Drug development: the journey of a drug from the lab to the shelf
Every year a few dozen new drugs are cleared for use, but in their wake tens of thousands of drug candidates will be dropped. The research and development journey for these new drugs to come to market will have taken around 12 years and cost around £ 1.15 billion.
The journey will have started in a university laboratory where researchers, funded by research organizations or the pharmaceutical industry, have undertaken fundamental research to understand the processes that cause disease, often at the cellular or molecular level. It is through a better understanding of disease processes and pathways that targets for new treatments are identified. It could be a gene or protein determining the disease process that a new treatment could interfere with, for example by blocking an essential receptor.
Once a potential target has been identified, the researchers will then look for a molecule or a compound acting on this target. Historically, researchers have looked to natural compounds from plants, fungi or marine animals to provide the basis for these drug candidates, but increasingly scientists are using the knowledge gained from studying the genetics and proteins to create new molecules using computers. Up to 10,000 compounds can be considered and reduced to just 10 to 20 that could theoretically interfere with the disease process.
The next step is to confirm that these molecules are working and that they are safe. Before molecules are given to humans, safety and efficacy tests are performed using computer models, cells and animals. About half of the candidates pass this preclinical testing step and these remaining five to ten compounds are now ready to be tested in humans for the first time. In the UK, Medicines and Health Products Regulatory Agency (MHRA) approval is required before any human testing can take place. The company will file a clinical trial application (CTA), which will be reviewed by medical and scientific experts, who will decide whether or not sufficient preliminary research has been conducted to allow testing in humans to continue.
FDA Approved New Molecular Entities (NMEs)
Source: FDA / Regulatory Affairs Professional Society
Number of companies with at least one new molecular entity (NME) approved by the FDA
Source: FDA / Regulatory Affairs Professional Society
If an ACT application is accepted, the safety and pharmacology of a drug candidate will first be tested in a small group of healthy volunteers in a phase 1 trial. Small doses of the compound will be administered to a patient. group of 20 to 100 healthy volunteers closely monitored. At least half of the compounds will generally be considered safe enough to move on to phase 2 trials.
Phase 2 studies look at how well a compound works in volunteer patients who have the disease the drug is supposed to treat. To avoid unnecessary exposure of a volunteer to a potentially harmful substance, these studies use as few patients as possible to provide sufficient statistical power to determine effectiveness, typically 100 to 500 patients, who are continuously monitored and evaluated. The objective of phase 2 studies is to determine the most effective dose and method of administration (eg, oral or intravenous), the appropriate dosing interval, and to reconfirm the safety of the product. Most drugs that fail in clinical trials make it to phase 2 because they are ineffective, have safety concerns, or have intolerable side effects.
Candidates who pass phase 2 will then be tested on a much larger patient population in phase 3 trials, often 1,000 to 5,000 at several international sites. The aim of these phase 3 trials is to reconfirm the results of phase 2 in a larger population and to identify the best dosage regimen. In doing so, the drug company must generate sufficient safety and efficacy data to demonstrate an overall risk-benefit ratio for the drug to allow for submission of an application for authorization to the regulatory authority. Despite the rigorous testing that has already taken place, around 10% of drugs will still fail at this point.
The drug development and market authorization process is similar across the world. For drugs that pass phase 3, a marketing authorization application is made to the national regulatory authority in most countries. In the UK this is the MHRA and in the US it is the Food and Drug Administration (FDA). However, in Europe, pharmaceutical companies now generally choose to make a central application to the European Medicines Agency (EMA) to obtain marketing authorization for the whole of Europe in order to avoid having to make multiple requests in individual countries. The presentation contains preclinical and clinical information obtained during testing, including information on the chemical composition and manufacturing process, the pharmacology and toxicity of the compound, human pharmacokinetics, the results of clinical trials and the proposed labeling.
If a license is granted, that is not the end of the process. Pharmaceutical companies in England and Wales need more than a market authorization for most patients to access treatment on the NHS – they also need the National Institute of Health and Care Excellence (NICE) to recommend that it be made available through the NHS. NICE makes decisions based on the cost and effectiveness of a treatment to determine whether the cost-benefit ratio it offers to the NHS is affordable.
Clinical trials can also continue. Regulatory authorities may require phase 4 trials for post-market safety surveillance (pharmacovigilance) or they may be undertaken by the company to allow them to target distinct markets. For example, to allow the drug to be used in patients with complex medical conditions or in pregnant women who have probably not participated in previous trials, and to ensure that they do not interact with other drugs.
Pharmaceutical companies will patent any promising molecule early in the development process. Patenting prevents other companies from copying it for 20 years and covers many aspects of the intellectual property of a drug, including its manufacture, formulation and, in some cases, use.
The purpose of the patent is to enable the pharmaceutical company that developed it to recover its development costs and make a profit to cover the costs of developing drugs that failed in the testing process, as well as to invest in the development of future innovative drugs. . By the time a drug has passed the required tests and has been authorized, half of the patent term will generally have expired.
Once a patent on a drug has expired, generic versions of the drug can be manufactured and marketed. For some drugs, the period of patent protection can be extended up to an additional five and a half years, provided that this does not take the time that the drug is under patent protection beyond 15 years from the date to. for which it has received regulatory approval.
As drugs and their development have become more complex and costly, requests for information from regulatory agencies have also become more complex. In response, channels of communication have opened up between drug companies and regulators well in advance of submissions to ensure that companies compile all the relevant data required for a successful submission. The MHRA has set up a dedicated innovation office to advise and support companies. Its main objective is to help developers of new drugs and companies developing unique products such as gene and cell therapy, nanomedicines or treatments involving new delivery systems or produced by new manufacturing processes.
Meanwhile, NICE is offering a paid advisory service to drug developers to help ensure they generate the evidence they will need to support a NICE assessment. NICE recommends that any advice be sought after the first human trials to aid in planning the larger trial program.
For every 25,000 compounds that start in the lab, 25 are tested in humans, 5 hit the market, and only one recovers what was invested. The high cost of current drug development, coupled with the trend towards complex drugs and the use of genomic markers to predict response to drugs (personalized drugs), may mean that in the future we will see a process of more flexible drug development and regulatory framework.