The Accelerating World of Drug Discovery and Commercialization

For millennia, new drugs appeared only occasionally, and often as a matter of luck or serendipity. Then, beginning in the 19th century, researchers began to perform systematic scientific research, but progress remained slow.

However, since the emergence of widespread information technology and molecular genetics in the 1970s, the whole field has exploded. Now, a wide range of new techniques is turbo-charging that process.

There are three reasons why this is now increasingly important:

- First, globalization has steadily increased the vulnerability of the world’s population to pandemics, airborne pathogens, and viruses.

- Second, the over-prescription of antibiotics has increased the resistance of many so-called “superbugs” to existing drugs, leading to the urgent need for the development of new, more powerful antibiotics.

- Third, the demand for customized drugs and treatment therapies is rising rapidly as the personalized medicine trend accelerates.

Let’s examine the latest breakthrough technologies and innovative business models that are promising better health for patients?and greater wealth for investors.

Until recently, pharmaceutical firms frequently relied on universities to carry out the clinical trials on human patients that the FDA requires before it approves a new drug. But academic researchers are notorious for taking their time to design, conduct, and publish the results of the trials.

So companies have increasingly used a relatively new entity called a contract research organization (CRO). CROs are private companies that not only complete clinical trials faster and at lower costs than academic researchers; they are also more open to using new technologies.1 And because they are not restricted to a specific country, CROs can test new drugs on patients in other countries, where there are fewer legal restrictions on testing, which speeds up the drug development process.

In fact, foreign research subjects account for a rapidly growing share of the participants in clinical drug trials. This is happening because Americans already take so many drugs that it is becoming more difficult to find patients who haven’t already taken other drugs that could distort the results of the research.2

Furthermore, by expanding the pool of potential test subjects, pharmaceutical companies are able to avoid delays in finding enough subjects for a study in the U.S.

CROs and foreign research subjects are the equivalent of the outsourcing and off shoring trends that have lowered costs and increased productivity in countless industries. Just as those forms of outsourcing help manufacturers avoid regulatory burdens, off-shoring clinical trials permit pharmaceutical companies to avoid delays imposed by U.S. regulators.

Another business best practice that the pharmaceutical industry is adapting is crowdsourcing. According to a report in the Journal of General Internal Medicine, a research team from the Perelman School of Medicine at the University of Pennsylvania has run experiments that suggest that the combined efforts of ordinary citizens across the world could speed up healthcare research, while improving the quality of that research and slashing the cost.3

As the study’s senior author, Raina Merchant, MD, an assistant professor of Emergency Medicine at Penn, explains, “While the concept of ‘citizen science’ has been in existence for more than a century and crowdsourcing has been used in science for at least a decade, it has been utilized primarily by non-medical fields and little is known about its potential in health research.”

Merchant’s team successfully used crowdsourcing in a recent study to locate and catalog the locations of life-saving automated external defibrillators throughout Philadelphia. The study led to the identification of more than 1,400 AEDs in public places. The team plans to replicate the study in other major cities across the U.S.

For a series of 21 other studies, the team used crowdsourcing to perform a literature search for health and medical research articles using two free Web sites: Yahoo! Answers and Quora. More than 136,000 people participated in such activities as tracking H1N1 influenza outbreaks in near real time, or classifying different types of polyps in the colon.

The Penn team isn’t alone in touting the potential benefits of crowdsourced medical research. A team of researchers from Harvard Medical School, Harvard Business School, and London Business School reached the same conclusion.

As reported in the scientific journal Nature Biotechnology, the researchers demonstrated that a crowdsourcing platform pioneered in the commercial sector can solve a complex biological problem more quickly than conventional approaches?and at a fraction of the cost.4

Partnering with TopCoder, a crowdsourcing platform with a global community of 450,000 algorithm specialists and software developers, the researchers identified a program that can analyze vast amounts of data, in this case from the genes and gene mutations that build antibodies and T-cell receptors.

