How Does A New Drug Get From The Lab To You?

Overview 

In 2023, 55 new drugs were approved, almost 50% more than the previous year. However, this number is much smaller than the thousands of drug candidates that failed to progress through clinical trials, and thus approval. Research and development of new drugs that reach the market is a long and costly process, taking an estimated 12 years, and costing £1.2 billion. 

You may be wondering what exactly makes drug development so lengthy and expensive. In order to be deemed safe for use, they must undergo a complex process, including rigorous trials and testing, regulatory approval and quality control before they are finally distributed by manufacturers. 

This article will detail the drug development process, starting with ideas in the laboratory, and making it through clinical trials, to be proven safe and effective for use by patients and customers.

Drug discovery and development 

Laboratory research 

The drug development journey begins in the laboratory by researchers with grants from research bodies in the pharmaceutical industry. Researchers gain a better understanding of diseases at a cellular or molecular level.¹ They typically discover new drugs from:

• Testing of molecular compounds to discover beneficial effects against a large number of diseases 
• Novel insights into a disease to design a product that reverses or stops the effects of the disease
• Existing treatments with different uses
• Novel technologies, including those with new pathways of targeting medical products to specific sites in the body or to manipulate genetic material.

At this stage, tens of thousands of compounds are reduced to 10-20 possible candidates.

Preclinical trials

Before new drugs can be tested in humans, safety and efficacy tests are carried out to ensure they will not cause toxicity.² There are two types of preclinical studies:

• In vitro - Experiments conducted outside of a living organism, using cells and tissues. This test is used to observe drug interaction at a cellular level
• In vivo - Experiments conducted in a living organism, using animals as an experimental model to study drug efficacy, toxicity and dosage.² 

In the UK, approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) is required to ensure testing in humans can proceed. 

Approximately 5-10 of these remaining compounds are successful through preclinical trials. 

A summary of the process of FDA drug approval. Source: Wikimedia Commons 

Clinical trials 

Clinical trials consist of studies conducted in humans and categorised into four phases.

Phase I

Phase I trials are small, generally involving 20-100 healthy volunteers who do not take other treatments. They involve administering small doses of the compound to the volunteers, who are closely monitored. The dose is increased in small increments to find the highest dose that does not cause harmful side effects.

 The test objectives of phase I trials include determining:

• Safety
• Dosage
• Side effects
• Pharmacokinetics of the new drug, including how it is absorbed, distributed, metabolised and excreted by the body 
• Route of administration, for example, whether it should be given orally or intravenously.³

Phase I trials can take several months, with approximately 70% of drug candidates passing this stage. If a safe dose is found, the new drug compound progresses to phase II testing.

Phase II

Phase II trials study the effectiveness of new drugs on a particular disease or condition, evaluating whether the new drug improves the disease it targets and at what dose. This randomised trial typically involves 100-300 volunteers and gives insights into adverse events and their management.⁴

Phase II trials can last from several months to a few years. In phase II most drug candidates fail to progress further as they are discovered to be ineffective against diseases, have problems with safety or have intolerable side effects. Approximately 33% of drugs move onto phase III trials.⁴

Phase III

Phase III trials involve comparing the efficacy and safety of the new drug treatments to the current standard- treatment to determine which is superior.⁴

This randomised and blinded phase requires several thousand volunteers over multiple international sites for drug testing, and can last for several years. This is to confirm the findings in phase II trials in a larger population and identify the best dosage regimen. However, at this stage, an estimated 10% of drugs fail. 

In phase III, pharmaceutical companies must produce sufficient efficacy and safety data to show an overall benefit for the medicine. During this phase, the majority of patient safety information on approved medicines is gathered.⁴ 

After phase III is completed, the company can send a submission for approval to market the drug, called a New Drug Application (NDA). NDAs contain all of the scientific data gathered during all trials.    

Phase IV

Phase IV trials are typically conducted after the drug has been approved and is on the market. These trials are also referred to as post-marketing drug safety monitoring. 

Phase IV trials aim to discover:

• New and rare side effects that were not observed during previous trials
• How well the new treatment works over a longer time frame in a wider population 
• The long-term risks and benefits.

