Q37:Â Please define, in your own words, what are Elimination Rate Constant and Half-life?
Answer: Elimination rate constant is a value used in pharmacokinetics to calculate the rate at which drugs are removed from the system.
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Half-life: The duration of action of a drug is known as its half life. This is the period of time required for the concentration or amount of drug in the body to be reduced by one-half. We usually consider the half life of a drug in relation to the amount of the drug in plasma. A drug’s plasma half-life depends on how quickly the drug is eliminated from the plasma. A drug molecule that leaves plasma may have any of several fates. It can be eliminated from the body, or it can be translocated to another body fluid compartment such as the intracellular fluid or it can be destroyed in the blood. The removal of a drug from the plasma is known as clearance and the distribution of the drug in the various body tissues is known as the volume of distribution. Both of these pharmacokinetic parameters are important in determining the half life of a drug.
Here is the symbol to represent the half-life: t½.
Q36: Define  the term “Second Messenger Systems?
 Answer:
Second Messenger Systems
Second messenger systems are complexes of regulatory (eg, G-proteins) and catalytic (eg, adenylate cyclase, phospholipase C) proteins, which are activated by NTs (first messengers) to form specific chemicals or second messengers (eg, cAMP, inositol triphosphate or IP3, diacylglycerol or DAG).
Adenylate cyclase-cAMP is the best known second messenger system.  Here, the first messenger (NT, hormone) binds to the receptor activating a stimulatory G-protein  (Gs) by displacing guanosine diphosphate (GDP) with guanosine triphosphate (GTP). G-proteins consist of alpha, beta, and gamma subunits; the alpha unit binds the guanine nucleotide and provides specificity for receptors.  The activated protein amplifies the signal of the first messenger and activates adenylate cyclase.  This enzyme converts adenosine triphosphate (ATP) to cAMP, which activates specific phosphorylating enzymes or protein kinases to produce the physiologic response.  The action of cAMP is terminated by the enzyme phosphodiesterase.  In addition to the stimulatory G-protein, inhibitory G-proteins (Gi) exist.  By activation of a different receptor and this Gi, adenylate cyclase is inhibited.  In each category, different G-proteins have been identified (Gs1, Gs2, Gs3 and Gi1, Gi2, Gi3).
Phosphoinositide system – generates 2 second messengers, IP-3 and DAG.  Upon receptor stimulation and G-protein activation, phospholipase C is stimulated, which hydrolases membrane phosphatidyl inositol 4,5-biphosphate into IP-3 and DAG.  IP-3 releases calcium from intracellular stores, and DAG activates protein kinase C. Effects on ion channels or phosphorylation of specific proteins causes the physiologic effects.
Types of secondary messenger molecules
There are three basic types of secondary messenger molecules:
These intracellular messengers have some properties in common:
They can be synthesized/released and broken down again in specific reactions by enzymes or ion channels.
Some (like Ca2+) can be stored in special organelles and quickly released when needed.
Their production/release and destruction can be localized, enabling the cell to limit space and time of signal activity.
Common mechanisms of secondary messenger systems
There are several different secondary messenger systems (cAMP system,phosphoinositol system, and arachidonic acid system), but they all are quite similar in overall mechanism, though the substances involved in those mechanisms and effects are different.
In all of these cases a neurotransmitter binds to a membrane-spanning receptor proteinmolecule. The binding of the neurotransmitter to the receptor changes the receptor and causes it to expose a binding site for a G-protein. The G-protein (named for the GDPand GTP molecules that binds to it) is bound to the inner membrane of the cell and consists of three subunits: alpha, beta and gamma. The G-protein is known as the “transducer.”
When the G-protein binds to the receptor, it becomes able to exchange a GDP (guanosine diphosphate) molecule on its alpha subunit for a GTP (guanosine triphosphate) molecule. Once this exchange takes place, the alpha subunit of the G-protein transducer breaks free from the beta and gamma subunits, all parts remaining membrane-bound. The alpha subunit, now free to move along the inner membrane, eventually contacts another membrane-bound protein – the “primary effector.”
The primary effector then has an action, which creates a signal that can diffuse within the cell. This signal is called the “secondary messenger.” (The neurotransmitter is the first messenger.) The secondary messenger may then activate a “secondary effector” whose effects depend on the particular secondary messenger system.
