approvals, and ultimately quicker patient access to therapies.
For example, sponsors working with mRNA and other genetically engineered therapies in North America not only have to go through institutional review board (IRB) review, they also have to navigate additional requirements from the U.S. National Institutes of Health (NIH) Office of Science Policy Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines).7 These requirements usually involve an additional biosafety risk assessment review from an institutional biosafety committee (IBC) in addition to IRB review.
NIH Guidelines apply for any research involving recombinant or synthetic nucleic acids (e.g. genetically engineered materials) that receives NIH support or takes place at sites that have received NIH support for such research. Even when there is zero NIH support, IBC review is considered a best practice. IBC review and inspection helps sites ensure they are fully prepared by identifying areas for improved biosafety protections and calling out gaps in current standard operating procedures (SOPs). Proactive coordination and integration of these separate review processes can speed trial timelines and help sponsors consistently address any potential concerns or issues.
Sites can also be better prepared by pre-registering an IBC. The NIH takes six to eight weeks or more to approve a new registration, in addition to IBC review time—so by registering an IBC before they even have a trial, sites can save a month or more in startup time over a site that waited to register.
Clinical trial sites looking to host gene therapy studies must be prepared in other ways, as well, both in terms of knowledge and infrastructure. Gene therapy studies require specialized infrastructure for manufacturing, storing, and administering genetic material to adhere to strict biosafety guidelines. Something as simple as having an upholstered chair in the infusion room—which would pose an unacceptable contamination risk if genetic materials were to spill—would require the site to rethink their current processes. Rigorous training is also key due to the added risk of spreading genetic material to caregivers and others in close contact with patients. Research staff must be specially trained to handle, deliver, and dispose of this material safely.
Of course, these measures can seem intimidating for sites that are already cost-constrained. Large academic medical centers with more resources and experience are more likely to be well-positioned for these studies. For instance, they may already have conducted bench, animal, and/or agricultural research with genetic engineering or have the funding to make any needed adjustments such as purchasing special equipment. But to maximize the potential number of sites where this research can be conducted—and therefore reach more potential participants—sponsors might consider providing help in the form of financial assistance, training curricula, SOP guidance, and more to smaller sites seeking to conduct gene therapy research.
“Logistical complexities, depending on the investigational medicine and therapeutic area, are among the most complicated challenges in gene therapy trials,” added Johnston. “From collecting the specimen from the patient, modifying it, storing it, transporting it, and then returning it back to the patient all comes with tremendously unique logistical challenges and requires equally unique equipment, technology, and expertise. And it can be cost-prohibitive.”
First, it’s crucial for patients to adhere strictly to the protocol provided by the clinical trial team, including following medication schedules, maintaining specific hygiene practices, and attending all study visits. They should strive to maintain optimal health to enhance the body’s response to gene therapy. And to avoid delays, patients should maintain open and honest communication with the clinical trial team, reporting any changes in symptoms, side effects, or general health as soon as they occur.
Trial participants also need to be in it for the long haul. Because gene therapy interventions aim to produce lasting effects, even cures, they typically require long-term patient follow-up to assess efficacy and safety. But they may also need to have incredible patience.
Johnston explained, “There are many complexities that can impact study progress. For example, unpredictable logistical challenges like a weather event or vehicle accident could delay a temperature-sensitive delivery to a site, or data review outcomes could require an indeterminate pause period. Patience and agility are must-haves, but it is difficult for patients potentially depending on this new therapy to save or change their lives.”
Lastly, the industry cannot forget the patient. Involving patients and patient advocacy groups in the regulatory process can help ensure that the development of gene therapies is aligned with patient needs and priorities, as well as shed light on risk-benefit perspectives from a patient’s viewpoint. The more these perspectives are considered from the beginning, the greater the chance of a trial’s success.
Rita Naman, co-founder of the Mighty Milo Foundation, emphasizes the need for a more collaborative and patient-centered approach to gene therapy development.
