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The fundamentals behind scientific research and breakthroughs rely on clinical trials to demonstrate efficacy, safety, and necessity when providing crucial treatment through therapeutic treatments.
Advanced therapeutic medicines (ATMPs) have greatly expanded the options available to patients facing a range of diseases. These innovative cell and gene therapies have demonstrated impressive effectiveness, but their high costs, complex manufacturing processes, and lengthy development timelines, though progressive, are just a few of the many challenges the industry faces.
Cell and gene therapies have become a significant part of the pharmaceutical industry’s clinical and preclinical pipelines. Many diseases, illnesses and conditions have unmet medical needs. Modern medicine has come a long way, drastically improving healthcare and patient care. The fundamentals behind scientific research and breakthroughs rely on clinical trials to demonstrate efficacy, safety, and necessity when providing crucial treatment through therapeutic treatments. Cell and gene therapies have the potential to be a long-term treatment. Transferring scientific knowledge, facts, and discoveries into pharmaceutical products can be tedious, jarring, and at times, feel stagnant. However, the longevity of these therapies has the promise to be groundbreaking in the way we tackle unmet medical needs.
The Crucial Role of Clinical Trials
The process of developing drugs relies on clinical trials, which are both complex and expensive. While there is never a guarantee of success, the impact on medical research and healthcare is significant. Clinical trials provide a unique opportunity to explore new treatments for various diseases, although there are many challenges to overcome and a need for patience
Clinical trials play a crucial role in the development of ATMPs, which are subject to a specialized regulatory framework. Regulatory bodies such as the FDA and EMA require clinical research to have clear objectives, with the aim of improving the quality of life for individuals with life-threatening or chronic illnesses while minimizing risks.
Clinical trials are divided into 5 (V) phases, but there are 3 (I-III) main phases of clinical trials.
What are the Different Phases of Clinical Trials?
Clinical trials typically progress through several phases:
- Phase I: This phase focuses on assessing the safety and dosage of the experimental treatment. It usually involves a small number of healthy volunteers or patients.
- Phase II: Phase II trials expand the participant pool to further evaluate safety and begin assessing the treatment’s efficacy in a larger group of patients.
- Phase III: In this phase, researchers gather extensive data on both safety and efficacy. It often involves randomized controlled trials that compare the new therapy to existing treatments or placebos, and it includes a larger number of participants at multiple locations.
- Phase IV: After treatment is approved and on the market.
- Phase V studies continue to evaluate and monitor the therapy’s real-world effectiveness, safety, and long-term benefits.
What are the Risks and Benefits of Participating in a Clinical Trial?
Participating in a clinical trial offers both potential benefits and risks:
Benefits:
- Access to cutting-edge treatments that may not be available otherwise.
- The opportunity to contribute to medical science and help advance healthcare.
- Close monitoring by healthcare professionals.
- Some trials offer compensation or reimbursement for expenses.
Risks:
- Potential side effects or adverse reactions to the experimental treatment.
- Uncertainty about the treatment’s effectiveness compared to standard therapies.
- The commitment of time and effort required for regular follow-up and data collection.
- Possible placebo treatments (in some trials), which may not provide therapeutic benefit.
It’s important for individuals considering participation in a clinical trial to thoroughly discuss the potential risks and benefits with the trial’s investigators and make an informed decision based on their own medical needs and circumstances. Informed consent is a critical part of this process, ensuring that participants are aware of what they are getting into and can withdraw from the trial at any time if they choose to do so.
Challenges in Clinical Trials
Launching clinical trials poses challenges such as regulatory complexities, patient recruitment, and retention, especially when focusing on rare diseases. Sustained patient engagement and support throughout the trial and afterward are essential components of successful trials.
Real-World Evidence and its Significance
While clinical trials are imperative, real-world evidence complements them by offering insights into a treatment’s performance in everyday clinical practice. This evidence draws from diverse sources providing a more comprehensive view of a therapy’s effectiveness and safety.
Real-world evidence can highlight long-term outcomes not fully captured in clinical trials due to potential underrepresentation, coexisting health conditions, or demographic variations. It contributes to understanding the therapy’s potential across diverse patient profiles.