Calcium ions are responsible for many important physiological functions, such as in muscle contraction. It is normally bound to intracellular components even though a secondary messenger is a plasma membrane receptor. Calcium regulates the protein calmodulin, and, when bound to calmodulin, it produces an alpha helical structure. This is also important in muscle contraction. The enzyme phospholipase C producesdiacylglycerol and inositol triphosphate, which increases calcium ion permeability into the membrane. Active G-protein open up calcium channels to let calcium ions enter the plasma membrane. The other product of phospholipase C, diacylglycerol, activatesprotein kinase C, which assists in the activation of cAMP(another second messenger).
Q35:Â What is important to know regarding investigative drug administration from a general principles of pharmacology perspective?
Answer:Â Drugs are compounds almost always foreign to the body. As such, they are not continually being formed and eliminated as are endogenous substances. The processes of inputting, distributing, and eliminating drugs are therefore of paramount importance in determining the onset, duration, and intensity of effectand should be considered regarding investigative drug administration.
DRUG ABSORPTION
The process of drug movement from the site of administration toward the systemic circulation.
The processes by which drugs move across a biologic barrier include passive diffusion, facilitated diffusion, active transport, and pinocytosis
Oral Administration
Because the oral route of administration is the most common, absorption usually refers to the transport of drugs across the membranes of the epithelial cells within the GI tract. Absorption after oral administration is confounded by differences down the alimentary canal in the luminal pH; surface area per luminal volume; perfusion of the tissue, bile, and mucus flow; and the epithelial membranes. The faster absorption of acids in the intestine compared with the stomach appears to contradict the hypothesis that the nonionized form of a drug more readily crosses membranes.
Gastric emptying and intestinal transit time: Because the absorption of virtually all compounds is faster from the small intestine than from the stomach, the rate of gastric emptying is a controlling step. Food, especially fatty foods, slows gastric emptying, which explains why some drugs are recommended to be taken on an empty stomach when a rapid onset of action is desired. The extent of absorption may be enhanced by food if the drug is poorly soluble (e.g., griseofulvin) or reduced if degraded in the stomach (e.g., penicillin G). Drugs that affect gastric emptying (parasympatholytic agents) also affect the rate of absorption of other drugs.
Parenteral Administration
Direct placement of a drug into the bloodstream (usually IV) ensures complete delivery of the dose to the general circulation. However, administration by a route that requires drug transfer through one or more biologic membranes to reach the bloodstream precludes a guarantee that all of the drug will eventually be absorbed. Intra-muscular (IM) or Sub-cutaneous (S.C.). injection of drugs bypasses the skin barrier, but the drug must penetrate the capillary walls. Because the capillaries tend to be highly porous, the perfusion (blood flow/gram of tissue) is a major factor in the rate of absorption. Thus, the injection site can markedly influence a drug’s absorption rate.
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BIOAVAILABILITY
The rate at which and the extent to which the active moiety (drug or metabolite) enters the general circulation, thereby gaining access to the site of action.
Although a drug may be absorbed completely, its rate of absorption may also be important. It may be too slow to attain a therapeutic blood level in an acceptable period of time or too rapid, resulting in toxicity from high drug levels just after each dose.
Causes of Low Values of Bioavailability
When a drug rapidly dissolves from a drug product and readily passes across membranes, absorption from most sites of administration tends to be complete. This is not always the case for drugs given orally. Before reaching the vena cava, a drug must move down the alimentary canal and pass through the gut wall and liver, which are common sites of drug metabolism ,thus, the drug may be metabolized before it can be measured in the general circulation. This cause of a decrease in drug input is called the first-pass effect. A large number of drugs show low bioavailabilities owing to extensive first-pass metabolism. In many instances, the extraction is so complete that the bioavailability is virtually zero ( isoproterenol, norepinephrine, phenacetin, and testosterone).
