DRUG DISCOVERY FOR THE NONEXPERT

Ben Levinson
1 hour ago
12 min read

by Benjamin Levinson, MD

Drug discovery is a long and complicated process that entails the search for, and development of, an agent (chemical or biological) that will offer treatment of a human malady. A drug company invests extensive time and resources into this search. As one professional has said, ‘We find a chemical or biological substance and then wrap in scientific data to treat a disease of interest.’ This process of discovery begins in the laboratory and only after a successive series of studies of potential effectiveness and safety in animal models is the agent available for human evaluation. It then is studied in various so-called ‘phases’ until enough information is gained to meet the regulations, as set by the government, for widespread human use.

INTRODUCTION

It is the purpose of this discussion to offer insight to those people unfamiliar with the process of drug discovery. By way of history, prior to the modern approach to drug discovery, therapeutic advancements were based on observation of what ‘worked.’ For example, Edward Jenner overheard two milkmaids mention to each other that after they had cowpox, they did not contract smallpox after exposure to it. This gave him the idea to expose people to cowpox in the hope of preventing smallpox. It worked and the era of vaccines was born (1). Then there is the story of Ignatz Semmelweis who did the first controlled clinical trial to prevent childbed or puerperal fever. He had one group of medical students wash their hands in carbolic acid before examining pregnant women and another examined them without washing hands. He noted the incidence of the fever was significantly reduced in the group that washed their hands. This began the age of antiseptic use (2). Finally, in Africa, it was found that ingestion of the bark of the cinchona tree would help treat malaria (3).

Unfortunately, there was a terrible downside to this approach. Individuals who had no scientific background or who were simply unscrupulous would make a claim about the value of a particular substance and try to sell it to unwitting individuals who were suffering. This so-called ‘snake oil’ could contain anything as there were no governmental controls over this. With the advent of the Pure Food and Drug Act, it was mandated that whatever was stated on the label of the treatment has to actually be in the container in the same amount. Ultimately this was expanded to include the mandate that the label had to describe the dose to be used for the aliment and prove it was effective for that issue. These laws together created a scientific basis for drug development that offers protection for the public.

Modern drug discovery is not a matter of what ‘works.’ The primary goal is to find the way in which a disease develops in the body and then seek a means to reduce or eliminate the malady. It is a complicated process that involves experiments and observations of a disease to create an animal model of how it affects the body. Then, consideration is given on how to approach the problem in a manner that ultimately benefits human health.

Pharmaceutical companies have to obtain finances in order to meet the standards set by the government. The process entails identification of a therapeutic, synthesis of it in quantities that can be used for testing, cellular and animal testing, and finally human trials. Thus, it is a very costly and time-consuming process. It is important to note that many potential drug candidates never make it through the rigid testing requirements for human use.

IDENTIFICATION OF A THERAPUETIC

The principle of drug discovery rests on the fact that there is some receptor in the body that can cause a disease. The goal is to find a molecule or substance that can interact with this receptor, which is typically a protein, so as to affect it in a manner that alters the disease course in the direction of returning to health. This is called the ‘lock and key model’ of drug research where the receptor is the ‘lock,’ and the therapeutic molecule is the ‘key.’

Imagine sitting in front of a computer screen and looking at the structure of various proteins to determine places that could be marked for intervention to change how a protein functions in the body. This is a far cry from the cowpox days of Edward Jenner, yet this is how many drugs are discovered. The people who do this work in a field called bioinformatics. They are usually biochemists, medicinal chemists or molecular biologists or a combination of these various specialists.

Of course, the above approach is not the only means to discover new therapeutics. Observation still plays a significant role, but only as a beginning to a lengthy process of evaluation. For example, the drug captopril began as an observation that snake venom from a particular species would cause a drop in blood pressure. After careful refinement of the venom, a protein was isolated that could reduce blood pressure. This protein was then synthesized and studied. It was found that it could inhibit the enzyme that causes an increase in blood pressure. This enzyme was called angiotensin-converting enzyme. The protein was then purified and given to patients who had high blood pressure intravenously. Remarkable success was achieved. But the story did not end there. Through sophisticated chemistry techniques the protein was studied, and an oral form was developed. This created the drug now known as captopril and birthed the era of angiotensin-converting enzyme inhibitors or ACE inhibitors for treatment of high blood pressure, which is also known clinically as hypertension. Millions have benefitted from its use (4).

SYNTHESIS

During a basic organic chemistry course in college, one quickly learns the difficulty in synthesizing a molecule. Yet, there are talented chemists who take on this challenge on a daily basis.

