innovation.org - Inside Drug Discovery

Inside Innovation: The Drug Discovery Process

The path from understanding a disease to treating it is long, difficult and expensive, but it is the mission of pharmaceutical research companies to face these challenges. For the first time in history, scientists are beginning to understand the inner workings of human disease at the molecular level. Recent advances in genomics, proteomics and computational power present new ways to understand illness. The task of discovering and developing safe and effective drugs is even more promising as our knowledge of disease increases.

It takes about 10-15 years to develop one new medicine from the time it is discovered to when it is available for treating patients. The average cost to research and develop each successful drug is estimated to be $800 million to $1 billion. This number includes the cost of the thousands of failures: For every 5,000-10,000 compounds that enter the research and development (R&D) pipeline, ultimately only one receives approval.

These numbers defy imagination, but a deeper understanding of the R&D process can explain why so many compounds don’t make it and why it takes such a large, lengthy effort to get one medicine to patients. Success requires immense resources — the best scientific minds, highly sophisticated technology and complex project management. It also takes persistence and, sometimes, luck. Ultimately, though, the process of drug discovery brings hope and relief to millions of patients.

Pre-Discovery
Understanding the disease
Before any potential new medicine can be discovered, scientists work to understand the disease to be treated as well as possible, and to unravel the underlying cause of the condition. They try to understand how the genes are altered, how that affects the proteins they encode and how those proteins interact with each other in living cells, how those affected cells change the specific tissue they are in and finally how the disease affects the entire patient. This knowledge is the basis for treating the problem.

Researchers from government, academia and industry all contribute to this knowledge base. However, even with new tools and insights, this research takes many years of work and, too often, leads to frustrating dead ends. And even if the research is successful, it will take many more years of work to turn this basic understanding of what causes a disease into a new treatment.

The Pre-Discovery stage also includes:
Target Identification: Choosing a molecule to target with a drug
Target Validation: Testing the target and confirming its role in the disease
Learn more in the full brochure



Drug Discovery
Finding a promising molecule (a “lead compound”) that could become a drug
Armed with their understanding of the disease, scientists are ready to begin looking for a drug. They search for a molecule, or “lead compound,” that may act on their target to alter the disease course. If successful over long odds and years of testing, the lead compound can ultimately become a new medicine.

There are a few ways to find a lead compound:

Nature: Until recently, scientists usually turned to nature to find interesting compounds for fighting disease. Bacteria found in soil and moldy plants both led to important new treatments, for example. Nature still offers many useful substances, but now there are other ways to approach drug discovery.

De novo: Thanks to advances in chemistry, scientists can also create molecules from scratch. They can use sophisticated computer modeling to predict what type of molecule may work.

High-throughput Screening: This process is the most common way that leads are usually found. Advances in robotics and computational power allow researchers to test hundreds of thousands of compounds against the target to identify any that might be promising. Based on the results, several lead compounds are usually selected for further study.

Biotechnology: Scientists can also genetically engineer living systems to produce disease-fighting biological molecules.

The Drug Discovery stage also includes:
Early Safety Tests: Performing initial tests on promising compounds
Lead Optimization: Altering the structure of lead candidates to improve properties
Learn more in the full brochure


Preclinical Testing
Performing lab and animal testing to determine if the drug is safe enough for human testing

With one or more optimized compounds in hand, researchers turn their attention to testing them extensively to determine if they should move on to testing in humans.

Scientists carry out in vitro and in vivo tests. In vitro tests are experiments conducted in the lab, usually carried out in test tubes and beakers (“vitro” is “glass” in Latin) and in vivo studies are those in living cell cultures and animal models (“vivo” is “life” in Latin). Scientists try to understand how the drug works and what its safety profile looks like. The U.S. Food and Drug Administration (FDA) requires extremely thorough testing before the candidate drug can be studied in humans.

During this stage researchers also must work out how to make large enough quantities of the drug for clinical trials. Techniques for making a drug in the lab on a small scale do not translate easily to larger production. This is the first scale up. The drug will need to be scaled up even more if it is approved for use in the general patient population.

At the end of several years of intensive work, the discovery phase concludes. After starting with approximately 5,000 to 10,000 compounds, scientists now have winnowed the group down to between one and five molecules, “candidate drugs,” which will be studied in clinical trials

The Preclinical Testing stage also includes:
Investigational New Drug (IND) Application and Safety: Filing IND with the FDA before clinical testing can begin; ensuring safety for clinical trial volunteers through an Institutional Review Board
Learn more in the full brochure


Clinical Trials
Testing in humans to determine if the drug is safe and effective

A candidate drug must go through extensive studies in humans, and it must prove to be safe and effective before the FDA will approve it. This process involves a series of clinical trials, each with its own specific goals and requirements. Physicians carry out each trial working with patients in hospitals, offices and clinics, and coordinating closely with the sponsor company. The clinical trials process is both expensive and time-consuming, and ends more often in failure than success. From start to finish it takes an average of 6-7 years.

The Clinical Trials stage includes:
Phase 1 Clinical Trial: Performing initial human testing in a small group of healthy volunteers
Phase 2 Clinical Trial: Testing in a small group of patients
Phase 3 Clinical Trial: Testing in a large group of patients to show safety and efficacy
Learn more in the full brochure


New Drug Application (NDA) and Approval
Submitting application for approval to FDA

Once all three phases of the clinical trials are complete, the sponsoring company analyzes all of the data. If the findings demonstrate that the experimental medicine is both safe and effective, the company files a New Drug Application (NDA) — which can run 100,000 pages or more — with the FDA requesting approval to market the drug. The NDA includes all of the information from the previous years of work, as well as the proposals for manufacturing and labeling of the new medicine.

FDA experts review all the information included in the NDA to determine if it demonstrates that the medicine is safe and effective enough to be approved (see sidebar — How Does the FDA Decide to Approve a New Drug?). Following rigorous review, the FDA can either 1) approve the medicine, 2) send the company an “approvable” letter requesting more information or studies before approval can be given, or 3) deny approval.

Review of an NDA may include an evaluation by an advisory committee, an independent panel of FDA-appointed experts who consider data presented by company representatives and FDA reviewers. Committees then vote on whether the FDA should approve an application, and under what conditions. The FDA is not required to follow the recommendations of the advisory committees, but often does.


Manufacturing
Going from small-scale to large-scale manufacturing is a major undertaking. In many cases, companies must build a new manufacturing facility or reconstruct an old one because the manufacturing process is different from drug to drug. Each facility must meet strict FDA guidelines for Good Manufacturing Practices (GMP).

Making a high-quality drug compound on a large scale takes great care. Imagine trying to make a cake, for example, on a large scale — making sure the ingredients are evenly distributed in the mix, ensuring that it heats evenly. The process to manufacture most drugs is even more complicated than this. There are few, if any, other businesses that require this level of skill in manufacturing.


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innovation.org - Inside Drug Discovery