The 2 other most frequent causes of low bioavailability are an insufficient time in the GI tract and the presence of competing reactions. Ingested drug is exposed to the entire GI tract for no more than 1 to 2 days and to the small intestine for only 2 to 4 h, unless gastric emptying is considerably delayed. If the drug does not dissolve readily or if the drug is incapable of penetrating the epithelial membrane (highly ionized and polar), there may be insufficient time at the absorption site. Not only is the bioavailability low in this case, but it tends to be highly variable. In addition, individual variations in age, sex, activity, genetic phenotype, stress, disease ( achlorhydria, malabsorption syndromes), and previous GI surgery can alter and further increase variability in drug bioavailability.
Reactions that compete with absorption can reduce bioavailability – include complex formation; hydrolysis by gastric pH or digestive enzymes ;conjugation in gut wall ; adsorption to other drugs and metabolism by luminal microflora.
DRUG ELIMINATION
The sum of the processes of drug loss from the body. Removal of drugs from the body occurs by metabolism and excretion.
METABOLISM
The process of chemical alteration of drugs in the body. The liver is the principal, but not the sole, site of drug metabolism. Some metabolites are pharmacologically active. When the substance administered is inactive and an active metabolite is produced, the administered compound is called a pro-drug.
Changes with Age
Neonates have partially developed liver microsomal enzyme systems and, consequently, have difficulty with the metabolism of many drugs. Elderly patients often show a reduced ability to metabolize drugs. The reduction varies depending on the drug and is not as severe as that in neonates.
Individual Variation
Variability among individuals makes it difficult to predict the clinical response to a given dose of a drug. Some patients may metabolize a drug so rapidly that therapeutically effective blood and tissue levels are not achieved; in others, metabolism may be so slow that toxic effects result with usual doses. Concurrent disease states, particularly chronic liver disease, drug interactions, especially those involving induction or inhibition of metabolism, and other factors also contribute.
PRECLINICAL AND CLINICAL EVALUATION OF TOXICITY
Before a drug is approved for general clinical use by the FDA, preclinical and clinical data showing substantial evidence of safety and efficacy are required by law. Drug studies proceed through various phases, as follows.
Preclinical Investigation (Animal Studies)
Animal studies used to determine or define the safety of a drug include studies of acute, subchronic, and chronic toxicity in several animal species.
The initial acute toxicity studies are to determine the median lethal dose (LD50), the toxic symptoms developed by the animals, and the time that they appear. At least 3 species of animals, one not a rodent, are usually used, and acute toxicity is usually determined by more than one route of administration.
Subchronic toxicity studies are conducted in at least 2 animal species and usually consist of daily administration of the test drug for up to 90 days. In each species, at least 3 dose levels are used, varying from the expected therapeutic doses to levels high enough to produce toxicity.
Chronic toxicity studies are carried out in at least 2 species, one of which is not a rodent. These studies usually last for up to the lifetime of the animal, but their length will depend on the intended duration of administration of the drug to humans.
Clinical Investigation (Human Studies)
Some adverse effects of drugs cannot be discerned in animals; e.g., dizziness, nausea, headaches, ringing in the ears, heartburn, and depression. It has been estimated that >= 50% of undesirable drug effects seen most frequently can be ascertained only during human trials.
Phase 1 represents the first administration of a new drug to man. A small number of closely monitored subjects, mainly healthy volunteers, are usually involved. Initially, each receives a single dose of the drug to determine a safe dose range and assess pharmacokinetic data. The primary objective of this necessarily cautious phase of the investigation is to determine a safe and tolerated dosage in humans; however, observation of toxicity, if it occurs, and of absorption, metabolism, and excretion may also be made during Phase 1.
Phase 2 begins after satisfactory preliminary evidence regarding safety has been obtained. It involves the supervised administration of the drug to patients for treatment of, or prophylaxis against, the disease or symptoms for which the drug is intended. These studies usually are conducted in randomized clinical trials comparing the new drug with the prototype drug, if any, for a particular indication. Often this is the first opportunity to observe the effect of long-term administration of the drug to humans.
Phase 3 begins after the initial phases have provided reasonable evidence of safety and efficacy. It consists of more widespread clinical trials that may move from the realm of clinical investigators to practicing physicians. Phase 3 extends up to the time the drug is released for general use.
Phase 4 is the study of the actual use of the drug in medical practice and, though often not recognized as a phase of clinical investigation, is a most important one from a clinical standpoint.