When a potential molecule is identified that can interact with what is known as a ‘target’ receptor, several versions are synthesized to determine the one with the structure that will be of most benefit. This entails a screening process where the molecule or molecules are tested in various animal models of the disease to determine which one is most successful. Sometimes there are several which are similar in effect. If there is more than one, then it becomes a matter of deciding which is the easiest and most cost-effective to synthesize on a large scale.

But first, the potential drug candidate must be patented in what is called a composition of matter patent that allows the company exclusive rights to develop and manufacture the drug for a specific period of time, usually about 17 years after the patent application is approved. Of course this does not mean the drug is approved. No, that is a lengthy process which has just begun.

NON-CLINICAL OR ANIMAL TESTING

Many animal rights groups have great concern about the use of animals in the testing process. However, this must be weighed against the value of such testing to confirm the effect of the drug in a disease and its safety before human use. This is a regulatory requirement of the government that cannot be circumvented if a drug is to be administered for human use.

Animal testing actually begins on cells to determine if the potential drug candidate will cause any genetic damage. After this, the drug is tested in animal models of the disease to confirm its efficacy. Then, at least two animal models are evaluated to determine safety and toxicity with increasing doses. The goal is to reach a safe and effective dose that could be given to humans based on calculations that compare animal and human biology. Often blood levels are obtained so that calculations can be made for potential human use.

In many cases the disease of interest may not have a good model in animals. For example, in human spinal cord injury, animals will respond differently to treatment than humans because of the unique structure of the human neurological spinal cord. There are animal approximations that are acceptable to government regulators. As long as the drug is safe at calculated doses, the government will usually let the drug proceed into human studies, particularly if there is an unmet medical need for the drug.

At this point, if the company has a drug candidate that it believes is safe and effective in a disease model, it will meet with the government regulators. In the US this is the Food and Drug Administration (FDA) in what is termed a pre-IND meeting to provide data and discuss plans for human study. The IND is called Investigational New Drug application. The FDA will then assign a special number for the IND called a pre-IND number and designate members of its organization to work with and advise the company as well as maintain regulatory oversight for the further development of the drug for human use.

HUMAN EVALUATION

It is important to recognize that at this point, much time and effort have been expended, and a great deal of money has been spent without any return thus far. The previous process has taken at least a couple of years and has whittled away some of the patent exclusivity that has been granted. Yet, the drug candidate has only begun its long journey to the clinic which may take another five to seven years.

PHASES OF CLINICAL DEVELOPMENT IN HUMANS

The development of a new drug candidate occurs in Phases simply named Phase1,2, and 3. Phase 1 is typically reserved for evaluation in healthy volunteers, although in the more potentially toxic drugs, such as drugs used in cancer, this phase may be carried out in patients.

PHASE 1

The primary goal of this aspect of the program is to determine how the body affects the drug, this is in contrast to later phases where the primary interest is in how the drug affects the body, particularly the disease of interest.

When a drug is administered it undergoes absorption, distribution, metabolism, and excretion or ADME. This is typically done in healthy volunteers. In the very first-in-human study, the company will usually choose a starting dose that is one tenth to one one-hundredth the dose that did not cause any adverse events in animals, commonly called the no observable adverse event level or NOAEL dose. Doses will then be doubled as long as there are no safety concerns until a dose level is reached that is above that which is predicted to be efficacious based on animal studies.

To perform this study, and indeed, all future studies, a document is written called a ‘protocol’ which carefully defines how the drug is administered, the doses to be used, and the clinical, laboratory and other study data that need to be collected. A protocol is typically sent to a hospital or facility that can perform the evaluation requested on the desired population. A licensed physician or appropriate health care provider must then sign the protocol indicating acceptance of the willingness to perform the study. This protocol must be approved by a board that protects human subjects and is independent of the company. This is called the Institutional Review Board or IRB. In addition, a company must submit the protocol to the FDA and wait 30 days before it can institute the study- in case the FDA has any concerns.

Data are then entered onto a form called a Case Report Form which serves as the repository for all data related to each patient. These data are then sent to a central computer database where statistical analysis of safety is performed. In addition, in Phase 1 studies the ADME evaluations are carried out on blood and urine (and sometimes fecal) concentration of the drug candidate. The ADME evaluations fall under the heading of Pharmacokinetics, which is a sub-discipline of pharmacology.

In addition, Phase 1 studies are performed to determine ADME in various populations who might take the drug such as people with various degrees or renal or liver impairment. Studies like this are done to determine if food or age affects ADME. And, there are studies to determine if a particular ethnic group has an ADME that is different than the one tested in healthy volunteers. These studies are divided into single dose and multiple dose evaluations. The multiple dose studies are designed to determine blood levels in a person who must use the drug chronically to determine ADME and safety.

