DRUG TOXICITY

DRUG TOXICITY

       The physicians prescribe drugs to prevent, cure and treat disease. Sometimes those drug may be toxic to certain patients because of genetic transmission, non-selective action, inappropriate administration of the prescribed drug. The United States Food and Drug Administration (FDA) spends $1 trillion to ensure the new drug molecules are not quite dangerous. Many pharmaceutical companies spend a big awesome amount of money in clinical trial study to understand safety dose of new drug. E.g.- Acetaminophen drug is turn to be lethal when it is administered in supratherapeutic doses. 

Medicines

     All the research found that no drug is entirely specific. All drugs have both primary intended effects and secondary unintended and unexpected effects, the later is known as side effects or adverse effects. Adverse effects can vary nuisance to life-threatening in animal as well as human body. This side effects make many patients to take drugs on a regular basis.Toxicity may be caused by the inhibition of intended drug target which is also known as on-target adverse effects. Side effects also may be occurred by the inhibition of unintended drug targets known as off-target adverse effects. 
     A drug that causes more harm rather than being good approach in an individual patient depends on many factor genetic transmission, patient's age and sex, several condition like pregnancy, diabetes etc. Many research study has found that very old or very new drug has more tendency to exert the toxic effects because of age dependent difference in pharmacokinetic properties. Drug metabolism which is a genetic factor can alter how a patients responds to a drug. Side effects seemed to be more likely to happened in patients with preexisting effects like kidney or liver dysfunction, pregnancy, depressed immune function.

ADVERSE EVENTS AND SAFETY MONITORING IN CLINICAL TRIAL

ADVERSE EVENTS AND SAFETY MONITORING

    The adverse events are monitored during clinical trials for the protection of the subjects enrolled in the trial as well as for protection of the patients and proper use of the drug, once it is marketed. Monitoring safety during a clinical trial is one of the most important tasks a Clinical research associate performs. At the same time, safety reporting in one of the most difficult things for the study site to do correctly. There are often misunderstandings about what is necessary for reporting on safety issues in trials, stemming at least in part because of the differences in clinical studies as compared to clinical practice. Also, although the regulations charge the investigator with protecting the rights, safety and well-being of subjects in trials. Here the regulations are demonstrated below.

Adverse Events

Safety Reports- The investigator must report to the sponsor about any adverse effects which may be appeared after the administration of new drug molecule. If the adverse effects is found in any moment, the sponsor must be acknowledged it by the investigator immediately.

Adverse Effects- Adverse effect is any undesirable or unintended consequence of new drug administration.

Adverse Events- Adverse event is used to mean any untoward medical occurrence that may present during treatment with new drug molecule in clinical trial but it does not have relationship with this treatment.

Adverse Drug Reaction- Adverse drug reaction is defined as any noxious change which is suspected to be present in the participating subjects due to administration of new drug, requires immediate treatment by decrease in dose. It helps to indicate the cautions for the future use.

    In clinical trial study the sponsor must be required to inform to FDA(Food & Drug Administration) about any serious, unexpected adverse events related to investigational drug withing fifteen day of the time period.

BIOMEDICAL STATISTICAL STUDY

OVERVIEW OF BIOMEDICAL STATISTICS

Biostatistics

     Statistics is the science of collecting, describing and analyzing of data that is subjected to random variation. The descriptive statistics presents and summarizes collected data to characterize features of its distribution. Inferential statistics presents sample data in order to estimate or predict characteristics of the larger population from which the sample is drawn. It refers to the subject of scientific activity which deals with the theories and methods of collection, analysis and interpretation of such data.

      Biostatistics is the term used when tools of statistics are applied to the data that is derived from biological sciences. Biostatistics begins with descriptive statistics. This implies summarizing a data series from a sample or population.   

      Data which are values of a variable constitutes the raw material for statistical work. Their are mainly two types of data applied in this study. One is Categorical data and another one is numerical data.Qualitative data are best summarized by grouping the observations into categories and counting the numbers in each, they are known as categorical data. The second one, quantitative data always have the values expressed as numbers and the difference between values have numerical meaning, they are also referred to as numerical data.

     

There are some application and uses of Biostatistics given below: 

• To compare the efficacy of a particular drug.
• To find out an association between two attributes such as cancer and smoking.
• To identify signs and symptoms of a disease or syndrome. E.g.- cough & typhoid is found by chance and fever is found in almost every case.
• To test usefulness of sera and vaccines in the field-the percentage of attacks or deaths among the vaccinated subjects is compared with that among the unvaccinated ones to find whether the difference observed is statistically significant. 

