Natural History Research: Accelerating Life-Saving Oncology Drugs & Reducing Placebos
The realm of medical research, particularly in the challenging field of oncology, is constantly seeking innovative ways to develop life-saving treatments more efficiently and ethically. A powerful new approach, known as natural history research (NHx), is transforming how clinical trials are conducted, especially for rare diseases. This type of research is leading to more effective decision-making in oncology clinical trials, significantly reducing the need for placebos and ensuring that more patients can access potentially life-saving drugs faster.
Globally, over 7,000 different rare diseases affect more than 30 million people in the US alone. Many of these conditions are life-threatening, and sadly, most do not yet have effective treatments. A rare disease is officially defined in the US by the Orphan Drug Act of 1983 as a condition affecting fewer than 200,000 people. Due to the small number of patients, these conditions typically don't attract the same level of investment in research and development as more common diseases. To address this critical gap, the pharmaceutical industry develops "orphan drugs" specifically designed for these rare conditions. Governments, like those in the US and EU, offer incentives through the Orphan Drug Designation program, such as tax credits, exemptions from user fees, and potentially seven years of exclusive market rights after approval, to encourage their development.
However, developing drugs for rare diseases is notoriously difficult. The complex underlying biology of these conditions, combined with a significant lack of understanding about how they naturally progress over time, makes designing and carrying out clinical trials particularly challenging. This "information deficit" highlights the urgent need for more research into these diseases. Recognizing this, major health authorities worldwide have emphasized the importance of natural history research. For instance, the US Food and Drug Administration (FDA) published draft guidelines in 2019 on the growing role of NHx research in addressing unmet health needs, particularly for rare diseases. The European Medicines Agency (EMA) and Japanese PMDA have issued their own guidance, with the Australian TGA adopting the FDA's version in February 2023.
So, what exactly is natural history research? In simple terms, it involves tracking the course of a disease without interfering with it through trial-specific treatments or interventions. These studies use a variety of existing patient information, including retrospective data from registries, medical records, and prospective observational studies. By looking at this real-world data, researchers can gain a much deeper understanding of several key aspects of a disease:
How the disease progresses over time.
The typical clinical outcomes patients experience.
The overall burden of the disease on patients.
How patients respond to current standard treatments or management strategies.
The potential market for new drug therapies.
Which patients are most suitable for clinical trials.
This comprehensive understanding is incredibly valuable for drug developers. It allows them to design and execute clinical trials that are more efficient and adaptable, helping them make better decisions about drug dosages and how to group participants. Ultimately, this leads to more accurate data, more successful trial outcomes, and faster regulatory review.
The untapped potential of real-world data is truly remarkable. These studies can significantly improve clinical trials by providing crucial evidence that helps predict how a drug might perform outside the highly controlled environment of a traditional trial. This real-world information can be integrated at any stage of a trial, complementing the data collected directly from participants and doctors. Both looking back at past data (retrospective studies) and observing patients over time (prospective studies) can reveal important insights about biomarkers (biological indicators), genetics, and specific disease subtypes that could influence how well a treatment works. This is particularly critical in oncology, where precision medicine relies heavily on identifying specific biomarkers to guide the selection of targeted therapies.
By accessing and analyzing real-world data, developers can build stronger clinical development plans. These plans are based on solid epidemiological assumptions (how diseases spread and affect populations) and clearly defined goals for success, which are essential for getting drugs approved quickly and improving their chances of market success. In oncology trials, this data-driven approach also has significant benefits for patients. It can reduce the burden on patients by minimizing unnecessary procedures and streamlining monitoring, while also increasing their access to investigational treatments. This ultimately improves the patient experience and helps keep them engaged in the trial.
One of the most transformative applications of natural history research is in reducing the use of placebos in oncology trials through the creation of "synthetic external control arms". Traditional randomized clinical trials (RCTs) are considered the gold standard for testing new drugs, but they often face challenges, especially for rare diseases. It can be very difficult to find enough patients for these trials when the disease population is already tiny. Furthermore, patients might be reluctant to join a trial if they know there's a chance they won't receive the actual experimental treatment. This becomes a significant ethical concern in oncology, where the treatment could potentially be life-saving.
