Drug+Development+process

Drug development process is a multistep process that requires a substantial investment of resources. Define each of the following terms as it applies to the drug development process. For each study phase, state its location within the drug development process. Orphan disease, drug development timeline (Joseph & Lucas) Orphan disease is defined as a disease which the cure for has not been discovered or researched by pharmaceutical industry. The reason for lack of interest by pharmaceutical industry is that there are very little financial gains from discovering the cure. There are two types of orphan diseases: rare disease and a common disease. Examples of a common disease are tuberculosis, cholera, typhoid and malaria. Once the drug has been identified as cure for the disease. The timeline for drug development depends on clinical trials on animals and than humans. Joe & Lucas, is the timeline for drug development for orphan disease different than the timeline for normal drug development? (Elita)

References: Medicinenet.com. 2002, Definition of Orphan disease. Medicine Net. Retrieved October 1, 2010 from []

Medscape Today. 2001. Drug Approval Process: Drug Development. J AM Board Family Med. 2001;14(5). Retrieved October 1, 2010 from []

Average timeline (and cost) to develop drug the discovery, development, testing, and marketing of a single, new drug may cost between $50 to 100 million dollars over a 7- to 10-year period.

Preclinical studies (Mary B & Mary M)
The testing of experimental drugs using test tubes and beakers in the lab (in vitro) or in living animals (in vivo) is referred to as preclinical trials (U.S. National Library of Medicine, 2008). Preclinical studies are performed after the discovery phase and are required before any clinical trials (phase 1 to 3) on humans begin (Pharmaceutical Research and Manufacturers of America [PhRMA], 2007). This phase is also used to determine how to develop enough amount of the drug to support clinical trials (PhRMA, 2007). The amount of time for the drug discovery and preclinical phase can take several years (PhRMA, 2007).

References:

Pharmaceutical Research and Manufacturers of America (PhRMA). (2007). Drug discovery and development: Understanding the R&D process. Washington, DC: Author. Retrieved from: http://www.innovation.org/drug_discovery/objects/pdf/RD_Brochure.pdf

U.S. National Library of Medicine. (2008). Glossary – ClinicalTrials.gov. Bethesda, MD: Author. Retrieved from: http://clinicaltrials.gov/ct2/info/glossary

__** Clinical studies (Aimee & Shannon) **__ A Clinical Study is defined as a prospective study which compares the effect and value of a drug intervention against a control in human beings (Friedman, Furberg, & DeMets, 1998). Clinical studies contain a control group that the intervention group is compared.

Clinical studies focus on the design and analysis of randomized trials comparing the effectiveness of one or more interventions with a control. There are several steps/phases of clinical research that must occur before this comparison can be implemented. (Friedman et al., 1998).

Clinical studies occur in 3 phases:

**Phase I** requires early data obtained from humans. The first phase in developing a drug is to understand how well it can be tolerated in a small number of patients in low doses (Friedman et al., 1998). Phase I which tests the safety of the drug, occurs on healthy individuals and determines how a drug is absorbed metabolized and secreted. (Parkinson Study Group, 2010) The results of these studies determine whether a drug will be approved for the market. (Medicine.net, n.d.) There are 4 types of outcomes of these Clinical studies Positive trial (Drug is beneficial), Non-inferior trial (Drug is equivalent to current drugs), Inconclusive trial (Drug is not inferior or superior) and a Negative trial (Drug is inferior to current drugs). (Medicine.net, n.d.) Clinical studies take place after Research and development, Patient protection, pre-clinical testing, clinical trial application (Canadian Pharmacist Association, n.d.) and before producing and marketing the drug. (Parkinson Study Group, 2010)
 * Phase II** tests the drug on people with the condition, how safe it is for them and how effective it is. (Parkinson Study Group, 2010)
 * Phase III** is designed to assess the effectiveness of the new intervention and the role in the clinical practice (Friedman et al., 1998). Phase III tests the drug and a large scale, wide range of participants help to determine the drugs overall affects and effectiveness. (Parkinson Study Group, 2010) Many assumptions for Phase III depend on the outcomes of Phase I and Phase II studies (Friedman et al., 1998).

