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Clinical Trials in Drug Approval
Clinical trials are the clinical studies that involve human volunteers; here termed as subjects or patients that are designed to improve the medical knowledge, determine the efficacy of a new drug in the humans for diseases which has no certified or proven treatment/therapy, or sometimes done just for comparison with another drug for same ailment to determine whichever is more effective with lesser side effects. It also helps determine which dose/concentration of a particular drug would be best for different stages of the same disease. Clinical trials are highly crucial to be conducted before the drug is marketed to make sure the drugs are tested and certified for usage.

These studies always involve a team of experts from Medical & Pharmaceutical sectors to make sure there is compliance in trials with the protocols. The government of the country where the study is held is also involved to make sure the protocols follow the standards set by that particular government and also to make sure that the practice is ethical and patient safety is of highest importance. This study may either be interventional or observational type. In interventional, the patients or the subjects are given specific medical products as per the designed protocol by medical experts or investigators. This medical product could be drugs, devices, vaccine, etc.

In the observational studies, the interventions maybe given to a group of the population but it is mainly for the investigator to observe the health consequences or development in that group with respect to their lifestyles.

A complete clinical trial includes four main stages, collectively known as the Phases of clinical trials. The four clinical phases and drug development in each phase is defined below. However these phases may not always occur in the same chronological order. Sometimes a drug is evaluated in just 2 phases and sometimes the clinical trials may occur in such a fashion that two different phases may overlap each other.

Phase I: This is the primary stage where the first safety trials on a new drug is done in order to establish the exact dose range that is tolerated by the subjects. The dosage type maybe single or multiple. Usually this trial is conducted on severely ill patients like in cases of cancer, and in case of less ill patients, it involves pharmacokinetic studies. Pharmacokinetic studies are generally considered as phase I study.  Pharmacokinetic study can be easily defined as the study of what the body of living organism does to the drug from the moment it is absorbed by the body, distribution within the body, its metabolism to excretion.

Phase IIa: This is the first part of the 2nd phase of the clinical trial that involves the evaluation of the efficacy and safety of the drug in a group of selected population. The population here is usually patients with ailments to be treated or to prevent it. This phase concentrated on the dose-response , what type of patients are involved, Objectives may focus on frequency of intervention, dose-response, type of patient, and many other factors that are crucial in determining the safety and efficacy level. This phase may be  referred to as pilot trials.

Phase IIb: The objectives of this phase is same as that of the phase IIa, and may sometimes be referred to as pivotal trials. The conditions and factors for evaluation of efficacy and safety may also be same as phase IIa, however this phase represents absolutely thorough and careful, uncompromising display of the drug efficacy.

Phase IIIa: Phase III begins after the drug efficacy has been demonstrated but before the regulatory submission of New Drug. This phase is conducted on the group of population for whom the drug was actually intended to begin with. In IIIa clinical trials a data is generated based on both safety and efficacy but in relatively large numbers of subjects or patients in both controlled and uncontrolled trials. This trial may involve 2 group of patients for comparison of the drug interaction in the body against a placebo. This phase often provides much of the information needed for the labeling of the drug.

Phase IIIb: This phase is conducted after regulatory submission of dossier or an NDA, but prior to the drugs approval by the regulatory body and marketing of the drug. These trials may add on to earlier studies, sometimes may be the end of the clinical studies, or sometimes be directed towards Phase IV evaluations. This is the period between regulatory submission and approval of the drug for marketing authorization.