Since the immune system takes a limited number of genes and recombines them to fight a seemingly infinite number of invaders, predicting these genetic configurations has proven a massive challenge, with few good solutions. The program identified through this crowdsourcing experiment succeeded with an unprecedented level of accuracy and remarkable speed.

The researchers offered TopCoder what they thought would be an impossible goal: to develop a predictive algorithm that was an order of magnitude better than the NIH’s standard algorithm, known as BLAST, and that could scale up to the mounting data demands.

In only two weeks, viable solutions came from 122 different individuals. Among these, 16 were more accurate?and up to 1,000 times faster?than BLAST.

According to the team, “Not only did the best entries achieve truly superior performance, but also this kind of crowdsourcing has the potential to be a general solution for a whole class of problems in biology. No single university or institution has the bandwidth and resources to achieve this kind of result so quickly and efficiently.”

At the same time that these innovative business practices are increasing the productivity and efficiency of medical research, a wave of new technologies is leading to the faster development of better drugs.

For example, medicines that are personally tailored to your DNA are becoming a reality, thanks to the work of U.S. and Chinese scientists who developed statistical models to predict which drug is best for a specific individual with a specific disease.

The current method of prescribing medication now sometimes includes a pharmacogenomic approach, but researchers recognize the limitation of this approach in predicting a response to a particular drug and dosage combination.

Pharmacogenomics uses a person’s genes to explain the difference between how one person responds to a drug compared to another. The new research, reported in Advanced Drug Delivery Reviews, takes this field one step further by also including information about how the body processes a drug and how the drug acts in the body.5

A team led by Rongling Wu, director of the Center for Statistical Genetics at the Penn State College of Medicine, looked at pharmacokinetics, which influences the concentration of a drug reaching its target, and pharmacodynamics, which determines the drug response.

The researchers created a statistical analysis framework of differential equations that they expect will help doctors and pharmacists, by simulating such variables as the interactions within a patient’s body between proteins and DNA.

The framework characterizes a drug’s absorption, distribution, and elimination properties, yielding information on pharmacological targets, physiological pathways, and, ultimately, disease systems in patients, resulting in predictions of treatment effectiveness. The information is combined with information about the patient’s genes, proteins, and metabolism.

This will enable doctors to predict how each patient will react to a drug before it is prescribed, enabling individuals to receive just the right dosage of the most effective drug, or the optimal combination of drugs, to treat a medical condition.

Other advances are improving the delivery of drugs to the precise cells in the body where they are needed.

For example, scientists have developed a new class of drugs called siRNAs, (for small interfering RNAs), that can target a specific gene that causes a disease. The challenge so far has been how to deliver the knock-out blow to cells in the liver, because the liver reacts to the siRNA drug by coating it in globules called endosomes that prevent the drug from reaching the cells’ DNA to exert its gene silencing effect.

Now, according to research published in the journal Nucleic Acid Therapeutics, a team led by So C. Wong from Arrowhead Madison Inc. has invented an innovative new delivery technique that is 500 times more effective.6

The researchers co-injected a polymer with the drug that also targets the liver and, once inside liver cells, breaks open the endosomes, releasing the siRNA drug.

Another breakthrough is a new technology that allows researchers to prove that the drug is being delivered where it is needed, and only where it is needed. Currently, researchers can only hypothesize that a drug has reached its intended target, or conduct numerous studies using control groups that haven’t received the drug.

Demonstrating that a new drug actually makes an impact on the intended target in the body without affecting the surrounding tissue is essential to winning approval for the drug to be marketed.

Now, several new methods have been developed to make it easier to produce such evidence.

One new technique, conceived at Lund University in Sweden, involves a special type of mass spectrometry that can be used on drugs without the need to add any radioactive labeling that could change the behavior of the drug. With this method, researchers Gyorgy Marko-Varga and Thomas Fehniger have managed to create a molecular image of the drug in the tissue.

