D.1.2

=**__D.1.2 Outline the stages involved in the research, development and testing of new pharmaceutical products.__**=

1. Isolation or Chemical Synthesis 2. Laboratory Studies 3. Animal Testing to determine the Lethal Dose (LD50) 4. Clinical Testing to determine the Effective Dose (ED50). 5. Approval by the FDA for market
 * Stages of Development** (Ms. Knowles version)

//Example://

> - //Eg. an anomaly such as an **extra enzyme** in people with high blood pressure.//
 * 1) Scientists select a **target** (//Eg. People with high blood pressure.//)
 * 2) Then, they **research** the differences between people with hypertension (high blood pressure) a perfectly healthy person (or the control).
 * 1) Then, the scientists will breed genetically altered mice which may possess that enzyme.
 * 2) Then they can introduce a new drug and **test it on the mice** to study its effects on the enzyme levels.
 * 3) After thorough animal testing, the scientists can **test a group of people**. (//Eg. 100 healthy volunteers//)
 * 4) Scientists will then administer the drug, along with placebos. Often a blind or double blind test is used.

Additional information on the development process from initial research to human testing can be found here: [|Research Process]

The healthy test group must be monitored for the appearance of adverse effects. After this extensive process, the drug may be released into the pharmaceutical market for those who have hypertension. However, the company still has to closely monitor the drug because all drugs have side effects. (As told by Chao-Pin Lee)

 The **lethal dose** (**or LD50**) test measures the amount of a toxic substance that will, in a single dose, kill 50 percentage of animals in a test group. "To avoid interference with results," no painkillers are administered.

An **effective dose** in pharmacology is the amount of drug that produces a therapeutic response/effect in 50% of the people taking it, sometimes also called **ED-50**.

__General Drug Development Procedures:__

Research/Development u Generally done in labs funded by pharmaceutical companies, although government – funded research facilities also exist. u Computer simulations and modeling programs can be used to design molecules that interact with specific biological targets. Information regarding existing molecules are also available in various databases for testing in simulation programs for a particular type of reaction with a biological target. u Drugs, however, are not always designed with a purposed. Some drugs are tested for one purpose and shown to have a particular other effect, which may be further developed to treat a completely different ailment (e.g. Sildenafil)

Testing -Animal Studies: Government regulation agencies such as the FDA are closely consulted in the design of animal trials since many ethical considerations must be made. Animal studies are necessary in order to identify whether or not a particular substance will be toxic and only once a drug has passed the animal toxicology study can the drug be administered to humans in clinical trials. Usually two mammalian species are tested, such as rats and guinea pigs, using single and repeated dose administration regimens. If the drug is to counteract a specific disease or illness, animals may either be given the disease or specific strains of the animal may be bread (e.g. diabetic rats). Reproductive toxicology tests are also conducted to determine the effects of the drugs on fertility, embryogenesis, and fetal malformation.

-Clinical trials: Once the animal studies have suggested an appropriate dose and adequate evidence that the drug may be effective and appears to be safe, trials on humans begin. Clinical trials are conducted under a very strict set of rules to ensure ethics and safety to its participants and are designed in consultations with drug regulators such as the FDA.


 * Drug Approval and Commercialization**

(http://www.accesscr.com.au/upload/Image/Drug%30Development%20Process%20jpg.jpg)

Assess how the drug is absorbed, distributed, metabolized, and excreted by the body (pharmacokinetics) and helps to establish the safe dose for Phase 2 trials. There are 3 different kinds of Phase 1 trials: Phase 1: First stage of human testing (groups of 20-50 healthy volunteers)

SAD: Single Ascending Dose (small groups of subjects are given a single dose of the drug and observed) MAD :Multiple Ascending Dose (done to get a better understanding of the pharmacokinetics & pharmacodynamics of multiple doses of the drug) Food Effect: Investigate differences in absorption of the drug by the body, caused by eating before the drug is given Phase 1: Pharmacodynamics - Examine effects of the drug (e.g. heart rate, blood pressure, cognitive effects) Usually conducted in 50-100 patients with the disease, rather than healthy volunteers. In both phases I and II, very low dosages are given to a small number of people who are then monitored closely in a purpose-designed early phase unit which is similar to an ICU with around 10 beds and equipped with sophisticated monitoring and emergency treatment facilities. If the first participants show no ill effects, the dosage is increased in the next group. This process is repeated several times until a minimum effective and maximum tolerated dose is established (ED50 and LD50).

Phase 2: Usually randomized comparative double-blinded studies with larger numbers of patients (generally several hundred) with a particular disease or condition which the new drug is supposed to help with. The comparator is either a placebo or an active drug already well established as treatment for the disease under investigation (or both). Effectiveness and safety of the drug are tested and the dosage range is further adjusted. The cost-effectiveness of a drug is sometimes analyzed during this phase of clinical trials. In order to detect that an adverse event has a particular incidence, 3 times as many patients need to be exposed to the drug. (e.g. to detect a 1 in 1000 event, 300 patients need to be exposed).