**__ References __**

Canadian Pharmacist Association. (n.d.). Drug Approval Process. Retrieved September 29, 2010 from []

Medicine.net. (n.d.). Definition of Clinical Trials. Retrieved September 29, 2010 from []

Friedman, L.M., Furberg, C. and DeMets, D.L. (1998). Fundamentals of clinical trials. Retrieved Oct 1, 2010 from []

Parkinson Study Group. (2010). What is a clinical trail? Retrieved September 28, 2010 from []

In vivo studies (Sandra & Teresa) In vivo studies are experiments conducted in living cell cultures and animal models. This stage is done to help determine if a new drug is safe enough for human testing. Animal species provide a very useful model to determine whether a new chemical or drug cause pharmacological or toxicological effects on humans. The drug metabolism in humans and animals plays a very beneficial role in the rational selection of animal modes for toxicology studies. By performing tests on animals scientists try to better understand how the drug works and what its safety profile will look like.

In vitro studies (Rayhan & Tamara) In vitro: A study, procedure or experiment that is performed outside the living organism such as in a test tube or laboratory dish. In vitro studies allow us to describe biological phenomena & mechanisms that occur at cellular, biochemical and molecular levels. In the drug development process, in vitro studies provide information about drug metabolism, permeability, human enzymes and potential human drug toxicity (Apredica). To speed drug development process, to avoid drug toxicity in living organism and to reduce costs, drug companies take advantage of in vitro research options before employing in vivo research (Apredica). When a drug enters the body, it is eliminated by metabolism or excretion. When elimination occurs by metabolism, the different routes of metabolism can affect the drug’s safety and efficacy. For instance, if a drug is eliminated by a single metabolic pathway, the individual differences in metabolic rates can lead to significant differences in drug and metabolite concentrations in the tissue and blood. In the drug interaction and drug metabolism in vitro studies, some interactions can lead to a significant decrease or increase in the tissue and blood concentrations of a drug and metabolite which can result in drug toxicity. In the drug development process, these types of adverse changes affect drug’s safety and efficacy profile, and help companies identify drugs with a narrow therapeutic index. An understanding of metabolic pathways and drug-drug interaction is very important in the development process in vitro to identify unacceptable levels of toxicity (U.S. Food and Drug Administration, 1997). It is important to learn at an early stage of drug development, whether it is eliminated by excretion or metabolism. If it is cleared by metabolism, the metabolizing route should be understood as this information aids in identifying implications of metabolic differences between individuals and certain drug-drug interactions. This information can aid drug companies in determining whether pharmacologic properties of certain metabolites shall be explored further. There have been major advances in the use of human tissues and enzymes in vitro studies to further examine drug-drug interaction and drug metabolism in vitro before employing in vivo research (U.S. Food and Drug Administration, 1997). REFERENCES: //Apredica: Optimize your in vivo preclinical research.// Retrieved September 30, 2010, from Apredica Web site: http://www.apredica.com/invivo.php //(1997). Guidance for industry: Drug metabolism/drug interaction studies in the drug development process: Studies in vitro.// Retrieved September 30, 2010, from U.S. Food and Drug Administration, Centre for Drug Evaluation and Research Web site: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072104.pdf

__**Phase I Studies (Evelyn & Brenda)**__ After many years of laboratory research on animals and human cells, a drug can then be approved for testing on humans. Clinical trials are performed to collect data on the safety and efficacy of a new drug. These trials take many stages to complete and are known as Human Clinical Trial Phases. Phase I studies must have approval from an ethics committee and relevant regulatory body. Phase I is the initial phase of testing which determines the safety of the drug. It usually takes several months and is performed on a small group of 20-100 healthy volunteers who are paid for their participation. Phase I is specific as it investigates the safety, toleration, pharmacodynamics, pharmacokinetics, absorption, metabolized and excretion of the drug. Side effects that occur are also observed. This phase begins with a very small dosage and it is gradually increased and then followed by multiple doses. If the drug being studied is not well tolerated such as severe adverse reactions, significant ECG abnormalities or significant abnormalities, then its development is stopped. During Phase I, 70% of experimental drugs will pass on to Phase II. However, when a drug reaches the clinical phase, it is estimated that only 1 in 10 drugs will make it to the market.