Q34:Â Please prepare some proper advertising for the imaginary drug, Happymycin, that would treat Mood Disorders (Depressions) as a prescriptive drug only?
Happymycin is prescribed for the treatment of depression–that is, a continuing depression that interferes with daily functioning. The symptoms of major depression often include changes in appetite, sleep habits, and mind/body coordination; decreased sex drive; increased fatigue; feelings of guilt or worthlessness; difficulty concentrating; slowed thinking; and suicidal thoughts.
Happymycin is also prescribed to treat obsessive-compulsive disorder. An obsession is a thought that won’t go away; a compulsion is an action done over and over to relieve anxiety. The drug is also used in the treatment of bulimia (binge-eating followed by deliberate vomiting). It has also been used to treat other eating disorders and obesity.
In addition, Happymycin is used to treat panic disorder, including panic associated with agoraphobia (a severe fear of being in crowds or public places). People with panic disorder usually suffer from panic attacks–feelings of intense fear that develop suddenly, often for no reason. Various symptoms occur during the attacks, including a rapid or pounding heartbeat, chest pain, sweating, trembling, and shortness of breath.
In children and adolescents, Happymycin is used to treat major depression and obsessive-compulsive disorder.
Happymycin Weekly is approved for treating major depression.
Happymycin  belongs to the class of drugs called selective serotonin re-uptake inhibitors (SSRIs). Serotonin is one of the chemical messengers believed to govern moods. Ordinarily, it is quickly reabsorbed after its release at the junctures between nerves.
Most important fact about Happymycin
Serious, sometimes fatal, reactions have been known to occur when Happymycin is used in combination with other antidepressant drugs known as MAO inhibitors, including Nardil and Parnate; and whenHappymycin is discontinued and an MAO inhibitor is started. Never take Happymycin with one of these drugs or within at least 14 days of discontinuing therapy with one of them; and allow 5 weeks or more between stopping Happymycin and starting an MAO inhibitor. Be especially cautious if you have been taking Happymycin in high doses or for a long time.
If you are taking any prescription or nonprescription drugs, notify your doctor before taking Happymycin.
How should you take Happymycin?
Happymycin should be taken exactly as prescribed by your doctor.
Happymycin  usually is taken once or twice a day. To be effective, it should be taken regularly. Make a habit of taking it at the same time you do some other daily activity.
–If you miss a dose…
Take the forgotten dose as soon as you remember. If several hours have passed, skip the dose. Never try to “catch up” by doubling the dose.
–Storage instructions…
Store at room temperature.
What side effects may occur?
Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Happymycin.
·More common side effects may include:
Abnormal dreams, abnormal ejaculation, abnormal vision, anxiety, diarrhea, diminished sex drive, dizziness, dry mouth, flu-like symptoms, flushing, gas, headache, impotence, insomnia, itching, loss of appetite, nausea, nervousness, rash, sex-drive changes, sinusitis, sleepiness, sore throat, sweating, tremors, upset stomach, vomiting, weakness, yawning
Q2:Â As a CRA, choosing a new patient recruitment strategy, how would you use benchmarking and metrics to improve patient enrolment ?
Answer: As a CRA I would think about how to organize an interactive survey among potential study volunteers.Then I will create a series of targeted questions based on information from previous patient polls, and feedback from the audience, aimed at understanding the potential study volunteer. I will also try to add questions about the previous study inorder to compare with the new study.I will then post this collectively developed questionaire online and invite potential study volunteers to complete it.Once I got the answers from the patients I will try to analyse what patient wants in a new trial by using metrics and benchmarking and then choose a recruitment strategy that will best suits the patient.
Q32:Please list, in general terms, the principles of safety pharmacology studies in humans?
Answer:
Since pharmacological effects vary depending on the specific properties of each test substance, the studies should be selected and designed accordingly. The following factors should be considered:
1. Effects related to the therapeutic class of the test substance, since the mechanism of action may suggest specific adverse effects (e.g., proarrhythmia is a common feature of antiarrhythmic agents)
2. Adverse effects associated with members of the chemical or therapeutic class, but independent of the primary pharmacodynamic effects (e.g., antipsychotics and QT prolongation)
3. Ligand binding or enzyme assay data suggesting a potential for adverse effects
4. Results from previous safety pharmacology studies, from secondary pharmacodynamic studies, from toxicology studies, or from human use that warrant further investigation to establish and characterize the relevance of these findings to potential adverse effects in humans
During early development, sufficient information (e.g., comparative metabolism) may not always be available to rationally select or design the studies in accordance with the points stated above; in such circumstances, a more general approach in safety pharmacology investigations can be applied.