The Rebirth of Agustín Cáceres
Buenos Aires, Argentina. The day Agustín Cáceres received his new ‘gene’ was marked as ‘renacido’ (reborn) by his parents Alberto and Marcela. Spending his first few months alive in isolation for the fear that the slightest cold or illness could be fatal, Agustín had a rare, inherited illness that left his bone marrow unable to develop T-lymphocytes. The white blood cells needed for fighting virus infection were severely deficient. SCID-X1 is an X-linked, severe combined immunodeficiency, better known as ‘bubble boy disease,’ caused by mutations in the IL2RG gene, only affecting boys and claiming the life of the Cáceres’ 5-month-old-first-born, Ivan. Jeremías, born after Ivan was born healthy. In an attempt to safeguard future siblings, The Cáceres’ decided to bank stem cells from Jeremías umbilical cord blood. Unfortunately, the future sibling born in 2010, Agustín’s tissue type was not compatible with his brother’s.
Without the genetic breakthrough by doctors at Boston Children’s Hospital 10 years ago, Agustín would have likely died before his first birthday.
In 2010, led by Dr David Williams, a team of researchers found a safer way to deliver DNA into patients’ cells. At the time, gene therapy wasn’t new but earlier European trials had one-quarter of patients developing treatment-related leukemia. Dr Williams decided to address the serious problem, collaborating with other gene therapy centers to develop a self-inactivating gamma retrovirus designed to eliminate the risk of triggering the expression of genes that could lead to leukemia.
Agustín was the first to receive gene therapy at Boston Children’s Hospital as part of an international clinical trial. His blood stem cells were infused with the retrovirus and a healthy copy of the gene. Six months later, he began producing functional T cells. Since then, the gene therapy has made significant progress, giving Agustín the opportunity to have an active childhood.
The Journey of Opie Jones: Diagnosis, Relapse and CAR T-Cell Therapy
5-month-old Opie Jones was born well, but as he grew, seemed quieter than usual and started to look pale. Concerned mother Lucy, as any mother would, took him to the doctor. After being examined, the general practitioner noticed his swollen abdomen and requested a visit to the hospital. Opie had a white blood count of over 600 and was immediately rushed to Addenbrooke’s Hospital, Cambridge, spending five days in Intensive Care. Opie, the youngest of five children, was diagnosed with cancer – high-risk KMT2A gene-rearranged infant acute lymphoblastic leukemia (ALL).
Having not responded to steroid treatment, Opie was urgently placed in the high-risk category and told within days, that he would need a bone transplant. At the time, the NHS had recently made CAR T-cell therapy available for children, however, only those who had relapsed were eligible.
In February 2021, Opie received a bone marrow transplant from an American donor. After 5 weeks in isolation in Leeds Hospital, Opie’s family could take him home. Opie seemed to have been responding well showing all the right signs. In May 2021, his central line was removed to receive his 3-month bone marrow aspirate. It took only days for Opie and his family’s world to ‘shatter’. In the molecular study of the aspirate, a small percentage of leukemia cells were found. Opie had relapsed. His chance of survival relied on something other than traditional medicine.
Opie was referred to Great Ormond Street Hospital, London, and accepted for the CAR-T treatment. His cells were harvested and sent to New Jersey to be made into CAR T-cells, in the meantime, Opie began chemotherapy and immunotherapy.
Opie received his CAR T-cells on July 28, 2021. After 4 weeks in hospital, Opie could return home. The conditioning treatment was comparatively different from the bone marrow transplant. Today, Opie remains happy and well, of which the Opie Foundation was started.
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Unfavorable Outcomes: Where the Risks Are
Clinical trials hold promise for addressing unmet medical needs, yet they come with inherent risks. Despite the potential benefits, not all trials yield favorable outcomes. Efforts to minimize risks involve continuous progress and rigorous regulatory measures.
In 2021, a significant clinical trial at the UMass Chan Medical School offered a glimmer of hope to Alissa Feldborg, who suffered from a fatal ultra-rare genetic disease. Diagnosed at just 8 months old, her parents, Thomas Feldborg and Daria Rokina, were initially told to prepare for the worst.
