Image from medscape.com
As a retired FDA involved in the development of new drugs in the
Division of Anti-Infective Drug Products, Office of New Drug Chemistry, I
had often been asked by several of my blog readers to write a summary
and an overview of new drug development in the US. I had been postponing
it, because I thought the subject is confidential, but when I started
browsing in the WEB today, I found several articles on the subject. I
even found a Chemistry manufacturing supplement that I had approved
several years ago. The letter of approval and the chemist review was
printed in the Internet. However, the specifics of the supplement was
erased in the approval letter as well as in the chemist review. The
patent of the drug discussed had expired, so it is open to generic
companies, otherwise the chemist review and letter of approval will
never be made public. I am getting out of the subject, but let me start
on the subject right now.
New Chemical Entity (NCE) development
Broadly the process can be divided into pre-clinical and clinical work.
Pre-clinical.
New Chemical Entities (NCEs)(also known as New Molecular Entities
(NMEs)) are compounds which emerge from the process of drug discovery.
These will have promising activity against a particular biological
target thought to be important in disease; however, little will be known
about the safety, toxicity, pharmacokinetics and metabolism of this NCE
in humans. It is the function of drug development to assess all of
these parameters prior to human clinical trials. A further major
objective of drug development is to make a recommendation of the dose
and schedule to be used the first time an NCE is used in a human
clinical trial ("first-in-man" (FIM) or First Human Dose (FHD)).
In addition, drug development is required to establish the
physicochemical properties of the NCE: its chemical makeup, stability,
solubility. The process by which the chemical is made will be optimized
so that from being made at the bench on a milligram scale by a synthetic
chemist, it can be manufactured on the kilogram and then on the ton
scale. It will be further examined for its suitability to be made into
capsules, tablets, aeresol, intramuscular injectable, subcuteneous
injectable, or intravenous formulations. Together these processes are
known in preclinical development as
Chemistry, Manufacturing and Control (CMC).
Note: The CMC portion of was my primary function as the Team Chemistry Leader during my employment with FDA
Many aspects of drug development are focused on satisfying the
regulatory requirements of 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 (effects 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
(e.g. the skin if the new drug is to be delivered through the skin).
While, increasingly, these tests can be made using in vitro methods
(e.g. with isolated cells), 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.
The information gathered from this pre-clinical testing, as well as
information on CMC, and 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 clinical phase.
Clinical phase.
Clinical trials involves three steps: Phase I trials, usually in
healthy patients, 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 a large, pivotal trials
to determine safety and efficacy in sufficiently large numbers of
patients
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, as well as effects
on systems not previously monitored (fertility, reproduction, immune
system, etc.). The compound will also be tested for its capability to
cause cancer (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.
As this drug discovery process becomes more expensive it is becoming
important to look at new ways to bring forward NCEs. One approach to
improve efficiency is to recognize that there are many steps requiring
different levels of experimentation. The early phase of drug discovery
actually has components of real innovation, components of
experimentation and components that involve set routines. This model of
Innovation, Experimentation, and Commoditization ensures that new ways
to do work are adopted continually. This model also allows the
discipline to use appropriate internal and external resources for the
right work.
Costs
Studies published by diMasi et al in 2003 report an average pre-tax
cost of approximately $800 million to bring a new drug (i.e. a drug with
a new chemical entity) 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
Health Economics, including an author from the US Federal Trade
Commission, was critical of the methods used by diMasi et al but came up
with a higher estimate of ~$1.2B. 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 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. 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).
Most Americans will not be able to afford new drugs if they do not have
insurance.
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
Act20 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.Code of Federal Regulations (CFR)
Code Of Federal Regulations (CFR)21. The final regulations published
in the Federal Register22 (daily published record of proposed rules,
final rules, meeting notices, etc.) are collected in the CFR. The CFR is
divided into 50 titles that represent broad areas subject to Federal
regulations. The FDA's portion of the CFR interprets the The Federal
Food, Drug, and Cosmetic Act23 and related statutes. Section 21 of the
CFR24 contains most regulations pertaining to food and drugs.
Note: I hope you found the above posting informative. My next
posting on this subject will be on the Chemistry, Manufacturing and
Control(CMC) Requirements for IND's and NDA's. If you find this posting
either boring or interesting, let me know via comments. Thank You.
Anonymous
said...You have a very informative article, I hope the FDA does not condone
your site for writing about their business. Would you know how much the
FDA charges drug companies for testing each of their new drugs from
start to finish? This must cost them a bundle because, FDA employs a
plethora of highly educated doctors, scientists, mathematicians and
business people. Jeffrey Ray