Understanding the Drug Development Process

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Drug development is a process that spans many years, from the initial phase of identifying potential drug candidates to testing for safety and efficacy in preclinical and clinical trials, acquiring approval from global regulatory bodies, and marketing to the general population. In this article, explore the different drug development phases, the reasons for high drug failure rates, and the strategies for improving and accelerating drug development.

What Is Drug Development?

Drug development is the process of identifying a new drug molecule and bringing it into clinical practice.¹ It encompasses the entire journey from designing a new drug to its commercial launch. In general, the full drug development process can be challenging and time-consuming, whereby each new drug requires an average investment of USD 1-2 billion.²

Drug Development Stages

Before the drug development process commences, scientists conduct computational studies, cellular assays, and genomic and proteomic research to identify a specific target molecule, such as an RNA strand, DNA sequence, protein, or metabolite, that plays an important role in disease incidence or progression.³ After researchers identify the therapeutic target, the drug development process begins, comprising five distinct steps.⁴

Step 1: Drug discovery

After discovering a therapeutic target, researchers use high-throughput and computational methods to screen compounds that may interact with the target and exhibit therapeutic efficacy against the disease.⁵ Subsequently, they conduct a series of in vitro and in vivo experiments for each compound to identify the most effective drug substance based on different factors such as efficacy, mode of action, dosage, administration route, absorption, distribution, metabolism and excretion (ADME), safety, viability, and overall performance. This phase may take on average 6 years. The most promising candidate undergoes further evaluation in the preclinical research phase.

Step 2: Preclinical research

Before evaluating if a drug is suitable for human treatment, scientists perform preclinical research via in silico, in vitro, or in vivo experiments to assess its potential side effects or toxicity.⁶ This phase typically requires 2 to 3 years, during which researchers determine drug dosage based on pharmacodynamic and pharmacokinetic assessments. They typically use at least two animal models to assess safety and select the most suitable administration routes. All preclinical research must comply with good laboratory practice (GLP) regulations to ensure high quality, integrity, and reliability.

Step 3: Clinical trials

Before beginning clinical trials, it is mandatory to submit an application to regulatory agencies, such as an Investigational New Drug (IND) to the US Food and Drug Administration (FDA) or a Clinical Trial Application (CTA) to the European Medicines Agency (EMA), with detailed information on the toxicity, efficacy, manufacturing information, and proposed clinical protocols (e.g., number of study participants and study duration).⁷ After the regulatory bodies approve an IND or CTA application, clinical trials commence, which assess the safety and efficacy of the drug in humans. This phase typically requires approximately 4 to 7 years for completion. This phase is usually divided into four subphases.

The key aspects assessed in different clinical trial phases may include the following.

• Phase 1 evaluates the safety, tolerability, and dosage of the therapeutic compound, and often involves a small number of participants, usually around 20 to 80 people.
• Scientists typically conduct Phase 2 assessments in several medical institutions located in different countries, and they usually recruit between 100 and 500 study participants. This phase highlights the therapeutic efficacy of the drug. Investigators divide Phase 2 further into Phase 2a and 2b. The former determines the optimal drug dose and the latter evaluates the overall efficacy of the pre-determined dosage in limited participants. Many drug candidates fail Phase 2 due to issues related to safety and effectiveness.
• Phase 3 trials evaluate the efficacy of the drug candidate in a large cohort of 1,000 to 5,000 patients across multiple clinical centers. This randomized, clinical trial phase determines the effectiveness of the drug relative to available standard of care therapies or a placebo. This phase is the most expensive part of drug development. Upon completion of a Phase 3 trial, investigators submit a New Drug Application (NDA) to the regulatory agencies to inform them about drug safety and efficacy. The drug might receive approval conditional on a suitable risk-benefit ratio.
• Scientists conduct Phase 4 trials, also referred to as post-marketing surveillance, when regulatory agencies ask for additional follow-up studies. This phase focuses on real-world data to assess long-term adverse effects across a much larger cohort of patients.

