Prescription drugs and vaccines revolutionized healthcare, dramatically reducing deaths from diseases and improving the quality of life around the world. But how do researchers, universities, hospitals and the pharmaceutical industry decide which diseases to develop drugs for?
In my work as director of the Health Outcomes, Policy, and Evidence Synthesis group at the University of Connecticut School of Pharmacy, I assess the effectiveness and safety of various treatment options to help physicians and patients make informed decisions. My colleagues and I are studying ways to create new drug molecules, deliver them into the body and improve their effectiveness while reducing potential harm. Several factors determine which avenues of drug discovery people in research and pharmaceutical companies focus on.
Funding drives research decisions
Research funding increases the pace of scientific discovery needed to create new treatments. Historically, major research supporters, such as the National Institutes of Health, the pharmaceutical industry, and private foundations, funded studies of the most common conditions, such as heart disease, diabetes, and mental disorders. A breakthrough therapy would help millions of people, and a small additional cost per dose would yield significant profits.
As a result, rare disease research was not well funded for decades because it would help fewer people and the cost of each dose had to be very high to make a profit. Of more than 7,000 known rare diseases, defined as affecting fewer than 200,000 people in the U.S., only 34 had therapies approved by the Food and Drug Administration before 1983.
The passage of the Orphan Drug Act changed this trend by offering tax breaks, research incentives, and extended patent lives for companies actively developing drugs for rare diseases. From 1983 to 2019, 724 drugs were approved for rare diseases.
Emerging social issues or opportunities can significantly impact the funding available to develop drugs for certain diseases. As COVID-19 raged across the world, Operation Warp Speed funding led to vaccine development in record time. Public awareness campaigns such as the ALS ice bucket challenge can also raise money directly for research. This viral social media campaign earned 237 scientists nearly $90 million in research funding between 2014 and 2018, leading to the discovery of five genes linked to amyotrophic lateral sclerosis, commonly called Lou Gehrig’s disease, and new clinical trials.
How science approaches drug development
To create breakthrough treatments, researchers need a basic understanding of which disease processes to enhance or block. This requires the development of cell and animal models that can simulate human biology.
It can take many years to research possible treatments and develop the final product ready for human testing. Once scientists identify a potential biological target for a drug, they use high-throughput screening to quickly assess hundreds of chemical compounds that could have a desired effect on the target. They then modify the most promising compounds to enhance their effects or reduce their toxicity.
When these compounds produce mediocre results in the laboratory, companies are likely to abandon development if the estimated potential revenue from the drug is less than the estimated cost to improve the treatments. Companies can charge more for drugs that dramatically reduce death or disability than for drugs that only reduce symptoms. And it’s more likely that researchers will continue working on drugs that have greater potential to help patients. Ultimately, to gain FDA approval, companies must demonstrate that the drug causes more benefits to patients than harm.
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Sometimes researchers know a lot about a disease, but the available technology is insufficient to produce a successful drug. Scientists have long known that sickle cell disease is the result of a defective gene that causes cells in the bone marrow to produce poorly formed red blood cells, causing severe pain and blood clots. Scientists lacked a way to solve the problem or work around it with existing methods.
However, in the early 1990s, basic scientists discovered that bacterial cells have a mechanism for identifying and editing DNA. With that model, researchers began working painstakingly to develop a technology called CRISPR to identify and edit genetic sequences in human DNA.
The technology eventually progressed to the point where scientists could successfully target and edit the problematic gene in patients with sickle cell disease to produce normally functioning red blood cells. In December 2023, Casgevy became the first CRISPR-based drug to be approved by the FDA.
Sickle cell disease was an excellent target for this technology because the disease was caused by a single genetic problem. It was also an attractive disease to focus on because it affects approximately 100,000 people in the US and is costly to society, resulting in many hospitalizations and lost work days. It also disproportionately affects black Americans, a population underrepresented in medical research.
Real world drug development
To put all these parts of drug development into perspective, let’s look at the leading cause of death in the US: cardiovascular disease. While there are several drug options available for this condition, there is an ongoing need for more effective and less toxic medications that reduce the risk of heart attacks and strokes.
In 1989, epidemiologists discovered that patients with higher levels of bad cholesterol (LDL cholesterol) had more heart attacks and strokes than patients with lower levels. Currently, 86 million American adults have elevated cholesterol levels that can be treated with medications such as the popular statins Lipitor (atorvastatin) or Crestor (rosuvastatin). However, statins alone cannot help everyone reach their cholesterol goals, and many patients develop unwanted symptoms that limit the dose they can receive.
That’s why scientists developed models to understand how LDL cholesterol is produced in and removed from the body. They found that LDL receptors in the liver removed bad cholesterol from the blood, but a protein called PCSK9 destroys them prematurely, causing bad cholesterol levels in the blood to rise. This led to the development of the drugs Repathy (evolocumab) and Praluent (alirocumab) that bind to PCSK9 and prevent its action. Another drug, Leqvio (inclisiran), blocks the genetic material that codes for PCSK9.
Researchers are also developing a CRISPR-based method to treat the disease more effectively.
The future of drug development
Drug development is driven by the priorities of their funders, be they governments, foundations or the pharmaceutical industry.
Based on the market, companies and researchers tend to study common diseases with devastating societal consequences, such as Alzheimer’s disease and opioid use disorders. But the work of advocacy groups and foundations can increase research funding for other specific diseases and conditions. Policies such as the Orphan Drug Act also create successful incentives to discover treatments for rare diseases.
However, in 2021, 51% of drug discovery spending in the US targeted just 2% of the population. How to strike a balance between providing incentives to develop wonder drugs for a few at the expense of the many is a question that researchers and policymakers are still grappling with.
This article is republished from The Conversation, a nonprofit, independent news organization providing facts and analysis to help you understand our complex world.
It was written by: C. Michael White, University of Connecticut.
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C. Michael White does not work for, consult with, own shares in, or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond his academic appointment.
