Understanding the Pharmaceutical Drug Development Life Cycle

The Drug Development Life Cycle

The United States Food and Drug Administration is the primary regulatory agency for the drug development life cycle in the US. The organization identifies five critical stages of drug development, including the following:

1. Discovery and development
2. Preclinical research
3. Clinical research
4. FDA review
5. FDA post-market safety monitoring

Discovery and Development

Discovery and development, the first step in the new drug development process, typically start in the lab. As the idea arises for a particular treatment, investigators take to the lab to refine the concept.

Researchers’ discoveries may be prompted by new evidence on disease processes, extensive testing of molecular compounds, noted outcomes of existing treatments, or the availability of new technologies.

Sometimes drug discovery is accidental. Most notably, the discovery of penicillin, a common antibiotic, resulted from the accidental contamination of a bacteria plate with the drug, which yielded bacteria-free zones. While not all findings are easy and happy accidents, scientists and researchers source their theories from multiple places.

It is also important to understand that the discovery process does not necessarily narrow down the treatment to a singular drug candidate or formulation. Instead, it often provides multiple options that can be narrowed down with testing.

After the potential compounds are narrowed down and one is identified, pharmaceutical researchers can begin the development process. This rigorous procedure involves analyzing multiple branches of the compound’s pharmacology, including pharmacokinetics and pharmacodynamics.

This part of the drug development life cycle allows researchers to gain insight into the drug’s mechanism of action, benefits, ideal dosage and administration, side effects or potential adverse events, differential impacts on diverse populations, drug-to-drug interactions, and efficacy.

Preclinical Research

Once researchers have gained enough insight from the discovery and development process, they can begin the preclinical phase, which is vital in getting drugs to clinical studies. Preclinical research is often used to test the safety of the product. There are two types of preclinical testing: in vitro and in vivo studies.

In vitro studies do not require a living organism. Many researchers use cell and tissue cultures for in vitro preclinical trials.

Meanwhile, in vivo studies on non-human living organisms have historically been the gold standard for preclinical research. These types of test subjects are often referred to as animal models. In vivo trials require drug developers to strictly follow the FDA’s Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies.

Until December 2022, the FDA, like many other regulatory authorities, required data from animal trials to support all investigational new drugs (INDs) before progressing to human trials. However, as officials passed the FDA Modernization Act 2.0, many manufacturers may request to use alternative preclinical models to justify clinical trials throughout the IND approval process.

These alternative preclinical research options may include organ-on-a-chip models, tissue bioprinting, human volunteering, and in silico models.

Clinical Research

The clinical development stage involves clinical trials, which most clinicians and investigators point to when justifying a drug’s clinical use.

Scientists hoping to start a clinical trial in the US must develop a robust clinical trial protocol and submit it to the FDA with animal study results, manufacturing information, other data from prior human research, and the background of the principal investigator in an IND application.

Upon approval of the application, clinicians may begin phase I clinical trials by recruiting a few study participants — healthy volunteers or people with the targeted condition — to test the drug’s safety and dosage. Roughly 70% of phase I trials will yield satisfactory results and move to phase II studies, which recruit a larger patient population and monitor for efficacy and side effects.

Very few drugs, roughly one-third, move on to phase III clinical trials, which recruit hundreds to thousands of patients over a more extended period to monitor adverse reactions and efficacy. Approximately 25–30% of phase III studies receive FDA approval and are monitored post-market approval in phase IV studies.

FDA Review

Upon completing phase III clinical trials, researchers may submit a New Drug Application (NDA) for small molecule drug products and a Biological License Application (BLA) for biological products to the FDA, including clinical results, safety information, patent information, directions for use, proposed labeling, and more.

An FDA advisory committee will provide recommendations, and the FDA will issue a regulatory approval or denial within ten months of the application submission. However, some drugs receive an expedited review process if they have Fast Track, Breakthrough Therapy, Accelerated Approval, or Priority Review designation.

FDA Post-Market Safety Monitoring

The last step in the drug development process is FDA post-market drug safety monitoring. During post-market monitoring, the FDA will regularly inspect the manufacturer, review drug advertisements, follow up on reported problems, and conduct active surveillance.