Step 4: Regulatory approval

Once a drug successfully moves through clinical trials, regulatory bodies review the data to assess the drug’s clinical efficacy against the disease and whether it is well tolerated in humans. ⁸ A team of experts, including doctors, microbiologists, statisticians, chemists, and pharmacologists, reviews the clinical trial findings. Once the drug receives approval, pharmaceutical companies manufacture and commercially launch the drug.

Step 5: Post-market monitoring

Even after determining the safety and efficacy of a drug, there is a possibility that new concerns may arise during treatment after approval. The regulatory bodies assist with post-market surveillance via several programs.⁹ For example, the FDA supports post-market safety monitoring through programs such as MedWatch, where healthcare professionals and consumers report serious issues related to medical products.

Why Is the Drug Development Failure Rate High?

Although scientists and pharmaceutical companies invest a significant amount of time and funds to develop new drugs, there is no guarantee that a drug candidate will succeed. Multiple factors contribute to the low success rates for developing new drugs, including the lack of validated diagnostic and therapeutic biomarkers for many diseases and the inability to rely on published data.¹⁰

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Even after a successful preclinical phase, a drug could fail to clear clinical trials, for instance because animal models may not accurately mimic disease processes in humans.¹¹ Incomplete knowledge of underlying disease progression mechanisms or a drug's precise mode of action may also lead to clinical trial failures.¹²

The lack of sharing negative results between research groups leads to the same errors being committed and wastage of productive resources.¹³ More scientific collaborations and proper data sharing could effectively reduce drug testing failures.

Strategies to Improve and Accelerate Drug Development

Over the years, scientists have adopted several strategies to boost the success rates in the drug discovery and development process. These strategies include genomics and proteomics approaches, expanding existing drug applications, and implementing pharmaceutical modeling and artificial intelligence (AI) to reduce the time required to develop new drugs.

Pharmaceutical modeling

Pharmaceutical modeling involves in silico simulations that help researchers predict variable characteristic features of a drug molecule, such as pharmacodynamic and pharmacokinetic profiles. Computer-aided drug design (CADD) guides the drug optimization process by providing invaluable information that enables scientists to enhance the drug-target binding affinity and optimize pharmacokinetic properties such as drug metabolism, distribution, excretion, and toxicity.¹⁴ This approach helps identify therapeutic candidates while filtering out the compounds that are highly unlikely to be successful in the development pipeline because of intolerable toxicological profiles or poor physicochemical properties.

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Artificial intelligence

Researchers use AI in the drug discovery and development process to rapidly screen billions of molecules and identify potential compounds against validated biological targets.¹⁵ For example, they use AI-based tools such as XenoSite and SMARTCyp to determine drug metabolism sites.¹⁶ These approaches have significantly reduced time otherwise required to identify drug candidates. Researchers also use AI to efficiently manage clinical trials and ensure optimal use of resources.¹⁰

Target-based screening

High-throughput target-based screening for lead compounds enables optimal target site selection for maximum drug interaction and minimum non-specific binding.¹⁷ This approach utilizes technological advances in molecular biology, computational modeling, proteomics, and genomics. The key advantages of a target-based drug screening strategy are its simplistic approach, capacity to uncover the underlying mechanism of action, and ability to promote faster drug development.

Drug repurposing and repositioning

Drugs developed for a specific clinical application may be beneficial in other therapeutic areas beyond the original indications. These drugs can be repurposed to treat new diseases without requiring structural modifications.¹⁸ For example, scientists primarily developed sildenafil for pulmonary arterial hypertension treatment, but have since learned that it can also help prevent gastric cancer growth.¹⁹

Drug repositioning is another strategy where researchers modify the primary molecular structure to accentuate a desirable side activity while weakening the primary effect.²⁰ The key advantage of drug repurposing and repositioning is quicker development because of existing pharmacokinetic and toxicological data along with other important information concerning the drug molecule.

Future Considerations

Open science partnerships, where the consortia model connects all stakeholders, could promote a more efficient drug discovery and development process.²¹ This collaboration would allow a “cross-fertilization” where each stakeholder can benefit from the other’s progress.

The advent of simple and fast methods for detecting target genes has triggered the transition of medicinal chemistry to the precision medicine era. Precision medicines mark a new relationship between genomics and drug discovery, and scientists are currently exploring this field in the oncology domain and beyond.²²