This is where synthetic external control arms (SCAs) come in. Instead of creating a separate group of patients who receive a placebo or the current standard treatment, data from natural history studies can be used to form a "virtual" control group. This allows researchers to compare the results of the patients receiving the new experimental drug against a wealth of existing evidence about how the disease progresses in patients who did not receive the investigational therapy. The FDA supports the use of these externally controlled clinical trials, provided that the synthetic control group is very similar to the group receiving the new drug, and careful methods are used to reduce any bias in patient selection.
A compelling example of this in action is the pivotal trial for tazemetostat, a drug for a rare and aggressive cancer called epithelioid sarcoma (ES). Epithelioid sarcoma is incredibly rare, making up only about 1% of all soft tissue sarcomas in the US, which themselves account for just 1% of all adult cancers. For the tazemetostat trial, an external control arm was developed using natural history data from ES patients who were receiving standard therapies. This allowed researchers to better understand the unmet medical needs in this specific cancer and clearly demonstrate the potential benefits of tazemetostat in a patient population that is very difficult to study. Based on the successful outcome of this Phase II trial, the FDA granted accelerated approval for tazemetostat in January 2020 for eligible adult and pediatric patients.
The use of synthetic control arms in rare oncological disease research is a growing trend. As of March 2025, GlobalData's Clinical Trials database recorded 214 ongoing rare cancer trials that utilize a historical control, with the majority (69%) being Phase II trials. This growing adoption highlights the significant advantages of this approach. By using the synthetic control arm method, fewer patients are assigned to placebo or standard-of-care groups, ensuring that more patients have direct access to a potentially life-saving drug. This innovative method also contributes to faster trials and reduced time for drugs to reach the market.
In conclusion, the landscape of rare diseases remains incredibly complex, with millions of individuals urgently needing better diagnostic tools and treatment options. While significant progress is being made, the challenges are still substantial. However, natural history research, particularly through the strategic application of synthetic control arms, is fundamentally changing how oncology clinical trials are conducted. This data-driven approach is empowering more effective decision-making, improving trial efficiency, and most importantly, accelerating patient access to innovative and potentially life-saving therapies. Continued commitment to and investment in natural history research are essential to addressing the pressing unmet medical needs of patients with rare disorders worldwide.
Natural History Researchers:
Dr. Roger Arliner Young: Dr. Young was a pioneering marine biologist and the first Black woman to receive a PhD in zoology in 1940 from the University of Chicago. She was also the first Black woman in her field to have her research paper, "On the Excretory Apparatus of Paramecium," published in the prestigious journal Science in 1926. Her career involved studying the structural biology of single-celled organisms, often working alongside her mentor Dr. Ernest Everett Just at the Marine Biological Laboratory at Woods Hole.
George Washington Carver: George Washington Carver was a renowned agricultural scientist and botanist. Born into slavery, Carver became a leading figure in American agriculture and one of the most famous Black men of his time. He is widely known for promoting crop rotation methods to help replenish soil nutrients in the Southern states, and for his work with peanuts and sweet potatoes. Carver understood the interconnectedness between the health of the land and people, embracing concepts of modern environmentalism and sustainable food systems.
Isabella Aiona Abbott: Known as the "First Lady of Limu," Isabella Aiona Abbott was a Hawaiian ethnobotanist who specialized in the study of Pacific marine algae, also known as limu. As the first Native Hawaiian woman to earn a Ph.D., according to Science Buddies and a Stanford marine botanist, she became a world expert on edible seaweed. Abbott integrated seaweed into her cooking and shared knowledge of Hawaiian culture through its culinary traditions, which was highlighted in a 1987 Gourmet article, notes the Biotechnology Innovation Organization.
