BMS 113 · Common Core (Tronc commun)Section 2.5 · Sources of drugs
Section 9 of 31
Developing a new drug
Describe preclinical and clinical testing, and explain why drug development is long, costly and tightly regulated.
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Why this matters
Without this, you cannot explain why a promising molecule takes years to reach a patient or why a licensed drug can still be withdrawn. The phases also tell you what kind of evidence stands behind a treatment you prescribe. This is the bridge from sources and synthesis in Units 2.1 to 2.4 to naming and safe use in Unit 2.6.
What you need to know first
You should already know that a medicine has an active ingredient and a dose, and that animal studies come before any use in people. Unit 1.4 explains the right dose, and Unit 2.1 introduced standardisation and batch control.
Words to know (6)
Preclinical testing
Testing a candidate medicine on animals or on living cells outside a body, before any testing in people. Acute toxicity and teratogenicity are checked during preclinical testing.
Clinical trial
A study of a medicine in human volunteers, run in four successive phases. Phase I is the first clinical trial of a candidate in human beings.
Investigational new drug
A candidate substance that is still being studied and has not yet been approved for sale. Thousands of investigational new drugs are evaluated before one reaches the market.
New chemical entity
An active substance that has never before been approved for marketing. A first-in-class molecule is a new chemical entity when it is submitted for approval.
Pharmacovigilance
The continuous monitoring of a marketed medicine for efficacy and toxicity, also called Phase IV. Reports from practitioners feed pharmacovigilance after a drug is sold.
Patent
A temporary right to be the only producer and seller of a drug, granted so the manufacturer can recover development costs. The patent lets one company market the drug under its trade name for about seven years.
One idea at a timeIdea 1 / 7
In one sentence Every new medicine starts as an investigational new drug, and about one in a thousand new chemical entities ever reaches preclinical testing.
Every new medicine begins as an investigational new drug
Scientists all over the world are in a continuous effort to develop new medicines to combat new diseases or to improve existing therapies for old ones. The synthesis and evaluation of thousands of investigational new drugs, or INDs, is usually necessary before new drugs are introduced on the market. The development of new drugs and drug therapies is a tedious and resource-demanding process that may take seven to fifteen years or more. When the candidate is a substance never before approved, it is called a new chemical entity, or NCE. About one in a thousand new chemical entities reaches the preclinical stage at all, which shows how much work is set aside before any testing in humans begins.
For example
A laboratory may prepare and screen hundreds of related molecules in a year; only a handful become investigational new drugs, and most of those will still fail.
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What fraction of new chemical entities reaches the preclinical stage?
Show the answer
About one in a thousand, which is why most laboratory work never becomes a medicine for patients.
Read detailed explanations
Why Phase I uses healthy volunteers and Phase II uses patients
The design of the first two phases follows directly from their questions. Phase I asks what the human body does to the drug and how much can be tolerated, so it needs people who are not ill: a patient’s disease, other medicines and altered organ function would make it impossible to tell whether a symptom came from the drug or from the illness. Phase I is therefore small, conducted in one centre, and uses 20 to 80 healthy young adult volunteers, usually males; the goal is the tolerable dose together with early evidence on safety and efficacy. Phase II asks a different question: does the drug actually work in the disease it is meant to treat, and at what dose? That question can only be answered in patients, so Phase II uses 100 to 500 adult volunteer patients, usually at several centres, and determines safety, efficacy and the recommended dose. This is why only about 33% of molecules pass Phase II: a dose can be perfectly tolerable in healthy volunteers and still fail to help patients. Reading the phases as a sequence of questions makes their numbers and their order logical rather than arbitrary.