A hierarchy of organ systems can be developed according to their importance with respect to life-supporting functions. Vital organs or systems, the functions of which are acutely critical for life (e.g., the cardiovascular, respiratory, and central nervous systems), are considered to be the most important ones to assess in safety pharmacology studies. Other organ systems (e.g., the renal or gastrointestinal system), the functions of which can be transiently disrupted by adverse pharmacodynamic effects without causing irreversible harm, are of less immediate investigative concern. Safety pharmacology evaluation of effects on these other systems may be of particular importance when considering factors such as the likely clinical trial or patient population (e.g., gastrointestinal tract in Crohn’s disease, renal function in primary renal hypertension, immune system in immunocompromised patients).
ï‚·Â Â Â Â Â Â Â Â Â General Considerations on Test Systems
Consideration should be given to the selection of relevant animal models or other test systems so that scientifically valid information can be derived. Selection factors can include the pharmacodynamic responsiveness of the model, pharmacokinetic profile, species, strain, gender and age of the experimental animals, the susceptibility, sensitivity, and reproducibility of the test system and available background data on the substance
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ï‚·Â Â Â Â Â Â Â Â Â Use of In Vivo and In Vitro Studies
In vitro systems can be used in supportive studies (e.g., to obtain a profile of the activity of the substance or to investigate the mechanism of effects observed in vivo).
In conducting in vivo studies, it is preferable to use unanesthetized animals. Data from unrestrained animals that are chronically instrumented for telemetry, data gathered using other suitable instrumentation methods for conscious animals, or data from animals conditioned to the laboratory environment are preferable to data from restrained or unconditioned animals. In the use of unanesthetized animals, the avoidance of discomfort or pain is a foremost consideration.
Experimental Design
a. Sample Size and Use of Controls
The size of the groups should be sufficient to allow meaningful scientific interpretation of the data generated. Thus, the number of animals or isolated preparations should be adequate to demonstrate or rule out the presence of a biologically significant effect of the test substanceThe exclusion of controls from studies should be justified.
b. Route of Administration
In general, the expected clinical route of administration should be used when feasible. Regardless of the route of administration, exposure to the parent substance and its major metabolites should be similar to or greater than that achieved in humans when such information is available. Assessment of effects by more than one route may be appropriate if the test substance is intended for clinical use by more than one route of administration (e.g., oral and parenteral) or where there are observed or anticipated significant qualitative and quantitative differences in systemic or local exposure.
D. Dose Levels or Concentrations of Test Substance
1. In Vivo Studies
In vivo safety pharmacology studies should be designed to define the dose-response relationship of the adverse effect observed. The time course (e.g., onset and duration of response) of the adverse effect should be investigated, when feasible. Generally, the doses eliciting the adverse effect should be compared to the doses eliciting the primary pharmacodynamic effect in the test species or the proposed therapeutic effect in humans, if feasible. It is recognized that there are species differences in pharmacodynamic sensitivity. Therefore, doses should include and exceed the primary pharmacodynamic or therapeutic range. In the absence of an adverse effect on the safety pharmacology parameters evaluated in the study, the highest tested dose should be a dose that produces moderate adverse effects in this or in other studies of similar route and duration. These adverse effects can include dose-limiting pharmacodynamic effects or other toxicity. In practice, some effects in the toxic range (e.g., tremors or fasciculation during ECG recording) may confound the interpretation of the results and may also limit dose levels. Testing of a single group at the limiting dose as described above may be sufficient in the absence of an adverse effect on safety pharmacology endpoints in the test species.
2. In Vitro Studies
In vitro studies should be designed to establish a concentration-effect relationship. The range of concentrations used should be selected to increase the likelihood of detecting an effect on the test system. The upper limit of this range may be influenced by physico-chemical properties of the test substance and other assay specific factors. In the absence of an effect, the range of concentrations selected should be justified.
