Development of drug
- 1. DEVELOPMENT& REGULATION OF DRUGS Dr. Mahmoud Naga JANUARY 1, 2018 ST. HIND ALSHANKITI -
- 2. Development& Regulation of Drugs The development of a drug from an initial idea to its entry into the market is a very complex process which can take around 5-10 years and cost billions. The idea for a new development can come from a variety of sources which include the current necessities of the market, new emerging diseases, academic and clinical research, etc... Once a target for discovery has been chosen, the pharmaceutical industries or the associated academic centers work on the early processes to identify the chemical molecules with suitable characteristics to make the targeted drugs 1. DRUG DISCOVERY The discovery of a new chemical entity that modifies a cell or tissue function is but the first step in the drug development process. Once shown to be effective and selective, a compound which is to be discovered must be completely free of toxicity, should have good bioavailability and marketable before it can be considered to be a therapeutic entity Figure 1 the development of drugs
- 3. IDEA Typically, researchers discover new drugs through: (1) identification or elucidation of a new drug target. (2) rational design of a new molecule based on an understanding of biologic mechanisms and drug receptor structure. (3) screening for biologic activity of large numbers of natural products, banks of previously. discovered chemical entities, or large libraries of peptides, nucleic acids, and other organic molecules. (4) chemical modification of a known active molecule, resulting in a me-too analog. (Muntha, 2016) Once a new drug target or promising molecule has been identified, the process of moving from the basic science laboratory to the clinic begins. This translational research involves the preclinical and clinical steps. 2. DEVOLEPMENT Drug development takes place in many stages and these stages are under management of FDA what is FDA The FDA is the administrative body that oversees the drug evaluation process in the USA and grants approval for marketing of new drug products. To receive FDA approval for marketing, the originating institution or company (almost always the latter) must submit evidence of safety and effectiveness. Outside the USA, the regulatory and drug approval process is generally similar to that in the USA. The FDA’s authority to regulate drugs derives from specific legislation. If a drug has not been shown through adequately controlled testing to be “safe and effective” for a specific use, it cannot be marketed in interstate commerce for this use. (FDA, 2018 ) IND: The United States Food and Drug Administration's Investigational New Drug NDA: The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S.
- 4. DRUG SCREENING Drug screening is the process by which potential drugs are identified and optimized before selection of a candidate drug to progress to marketing. It can involve screening large libraries of chemicals for a particular biological activity in high-throughput screening assays. And it’s divided into 2 types: in-vitro which is proceed in lab and in-vivo which is preclinical and then clinical test (trails) 1. PRECLINICAL SAFETY & TOXICITY TESTING Drugs are always toxic at some dose. the process which seeks to define the toxicities of drugs and the therapeutic index of it comparing to its benefits and risks is an essential part of the new drug discovery. The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the most relevant toxicities to be monitored in clinical trials. Acute toxicity testing Acute toxicity testing is carried out to determine the effect of a single dose on a particular animal species. In general, it is recommended that acute toxicity testing be carried out with two different animal species (one rodent and one no rodent). In acute toxicological testing, the investigational product is administered at different dose levels, and the effect is observed for 14 days. All mortalities caused by the investigational product during the experimental period are recorded and morphological, biochemical, pathological, and histological changes in the dead animals are investigated. (Parasuraman, 2011 ) Mutagenicity testing is used to assess submicroscopic changes in the base sequence of DNA, chromosomal aberrations, and structural aberrations in DNA including duplications, insertions, inversions, and translocations. (Parasuraman, 2011 ) Effect on reproductive performance Two species, usually one rodent and rabbits. Test effects on animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal development. (Bertram G. Katzung, 2012) Chronic toxicity testing Chronic toxicity studies are conducted with a minimum of one rodent and one no rodent species. The test compound is administered over more than 90 days, and the animals are observed periodically. A chronic toxicology study provides inferences about the long-term effect of a test substance in animals, and it may be extrapolated to the human safety of the test substance. (Parasuraman, 2011 )
- 5. approximately 50% of the animals. Presently, the LD50 is estimated from the smallest number of animals possible. These doses are used to calculate the initial dose to be tried in humans, usually taken as one hundredth to one tenth of the no-effect dose in animals. (Bertram G. Katzung, 2012) 2. Clinical Trials. In a clinical trial, participants receive specific interventions according to the research plan or protocol created by the investigators. Clinical trials used in drug development are sometimes described by phase. These phases are defined by the Food and Drug Administration (FDA). Once a new drug is judged ready to be studied in humans, a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA The IND includes (1) information on the composition and source of the drug, Carcinogenicity testing Both rodents and no rodent animal species may be used in carcinogenicity testing. The tests are carried out over the greater portion of an animal's lifespan. During and after exposure to test substances, the experimental animals are observed for signs of toxicity and development of tumors. If these are not found, a test may be terminated after 18 months in the case of mice and hamsters and after 24 months with rats. If the animals are healthy, hematological analysis is performed after the 12 months and the 18 months, respectively, and the study is terminated. The animals are sacrificed, and gross pathological changes are noted, and histopathological studies are carried out on all the tissues. (Parasuraman, 2011 ) Table 1 Toxicity testes