Drug Development Life Cycle Challenges

The pharmaceutical industry faces many problems in the drug development life cycle, considering the extensive process. The length of the drug development life cycle may contribute to many challenges. According to the US Government Accountability Office (GAO), the average drug development life cycle takes 10–15 years.

The length of the process creates more opportunities for the study to fail. Studies may fail for various reasons, including inadequate participant retention, drug toxicity or toxicology concerns, medication inefficacy, lack of funding, and more. This failure means the therapy for that disease or condition is set back, causing drug lag.

Beyond that, if drugs fail, the manufacturer or sponsor may suffer significant losses depending on where they were in the development life cycle. A Deloitte Consulting Life Science Strategy Analytics Practice report calculated that the year-over-year increase in research and development costs between 2021 and 2021 was roughly $300 million, bringing the average to approximately $2.3 billion. A substantial financial loss may delay further advancements or research.

Knowledge Gaps

Although researchers attempt to bring the most cutting-edge data and technology to the forefront of research, knowledge gaps can be an enormous challenge in the drug development life cycle. For example, if a researcher does not fully understand the pathophysiology of a disease, it can be hard to narrow down compounds for new medicines or treatments.

Additionally, animal models’ preclinical data does not provide enough insight into human applications.

“The drug development model is broken or highly challenged because most drugs fail when they get to the clinic,” said Don Ingber, MD, PhD, founding director of Harvard University’s Wyss Institute for Biologically Inspired Engineering and chair professor at Harvard and Boston Children’s Hospital, in an interview with LifeSciencesIntelligence.

Part of the problem is that researchers use animal models, which may share some genes with humans but will not provide a complete view of the efficacy and safety of drugs. The lack of early-stage human data in the drug development life cycle creates a knowledge gap that may persist until late-stage clinical trials.

Lack of Clinical Trial Diversity

Aside from the accidental knowledge gaps perpetuated by the protocols and natural limitations in the drug development life cycle, a lack of clinical trial diversity may complicate the drug development process. Recently, many reports or discoveries have supported the idea that clinical trial participants are not diverse, meaning that when a drug is approved, it may only work on a small subset of the patient population, which may lead to recalls or follow-up studies.

According to a 2022 Phesi analysis, roughly 40% of US cancer clinical trials do not include a single Black patient, despite Black patients having the shortest survival rate. Beyond that, in 2022, researchers concluded that many medical devices, including pulse oximeters and infrared thermometers, did not work as well on Black patients compared to their White counterparts.

With so many patient populations excluded or not actively recruited for clinical trials, lacking diversity may mean a limited reach for the drug developer or manufacturer.

Best Practices for the Drug Development Life Cycle

Despite the challenges associated with the drug development process, there are ways to minimize the risks associated with drug development, improve the drug approval process, and facilitate the efficient development of safe and effective drugs.

One of the best practices is to follow guidelines set by the FDA — or other appropriate regulatory agencies, such as the EMA. The FDA provides guidelines and protocols for each stage of the drug development process, detailing best practices, necessary actions, and more.

Beyond following the appropriate guidance, researchers may also want to conduct in-depth preclinical research before investing money in clinical trials. With the changes made by the FDA Modernization Act 2.0, researchers may be able to use more advanced preclinical research tools.

For example, organ-on-a-chip models may provide additional insights into a drug’s impact on human cells.

Additionally, when planning a clinical trial and drafting a protocol, clinical researchers must be cognizant of the participant population they recruit. The participant population should accurately represent the patient population affected by the drug target.

Researchers may also consider opting for adaptive clinical trials, which allow investigators to adjust aspects of the trial without significantly impacting the clinical trial budget.

The drug development life cycle is a complex but critical component of comprehensive healthcare and scientific advancement. The stakeholders' goal moving forward is to ensure that drugs are safe and effective while making the process more efficient. Without a robust and efficient drug development life cycle, pharmaceutical companies are not likely to thrive, and patient care will be compromised.