Phase IV: This phase is generally for observational purpose, but can sometimes be interventional too. This phase is conducted in order to provide with additional information about the drug’s efficacy or safety profile. Different age groups, or population from different ethnicity, races, are targeted in this phase. Previously unidentified reactions can be observed in this phase gradually adverse reactions or serious adverse effects are determined along with  related risk factors. This is very important for Phase IV because if a marketed medicine is to be evaluated for unknown indication, then those clinical trials are  considered first as interventional and then continued as Phase II clinical trials. The term post-marketing surveillance is generally used to describe the study period following the marketing of drug. During this the studies conducted are observational or non-experimental.
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Clinical trials are studies to find out whether the drug is safe and effective for people. They may be patients with a disease, or healthy people wanting to contribute to the advancement of medical knowledge. Although early medical experimentation was often performed, the use of a control group to provide an accurate comparison for the demonstration of the intervention's efficacy, was generally lacking. For instance, Lady Mary Wortley Montagu, who campaigned for the introduction of inoculation (then called variolation) to prevent smallpox, arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor (1). Similar experiments performed by Edward Jenner over his smallpox vaccine were equally conceptually flawed.Thefirst  clinical trial was conducted by the physician James Lind. The disease scurvy, now known to be caused by a Vitamin C deficiency, would often have terrible effects on the welfare of the crew of long distance voyages (2). In 1740, the catastrophic result of Anson's circumnavigation attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy. John Woodall, an English military surgeon of the British East India Company, had recommended the consumption of citrus fruit  from the 17th century, but their use did not become widespread.The potential treatments identified to have therapeutic potential in the Basic Research stage are then tested in animals for their ability to be delivered to the target organ and tissue to determine how well they are cleared from the system, and to determine their toxicity, safety, and effectiveness. Several potential treatments that do not pass certain tests may be dropped at this stage since they may seem too risky for further development for use in patients (3). The development of new pharmaceutical drugs is essential in order to improve the quality of drug.Clinical trials may be costly, depending on a number of factors. The sponsor may be governmental organization or apharmaceutical, biotech or medical  company. Certain functions necessary to the trial, such as monitoring.may be managed by contract research organization or a central laboratory.Clinical trials haveaimportant role in drug development.Clinical trials are experiments done in clinical research. Such biomedical or behavioral research (4,5).  on human  and animals participants are designed to answer specific questions about biomedical or behavioral interventions, including new treatments  as novel vaccines, drugs and medical devicesand known interventions that warrant further study and comparison. Clinical trials generate data on efficacy and safety (6) . They are possible only after they have received health authority committee approval in the country. There are two goals to testing medical treatments: to learn whether they work well enough, called effectiveness and to learn whether they are safe enough, called safety". Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition. The benefits must outweigh the risks (7). In the US, the elderly constitute only 14% of the population, while they consume over one-third of drugs. People over 55 (or a similar cutoff age) are often excluded from trials because their greater health issues and drug use complicate data interpretation, and because they have different physiological capacity than younger people(8). Women, children and people with unrelated medical conditions are also frequently excluded. For women, a major reason for exclusion is the possibility of pregnancy and the unknown risks to the fetus.
What is clinical research

Clinical trials are conducted to collect data regarding the efficacy and safety for new drug development. Several stages of approval in the clinical trials process before a drug or device can be sold in the consumer market, if ever.Drug testing begins with extensive laboratory research which can involve many years of experiments on animals and human.  If the laboratory research is successful, researches send the data for approval to continue research and testing in humans.
Once approved, human testing of experimental drugs can begin and is typically conducted in different phases. Each phase is considered a unique trial and, after completion of a phase, investigators are required to submit for approval.

Human Clinical Trial Phases:

Phase I  Thisstarting phase of drug testing, which can take many  months to complete, usually includes a some 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 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.

Phase II studies test the efficacy of a drug.. This 2ndphase of testing may  last from several months to 2 years, and involves up to several hundred patients. Most phase 2ndstudies are randomized trials where one group of patients receives the experimental drug, while a second "control" group receives a standard treatment. Often studies are "blinded" which means that neither the patients nor the researchers received the experimental drug. This allows investigators to provide the pharmaceutical company. About one-third of experimental drugs successfully complete both Phase I and Phase II studies.

Phase III studies involve randomized and blind testing in many hundred to many thousand patients. This large-scale testing, which may last many years, provides the pharmaceutical company with a more thorough understanding of the effectiveness of the drug.the benefits and the range of possible adverse reactions. 80.5% to 90.2% of drugs that enter Phase 3rdstudies successfully complete.. Once Phase 3rdis complete, a pharmaceutical company can request approval for marketing the drug.
Phase IV is called Post Marketing Surveillance Trials, is conducted after a drug. 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 drugs long-term effectiveness and impact on a patients 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.

