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VP, Rare Diseases & PediatricsPremier Research
The history of gene medicine is filled with hope, tragedy, and successes. VP of Rare Diseases & Pediatrics for Premier Research, Angi Robinson, writes how patient well-being must always prevail, and challenges mustn’t stop us from helping solve unmet medical needs.
The field of gene medicine has a history filled with hope and tragedy, successes and cautionary tales. The world’s first gene therapy was approved in Europe in 2012, only to be taken off the market five years later due to regulatory and commercial barriers. Now, more than six years after the first approval, gene therapy clinical development is thriving. And the path to patients in research settings, and ultimately to market, continues to evolve as new milestones are met and newcomers abound.
Since mid-2017, the FDA has approved three new gene therapy products, and the agency’s expressed commitment to advancing development of these treatments points to improving prospects for emerging therapeutics. This is good news for those with rare diseases and unmet medical needs, but for these new options, the trajectory from concept to trials to regulatory approval and commercial availability is a uniquely complex, but not impossible, pathway.
New therapeutic reality
“Once just a theory, gene therapies are now a therapeutic reality for some patients,” Dr. Scott Gottlieb, the former FDA commissioner, wrote in July 2018 when announcing steps the agency was taking to support development of new drugs. “Gene therapies are being studied in many areas, including genetic disorders, autoimmune diseases, heart disease, cancer, and HIV/AIDS. We look forward to working with the academic and research communities to make safe and effective products a reality for more patients.”
Gottlieb pointed to the agency’s recent approval of three gene therapy drugs:
· Kymriah, a treatment for B-cell acute lymphoblastic leukemia.
· Luxturna, a drug for patients with inherited retinal disease.
· Yescarta, a treatment for non-Hodgkin’s lymphoma.
Considering the scarcity of gene therapy drugs and the enormous effort and expense involved in conducting human trials, the emergence of three new therapies inside of a year is encouraging for sure. Still, Gottlieb cautioned, there is much we don’t understand about how these products work, how to administer them safely, and whether they will continue to work properly without causing adverse side effects in the long term.
Accordingly, the commissioner issued six scientific guidance documents intended as the basis of “a modern, comprehensive framework” for advancing the field of gene therapy while ensuring that new products meet the agency’s standards for safety and efficacy.
Three of the documents focus on therapeutic areas where gene therapy is seen as having especially strong potential: hemophilia, retinal disorders, and rare diseases. The other three are updates to existing FDA guidance on manufacturing issues related to gene therapy, targeting these compounds’ safety, quality, potency, and purity; testing of retroviral vector-based gene therapy products; and the design of long-term follow-up observation of patients.
What is emerging here, on the part of the agencies, sponsors, researchers, and the rest of the drug development community, is a shift in emphasis. After a slow start, gene therapy has moved beyond the theoretical realm, and it’s widely accepted that many new treatments will appear on the market in the relatively near future.
Advice for sponsors
So how do we proceed? The answer is carefully, with a lot of deliberation and planning and proper stakeholder engagement. Here are some things sponsors should consider:
How far? How fast? Some operational recommendations
The question is no longer what could result from these advanced therapies, but how far and how fast science and drug development will evolve in the years ahead.
These questions create new and bigger challenges for those of us on the research side, who need to balance the speed and distance of progress with a carefully charted course through evolving terrain. Here are some recommendations:
Patients need comprehensive information as part of the education and consenting process. Accurate and balanced information, like that which is being developed by the ARM Foundation, is necessary to support research and treatment discussions. Transparent upfront discussions with early-phase patients, as their participation may be altruistic in research whose immediate clinical benefit is minimal to nonexistent. Phase I trials are not efficacy trials but safety trials, and participants often receive lower than therapeutic doses and may not be eligible for future trials. We need to provide materials and help sites educate patients accordingly.
Overcoming the logistics
Patients often must travel great distances, as gene medicine trials tend to be concentrated at a small number of sites that have the administrative infrastructure, expertise, and equipment to handle the stringent requirements for starting and executing an advanced therapy trial. Getting patients to the sites at the right time can be a challenge, especially when they need to undergo immuno-suppression prior to receiving the study drug-so we need to make participants understand the importance of their consistent participation and provide the appropriate patient-focused support such as patient travel services and home nursing.
Working with sites
A thorough qualification and training process is needed, even at facilities that have previously performed these trials. Sites may have highly specific requirements and/or restrictions about the receipt and handling of advanced therapy drugs, and step-by-step training and rehearsal make for the most prepared sites. For example, for a recent CAR T study, we did dry runs with mock study drug vials from the distribution center to verify that packaging, documentation, and handling were correct for each country and site.
The long haul
Patients in gene therapy trials must commit to lengthy follow-up monitoring-for five to as much as 15 years-to gauge the treatment’s durability and the occurrence of side effects, adding logistical and operational complications. In 2018, the FDA issued 36 pages of draft guidance on long-term monitoring following administration of gene therapy products, listing numerous clinical considerations for devising protocols for follow-up. We need to understand the guidance as it relates to each therapy and plan for how to collect the data in a way that’s sustainable, considering options like virtual trials and electronic data gathering.
Patients already receiving adequate (if less than ideal) treatment can be especially reluctant to consider gene therapy trials. Hemophilia is a good example. Many patients are living relatively healthy, active lives using established treatment regimens. As appealing as the idea of a cure might be, will they commit to the disruption of a clinical trial and the prospect of years of follow-up? Again, we need to provide materials and help sites educate patients accordingly, and design trials and methods of follow-up that impose the least burden.
The example of hemophilia raises a conundrum for the industry, which-like the FDA-considers it among the most promising indications for gene therapy treatment. In many ways, it also embodies the unprecedented opportunities and complexities inherent in gene therapy clinical trials.
Patient safety and well-being must always prevail, and challenges mustn’t stop us from helping to advance novel cures for unmet medical needs. With the proper vigilance, planning, and patient-first mindsets, we will continue taming the complexities inherent in these trials and help clear more pathways to medical and commercial success.
Angi Robinson is the Vice President of Rare Diseases & Pediatrics at Premier Research.
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