Hello everybody,

I would like to start my blog by writing a more optimistic post and discuss how the new drugs are discovered and developed.

Often, when I meet people and introduce myself as a research oncology scientist, they ask me: Why does it take “them” so long to discover new medicines and why are these so expensive? I will try to answer these questions and explain in a simple way,  why is it such a costly and long-term process.

Successful drugs take at least ten years from conception to clinic, costing upwards of $2.6 billion. The exception is a newly approved drug Tagrisso– it took around seven years, only 2.5 of which- for clinical trials. It is prescribed to people diagnosed with a specific form of non-small cell lung cancer. For more information: https://www.astrazeneca.com/our-company/media-centre/press-releases/2015/TAGRISSO-AZD9291-approved-by-the-US-FDA-for-patients-with-EGFR-T790M-mutation-positive-metastatic-non-small-cell-lung-cancer-13112015.html .

Unfortunately, there is a high attrition rate (drug failure) which causes around 90% of the drugs to fail after the first clinical trials. Drug safety tests have a great impact on drug development leading to drug withdrawals. Therefore, to avoid highly expensive late-stage failures (the later stage is, the more expensive it is), toxicology assays have been developed to identify drugs that are highly probable to fail at the early stages (“fail-early” strategy).

Therefore, the high cost of a newly developed medicine can be explained by the high attrition rate caused by the approval of only a few medicines out of the thousands and sometimes millions of compounds that have been tested during the early Research and Development (R&D).

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So, why drug development is such a long process?

This is because the whole process is divided into FIVE broad stages: basic research, drug discovery, drug development, FDA review and Clinical Use (Figure 1).

The pipeline of drug development

Figure 1: The pipeline of drug development. Adapted from: Hughes, et.al., 2011.

Below I will shortly introduce you to each of these elements. However, more information and in- depth review on drug discovery and development can be found at: http://www.fastbleep.com/biology-notes/37/114/636 

Drug discovery. 

During the initial stages of drug development or  basic research potential molecules (such as proteins) that are involved in disease are identified. It is a challenging process because these are involved in a variety of biological processes by being members of cellular pathways (so called links between the molecules).

Consequently, modification of certain pathways may have extreme toxic effects and be unsuitable for further drug development. Moreover, to become a good drug target (a molecule in the body, which upon interaction with a potential drug produces an effect, e.g.: prevents disease development), the molecule should be “druggable”, for instance, be a small molecule and express a biological effect upon its binding. Finally, it should be safe, efficacious and pass clinical and commercial requirements. The tests are done on cells, tissues and animal models to determine, whether potential medicine will influence the molecule.

the-impact-of-early-adme-profiling-on-drug-discovery-and-development-strategy

After the target is selected, during the drug discovery phase, the researchers try to narrow the library of compounds from thousands to a single lead compound, which in the future can become a potential medicine. A variety of approaches can be used, such as high-throughput screening (selects the most promising molecules out of thousands), genetically-engineered living systems that target the molecule of interest or creating a molecule from a living/ synthetic material.

Early safety tests of the promising compounds take place before the use in humans. At this stage, promising compounds are tested for pharmacokinetics (how the body processes the compound) and pharmacodynamics (the impact of a potential drug on the body systems and functions). Such tests are done in cells, animals or computational systems.  To become a successful drug, it must meet certain criteria: be Absorbed into the bloodstream, Distributed to the site of action, Metabolized efficiently, Excreted from the body and exert no toxic effects (ADME pharmacology testing).

In the next stage (Lead optimization) potential drugs are altered or “optimized” in their chemical structure to improve their properties. For instance, by reducing interaction with other proteins within the pathway, the potential side effects can be minimized.
When one or more compounds are identified, pre-clinical testing determines, whether these are safe to be used in humans. The studies in the living cells and animal models determine the drug’s mechanism of action and the potential adverse effects. At this stage, the way of producing large quantities of drugs to be used in clinical trials should be also established.

Drug development. Clinical trials. 

Pre-clinical research should exclude most potentially toxic compounds; however, it is important to determine any unexpected side effects with the human body. Prior to the clinical study, the aims of the research for each of the different phases are set up (Table 1) and the investigational new drug process (IND) begins. The IND application includes the data from in vivo and toxicity studies, manufacturing information and the study plans.

Table1

Table 1: Phases of clinical trials, highlighting: the number of participants involved, the aim and the focus of the research. Adapted from: (Pharma.org)

Regulations and Approval: FDA Review.

The Food and Drug Administration (FDA) regulatory review evaluates the complete data sets and proposes the labeling and manufacturing plans. Upon the positive confirmation of safety and efficacy results from the clinical trials, a new drug application (NDA) is submitted (where results from pre-clinical, clinical development programs, proposals for manufacturing and labeling are considered) to get approval for drug marketing.

Drug approval is a very long and thorough process and occasionally, additional screens and tests are requested to prove the novel drug has an advantage over the marketed drug.

Manufacturing: high quality production of new medicines on a large scale. 

The approved drugs can be administered to a small population of patients or to millions of people. In either case, during each stage of the manufacturing procedure, quality and safety checks are conducted to ensure that companies meet good manufacturing practice (GMP) requirements approved by FDA. During manufacturing, the cutting edge technologies are implemented (i.e.: nanotechnology) which are closely coordinated with the automation and software.

drug-manufacturing

Post-approval research and monitoring.

Upon completion of R&D work the drug research continues and monitors its efficacy and new long-term side-effects. Moreover, it can be repositioned to a new patient population. Additional beneficial properties of a drug can be revealed leading to expansion of its use. For instance, the drug’s therapeutic value is maximised when for a given indication it has a greater therapeutic value than seen during clinical trials, it can be used to target a different disease, has a new way of delivery or brings an advantageous effect when used as a combination therapy.

To summarize, drug development is a very long and complex process, sometimes taking up to 10-15 years to develop a new medicine. Increased understanding in human biology and disease biochemistry opens the doors for new advances in drug discovery and possibilities to discover a new treatment option. Considering the advances in research and medical innovations, there is a hope that  the success of drug development will improve in the near future.

I hope, this post helps to understand why is it such a long and expensive process to develop a single drug.

Thank you for your time.

I wish  ALL the readers a lot of HEALTH and a BRIGHT FUTURE!!! 

Anastacia

P.S. As usually, your comments are highly welcome!

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