__References__ Tanguay, M. (October 12, 2006) Regulatory Framework for Conducting Phase I Studies: a Comparison Between U.S., European Union and Canada. Retrieved from Anapharm Scientific and Regulatory Affairs Website: http://www.anapharm.com/site/upload/site/Generateur/MTanguay_Las%20Vegas_Reg%20Framework%20Phase%20I.pdf Tanmimi, N. & Ellis, P. (2009). Drug development: From concept to marketing! Nephron Clinical Practice, 113, 125-131. doi: 10.1159/000232592

Phase II studies (Mohammed & Alona)

Phase II studies are performed to determine the initial effectiveness of an investigational drug in patients with the condition or a disease of interest. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well controlled and closely monitored. A major focus is to find the appropriate dose(s) for the larger studies required in phase III. The primary phase II studies are dose-ranging and are designed to provide //proof of principle//. On an average, 100 to 300 patient volunteers participate in the primary phase II studies, which take approximately 2 years to complete.

During these studies, one also begins to identify side effects and toxicity at doses to be used later in phase III studies and likely after marketing. Phase II studies of drugs that are being evaluated for chronic use are typically 4 to 6 weeks in duration but can take up to 6 months, which allows for observation of any later occurring side effects, the assessment of tolerance or waning of a product’s beneficial or toxic activities. Although there is a tendency to try to do as much as possible in these early phase studies, rather than focus on the essential questions, one should have a simple study design in order to maximize the probability of determining if the drug is effective and has acceptable toxicity. Many products fail at this stage and are killed, which is desirable as necessary before embarking on the very expensive and labor intensive phase III study program.

A feature of phase II studies is the use of relatively homogeneous patient populations with very tight inclusion and exclusion criteria. This is done to increase the likelihood of identifying a positive effect and minimizing confounding variables. On the other hand, the results obtained may not accurately reflect the effectiveness of the drug in the more typical heterogeneous patient population.

In addition to the phase II studies that must be performed as part of the drug approval process, other studies may be undertaken before the phase II studies have been completed and the data analyzed. Studies may be performed for several reasons: to obtain additional information for publications, to identify potential other uses (e.g. new indications, areas of unmet medical need), to examine different dosing regimens, to explore new routes of administration, to define the role of concomitant drugs, and to determine the effects in special populations (e.g. the elderly, those with renal or hepatic disease, common comorbid conditions, pharmacogenetic variables).

Evens R. (2007). Drugs and Biological Development: From Molecule to Product and Beyond. US: Springer. Pp.108-109. Retrieved from UOIT on-line library on September 29, 2010.

Phase III studies (Joseph & Lucas)  I n Canada, Phase III is the final phase for clinical trial before before going further into Health Canada drug review process. If the drug is found to be extremely beneficial it is fast tracked through authorization process.(Canadian Pharmacist Association . 2007). Phase III studies further confirms effectiveness of the drug on wider sample size. This phase take approximately one to five years and tries to find ideal dosage for the drug to be effective. About 10% of investigational drugs tested will make it to phase III clinical trials. References Medscape Today. 2001. Drug Approval Process: Drug Development. J AM Board Family Med. 2001;14(5). Retrieved October 1, 2010 from []

Canadian Pharmacist Association. 2007. From Research Lab to Pharmacy Shelf. Canadian Pharmacist Association. Retrieved October 1, 2010 from []

Phase IV studies (Sunshine) After Phase III trials, if the results are positive, then a New Drug Submission can be made to the Therapeutic Products Directorate which is a branch of the Health Products and Food Branch of Health Canada (Alzheimer’s Society of Canada, 2009). If the drug is approved, then Phase IV trials are conducted to determine the drug’s effectiveness in comparison with another drug on the market (Technobec.com, 2008). The medication maybe also be tested on people with other medical conditions or have a different identifying criteria such as age or gender (Alzheimer’s Society of Canada, 2009, Technobec.com, 2008). Other observations on adverse side effects may also be found during a Phase IV clinical trial (Technobec.com, 2008).

Alzheimer’s society of Canada. (April 2009). Treatment Drug Approval Process. Retrieved from []

Technobec.com. (2008). What is Clinical Research. Retrieved from []