How are biotechnology medicines discovered and developed?

The first step in treating any disease is to clarify how the disease is caused. Many questions must be answered to arrive at an understanding of what is needed to pursue new types of treatments.
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How does a person get the disease? Which cells are affected? Is the disease caused by genetic factors? If so, what genes are turned on or off in the diseased cells?

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What proteins are present or absent in diseased cells as compared with healthy cells? If the disease is caused by an infection, how does the infectious organism interact with the body?

In modern labs, sophisticated tools are used for shedding light on these questions. The tools are designed to uncover the molecular roots of disease and pinpoint critical differences between healthy cells and diseased cells. Researchers often use multiple approaches to create a detailed picture of the disease process. Once the picture starts to emerge, it can still take years to learn which of the changes linked to a disease are most important. Is the change the result of the disease, or is the disease the result of the change? By determining which molecular defects are really behind a disease, scientists can identify the best targets for new medicines. In some cases, the best target for the disease may already be addressed by an existing medicine, and the aim would be to develop a new drug that offers other advantages. Often, though, drug discovery aims to provide an entirely new type of therapy by pursuing a novel target.

Selecting a target The term target refers to the specific molecule in the body that a medicine is designed to affect. For example, antibiotics target specific proteins that are not found in humans but are critical to the survival of bacteria. Many cholesterol drugs target enzymes that the body uses to make cholesterol.

Scientists estimate there are about 8,000 therapeutic targets that might provide a basis for new

If researchers decide to use a chemical compound. scientists try to prove the value of targets through research experiments that show the target’s role in the disease process. the target protein is deficient or missing. With automated systems. including enzymes. Most are proteins of various types. If the goal is to block the target protein with an antibody. a technology called drug screening is typically used. The mice used in this process are genetically modified to make human antibodies. it must go through extensive testing before it can be studied in humans. The amazing complexity of human biology makes it a challenge to choose good targets. cell receptors. Selecting a drug Once the target has been set. Potent compounds can be put through added tests to find a lead compound with the best potential to become a drug. Many drug safety studies are performed using cell lines engineered to . The cells that produce these specific antibodies are then extracted and manipulated to create a new cell line. and the goal is to enhance or replace it in order to restore healthy function. scientists can rapidly test thousands of compounds to see which ones interfere with the target’s activity. and cell-signaling molecules. Some targets are present in excess during disease. so the goal is to block their activity. In contrast. This can be done by a medicine that binds to the target to prevent it from interacting with other molecules in the body. the gene for that protein is used for making a recombinant version of the protein to give to patients. Biotechnology has made it possible to create therapies that are similar or identical to the complex molecules the body relies on to remain healthy. To reduce that risk. It can take many years of research and clinical trials to learn that a new target won’t provide the desired results. one common approach is to expose transgenic mice to the target so as to induce their immune systems to make antibodies to that protein. growth factors. The goal is to show that the activity of the target is driving the course of the disease. the next step is to identify a drug that impacts the target in the desired way. biologics are designed using genetic engineering. In other cases. If the goal is to provide a missing or deficient protein.medicines. which reduces the risk of allergic reactions in patients. Developing the drug Once a promising test drug has been identified.

etc. Some animal tests are still required to ensure that the drug doesn’t interfere with the complex biological functions that are found only in higher life-forms. The goals are to evaluate whether the drug appears effective. . Phase 1: Tests in 20 to 80 healthy volunteers and. and a drug must meet success criteria at each phase before moving on to the next one. Cell line models have decreased the number of animals needed for testing and have helped accelerate the drug development process. to further explore its safety. patients. Phase 2: Studies in about 100 to 300 the genes that are often responsible for side effects. how much of the drug reaches its target. The main goals are to assess safety and tolerability and explore how the drug behaves in the body (how long it stays in the body. There are three phases of clinical research.). and to determine the best dose. If a test drug has no serious safety issues in preclinical studies. sometimes. researchers can ask for regulatory permission to do clinical trials in humans.

the Food and Drug Administration evaluates new medicines. If the test drug shows clear benefits and acceptable risks in phase 3. 2009). when there are significant costs associated with recruiting patients and monitoring them for extended periods. and tolerability of the test drug with another drug or a placebo. fail cheap” is the goal. The goal is to compare the effectiveness. In the European Union. once clinical trials are well under way as is the case with Rezulin ( Anti diabetic and anti inflammatory drug) (Varma-O’Brien. . Biotechnology companies have been attempting to decrease the technical uncertainty surrounding a product before it enters the expensive stages of development – in particular Phases II and III. depending on the disease and the study design.. the European Medicines Agency manages that responsibility. If the medicine is approved. Why is it better to fail early? “Fail early. In the United States. A plan to monitor side effects in patients is also required. and additional trials may also be required by regulatory agencies. safety. Very few test drugs are able to clear all the hurdles along the way. regulators may still require a plan to reduce any risk to patients. Regulators review data from all studies and decide whether the medicine’s benefits outweigh any risks it may have.000 or more patients. No company wants to discover a major problem after millions of dollars and years of research have been invested. These are known as phase 4 studies. The whole drug development process takes 10 to 15 years to complete on average.Phase 3: Large studies involving 500 to 5. Very large trials are often needed to determine whether a drug can prevent bad health outcomes. the company can file an application requesting regulatory approval to market the drug. A company can continue doing clinical trials on an approved medicine to see if it works under other specific conditions or in other groups of patients. S.

and product decision. Clinical research is expensive. and whether the drug is based on a molecule not used before in any pharmaceutical product (a new molecular entity.B. They experience the biggest annual growth in complexity and execution as more data is gathered in these earlier phases. But the main expense is failure. Drug developers can remove some of the uncertainty in the outcomes of their research and improve their return on investment substantially. 2006). AstraZeneca does badly by this measure because it has had so few new drugs hit the market. Key to the quick win/fast fail approach is a feedback loop in which data gathered at the early proof of concept stage are fed back to discovery scientists for future benefit. . The Congress of the United States. For example. What is the rationale for the high costs of medicines developed by Pharma? Research and development costs vary widely from one new drug to the next. the likelihood of failure. demonstrating in the course of a year that a drug for Alzheimer’s does or does not alter the disease progression before it becomes symptomatic would produce savings over having to wait perhaps five years for the conclusion of a later-phase study. first efficacy dose. or NME) or instead is an incremental modification of an existing drug. This is demonstrated by Phase I and II protocols.Savings realised by avoiding late-stage R&D failures are re-invested in R&D to further enhance R&D productivity through work on candidate selection. including expenditures on failed projects and the value of forgone alternative investments (Marron D. Phase IV is expensive as more post-marketing data is collected for safety and marketing purposes. first human dose. A recent. widely circulated estimate put the average cost of developing an innovative new drug at more than $800 million. Similarly. Those costs depend on the type of drug being developed.

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