Phase 3: Post Registration After Phase 2, a new medicine is registered. Phase IV trials continue after registration and are usually randomized controlled trials and are designed to determine its clinical position (e.g. first-, second-, or third-line use), cost-effectiveness, and safety profile in certain patient populations. These trials are generally very large and involve thousands of patients over the course of several years. They are extremely expensive but often more useful than the earlier registration studies because they allow for a broader and more realistic sample goup.  Drug Approval and Commercialization:

Once Phase I to III is completed, the pharmaceutical company sponsor companies all the data about the new drug and these are assessed by government regulatory authorities (e.g. the FDA, TGA and Medsafe). Regulators examine evidence relating to the chemistry and manufacture of the new drug, the animal toxicology, and the clinical studies. A new medicine must have an acceptable benefit: harm ratio in a well-defined patient group to allow it to be registed for that specific indication. Once the new medicine has been approved, the sponsoring pharmaceutical company can begin to sell and promote it.  Not all drugs that begin the three-phase process will make it to the pharmacy and medicine cabinet. Some are shown to be unsafe, ineffective, unprofitable, or all of the above. Of 100 drugs for which investigational new drug applications are submitted to the FDA, about 70% will complete Phase 1 and go on to Phase 2. About 33% of the original 100 will go from Phase 2 to Phase 3. And 25-30% of the original 100 will clear Phase 3. Of the original 100 experimental drugs, about 20% will be approved for sale.

__The Thalidomide Case __

//**Overview**// In the 1950s, (First appearing in Germany), Thalidomide, a medicine that was developed and released by German company Grünenthal and designed to provide morning sickness relief and act as a sleep aid for pregnant women was not properly tested. As a result, over 10,000 human birth deformities occurred in newborn babies.

//**What is Thalidomide?**// - Empirical formula: C 13 H 10 N 6 O 4 - A white, odorless powder that exists as a mixture of the "S" and "R" forms (see more info below) - Given as capsules which are orally administered. - Originally designed to provide morning sickness relief and a sleep aid for pregnant women. - Was responsible for over 10,000 human birth deformities because the drug passed through the placental barrier and harmed the developing fetus.

- Was manufactured and sold/given as an [|Enantiomer] - (It possesed molecules which were mirror images of each other) (The R and S structure of the thalidomide enantiomer) The "S" enantiomer helped cure women of morning sickness. But the "R" enantiomer, its mirror image, caused birth defects (such as loss of limbs, short limbs) in the babies. For more warnings about it click [|here]

source: []
 * What scientists learned:** drugs have to be manufactured as a //single// enantiomer

//**Stages involved in research:**// At first, before putting Thalidomide out on the market, an extensive amount of animal tests were performed in Germany. On August 1, 1958, Chemie Grünenthal (the German manufacturer) described Thalidomide as the **best tranquilizer** for pregnant women to reduce morning sickness and induce sleep. In October 1960, the British license also launched Thalidomide (named as Distaval), assuring that it is "**completely safe**" for the pregnant women and nursing mothers to take.

By 1978, an plethora amount of stories and pictures were posted in public of **malformed births** whose mothers used Thalidomide during pregnancy.

Frances Kelsey found them insufficient, and thus **did not give FDA approval** for Thalidomide in the U.S.

Later, research showed that Thalidomide constricted blood flow during fetal development and led to limb disfigurement
 * Issues with research:** original company, Chemie Grünenthal, did not conduct thorough tests and the **trials ran were too quickly** to be complete.

Symptoms of peripheral neuritis appeared after the drug was first launched, not many scientists became suspicious, but " One such scientist, McCredie reported that the limbs of children with thalidomide malformations show changes analogous to those which can occur in the adult as a consequence of pathological alterations to peripheral nerves." This should have been an indicator to scientists to **not continue marketing the drug, but** **they obviously did.**

The drug firms did not take the drug off the market because their resumed animal test does not show the same symptoms. It was only when the evidences became overwhelming, Grünenthal finally take Contergan(Thalidomide) off the market.

"an estimated 10,000 children-but probably many more-born throughout the world as phocomelics, deformed, some with fin-like hands grown directly on the shoulders; with stunted or missing limbs; deformed eyes and ears; ingrown genitals; absence of a lung; a great many of them still-born or dying shortly after birth; parents under shock, mothers gone insane, some driven to infanticide." (Hans Ruesch, medical historian.) //**
 * //Adverse effects:

Birth defects in over 10,000 children of the drug consumers worldwide. (except for the U.S. where Frances Kelsey did not grant FDA approval for this drug; 17 US babies were born with Thalidomide effects)

Major deformities in limbs. The Thalidomide bonded to certain parts of the DNA which control the growth of limbs in fetuses. There were complications in figuring out the adverse effects because thalidomide only took effect at //certain stages// of development. Timing was everything concerning drug administration.

//**Results of the thalidomide case:**// As consequences to the thalidomide tragedy, - There has been an increase in animal testing of new drugs - Drugs are now specifically tested on pregnant animals to safeguard against possible effects on the human foetus. - The adverse effect that drugs could have on pregnant women were recognised. - Women were advised not to take any drug, illegal or legal, during pregnancy due to the dangerous effects it could have on the developing child.

http://www.animalvoices.org/ADAV/thalido.htm http://www.chm.bris.ac.uk/motm/thalidomide/first.html http://www.pnc.com.au/~cafmr/online/research/thalid2.html http://www.acde.org/parent/Pregnant.htm Ruesch, H., Slaughter of the Innocent, pp. 360-1. and the other links incorporated.
 * Sources**: