By Maggie Fu, University High School, Tucson, Arizona, USA
In a world awash in technological development, biomedical research finds itself at the cutting edge, bringing revolutionary drugs and medical devices to people in need. With so many breakthroughs, the most recent and significant of which being the COVID-19 vaccines, it becomes easy to overlook the difficulties and the strenuous process to both discover and develop a drug.
Approximately 43.7% of drug development is accounted for by the United States. On the international stage, most foreign countries go through the same stages but with the review of their own respective governmental agencies (Keyhani et al., 2010). Many foreign countries also seek U.S. Food and Drug Administration (FDA) approval for their drugs, mainly through clinical trials with American patients. That way, these internationally developed drugs may be available on the U.S. market.
In the United States, there are five stages that a drug passes through: discovery and development, preclinical trials, clinical trials, FDA Review, and finally FDA Post-Market Safety Monitoring (Pandey, 2020). This process is intentionally made to be as strict as possible in order to ensure that the safest and most efficient treatments are delivered to the public. However, one of the most considerable obstacles lies in the first step of drug discovery and development.
Figure 1. Overall drug discovery and development process (Forum on Neuroscience and Nervous System Disorders, 2014).
Almost all drugs are small molecules, meaning that they have a low molecular weight, which allows them to easily bind proteins and nucleic acids and alter their functions (NCI Dictionary of Cancer Terms). Proteins are essential in the regulation, function, and structure of cells and tissues, and nucleic acids play an essential role in protein synthesis; any malfunctions in the body’s homeostasis are caused by malfunctions in proteins. But through these small molecule drugs, the proteins are able to be reverted back to their original state. For example, a misfolded protein can cause much damage to cells and greatly impact the overall health of a person. In this case, the small molecule drug would work to either decrease the protein function and render it harmless or fix the protein by refolding it into its original state (Quick, 2015).
The relationship between proteins and small molecule drugs can be thought of as a puzzle. One needs to find the perfect puzzle piece to fit a specific protein in order to readjust its function. Consequently, the specificity of these drugs makes them increasingly difficult to discover and develop.
Firstly, the specific protein or nucleic acid (DNA and RNA) that will be targeted by the small molecule drug must be determined through a process called “target identification.” As simple as this may sound, it is quite difficult in practice. Biology is amazingly complex, and deciphering every specific function and mechanism is virtually impossible. The complexity and the ever-changing nature of these proteins create an immense challenge for researchers to discover the exact reason for a protein’s malfunction (Jogalekar, 2014). But when the malfunction is detected, researchers use a computational method known as High Throughput Screening to brainstorm possible molecules that may interact with the protein based on past data (Rowe says: et al., 2020). However, of the many outputs produced, few actually “fit” with the protein. Additionally, researchers must ensure that the few small molecules that do “fit” with the protein will not cause any other malfunctions.
After identifying the specific target, the small molecule must be validated, meaning that it must demonstrate some level of therapeutic effect. During the target validation process, the drug must be screened multiple times to determine its effectiveness. Out of all the small molecule puzzle pieces, some may not produce any effect, rendering it invalid (Rowe says: et al., 2020). After target validation, lead validation occurs. During this process, “leads,” chemical compounds that play a role in protein function modification, are recognized. These leads will then ultimately be developed into clinical drugs (Lee et al., 2001).
Lead optimization is the preclinical stage before the drug is entered into clinical studies. Preclinical studies are where the leads are tested on animal models to ensure that the drug’s efficacy and toxicity levels are safe and effective enough to distribute to people. Unfortunately, this is also the stage where most drugs fail – only about 5 in 5,000 drugs pass (Lee et al., 2001).
Figure 2. Process from Target Validation to Lead Optimization in Preclinical Studies (Lee et al., 2001).
After preclinical studies, clinical studies are conducted to determine the drug’s effectiveness in human beings; this step consists of four separate phases according to the FDA. During Phase I, the drug is tested for several months in less than 100 healthy volunteers who have been diagnosed with the disease in question. The main purpose of this phase is to determine the drug’s safety and dosage – about 70% of drugs make it past Phase I. Phase II requires that the drug be tested in several hundred diagnosed individuals to determine efficacy and possible side effects, which may last from several months to two years. Only about 33% of drugs make it past this phase. Phase III tests the efficacy of the drug while monitoring for any adverse effects, with up to several thousand diagnosed volunteers participating. Unfortunately, only 25-30% of drugs make it past Phase III. Phase IV is the final stage of clinical trials with several thousand diagnosed volunteers participating to ensure the full safety and efficacy of the drug. This means that less than 6% of drugs that enter clinical trials make it onto the market! Clinical trials are the costliest step of drug development (Commissioner, 2018).
After clinical trials have been approved, the drug must go through FDA investigation before it can be promoted on the market. Overall, it takes approximately 12 years for a drug to start from discovery and development to make it onto the market (Susan Duggan et al.).
In addition, the massive costs of drug discovery loom over all these scientific findings. According to a study conducted by Tufts Center for the Study of Drug Development, the average cost of developing a single drug sums up to approximately $2.6 billion (Sullivan et al., 2019). This staggering cost seems quite discouraging, especially given the probability that only around 1 in 5,000 drugs makes it into the market (Drug Approvals, n.d.).
The difficulties of drug research and development make it much less attainable in less-developed countries. The lack of funding and the education gap both lead to less potential and significant delays in developing new drugs. For example, in countries with tropical climates, particularly Bolivia, Brazil, Ethiopia, and Peru, Cutaneous Leishmaniasis (abbreviated CL) is a rampant and fatal disease. Unfortunately, these countries are also some of the poorest countries, and CL is not common in more developed regions such as Europe or North America. Developing countries have virtually little to no budget for drug research and development, leaving the duty to developed countries. However, pharmaceutical companies are essentially large corporations with a profit-driven perspective. Consequently, they are more hesitant to take on such a burden, so diseases such as CL remain largely neglected (Surur et al., 2020). One solution to this issue is building partnership and cooperation between developed and less developed countries.
Through efficient and increased funding, developed countries can work with less developed countries to establish an effective global network of drug development. They can provide educational assistance through training, sharing necessary resources, and making scientific knowledge universal. Although these pharmaceutical companies may see more short-term costs, the long-term benefits will definitely outweigh them. Hopefully, more pharmaceutical companies will seek to make drug development not just a national priority, but rather a global one.
References
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Article Thumbnail Image: https://www.flickr.com/photos/ajay_suresh/12424664043/ by Ajay Suresh