- 6. (2) chemical and manufacturing information, (3) all data from animal studies, (4) proposed plans for clinical trials, (5) the names and credentials of physicians who will conduct the clinical trials, and (6) a compilation of the key data relevant to study of the drug in humans that has been made available to investigators and their institutional review boards. It must pass 4 phases, 3 to get the approval from FDA and the 4th is post-marketing Phase I studies assess the safety of a drug or device. This initial phase of testing, which can take several months to complete, usually includes a small number of healthy volunteers (20 to 100), who are generally paid for participating in the study. The study is designed to determine the effects of the drug or device on humans including how it is absorbed, metabolized, and excreted. This phase also investigates the side effects that occur as dosage levels are increased. About 70% of experimental drugs pass this phase of testing. (Overview of Clinical Trials, 2014-2015) Phase II studies test the efficacy of a drug or device. This second phase of testing can last from several months to two years and involves up to several hundred patients. Most phase II studies are randomized trials where one group of patients receives the experimental drug, while a second "control" group receives a standard treatment or placebo. Often
- 7. these studies are "blinded" which means that neither the patients nor the researchers know who has received the experimental drug. This allows investigators to provide the pharmaceutical company and the FDA with comparative information about the relative safety and effectiveness of the new drug. About one-third of experimental drugs successfully complete both Phase I and Phase II studies. (Overview of Clinical Trials, 2014-2015) Phase III studies involve randomized and blind testing in several hundred to several thousand patients. This large-scale testing, which can last several years, provides the pharmaceutical company and the FDA with a more thorough understanding of the effectiveness of the drug or device, the benefits and the range of possible adverse reactions. 70% to 90% of drugs that enter Phase III studies successfully complete this phase of testing. Once Phase III is complete, a pharmaceutical company can request FDA approval for marketing the drug. (Overview of Clinical Trials, 2014-2015) 3- MARKETING After marketing, the drug is still in monitoring to either complete phase IV or to pulled from the market if it fails. Phase IV studies, often called Post Marketing Surveillance Trials, are conducted after a drug or device has been approved for consumer sale. Pharmaceutical companies have several objectives at this stage: (1) to compare a drug with other drugs already in the market; (2) to monitor a drug's long-term effectiveness and impact on a patient's quality of life; and (3) to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies. Phase IV studies can result in a drug or device being taken off the market or restrictions of use could be placed on the product depending on the findings in the study. (Overview of Clinical Trials, 2014-2015) Reasons for Pulling a Drug from the Market Risk of Health Problems - Sometimes further study reveals a connection between taking a drug and a potential health problem. Some pharmaceutical
- 8. drugs have been linked to an increased risk of heart attack, stroke, kidney failure, and other serious complications. Risk of Health Problems - Sometimes further study reveals a connection between taking a drug and a potential health problem. Some pharmaceutical drugs have been linked to an increased risk of heart attack, stroke, kidney failure, and other serious complications. Previously Unknown Drug Interactions - Mixing drugs can cause health problems. Sometimes a drug may be discovered to cause problems when taken with another drug, a certain type of vitamin, or certain foods. Manufacturing and Packaging Errors - Sometimes a problem at the factory will require a recall. A contamination problem may make a drug unsafe for consumption, or a packaging error may unseal a drug before it reaches the patient. Patent application The time from the filing of a patent application to approval for marketing of a new drug may be 5 years or considerably longer. Since the lifetime of a patent is 20 years in the USA, the owner of the patent (usually a pharmaceutical company) has exclusive rights for marketing the product for only a limited time after approval of the new drug application. Because the FDA review process can be lengthy, the time consumed by the review is sometimes added to the patent life. However, the extension (up to 5 years) cannot increase the total life of the patent to more than 14 years after approval of a new drug application. As of 2005, the average effective patent life for major pharmaceuticals was 11 years. After expiration of the patent, any company may produce the drug, file an abbreviated new drug application (ANDA), demonstrate required equivalence, and, with FDA approval, market the drug as a generic product without paying license fees to the original patent owner. (Bertram G. Katzung, 2012) REFERENCES Bertram G. Katzung, S. B. (2012). Basic & Clinical Pharmacology Twelfth Edition. McGraw- Hill. FDA. (2018 , 03 16). Retrieved from FDA. Muntha, P. (2016, 06 04). Drug Discovery & Development. Retrieved from Research & Reviews in Pharmacy and Pharmaceutical Sciences. Overview of Clinical Trials. (2014-2015). Retrieved from CenterWatch. Parasuraman, S. (2011 ). Toxicological screening. J Pharmacol Pharmacother, 74–79.