The role of clinical trials in drug approvals
• Pre-clinical studies
• Clinical trials
• Regulatory product submission
• Submission review
• Market authorization decision
• Public access
• Surveillance, inspection, and investigation
• The post-market part of the process begins with surveillance, inspection, and investigation when a drug has been made accessible to the public.

Potential benefits Clinical Trials:
When we take part in a clinical trial, we help others by advancing medical research. If we have a disease, there could be personal benefits.  
• we may get early access to a new promising treatment.
• The treatment may cure or control our condition. Even if  we are not cured, our quality of life might improve.
• We  may get additional access to expert health  because of the time we will spend with the research team involved in this study.

Potential risks Clinical Trials:
If  clinical trial is to get access to a new treatment, be aware that this may not happen. Clinical trials often compare a new drug to:
• an approved drug that is already on the market
• a placebo a dummy treatment with no active ingredients
In many cases, people are not told which treatment they are getting in order to generate unbiased results. Even if we get the new drug. It might be less effective than a treatment we were using before the trial. There is also a risk of serious side effects (short-term and long-term) as the safety profile of an investigational drug is not as well understood as an approved drug.A clinical trial can take up a lot of your time for things like travel, tests and even hospital stays.

Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators  the various IRBs that supervise the study, and  the regulatory agency for the country where the drug or device will be sold.For safety reasons, severclinical  trials of drugs are designed to  women of childbearing age, pregnant women, and women who become pregnant during the study. Some cases, the male partners of these women are also  required to take birth control.Once a drug has been approved, how is it monitored.Once a drug is on the market, regulatory controls. The distributor of the drug must report  new information received serious side effects including failure of the drug to produce the desired effect. The distributor studies that have provided new safety information and request approval for any major changes to the manufacturing processes, dose regime or recommended uses for the drug.

A clinical trial is an organized research study designed to investigate new methods of preventing, detecting, diagnosing, or treating an illness or disease, such as cancer. In some instances, clinical trials attempt to improve  quality of life. When studying cancer treatment, researchers generally attempt to determine whether a new method of treatment is superior to the standardtrials are extremely important in discovering new techniques to disease. For example, many of the advances in breast cancer detection and treatment resulted from clinical trials.Clinical trials are a type of research study to explore whether a medical treatment, drug, strategy or device is safe and effective for human use. The purpose of clinical trials is research, so the studies follow strict scientific standards. These standards protect patients and help produce reliable study results.

1. "Clinical Trials" (PDF). Bill and Melinda Gates Foundation. Retrieved January 2014.
2. J Med Invest. 2006 Aug;53(3-4):292-6. Clinical trials for drug approval: a pilot study of the view of doctors at Tokushima University Hospital.Yanagawa H1, Nishiya M, Miyamoto T, Shikishima M, Imura M, Nakanishi R, Ariuchi K, Akaishi A, TakaiS, Abe S, Kisyuku M, Kageyama C, Sato C, Yamagami M, Urakawa N, Sone S, Irahara M.
3. Young, Susan. "Foundation Medicine Joins Coalition Aiming to Shake Up Cancer Drug Trials | MIT Technology Review". Retrieved 2013-11-14.
4. "Adaptive Clinical Trials for Overcoming Research Challenges". Retrieved 2014-01-04.
5., 19 May 2014, Mumbai ISCR releases Guide for clinical trial participants on International Clinical Trials Day(Accessed on 20th May 2014)
6. Young, Susan. "Foundation Medicine Joins Coalition Aiming to Shake Up Cancer Drug Trials | MIT Technology Review". Retrieved 2013-11-14.
7. Rennan, Zachary (2013-06-05). "CROs Slowly Shifting to Adaptive Clinical Trial Designs". Retrieved 2014-01-05.

Reetu Yadav
Department of Botany
R.B.S. College, Agra.
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