Simplified Overview of New Drug Development in the US

David Katague working in the research laboratory, 1980

As a retired Food and Drug Administration(FDA) employee involved in the development of new drugs in the Division of Anti-Infective Drug Products, Office of New Drug Chemistry (ONDC), Center of Drugs and Evaluation Research (CDER), I had been often asked by several of my blog readers to write a simplified overview and the cost of new drug development in the US as well as the role of FDA.

I had been postponing it, because I thought the subject is confidential. However, when I started browsing the Internet, I found several articles on the subject. I even found several Chemistry Manufacturing Supplements that I had reviewed and approved several years ago.

The letters of approval and the chemist reviews were published in full, with the exception of the specifics in the supplement which were redacted in the approval letter as well as in the chemist review. The patent of the drugs discussed had expired, so it was now open to all generic companies for development. Otherwise the chemist review and the letter of approval will never be made public.

I know I am getting out of the topic, but the above information makes me feel that the subject of drug development in the US, its cost and the role of FDA is an important topic that should be of interest to all.

Drug development starts from new compounds that are man-made or synthesized in the laboratory. It may be discovered also from the extracts of plants and/or animals or even from the soil. It is also possible that new compounds that can cure cancer, Alzheimers disease and viral diseases can be found from the oceans, the tropical jungles of South America or from soils in the Philippines or in other parts of the world. These new compounds are called new chemical entity (NCE) or sometimes known as new molecular entities( NME).

In general the process of drug development can be divided into two steps: the pre-clinical(laboratory) and clinical (human) trials.

Pre-clinical (Laboratory)

The new chemical entities studied will have promising activity against a particular biological target thought to be important in the disease cure; however, little will be known about the safety, toxicity, pharmacokinetics and metabolism of this NCEs in humans.

During the pre-clinical trials all parameters of safety and toxicity of these drug candidates will be assessed and studied prior to the important and necessary human clinical trials. A major objective of this step is to make a recommendation of the proper dose and schedule to be used the first time it is used in a human clinical trial. This is known as "first-in-man" (FIM) or first human dose (FHD) trials.

In addition, drug development procedures are required to establish the physical and chemical properties of the NCE. Its chemical makeup, stability, solubility and other physical properties are studied rigorously. The process by which the chemical is made will be also optimized so that from being made at the bench on a milligram scale by a synthetic chemist, it can be manufactured on the kilogram scale in the pilot plant and then on the ton scale in the manufacturing facilities of the pharmaceutical firm.

These drug candidates will be further examined for their suitability to be made into capsules, tablets, aerosols, creams, ointments, intramuscular injectables, subcutaneous injectables, or intravenous formulations. After the active ingredient (drug substance) has been formulated into a capsules, creams, injectables, etc.., it known as the drug product. Together these processes are known in preclinical development as the Chemistry, Manufacturing and Control (CMC) procedures.

Many aspects of drug development are focused on satisfying the legal and regulatory requirements of the drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man.

It is a legal requirement that an assessment of major organ toxicity be performed, that is the effects of the drug on the heart and lungs, brain, kidney, liver and digestive system, as well as effects on other parts of the body that might be affected by the drug, for example the skin if the new drug is to be delivered through the skin.

These tests can be made using in vitro methods (e.g. with isolated cells), however many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined. Most common experimental animals are mice, rabbits and monkeys. These tests are called in vivo testing, the opposite of in vitro testing.

The information gathered from this pre-clinical testing, as well as the information on the CMC, is submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug application or IND. If the IND is approved, development moves to the human clinical phase. The reviews of INDs occupied about 10% of my time when I was still working for FDA.

Human Clinical phase

The human clinical trials involve three steps:

Phase I trials are conducted in small number of healthy patients to determine safety and dosing.

Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of sick patients.

Phase III trials are large pivotal trials to determine safety and efficacy in sufficiently large numbers of patients, preferably of all ages and to children if the drug is to be sold as a pediatric drug product. The larger the number of patients the better it is, with regards to the statistical vigor and integrity of the clinicl trials.