“For ultra-rare diseases like SPAX5, gene therapy offers a glimmer of hope where traditional treatments do not. But logistical hurdles make these therapies expensive and inaccessible,” explained Naman. “Closer collaboration with patients, industry, and regulators could streamline these processes, drive costs down, and speed trials. Patients like my son, and their caregivers, plus advocacy groups should be invited into the earliest discussions to prevent false starts or missed milestones in gene therapy development especially as the patient’s priorities don’t always line up with the sponsor’s.”
“Patients want access to novel gene treatments, and they want it fast. Sponsors want to deliver but fight logistical and financial obstacles. Regulators want to ensure safety first, especially considering such new, promising science,” concluded Johnston. “These three goals may seem conflicting at times, so we need to strike a balance of safety and speed, so patients don’t miss their only potential treatment opportunity.”
References
1. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states
2. https://www.oaepublish.com/articles/rdodj.2023.29
3. https://www.bloomberg.com/news/articles/2024-02-20/gene-therapy-makers-struggle-to-find-patients-for-miracle-cures?embedded-checkout=true
4. https://nationalpress.org/topic/peter-marks-fda-crispr-sickle-cell-gene-therapy/
5. https://www.ajmc.com/view/new-fda-pilot-program-will-provide-hands-on-regulatory-guidance-for-cell-and-gene-therapy-trials-in-rare-disease
6. https://endpts.com/fda-develops-pilot-to-harmonize-international-gene-therapy-regulations/
7. https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf
A seasoned industry veteran with more than 25 years of experience, James Riddle is senior vice president of global review operations at Advarra. Riddle’s expertise includes large program management and growth, operational processes, development and implementation of technology solutions, and management of large Human Research Protection Programs (HRPP), Biosafety programs (IBC) and Institutional Animal Care and Use programs (IACUC). Riddle has directed numerous clients in achieving Part 11 compliance and meeting computer system validation requirements. He can be reached at [email protected].
“We see great potential for gene therapies,” said Leslie Johnston, senior vice president of biotech delivery for Parexel. “As more products are approved, it will gain traction and more companies will look to expand their therapies into other therapeutic indications. This progress presents tremendous potential to change more patients’ lives across many different diseases.”
This could be gene therapy’s moment. But to fully seize it, the industry must clear some complex hurdles. Gene therapies pose several unique challenges for clinical research, including ethical and safety considerations, regulatory hurdles, precarious logistics, and potentially staggering costs. These challenges may already be having ramifications: New U.S. patients treated with gene therapies approved or in development are expected to fall by one-third from 2025 to 2034.3
The key to clearing these hurdles? Cooperation between sponsors, sites, regulators, patients, and other stakeholders is essential to expediting the advancement of life-saving gene therapies.
Regulators should address risks without limiting innovation
Gene therapy trials are strictly regulated—and rightly so, due to the novel nature of the intervention and the potential long-term consequences. Gene therapy interventions also carry inherent safety risks, including the potential for unintended genetic changes or adverse immune reactions. Ensuring patient safety requires rigorous monitoring and adherence to strict protocols.However, obtaining regulatory approval under these conditions is time consuming and resource intensive. To avoid hampering scientific progress, regulators should aim to ensure that requirements are appropriately rigorous without being unmanageably onerous.
Thankfully, the FDA is paying close attention to gene therapy and has demonstrated a desire to work with drug developers toward the success and approval of these treatments. Dr. Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER) at the FDA, has expressed his hope for an exponential, if not logarithmic, increase in gene therapy approvals.
“There is a lot of excitement that this could potentially make a big difference for the treatment of human disease,” said Dr. Marks in his remarks to the National Press Forum last November.4
The FDA is going beyond mere rhapsodizing and taking action to accelerate gene therapy. Last year, the agency launched a pilot program called Support for Clinical Trials Advancing Rare Disease Therapeutics, or START.5 This program is designed to accelerate the development and approval process for treatments targeting rare diseases by providing regulatory guidance, assistance, and incentives to sponsors conducting clinical trials in this field. The program represents an important step forward in fostering innovation and collaboration between regulatory bodies and sponsors.