As explained in the journal Analytical Chemistry, the tissue they examined came from biopsies from the lungs of patients with lung cancer and lung disease who inhaled a drug to dilate the airways. The examination showed the precise spatial distribution of the drug within the tissue.7

Using this method, scientists will be able to develop safer and more effective drug candidates, and bring them to market faster. The researchers also believe it could be used to help doctors select the right drug for a specific patient.

The second method for showing if drugs have reached the intended target was recently invented by scientists at the Nanyang Technological University (NTU). The new approach, called CETSA (for Cellular Thermal Shift Assay), will help scientists avoid most of the usual trial-and-error guesswork that plagues drug development.

As reported in Science magazine, CETSA’s inventor, Professor Par Nordlund from NTU’s School of Biological Sciences, claims that his discovery overcomes two critical challenges: how to identify the right proteins to target with a drug, and how to design drug molecules that are able to seek out and bind to these proteins efficiently.8

According to Nordlund, when drugs react with target proteins in a cell, the proteins are able to withstand higher temperature before turning solid. An example of protein precipitation is when liquid egg white, which is protein, turns solid when it is heated.

Nordlund explains, “By heating protein samples and finding out which proteins are ‘cooked’ and which are left ‘uncooked’ due to being more heat-resistant, we are able to know if the drugs had reached their target cells and if it had caused the desired binding to the proteins, blocking its functions.”

He adds, “With CETSA, costly and challenging drug development cycles can potentially be made more efficient, as the method can be used as a stringent control step at many phases of the process.”

Finally, other advances are enabling scientists to assemble potential drug compounds quickly. Drug molecules interact with their targets, such as proteins or enzymes, by attaching to them in a way that neutralizes the target’s undesirable effects in the body. This is sometimes called the “lock-and-key” method.

According to Science magazine, a team of scientists at Yale University has demonstrated a new approach that offers scientists far greater control over the three-dimensional structure of a key class of molecular compounds, making it easier to fashion drug molecules that fit their targets in the right way.9

Jonathan Ellman, the Yale chemist who led the experiment, explains, “Now we’ve got a lot more control over the shape and orientation of this class of drug compounds, and this essentially gives us greater flexibility in creating effective drugs.”

Ellman’s research focused on piperidines, a class of organic compounds widely found in pharmaceuticals, including quinine, morphine, oxycodone, Plavix, Cialis, and Aricept. Piperidines are the scaffolds upon which parts of the drug molecule can be displayed for binding to a drug’s targets.

Ellman’s team demonstrated a way to generate different piperidine derivatives by varying acid strength. In this way, it will be easy to make new piperidines easily, potentially expanding this important class of drugs to treat many medical conditions more effectively.

Ellman is publishing the research without patent constraints to permit drug developers to use it immediately to turn his team’s discovery into new drugs.

Based on this trend, the Trends editors offer the following forecasts:

First, by 2020, researchers will learn to identify the best drugs for most patients before treatment, which will reduce healthcare costs and improve patient outcomes.

Personalized medicine will enable doctors to prescribe the optimum treatment for each patient based on his or her genetic profile and individual reactions to various drugs. This will eliminate the costly and wasteful “trial and error” approach to prescribing drugs, which will allow patients to avoid the side effects and adverse reactions to receiving the wrong drugs, as well as preventing suffering while waiting for an effective drug to start working.

Second, crowdsourcing will increasingly be used to speed up healthcare research while reducing costs.

Some people might be skeptical that nonscientists will be adept at collecting data, but previous studies have shown that crowdsourced data can be quite accurate. According to the Perelman School of Medicine study’s first author, Benjamin Ranard, “Studies we reviewed showed that the crowd can be very successful, such as solving novel complex protein structure problems or identifying malaria-infected red blood cells with a similar accuracy as a medical professional.”10 Ranard and his colleagues recommend that other medical researchers involve crowdsourcing when their studies require problem solving, data processing, surveillance or monitoring, and surveying.

Third, by 2015, new IT-driven drug discovery methods will dramatically improve the productivity of pharmaceutical research.