Living in Copenhagen, Denmark, the family discovered the UMass gene therapy trial online and found Alissa met the criteria for participation. However, researchers cautioned that her advanced disease might limit the treatment’s effectiveness. Despite this, Alissa qualified for the trial, and her family endured a waiting period for the FDA’s approval of the gene therapy for the clinical trial.
In January 2021, at less than 14 months old, Alissa received two doses of gene therapy – one into her spinal cord and one directly into her brain. The initial months showed promise, her deterioration slowed, and there were notable improvements in her swallowing and coughing. Although the treatment extended her life, it did not substantially improve her vegetative state.
Alissa began to regress rapidly. Her seizures returned with a vengeance and her breathing became a struggle. In the last three weeks of her life, Alissa was resuscitated five times. The sixth resuscitation did not work. She died in April 2023.
Given the unfavorable outcome, Alissa’s family harbored no regrets about participating in the trial. The experience highlights the complex nature of clinical trials, where the pursuit of groundbreaking treatments is accompanied by uncertainties and the acknowledgment that not all patients may benefit.
The Case of Jesse Gelsinger
Perhaps the most infamous example for the industry, Jesse Gelsinger suffered from ornithine transcarbamylase deficiency, an X-linked genetic liver disease. Jesse’s condition was a milder form for which he was able to manage his condition with a restricted diet and medications. Jesse only had the ornithine transcarbamylase gene mutation in only one part of his cells – somatic mosaicism.
Despite his partial deficiency, he joined a clinical trial at the University of Pennsylvania aimed at treating severe cases of the disease in infants.
On September 13, 1999, Jesse, 18 years old, received an adenoviral vector injection carrying a corrected gene to assess the procedure’s safety. He passed away 4 days later, experiencing a severe immune response triggered by the viral vector that transported the correct gene into his cells. This led to multiple organ failure and brain death.
The FDA investigation uncovered rule violations by the trial’s scientists, including the inclusion of Jesse as a substitute participant despite high ammonia levels that should have excluded him from the trial. The university failed to report serious side effects, and information about similar deaths in monkeys was not disclosed in the informed-consent documentation.
The University of Pennsylvania, along with Children’s National Medical Center, agreed to pay fines exceeding $500,000 each to the government.
Clinical Data and Shaping the Future of Healthcare
Despite the promise of cell and gene therapies, challenges persist, including high manufacturing and development costs, regulatory hurdles, and the need for long-term follow-up. As advanced therapies evolve, digitalization, artificial intelligence, and other advanced technology integration can enhance the ability to analyze and interpret clinical and real-world data. These tools are essential in identifying treatment patterns, predicting patient responses, and optimizing therapeutic approaches for patients with unmet medical needs.
Clinical trials allow access to potential transformative treatments that some traditional medicines cannot offer. There are many success stories that follow from cell therapy and gene therapy, proven to meet unmet medical needs.
Cases such as Jesse Gelsinger’s demonstrated unsafe circumstances where cautionary procedures in clinical trials, imperatively within cell and gene therapy, are crucial when assessing patient safety within trials. Alissa Feldborg’s case demonstrated how not all therapies can have favorable outcomes in both extending a patient’s life expectancy as well as reversing or curing some diseases. As well as the success stories of advanced therapies, the challenges that persist in these novel modalities of medical care are still paving the way for future treatments and the advancement of medicine and the pharmaceutical industry.
Developing cell and gene therapies from concept to clinical application is a challenging and intricate process, but it can lead to significant transformations. Clinical trials and real-world evidence provide valuable information to help us understand these advanced treatments. By effectively managing the clinical trial process and using real-world studies, healthcare professionals and researchers can deliver safe, effective, and innovative therapies to patients in need. As science and technology continue to evolve, clinical data and real-world evidence will remain critical in shaping the future of healthcare.
Sources:
- Agustín Cáceres’s Story – Children’s Hospital
- Opie Jones’s Story – Emily Whitehead Foundation
- Alissa Feldborg – USA Today News
- Jesse Gelsinger – Nature
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