by Prescription drugs and vaccines have revolutionized healthcare, dramatically reducing death from disease and improving quality of life around the globe. But how do researchers, universities and hospitals, and the pharmaceutical industry decide which diseases to pursue developing 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 evaluate the effectiveness and safety of various treatment options to help clinicians and patients make informed decisions. My colleagues and I study ways to create new drug molecules, deliver them into the body and improve their effectiveness and reduce their potential harms. Several factors determine the drug discovery channels that 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 have funded studies of the most common conditions, such as heart disease, diabetes and mental health disorders. Head therapy would help millions of people, and a small markup per dose would generate big profits.
As a result, rare disease research was not well funded for years because it would help fewer people and the costs of each dose would have to be very high to make a profit. Of the more than 7,000 known rare diseases, defined as those affecting fewer than 200,000 people in the US, the Food and Drug Administration had approved therapy for only 34 of them before 1983.
The passage of the Orphan Drug Act changed this trend by offering tax credits, research incentives and long patent lives to 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 affect the funding available to develop drugs for certain diseases. When COVID-19 swept the world, funding from Operation Warp Speed led to the development of vaccines in record time. Public awareness campaigns such as the ALS ice bucket challenge can raise money directly for research. This viral social media campaign provided 237 scientists with nearly US$90 million in research funding from 2014 to 2018, leading to the discovery of five genes associated with amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease, and new clinical trials.
How science approaches drug development
To create breakthrough treatments, researchers need a basic understanding of the disease processes they need to improve or block. This requires the development of cell and animal models that can simulate human biology.
It can take many years to vet potential treatments and develop the finished drug product ready for testing in humans. Once scientists identify a potential biological target for a drug, they use high-throughput screening to rapidly assess hundreds of chemical compounds that may 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 have poor results in the laboratory, companies are likely to stop development if the estimated potential revenue from the drug is less than the estimated cost of improving the treatments. Companies can charge more money for drugs that significantly reduce death or disability than they charge for those that only reduce symptoms. And researchers are more likely to continue working on drugs that have greater potential to help patients. To get FDA approval, companies must ultimately show that the drug has more benefits for patients than harm.
Sometimes, researchers know a lot about a disease, but the technology available is not enough to produce a successful drug. For a long time, scientists have known that sickle cell disease is caused by a faulty gene that directs cells in the bone marrow to produce red blood cells poorly, causing severe pain and blood clots. Scientists had no way to solve or work around the issue with existing methods.
However, in the early 1990s, basic scientists discovered that bacterial cells have a mechanism to recognize and edit DNA. With that model, researchers began working hard to develop a technology called CRISPR to identify and edit genetic sequences in human DNA.
Technology eventually advanced to the point where scientists were able to successfully target the problematic gene in sickle cell patients and edit it to produce normally functioning red blood cells. In December 2023, Casgevy became the first CRISPR-based drug approved by the FDA.
Sickle cell disease made an ideal target for this technology because it was caused by a single genetic issue. It was also an attractive disease to focus on because it affects about 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, an underrepresented population in medical research.
Drug development in the real world
To put all these pieces of drug development into perspective, consider the leading cause of death in the US: cardiovascular disease. Although there are several drug options available for this condition, there is a continuing need for more effective and less toxic drugs that reduce the risk of heart attacks and strokes.
In 1989, epidemiologists found that patients with higher levels of bad cholesterol, or LDL, had more heart attacks and strokes than those with lower levels. Currently, 86 million American adults have elevated cholesterol levels that can be treated with drugs, such as the common statins Lipitor (atorvastatin) or Crestor (rosuvastatin). However, statins alone cannot achieve their cholesterol goals for everyone, and many patients develop unwanted symptoms that limit the dose they can receive.
So scientists have developed models to understand how LDL cholesterol is created and removed in the body. They found that LDL receptors in the liver remove bad cholesterol from the blood, but a protein called PCSK9 destroys them prematurely, increasing bad cholesterol levels in the blood. This led to the development of the drugs Repathy (evolocumab) and Praluent (alirocumab) which bind to PCSK9 and stop it from working. Another drug, Leqvio (inclisiran), blocks the genetic material coding 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, whether governments, foundations or the pharmaceutical industry.
Based on the market, companies and researchers tend to study very widespread diseases with devastating societal consequences, such as Alzheimer’s disease and opioid use disorder. But the work of advocacy groups and foundations can improve research funding for other specific diseases and conditions. Policies like the Orphan Drug Act also create successful incentives to find treatments for rare diseases.
However, in 2021, 51% of drug discovery spending in the US was directed at just 2% of the population. a question that researchers and policy makers are still grappling with.
This article is republished from The Conversation, a non-profit, independent news organization that brings you facts and analysis to help you make sense of 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 this, and has disclosed no relevant affiliations beyond their academic appointment.