BIOEQUIVALENCE STUDY IN CLINICAL TRIAL

BIOEQUIVALENCE STUDY AND BIOAVAILABILITY STUDY UNDER CLINICAL TRIAL 

       Bioequivalence study is defined as the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical dosage form becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. The documentation belong to this study can be useful to establish links between (a) early and late clinical trial formulations; (b) formulations used in clinical trial and stability studies, if different;(c) clinical trial formulations and to-be-marketed drug product. Bioequivalence studies are critical component in the post-approval period for certain changes in new drug application (NDA).

Bioequivalence study

    Another term named bioavailability is most important approach in bioequivalence study design. Bioavailabilty means the rate and extent to which the active substance or therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. In the major cases substances are intended to exhibit a systemic therapeutic effect, and a more practical definition can be given for taking into consideration that the substance in the general circulation is in exchange with the substance at the site of action.  

Bioavailability Study

      Bioequivalence of new drug product is to be done whether the extent and rate of absorption is not significantly different from the reference molecule when same dose is administered.

      Bioequivalence study should be carried out for the following types of formulations containing new active ingredient:

1. Oral solutions.
2. Oral and Non-oral formulations with immediate release and systemic action.
3. Modified release dosage form.
4. Fixed combinaiton product.
5. Parenteral formulations.
6. Gaseous formulation.
7. Locally applied product.

      The requirements of study approach may vary with the type of products or formulations. 

ENVIRONMENTAL DISEASES

ENVIRONMENTAL DISEASES

    

     The environment is composed of the outdoor and indoor and occupational environment occupied by small and large population. It also includes our own personal environment. The air we breathe from the environment and the food & water we consume from the environment and the exposure of toxic agents to the environment are major determinants of our health. Our personal environment is influenced by cigarette smoking, tobacco use, alcohol ingestion, therapeutic and non-therapeutic drug consumption and diet.

      The term environmental diseases refer to the conditions caused by exposure to chemical or physical agents in the ambient, workplace and personal environment, including diseases of nutritional origin.

Environmental Disease

Toxicology- It is defined as the science of poison including distribution, effects and mechanisms of action of toxic agents.

Poison- All the substances that are introduced by living organism causes illness or death.

Xenobiotics- They are the exogenous chemicals in the environment like air, water, food and soil that may be absorbed in the body through inhalation, ingestion and skin contact.

       Pollutants produce the disease conducting substances which are consumed by the several parts of human body such as skin, lung, GI tract (Gastrointestinal tract)  from the air, water, soil. They are absorbed into bloodstream thus causes the illness.

        In human body xenobiotics are subjected to phase I reactions i.e. hydrolysis, reduction and oxidation to produce primary metabolite which leads to phase II reactions such as glucuronidation, sulfation, methylation, conjugation to produce the secondary metabolite. This effects on cellular molecules like enzymes, receptors, membrane, DNA causing short and long term toxicological effects.

Air pollutants -Outdoor air pollutant includes Ozone, NO2, SO2, Acid aerosols etc. and indoor air pollutant includes Tobacco smoke, Wood smoke, radon, Formaldehyde etc.

Metal as environmental pollutants- lead, mercury, arsenic, camium.

Some diseases are informed below-

• hemolysis, bone-marrow suppression.
• Brain damage is prone to occur to the children
• kidney may develop tubular damage.
• several abdominal pain may occur.  

CLINICAL TRIAL INSPECTION PROGRAMME

CLINICAL TRIAL INSPECTION

    Clinical trial inspection programme generally covers all the sites of clinical trial and sponsor/ Clinical research organization (CRO) facilities involved in clinical trial of new chemical molecules including biologically active agent and medical device covered under Drug's & Cosmetic's Act.

Clinical Trial Inspection

Objectives:  

1. To verify the study with the Good Clinical Practice in compliance to protect the rights, safety and well being of the subjects involved in the clinical trial.
2. To verify the clearance and integrity of clinical trial data which are generated.
3. To verify the compliance with various regulatory decision as per Drugs & Cosmetics Act.

     The purpose of clinical trial inspection programme is to give direction to inspectors and sponsor for conducting inspection of site of clinical trial, activities of sponsor, investigator, monitor, audit involved in clinical trial and information to investigators, sponsor, clinical research organization about procedures for the inspection of clinical trial study. In the clinical research site an inspector is allowed to perform the inspection of the clinical trial site identification i.e. name, address etc. and the facilities of sponsor as well as CRO.

       Inspection is to be conducted before, during or after the end of research study. Inspection must be carried out as a routine surveillance. Actually clinical trial inspection is required to see the nature of clinical research study, regulatory function, data irregularities, participation of subjects in a proper way.

       The inspection consists of the verification of essential clinical research documents to determine all the activities is to be done in accordance with Good Clinical Practice (GCP), The Protocol, Schedule Y and another applicable regulatory requirements. After the completion of clinical trial, inspection is to be carried out to ascertain the comparison of data generated from the trial with source data which has been obtained from the information of the comparable drug which has been already marketed. 

