Bringing a new drug from discovery in the laboratory to the patient in the pharmacy is not a quick or an easy process, as demonstrated by the spotlight on vaccine development due to the current COVID-19 pandemic. While COVID-19 vaccines were produced at an accelerated pace, the process usually takes more than 10 years and can cost billions of dollars, facing numerous challenges along the way. However, there are many current and emerging solutions for challenges at each stage of the pharmaceutical discovery and development process.
The four main stages of drug development
The four main stages of drug development include:
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Drug Discovery
The first stage of pharmaceutical development involves how new potential drugs are discovered and is made up of the following key steps. Drug discovery generally takes three to six years to complete.
- Target identification: Involves finding the exact component of a condition or disease that is critical to its progression, relying heavily on current knowledge of that disease. The component in question could be a small molecule, nucleic acid, or protein and accurately identifying this target involves a variety of techniques, such as studying existing drugs, DNA microarrays, computational modeling, or affinity chromatography. Drug discovery can also involve phenotypic methods, but these tend to be more expensive and time consuming.
- Compound screening: Involves using many different automated technologies and arrays to look at tens of thousands of possible drug candidates for activity against the identified targets. Collaborative robots are just one solution to help speed up this process and make it more accurate. For example, some automated arrays can screen about 300,000 compounds in 24 hours.
- Lead discovery: Involves finding a biological therapeutic or “drug-like small molecule” that will successfully progress through the rest of the pharmaceutical development stages to become an approved medicine.
Because drug discovery efforts are often led by specialized groups, the data they produce can be siloed and inaccessible to the wider scientific community, leading to wasted time and energy on experiments and research into compounds unlikely to succeed in becoming approved drugs. Informatics solutions such as artificial intelligence and ELNs are helping to solve this key challenge in drug discovery.
Analytical technologies such as liquid chromatography and mass spectrometry are other critical tools in both this stage and later in the production process to confirm a drug product's safety and efficacy. Drugs can fail at any stage of development, but it is far worse for candidates to fail later in the process as more time and money has been invested by then. The key is to rule out poor candidates as early as possible.
Preclinical
The second major stage of drug development—the preclinical stage—involves testing how effective and safe the selected small molecule or therapeutic is in treating the disease target through the use of animal models. Success at this stage often does not translate to the next stage when drug candidates are tested on humans in clinical trials, because either the candidate is not sufficiently effective, or carries too much adverse risk. However, a variety of alternatives to animal testing are being developed that will more accurately model disease in humans, with the goal of eliminating animal testing and its ethical concerns, and speeding up the drug development process. Key steps of the preclinical stage of drug development include:
- Efficacy testing: Uses animal or cell culture models to test how well the drug candidate does in treating the target disease.
- Toxicology testing: Involves identifying if a drug candidate has any harmful side effects and exactly what those effects are using animal studies. Emerging alternatives to animal testing include computer and organ-on-a-chip models.
- Safety testing: Aims to show that a drug is safe and that any side effects can be properly managed. It again involves animal models as well as in vitro testing.
- Formulation: Involves the creation of the actual drug product by combining the biologically active component of the drug with other ingredients, and determining how the drug will be administered. The drug’s solubility, or how well it is absorbed into the body in concentrations high enough to work, is particularly important at this stage. Drugs with low solubility require doses that are too high to be practical, therefore it is a key factor in determining a drug’s success, particularly for those that are given orally. Methods for improving solubility include chemical and physical modifications, as well as the use of adjuvants and supercritical fluid processing.
According to Stuart Pengelley, an expert in biopharma application development at Bruker Daltonics, impurities such as host cell proteins (HCPs) in biologic products also present a major challenge in the preclinical stage because they can inhibit the drug’s effectiveness and present safety issues. In this article, he explores current methods for detecting and removing HCPs in biologics and how trapped ion mobility spectrometry and quadrupole time-of-flight mass spectrometry can help solve the HCP challenge.
Clinical
The clinical stage of drug development involves testing the potential treatment in humans through clinical trials to determine its safety and effectiveness in the human body. Clinical trials have three phases before the drug goes to market:
- Phase I: Involves testing the drug on 20-100 healthy volunteers or those with the condition or disease being treated to determine the treatment’s safety and what dosage is safe. This phase usually lasts several months.
- Phase II: Involves testing the drug on several hundred people who have the condition or disease being treated to determine side effects and effectiveness. This phase takes several months to two years to complete.
- Phase III: Involves testing the drug or treatment in 300-3,000 volunteers with the condition or disease and lasts one to four years. This phase further determines efficacy and safety, aiming to catch any adverse reactions that may have been missed in the previous studies.
After the drug is on the market, Phase IV studies continue to look at the safety and efficacy of the treatment and involve several thousand volunteers who have the condition or disease.
Key challenges in clinical trials include time, cost, and finding enough people to participate who accurately represent the diversity of the target population. However, digital simulations of patient populations could help manage such issues. The current pandemic has also made it especially difficult to recruit enough participants while meeting social distancing and other safety measures when conducting trials. Decentralized or virtual trials have helped meet these challenges and are likely to continue post-pandemic, according to this article in Clinical Lab Manager.
Another issue with clinical trials is that most focus on adults, presenting challenges to finding safe and effective treatments for children. In this Q&A, Matthew M. Laughon, MD, MPH, discusses this challenge in his own research and how he’s addressing such issues through clinical trial design.
Review and approval
Though the review and approval stage of pharmaceutical development is the final step, the review team is involved early in the process, providing guidance for any needed improvements at each stage. In the United States, the team from the US Food & Drug Administration (FDA) reviews and monitors all studies and protocols relating to the drug and is composed of experts in various scientific disciplines, including microbiology, chemistry, pharmakinetics, pharmacology, statistics, medicine, and project management.
Once the written evaluations from each team member are completed and examined by the FDA, the regulatory body may go to additional experts for recommendations before making their final decision, which is then communicated to the drug developer in an action letter.
This stage of drug development can take anywhere from a few months to several years, though the FDA is looking at reducing this time. According to Francisco Polidoro, Junior, PhD, an expert in strategy and management at The University of Texas at Austin, the time it takes to approve innovative new treatments is a key issue at this stage. He suggests that reviewing such drugs by old standards is a bottleneck in their approval and that a new framework is necessary to ensure they are approved as quickly as possible, while still confirming their safety.
Recent industry trends
With the rising demand for biopharmaceuticals and other key drug products, pharmaceutical contract development and manufacturing organizations (CDMOs) are seeing an increase in their workloads as pharmaceutical companies seek their services at various stages of the drug discovery and development process. In this Q&A Anish Parikh, VP of sales and marketing, drug products, at Curia Global, Inc., and Katie Schlipp, VP of laboratory operations in Wilmington, NC, at Alcami Corporation, discuss how they are managing this increase in demand through technology, staff, and processes.
While the drug discovery process is likely to remain complex and time consuming, there are many promising solutions—involving technology, scientific techniques, and management—that are poised to simplify some aspects and reduce the time and cost of bringing new treatments to those who need them.