These trials can evaluate drug safety in a real-world setting, providing evidence to better refine the safety of approved drugs.⁵ Phase IV testing can also evaluate whether the drug can be used in patients with complex medical conditions,  during pregnancy and to determine if they interact with other drugs. Phase IV trials can include thousands of participants. 

Regulatory approval

Once a new drug has progressed through clinical trials with evidence to support that it is safe and effective for its intended use, the pharmaceutical company can apply to regulatory authorities to be able to put the drug on the market, 

New drug application (NDA)

The purpose of an NDA is to demonstrate that a drug is safe and effective for its intended use to obtain a licence to market the drug. The pharmaceutical company must ensure that all information and data gathered from preclinical and clinical trials is included in the NDA. 

Alongside clinical data, drug developers may include:

• Patient information
• Safety information
• Directions for use
• Proposed labelling and prescribing information.

In the UK, NDAs are submitted to the MHRA, and in the rest of Europe, they are submitted to the European Medicines Agency (EMA).⁶ The Food and Drug Administration (FDA) reviews US submissions.

Review by regulatory bodies

Once an NDA is received by the regulatory bodies, a team will review it to ensure it is complete. If complete, the review team will have 6-10 months to decide whether to approve the drug. This includes:

• Conducting a full review of the application by each member, subject to a supervisory review 
• Travelling to clinical study sites for a routine inspection. This is to look for any evidence that could suggest manipulation or withholding of data and evidence
• Compiling individual reviews and reports to create a record for the regulatory body 
• A recommendation is issued by the review team, where it is subject to approval by a senior official.

However, if the NDA is found to be incomplete or not meeting regulatory standards, the review team can reject it. 

In England and Wales, if a drug is approved by the regulatory agency and a licence is granted, pharmaceutical companies require the National Institute of Health and Care Excellence (NICE) to recommend that it should be available through the NHS. NICE does this by determining whether the treatment is affordable to the NHS based on its cost and efficacy so that patients can benefit from promising medicines sooner and in a more accessible manner.⁷ 

At this stage, the regulatory authorities may request phase IV trials to be conducted for pharmacovigilance purposes.

Manufacturing and quality control

Scale-up and production of the licensed medicine follows approval by regulatory bodies. This initially involves a small scale-up to test the manufacturing processes. 

Large-scale drug manufacturing includes producing the drug in large quantities in batch facilities.⁸ During manufacturing, Good Manufacturing Practices (GMP) must be adhered to. GMP regulations are the minimum standard that the manufacturer must meet in their production processes, enforced by regulatory bodies who carry out inspections. 

Quality control during drug production ensures that the medication has been manufactured correctly and is safe to use. It is ensured by: 

• Testing of the product during production for defects or deviations from quality standards 
• Testing the final product for its purity and compliance with specifications
• Stability testing to determine the medicine’s storage conditions and shelf-life.

Drug distribution

A pharmaceutical company may apply for a patent for their newly approved drug, giving them exclusivity for 20 years. This means that only the owner of this branded drug can develop and sell it. After patent expiration, other pharmaceutical companies can create and sell it as a generic drug. 

Pharmaceutical manufacturers manage the distribution of drugs from the manufacturing facilities to wholesale drug distributors. Wholesale distributors purchase pharmaceutical drugs to distribute to their customers, such as pharmacies, hospitals and clinics. However, sometimes manufacturers bypass wholesalers and distribute directly to healthcare providers for faster delivery of their products.

Healthcare providers are then able to prescribe these new drugs to patients who need them.  

Summary

• Drug development involves rigorous and regulated stages of development to ensure its quality, safety and efficacy
• It begins as an idea in the laboratory following research and is subjected to preclinical trials to determine whether it is safe for use in humans 
• Following this, the drug enters four phases of clinical trials, where it is tested on human volunteers. During clinical trials, statistical data on factors such as toxicity, side effects, dosage, and comparison to the current standard of care is collected  
• To license a drug for marketing, a new drug application with the trial data results must be filed  to regulatory bodies for review  
• If the drug is approved for marketing by the regulatory authorities, the new drug also undergoes manufacturing and quality control, making sure it is produced consistently to meet regulatory standards
• Manufacturers distribute the drug to healthcare providers who can then prescribe it to patients for approved indications.