In addition, the FDA is working to harmonize global requirements for the review of gene therapies.6 Encouraging and facilitating international cooperation and harmonization of regulatory standards—including mutual recognition agreements and shared regulatory pathways for multinational clinical trials—can help streamline gene therapy development globally and help bring innovations to patients faster.
Even with this progress, regulators should continue to help accelerate gene therapy research by streamlining regulatory pathways specifically tailored to gene therapies. This means providing clear guidance on requirements for preclinical and clinical development, fostering collaboration between stakeholders to share knowledge and best practices, and offering expedited review processes for gene therapy products aimed at treating serious or life-threatening diseases.
With a staggering 2,500 cell and gene therapy investigational new drug applications (INDs) on file, the FDA approved just five cell and gene therapies in 2023. Dr. Marks has suggested that accelerated approval, which has successfully advanced cancer and HIV/AIDS treatments, may be the most appropriate path for this new category of treatments. But regulators also need to commit to proactively partner with developers to understand the patient population and the risks and benefits of each new therapy.
Likewise, researchers, industry stakeholders, and patient advocacy groups should engage with regulators to help them understand the unique challenges and opportunities in the field of gene therapy. This can help regulators adapt regulatory frameworks to ensure patient safety while expediting the development and approval of promising treatments.
Sites and sponsors must be prepared
Of course, sites and sponsors also have a crucial part to play in advancing this promising field of medicine. Clinical trial sites should enhance their capacity to conduct gene therapy trials safely and effectively—and sponsors should do their part to assist sites in these efforts.By working closely with clinicians and regulators, sponsors can ensure that the trial development process aligns with clinical needs and regulatory standards. Sponsors should have a thorough understanding of FDA requirements pertaining to design, preclinical testing, and long-term follow-up. Better alignment from the outset will lead to more efficient trial designs, faster regulatory approvals, and ultimately quicker patient access to therapies.
For example, sponsors working with mRNA and other genetically engineered therapies in North America not only have to go through institutional review board (IRB) review, they also have to navigate additional requirements from the U.S. National Institutes of Health (NIH) Office of Science Policy Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines).7 These requirements usually involve an additional biosafety risk assessment review from an institutional biosafety committee (IBC) in addition to IRB review.
NIH Guidelines apply for any research involving recombinant or synthetic nucleic acids (e.g. genetically engineered materials) that receives NIH support or takes place at sites that have received NIH support for such research. Even when there is zero NIH support, IBC review is considered a best practice. IBC review and inspection helps sites ensure they are fully prepared by identifying areas for improved biosafety protections and calling out gaps in current standard operating procedures (SOPs). Proactive coordination and integration of these separate review processes can speed trial timelines and help sponsors consistently address any potential concerns or issues.
Sites can also be better prepared by pre-registering an IBC. The NIH takes six to eight weeks or more to approve a new registration, in addition to IBC review time—so by registering an IBC before they even have a trial, sites can save a month or more in startup time over a site that waited to register.
Clinical trial sites looking to host gene therapy studies must be prepared in other ways, as well, both in terms of knowledge and infrastructure. Gene therapy studies require specialized infrastructure for manufacturing, storing, and administering genetic material to adhere to strict biosafety guidelines. Something as simple as having an upholstered chair in the infusion room—which would pose an unacceptable contamination risk if genetic materials were to spill—would require the site to rethink their current processes. Rigorous training is also key due to the added risk of spreading genetic material to caregivers and others in close contact with patients. Research staff must be specially trained to handle, deliver, and dispose of this material safely.
Of course, these measures can seem intimidating for sites that are already cost-constrained. Large academic medical centers with more resources and experience are more likely to be well-positioned for these studies. For instance, they may already have conducted bench, animal, and/or agricultural research with genetic engineering or have the funding to make any needed adjustments such as purchasing special equipment. But to maximize the potential number of sites where this research can be conducted—and therefore reach more potential participants—sponsors might consider providing help in the form of financial assistance, training curricula, SOP guidance, and more to smaller sites seeking to conduct gene therapy research.