The process of drug development does not stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined. The drug effects on systems not previously monitored such as its effect on fertility, reproduction, and immune systems will have to be conducted. The compound will also have be tested for its capability to cause cancer commonly known as carcinogenicity testing.

If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold.

In the US, this process is called a New Drug Application or NDA. Most NCEs, however, fail during drug development, either because they have some unacceptable toxicity, or because they simply do not work in clinical trials. In some cases, a drug originally studied for a specific disease turned out to be a better cure for another indication. A good example is Viagra originally studied for hypertension. Further testing however showed it was a better cure for erectile dysfunction.

Before a drug is approved for marketing, the manufacturing facility for that drug has to pass inspection conducted rigorously by the FDA field and research inspectors sometimes accompanied by the review chemist. This insures that the production facility follows good current manufacturing practices (GCMP) and the drug product marketed has all the qualities it purports and that is safe and effective.

The approval or disapproval of the CMC portion of the INDs and NDAs was my primary responsibility as a Chemistry reviewer and later as a Chemistry Team Leader during my employment with FDA from 1990 to 2002.

Cost of new Drug Development

Studies published by DiMasi et al in 2003 report an average pre-tax cost of approximately $800 million to bring a new drug to market. A study published in 2006 estimates that costs vary from around $500 million to $2 billion depending on the therapy or the developing firm.

A study published in 2010 in the Journal of Health Economics, including an author from the US Federal Trade Commission, was critical of the methods used by DiMasi but came up with a higher estimate of about $1.2 billion. Critic Marcia Angell, M.D., a former editor of the New England Journal of Medicine, has called that number grossly inflated, and estimates that the total cost is closer to $100 million. A 2011 study also critical of the DiMasi methods, puts average costs at $55 million.

Success rate

Candidates for a new drug to treat a disease might theoretically include from 5,000 to 10,000 chemical compounds. On average about 250 of these will show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these will qualify for tests on humans. Of the ten only two will finally be approved for marketing.

Drugs with high therapeutic importance such as cancer and anti-viral drugs are scheduled with the highest priority and are usually approved in a much shorter times than the standard drug candidates.

A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that start phase I trials are eventually approved for marketing. Now you know why the drugs you purchased in the pharmacy is very expensive ( except the generic drugs). I am sure that most Americans will not be able to afford new drugs if they do not have medical insurance.

FDA Role and Mission

The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency to protect the consumer's health, safety, and pocketbook. The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the U.S. With numerous amendments it is the most extensive law of its kind in the world.

The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under sanitary conditions; that drugs and devices are safe and effective for their intended uses; that cosmetics are safe and made from appropriate ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.

Conclusion

The new drug approval process in the US is considered to be the most strict in the world. On the average, it costs a company around $360 million to get one new medicine from the laboratory to the drug store, according to a February 1993 report by the Congressional Office of Technology Assessment. It takes between 10 to 12 years for an experimental drug to advance from the laboratory to the medicine cabinet. However, drugs with high therapeutic value are given the highest priority in scheduling and are normally approved much faster than the standard drugs. Only 5 in 5,000 compounds that enter preclinical testing make it to human testing. Only one of these five tested in people is finally approved for marketing. This rigorous process assures all consumers that the drug approved by FDA is not only safe but also effective and of good quality.

FDA's role does not end after approval. Post marketing activities are undergoing, such as monitoring of adverse reaction reports, and most of all the post approval changes in the manufacturing, chemistry and control procedures that are submitted to the agency for review.

Among the post approval changes that FDA has to approve are changes in the synthesis of the drug substance, changes in the formulation of the drug product, a change in location of the manufacturing facility as well as changes in the analytical procedure for testing the drug substance and/or drug product.

Guidances published by FDA informed the pharmaceutical firms the requirements and data needed to facilitate the approval of these changes. These submissions are called manufacturing and control supplements. The approval of these supplements occupied about 50% of my time when I was still working for FDA.

I hope you found the above article informative and now have a clear idea why new drugs are very expensive in the US.

Rederence: Wikipedia