Attrition: the arithmetic that makes drugs expensive
Two numbers explain the economics of drug development. About one in a thousand new chemical entities reaches the preclinical stage, and only about 33% of new molecules pass Phase II. Each failure consumes years of work, animal studies, laboratory time and clinical organisation, and the cost of all the failures must be recovered from the few products that succeed. This is why the process takes seven to fifteen years or more and why it is described as resource-demanding, and it is also why a successful manufacturer is granted a patent — about seven years of sole production and marketing under its trade name — to recover those costs and make a profit before others may produce the drug. Understanding attrition also explains a common public misunderstanding: the price of a new medicine reflects not only the cost of the one drug that reached the market, but the cost of all the candidates that did not. It also explains why research priorities tend to follow diseases that affect large, paying markets, and why the barriers described in developing countries — small budgets, weak technology and scarce trained multidisciplinary staff — are so difficult to overcome.
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From molecule to market
The path from thousands of candidate molecules through pre-clinical and clinical testing to licence, marketing, patent expiry and post-marketing surveillance.
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01 / 9Candidate new chemical entities
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Candidate new chemical entities
A new chemical entity (NCE) is an active ingredient that has not yet been approved for marketing. Thousands of candidate molecules are synthesised and screened for every one that eventually reaches the market, and most are abandoned before any animal is treated.
Schematic timeline; not to scale. The figures are the ranges given in the lecture notes, real programmes vary, and the FDA is given as the example regulator.
Key points to remember
✓Development takes seven to fifteen years or more, and about one in a thousand new chemical entities reaches preclinical testing.
✓Preclinical testing in animals and in vitro must show a candidate is effective and safe enough before human testing.
✓Phases I to III move from a few healthy volunteers to patients and then to thousands of patients.
✓Phase IV, or pharmacovigilance, watches the marketed drug and can lead to withdrawal.
✓The patent rewards the risk of development; developing countries also face economic, technological and staffing barriers.
Go deeper
Worked example
Following one candidate through the pipeline. A new chemical entity lowers blood pressure in rats. You are asked to describe, phase by phase, everything that must happen before it can be prescribed to patients in a clinic, and what each step adds to the evidence.
Preclinical testing: test on animals and in-vitro systems and collect pharmacokinetic, pharmacodynamic, acute toxicity, mutagenicity, carcinogenicity and teratogenicity data at various doses. Remember that only about one in a thousand NCEs reaches this stage.
FDA review of the investigational new drug: the agency decides whether the animal evidence is good enough to permit testing in human beings.
Phase I, the drug tolerance test: first exposure in humans, 20 to 80 healthy young adult volunteers, usually males, usually one centre; find the tolerable dose and determine safety and efficacy. Very few candidates pass.
Phase II, the dose and therapeutic effect test: 100 to 500 adult volunteer patients in multiple centres; establish safety, efficacy and the recommended dose. Only about 33% pass.
Phase III: 1000 to 3000 volunteer patients in multiple centres; the pharmacological profile is established and the candidate is licensed for marketing if it is safe, efficacious and potent, otherwise rejected.
Phase IV, post-marketing surveillance: the drug is continuously monitored, reports from practitioners are reviewed by a medicines review committee, and renewal or cancellation of the licence depends on that review.
Each phase answers a different question and removes more candidates. Approval is a judgement on the evidence available at a point in time, not a guarantee of safety; Phase IV continues the assessment for as long as the drug is marketed.
Common misconception
Many beginners think the four clinical phases describe four doses or four diseases. They are four successive stages of evidence-gathering, moving from a few healthy volunteers to hundreds of patients, then thousands, and finally to routine practice under continuous surveillance.
Check your reasoning
Why can a drug be licensed after Phase III and still be withdrawn later?
Reveal an answer
Because Phase III studies a few thousand selected patients over a limited period. Rare effects, effects in groups excluded from the trial, and long-term effects may not appear. Phase IV exists to detect them by monitoring the drug continuously once far more patients use it in ordinary conditions, and the licence can then be renewed or cancelled.
Where this comes from
BMS 113 General Pharmacology I lecture notes · Unit 2, pp. 14–17
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About this course and its sources
Bilingual lessons organised from the supplied BMS 113 General Pharmacology I lecture notes. Diagrams are original educational schematics; pharmacology, nursing and French-language review are pending.