If you had the power what disease would you like to cure?

What do you think? Have you ever had to take a medicine to treat an illness? Have you ever wondered how researchers determine if the medicines you take are safe or not?

How drugs are discovered.. Engineers often find it easy to see the body as a factory. Individual organs can be seen as machinery. The actual nuts, bolts, screwdrivers, and wrenches that make up all the machinery are the equivalent of proteins, little chunks of organic material that move things around in the body and attach them together.

Clinical Trials are the processes by which scientists test drugs and devices to see if they are SAFE and EFFECTIVE.

What is a Preclinical Trial? Preclinical trial - a laboratory test of a new drug or a new medical device, usually done on animal subjects, to see if the hoped-for treatment really works and if it is safe to test on humans.

Steps in Doing a Pre-Clinical Trial: Step One: Get an idea for a drug target. Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease. Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease. Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease. This information is from the website: http://www.ppdi.com/about_ppd/drug_development.htm#2

Finding the Right Target Is Not Easy Parkinson’s Disease Example: a disease which causes deterioration of the central nervous system over a period of time. This disease often impairs the patient’s movement, speech, and other functions. Picture from: http://curetal.com/curcuminparkinsons.html

How is Parkinson’s treated? Where should the focus be? Tremors or shaking occurs when cells in one part of brain die. These cells communicate using a chemical called dopamine. Drugs that replace dopamine work only for a few years. Other Parkinson’s symptoms (depression, sleep disorder, digestive problems, loss of brain function) have other causes. Another sign of Parkinson’s disease: many cells have deposits of a protein, synuclein. Four drug companies are developing drugs to counter synuclein, even though nobody knows if it is a cause or a consequence of Parkinson’s.

Drugs target specific points in biochemical pathways Biochemical pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by chemical reactions. Examples of different types of biochemical pathways: A E B D C A B C D E In a biochemical pathway, each step usually involves either adding atoms (synthesis) or taking certain atoms away (degradation) to produce a different compound. These steps are often enabled by enzymes that are specific for that step. Drug development can be aimed at blocking or enhancing the enzyme or directly reacting the drug with the compounds in the pathway. Any step in the pathway, for example from A to B, or B to C, might be a target for the right drug. * See slide note

Steps in Doing a Pre-Clinical Trial: Step Two: Develop a Bioassay A Bioassay is a “live” system that can be used to measure drug effect. It may be a culture of cells or organs or a whole animal. For example: Zebra-fish embryos - you can see effects of drugs on bone density, blood vessel growth and many other systems of the zebra-fish. Picture from: http://www.ceb.utk.edu/images/zebra4.jpg

Steps in Doing a Pre-Clinical Trial: Step Three: Screen the drug in the Bioassay. This is the actual test of the drug on the chosen bioassay. This will determine if the drug is SAFE and if it is EFFECTIVE in the bioassay (BEFORE it is ever tested on humans!)

Steps in Doing a Pre-Clinical Trial: Step Four: Establish what dosage amount of the drug is safe and what dosage amount of the drug is toxic. Most drugs have a toxic level or an amount at which the drug will become harmful instead of helpful.

Steps in Doing a Pre-Clinical Trial: Step Five: Application is made to the Food and Drug Administration (FDA) as an Investigational New Drug (IND). IND must show how the drug: Is manufactured. Appears (color, solubility, melting point, particle size, moisture content). Formulated (pills, liquid, etc. + inactive ingredients). Will be analyzed for purity, concentration, stability. Will be tested for safety (this will be the basis for allowing first use in humans).

Think Break: How are these steps like the steps of the Scientific Method? Why would research scientists use a Bioassay instead of a human subject to test a new drug? What percentage of drugs do you think get this far in the process? They really are the APPLIED steps of the scientific method. State the Problem: Will a new drug be effective and safe? Gather Background Information: The scientist will rely on past research and the basic research done before their proposed trial. Form a Hypothesis: For new drugs, the hypothesis is that the drug will be effective and safe, otherwise, the scientist would not spend the time and effort on the Pre-Clinical Trial. Conduct an Experiment: This involves screening the drug in the Bioassay. Analyze Data: Determining Safe and Toxic Doses and whether the drug was Effective. Forming a Conclusion: Will it be advantageous to continue testing the drug or not? Is it safe to continue on and test the drug on humans next? 2. Many times, the risks associated with using humans outweigh the potential benefits. Using a Bioassay like cells or fish embryos prevents unnecessary harm to people and pets. 3. Out of every 5,000 new compounds identified during the discovery process, only five are considered safe for testing in human volunteers after preclinical evaluations.

Review: Steps to New Drug Discovery Pre-Clinical Trials Get idea for drug target Develop a bioassay Screen chemical compounds in assay Establish effective and toxic amounts File for approval as an Investigational New Drug (IND) (leads to clinical trials)

Can you summarize the process? With a partner or your group, write a summary of the Pre-Clinical Trial Process. Use the following words to help you: Drug Safe Effective Basic Research Applied Research Target Biochemical Pathway Bioassay Toxic Investigational New Drug (IND)

Important for future therapies Clinical Trials Important for future therapies

http://www.bbc.co.uk/learningzone/clips/human-drug-trials/1464.html

Definition All clinical trials are prospective studies in which individuals are exposed and followed for an outcome (or a few different outcomes). The outcomes must be clearly defined.

What’s involved in a clinical trial? Forms need to be filed with the Internal Review Board. A committee determines whether the study is ethical. Protocol. Before conducting a clinical trial, a protocol must be written, describing exactly what you are going to do 3. Trial - On site Patient Monitoring and Data collection 4. Data analysis, write results and conclusions 5. Written report: includes clinical and statistical sections

The Placebo Effects “Inert” substitute for a treatment or intervention. “Inert” means the compound has no known activity that would be expected to affect the outcome It must look exactly the same as the tablet that you want to test!

Placebo Effects In actuality, a placebo effect is a psychosomatic effect brought about by relief of fears, anxiety or stress because of study participation. It's not just the little white pill that brings about the effect; it's the additional attention and the belief that your condition might be being treated with a superior new treatment. All outcomes affected by psychosomatics are prone to placebo effects.

Blinding, also called masking If the outcome can conceivably be affected by patient or investigator expectations, then blinding is important.

Types of Blinding Single Blind: The patient is ‘blind’ Double Blind: The patient and the investigator are ‘blind’ Triple Blind: The patient, investigator and data-cleanup people are ‘blind’. (The statistician can only be partially blinded since he/she has to know which patients are in the same treatment group.)