The ultimate goal is to determine if the studies in the Phase 1 program provide the blood level estimates from the animal models to treat the disease of interest without any serious safety concerns. Most of the time there are two or more doses that fit these criteria.

Note that at this point at a few million dollars have been spent, scientists and physicians from various disciplines such as analytical chemistry, chemical synthesis, medical safety have evaluated the data to determine if the drug candidate may be advanced to the next phase.

PHASE 2

This is the part of the program where the ‘proof of the pudding is in the tasting.’ Here the drug doses that have been selected that will be studied in the population of interest. Now the company has to find physicians or other qualified health care providers who have the patients. This is a time-consuming process of finding clinical investigators who work at sites where the patients can be studied. It costs the company money to finance these sites and assure the sites have all the requirements needed to do the study. For example, a pharmacy or other place to house the investigational drug, a clinical area to evaluate the patient, laboratory facilities to process blood samples of interest, special radiology equipment if needed, etc.

The qualification of the site and ongoing monitoring of the site to assure it meets the standards of FDA regulations as well as the operating procedures of the company falls onto a specialized group of people called Clinical Research Associates. These people are company employees who visit the site at regular intervals and assure data is collected properly and recorded on the care report form.

The company then creates a clinical protocol that is reviewed by a committee of specialists in the field to assure that the data will reveal if the drug candidate is efficacious and safe or not. This protocol has to be approved by the Human Subjects Committee, the IRB, for each site. This can take months in some cases. The FDA likes to see a dose range in this study to determine the starting dose that provides the optimum effect with minimum possibility of safety side effects.

If the data shows efficacy with an acceptable safety profile, then calculations are made so that the final phase can be implemented. At this point an End-Of-Phase 2 meeting will be held with the FDA to provide the data obtained thus far and provide plans for how the drug will be studied in a large trial or trial. These large trials can cost many millions of dollars and span many countries.

PHASE 3

One of the key things that must be done is that the drug candidate must be manufactured in massive quantities and it must or should be exactly or significantly similar to the drug that will be marketed by the company. Such syntheses require a large-scale which is done by people in the area of chemical process development. The drug must be stable for at least two years.

The company is then required to create two protocols. There are many different possible designs depending on the disease of study. However, the goal is the same: to have two studies that show a statistically significant difference between the drug candidate and the comparator. This statistical difference must be such that when the two studies are completed, there is only a one in four-hundred possibility that the result occurred by random chance alone. These studies are exceptionally large and data from safety is carefully reviewed.

Now the company will meet with the FDA in a pre-New Drug Application (NDA) meeting to discuss how the application will be submitted which will include all reports, summaries, manufacturing data, etc.

THE NDA

Finally, the company submits the NDA. The review process can take serval months. The agency will send representatives to the company and the various sites to verify the data that has been submitted. Once this is done, the FDA will review the proposed label the company desires for the drug and determine if the data submitted supports the proposed label. This is typically a label negotiation that can also take several months. After this, the company will receive a letter stating the drug may be marketed for patient use.

At this point, the company can see a return on its investment. However, the above description is idealized and assumes a drug candidate will meet all the requirements. Sadly, this happens only one in four times on average. Thus, the expense for these failed programs has to be calculated in the overall drug cost of the medications that make it to market. By the time a drug reaches the market, about seven to ten years of patent life have been used up so that only about seven to ten years of market exclusivity are available before another company can produce a generic version which is far less expensive. The other company is able to piggy-back on the efficacy and safety requirements that were met by originator company provided a couple of smaller clinical studies are performed to ensure the same blood levels are obtained as those of the originator company’s product.

SUMMARY

As can be seen, drug development in the pharmaceutical industry is a long, arduous, and expensive process with discovery, non-clinical and clinical testing. The result is a new medication that can be included in the medical armamentarium.

REFERENCES

1. Jenner, Edward. Vaccination Against Smallpox (Great Minds Series)

ISBN 10: 1573920649 / ISBN 13: 9781573920643

Published by Prometheus (edition Reprint), 1996

2. Childbed Fever: A Scientific Biography of Ignaz Semmelweis - Hardcover

Carter, K. Codell; Carter, Barbara R.

ISBN 10: 1138520349 ISBN 13: 9781138520349

Publisher: Routledge, 2017

3. Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D'Alessandro U. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011 May 24;10:144.

4. Cushman DW, Ondetti MA. History of the design of captopril and related inhibitors of angiotensin converting enzyme. Hypertension 1991;17;589–92.