“Logistical complexities, depending on the investigational medicine and therapeutic area, are among the most complicated challenges in gene therapy trials,” added Johnston. “From collecting the specimen from the patient, modifying it, storing it, transporting it, and then returning it back to the patient all comes with tremendously unique logistical challenges and requires equally unique equipment, technology, and expertise. And it can be cost-prohibitive.”
Patients must be fully on board
Of course, the most essential stakeholder in any clinical trial is the patient. In gene therapy research, which can be particularly demanding, patients must have a complete understanding of and commitment to their involvement. Understanding the potential risks and benefits can help patients make informed decisions and navigate the study process.First, it’s crucial for patients to adhere strictly to the protocol provided by the clinical trial team, including following medication schedules, maintaining specific hygiene practices, and attending all study visits. They should strive to maintain optimal health to enhance the body’s response to gene therapy. And to avoid delays, patients should maintain open and honest communication with the clinical trial team, reporting any changes in symptoms, side effects, or general health as soon as they occur.
Trial participants also need to be in it for the long haul. Because gene therapy interventions aim to produce lasting effects, even cures, they typically require long-term patient follow-up to assess efficacy and safety. But they may also need to have incredible patience.
Johnston explained, “There are many complexities that can impact study progress. For example, unpredictable logistical challenges like a weather event or vehicle accident could delay a temperature-sensitive delivery to a site, or data review outcomes could require an indeterminate pause period. Patience and agility are must-haves, but it is difficult for patients potentially depending on this new therapy to save or change their lives.”
Lastly, the industry cannot forget the patient. Involving patients and patient advocacy groups in the regulatory process can help ensure that the development of gene therapies is aligned with patient needs and priorities, as well as shed light on risk-benefit perspectives from a patient’s viewpoint. The more these perspectives are considered from the beginning, the greater the chance of a trial’s success.
Rita Naman, co-founder of the Mighty Milo Foundation, emphasizes the need for a more collaborative and patient-centered approach to gene therapy development.
“For ultra-rare diseases like SPAX5, gene therapy offers a glimmer of hope where traditional treatments do not. But logistical hurdles make these therapies expensive and inaccessible,” explained Naman. “Closer collaboration with patients, industry, and regulators could streamline these processes, drive costs down, and speed trials. Patients like my son, and their caregivers, plus advocacy groups should be invited into the earliest discussions to prevent false starts or missed milestones in gene therapy development especially as the patient’s priorities don’t always line up with the sponsor’s.”
In the fight for gene therapy breakthroughs, cooperation is key
The road to operationalizing gene therapy clinical trials is laced with land mines and potholes. To capture the full potential of novel gene therapy research, a new level of collaboration between sponsors, CROs, sites, oversight committees, regulatory bodies, and patients is paramount.“Patients want access to novel gene treatments, and they want it fast. Sponsors want to deliver but fight logistical and financial obstacles. Regulators want to ensure safety first, especially considering such new, promising science,” concluded Johnston. “These three goals may seem conflicting at times, so we need to strike a balance of safety and speed, so patients don’t miss their only potential treatment opportunity.”
References
1. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states
2. https://www.oaepublish.com/articles/rdodj.2023.29
3. https://www.bloomberg.com/news/articles/2024-02-20/gene-therapy-makers-struggle-to-find-patients-for-miracle-cures?embedded-checkout=true
4. https://nationalpress.org/topic/peter-marks-fda-crispr-sickle-cell-gene-therapy/
5. https://www.ajmc.com/view/new-fda-pilot-program-will-provide-hands-on-regulatory-guidance-for-cell-and-gene-therapy-trials-in-rare-disease
6. https://endpts.com/fda-develops-pilot-to-harmonize-international-gene-therapy-regulations/
7. https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf
A seasoned industry veteran with more than 25 years of experience, James Riddle is senior vice president of global review operations at Advarra. Riddle’s expertise includes large program management and growth, operational processes, development and implementation of technology solutions, and management of large Human Research Protection Programs (HRPP), Biosafety programs (IBC) and Institutional Animal Care and Use programs (IACUC). Riddle has directed numerous clients in achieving Part 11 compliance and meeting computer system validation requirements. He can be reached at [email protected].