In addition to the cutting-edge methods highlighted earlier, consider this startling breakthrough: A new computer program rapidly analyzes the complicated shapes of proteins and identifies how they might be “shape-shifted” by drugs. Conventional drug discovery is extremely expensive, time-consuming, and often heavily reliant on “lottery techniques” to identify useful drugs by chance. Drugs that act by shape-shifting work in a much smarter way that closely mimics natural mechanisms for control. The human body has an intricate set of mechanisms that regulate many of our critical functions by simply changing protein shape. In simple terms, these “shape-shifter” mechanisms allow the proteins to modulate their biological activity by changing their surface character. The new technology helps discovery of drugs that can carefully adjust these biological molecules. With this technology, a firm called Serometrix expects to reduce the number of early trial compounds from millions to hundreds, potentially shaving years and tens of millions of dollars off the discovery-development program.

A second example comes from Vanderbilt University, where biochemists have discovered that the process bacteria undergo when they become drug-resistant can act as a powerful tool for drug discovery.11 Bacteria have traditionally been the source of important drugs such as antibiotics and anti-cancer agents. Researchers looking for new bacterially synthesized drugs have long known that bacterial genomes contain a large number of “silent genes” that contain the instructions for making drug-like compounds. But, until now, scientists have found it is very difficult to find ways to turn on the production of these compounds, known as secondary metabolites. While investigating how bacteria develop drug resistance, Vanderbilt biochemists Brian Bachmann and John McLean discovered that strains of antibiotic-resistant bacteria express hundreds of compounds not produced by their progenitors, many of which are potential secondary metabolites. One of the daunting challenges is to rapidly inventory the tens to hundreds of thousands of molecules the bacteria construct to live, and then to read this inventory to understand how the bacteria compensate for their changing circumstances. The team developed strategies that allow it to automatically identify and compare the relative uniqueness and the relative abundance of tens of thousands of molecules from which a small set of novel compounds were discovered.

References List :
1. Financial Sense, July 7, 2011, “Feds Force State & Local Government Insolvency,” by Daniel Amerman, CFA. ⓒ 2011 by Financial Sense. All rights reserved. http://www.financialsense.com/contributors/daniel-amerman/2011/07/07/feds-force-state-and-local-government-insolvency2. Ibid.3. Union Watch, October 26, 2012, "Illinois State Government Faces Insolvency," by Mike Shedlock. ⓒ 2012 by Union Watch. All rights reserved. http://unionwatch.org/illinois-state-government-faces-insolvency/4. The PJ Tatler, June 29, 2013, “Moody’s: True Unfunded Liability in Illinois Pension Fund Is 65% Higher than the State Says,” by Rick Moran. ⓒ 2013 by PJ Media. All rights reserved. http://pjmedia.com/tatler/2013/06/29/moodystrue-unfunded-liability-in-illinois-pension-fund-is-65-higher-than-the-state-says/5. Union Watch, October 26, 2012, "Illinois State Government Faces Insolvency," by Mike Shedlock. ⓒ 2012 by Union Watch. All rights reserved. http://unionwatch.org/illinois-state-government-faces-insolvency/6. Ibid.7. Institute for Public Accuracy, May 31, 2013, “Social Security Has ‘A Large and Growing Surplus’,” by Nancy Altman. ⓒ 2013 by the Institute for Public Accuracy. All rights reserved. http://www.accuracy.org/release/social-security-has-a-large-and-growing-surplus/8. Project Syndicate, May 30, 2013, “America’s Misplaced Deficit Complacency,” by Martin Feldstein. ⓒ 2013 by Project Syndicate. All rights reserved. http://www.project-syndicate.org/commentary/america-s-misplaced-deficit-complacency-by-martin-feldstein9. National Bureau of Economic Research, July 2013, “Off-Balance-Sheet Federal Liabilities,” by James D. Hamilton. ⓒ 2013 by James D. Hamilton. All rights reserved. http://dss.ucsd.edu/~jhamilto/Cato_paper.pdf