ETHICAL ISSUES IN CLINICAL TRIALS

ETHICAL ISSUES IN CLINICAL TRIAL

      Ethics is an integral part of new drug molecule development. The main ethical issues are the needs and rights of each part of clinical trial kept maintaining as per as Guideline. Government appointed regulators and investigators who are involved in every study conducted on human beings have to be reviewed by an independent regulatory committee.

Ethical issues

     Clinical trial which form the best way to a new chemical molecule poses the big challenge to the Ethicist, as the potential clinical trial subject who is likely to benefit from a marketed drug, is also at the risk of adverse effects or adverse events of the investigational product (IP). If the human subjects participate in the clinical trial, the benefit risks ration of Investigational product can not be displayed and the new molecule can not be developed into a useful therapy.

      Ethical issues are mainly provided to ascertain the ensure about the requirement of clinical trial, available information about investigational product such as its benefits or risks to the subjects, benefit risk ratio of IP, study methodology, any physical risks or inconveniences that may occur in any time to the subjects. It also make sure that the subjects are informed about the risks and benefits of participating in the trial, the reimbursement provided for the participating in the trial. This must check the investigstor's compatibility to conduct the clinical trial and give the proper care to the subjects during each step of study. It includes the methods of listing the identification of the subjects and medical information and also tell when the trial results will be published. 

     Good Clinical Practice (GCP) provides the guidelines which helps to show the way to manage the ethical issues in a clinical trial.the investigator makes sure about the compliance the trial procedure and regulatory requirements as per as GCP guideline and Declaration of Helsinki to protect the life, health, privacy and dignity of the human subject.

CLINICAL TRIAL-INFORMED CONSENT

INFORMED CONSENT IN CLINICAL TRIAL

     Clinical research is a thoroughly study of new chemical molecule on human being for the purpose of being ascertain the molecule is useful to treat the disease or not. It consists of four phases. The candidate who participate in the study is also known as subject. During first and second phase healthy subjects are needed and in the later phases the unhealthy subjects join in the study. The subjects are provided a complete clear Informed Consent Form (ICF) which elaborate the body of clinical trial where they want to participate.

Informed consent form to the subject

    The informed consent is a very essential part of the clinical research body. The Informed Consent Form (ICF) is a subject's written agreement to voluntarily participate in a trial based on full disclosure by the researcher about nature of clinical trial,the trial procedures, financial implications for the appearance in trial, Potential benefits, Potential risks.

    The consent process during which information is disclosed is based on interview with the subject/ legally acceptable representative, after which the subject is given reasonable time to clarify doubts.

    The purpose of informed consent is to make transparency regarding the trial for the subject and enable subject make an informed choice regarding participation. It is safeguard for the subject as well as the researcher.

    Actually the consent form involve in giving subject adequate information concerning the study. ICF also helps in responding to the subject's questions. It must be sure that the subject understand it completely and The subject has to put a sign in ICF.

   Generally adult subjects who are capable of joining in the study, legally acceptable representatives of adult subjects who are not competent i.e. Unconscious subjects, Confused subjects etc. and legally acceptable representatives of minors. 

CLINICAL TRIAL-PHASES

CLINICAL RESEARCH

      As per the Guideline of Clinical Practice (GCP) a clinical trial is a research study on human subjects intended to discover or verify the clinical, pharmacological, and also pharmacodynamic effects of an investigational product and to find out any adverse reaction or adverse events of an investigational product and also to study about pharmacology i. e. absorption, distribution, mechanism and excretion of an investigational product with the object of ascertaining its safety and efficacy..   

Clinical Trial

      The total process of bringing a new chemical molecule from laboratory to get the approval of marketing is tedious and more expensive. But it has been found that the success rate of new molecule development is very low. It is found that one out of very 10,000 molecules has been found to treat disease. Before clinical research of the new molecule on human body, this study is to be tested on animal to ensure about toxicological and pharmacological effects of new chemical molecule which helps to select the dose is to be given and proper guidance to the clinicians.

      The clinical testing of new chemical molecule consists of four phases.

Phase I-  Researchers test an experimental molecule to determine a safe dosage range and identify side effects and is to be done in a small group of healthy human volunteers (20-100).

Phase II-  The experimental study of new chemical entity is given to a larger group of healthy volunteer (100-300) to find out its efficacy whether it is effective or not and also to evaluate its safety.

Phase III- The molecule is tested in a large group of patients (1,000-3,000) to confirm its effectiveness, monitor the adverse events or effects, compare it to commonly used in treatments and to make ensure about the new molecule is to be used safely.

Phase IV- Post marketing trial is needed to ascertain the information about the drug's risks, benefits and optimal use. Actually this study is to be done to compare this experimental molecule with another drugs already in the market.