F. Studies on Metabolites, Isomers, and Finished Products
In vitro or in vivo testing of the individual isomers should also be considered when the product contains an isomeric mixture.
Safety pharmacology studies with the finished product formulations should be conducted only for formulations that substantially alter the pharmacokinetics and/or pharmacodynamics of the active substance in comparison to formulations previously tested (i.e., through active excipients such as penetration enhancers, liposomes, and other changes such as polymorphism).
G. Safety Pharmacology Core Battery
The purpose of the safety pharmacology core battery is to investigate the effects of the test substance on vital functions. In this regard, the cardiovascular, respiratory, and central nervous systems are usually considered the vital organ systems that should be studied in the core battery.
H. Follow-up Studies For Safety Pharmacology Core Battery
Follow-up studies are meant to provide a greater depth of understanding than, or additional knowledge to, that provided by the core battery on vital functions. The following subsections provide lists of studies to further evaluate these organ systems for potential adverse pharmacodynamic effects. These lists are not meant to be comprehensive or prescriptive, and the studies should be selected on a case-by-case basis after considering factors such as existing nonclinical or human data. In some cases, it may be more appropriate to address these effects during the conduct of other nonclinical and/or clinical studies.
I. Conditions Under Which Studies Are Not Necessary
Safety pharmacology studies may not be needed for locally applied agents (e.g., dermal or ocular) where the pharmacology of the test substance is well characterized, and where systemic exposure or distribution to other organs or tissues is demonstrated to be low.
Safety pharmacology studies prior to the first administration in humans may not be needed for cytotoxic agents for treatment of end-stage cancer patients. However, for cytotoxic agents with novel mechanisms of action, there may be value in conducting safety pharmacology studies.
For biotechnology-derived products that achieve highly specific receptor targeting, it is often sufficient to evaluate safety pharmacology endpoints as a part of toxicology and/or pharmacodynamic studies; therefore, safety pharmacology studies can be reduced or eliminated for these products
J.Laboratory Practice (GLP)
It is important to ensure the quality and reliability of nonclinical safety studies. This is normally accomplished through the conduct of the studies in compliance with GLP. Due to the unique design of, and practical considerations for, some safety pharmacology studies, it may not be feasible to conduct these in compliance with GLP. It has to be emphasized that data quality and integrity in safety pharmacology studies should be ensured even in the absence of formal adherence to the principles of GLP. When studies are not conducted in compliance with GLP, study reconstruction should be ensured through adequate documentation of study conduct and archiving of data. Any study or study component not conducted in compliance with GLP should be adequately justified, and the potential impact on evaluation of the safety pharmacology endpoints should be explained.
Q31: Please list the Financial Disclosure Requirements of the FDA?
Answer:
Under the applicable regulations (21 CFR Parts 54, 312, 314, 320, 330, 601, 807, 812, 814, and 860), an applicant is required to submit to FDA a list of clinical investigators who conducted covered clinical studies and certify and/or disclose certain financial arrangements as follows:
1. Certification that no financial arrangements with an investigator have been made where study outcome could affect compensation; that the investigator has no proprietary interest in the tested product; that the investigator does not have a significant equity interest in the sponsor of the covered study; and that the investigator has not received significant payments of other sorts; and/or
2. Disclosure of specified financial arrangements and any steps taken to minimize the potential for bias.
Disclosable Financial Arrangements:
1. Compensation made to the investigator in which the value of compensation could be affected by study outcome. This requirement applies to all covered studies, whether ongoing or completed as of February 2, 1999.
2. A proprietary interest in the tested product, including, but not limited to, a patent, trademark, copyright or licensing agreement. This requirement applies to all covered studies, whether ongoing or completed as of February 2, 1999.
3. Any equity interest in the sponsor of a covered study, i.e., any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices. This requirement applies to all covered studies, whether ongoing or completed;
4. Any equity interest in a publicly held company that exceeds $50,000 in value. These must be disclosed only for covered clinical studies that are ongoing on or after February 2, 1999. The requirement applies to interests held during the time the clinical investigator is carrying out the study and for 1 year following completion of the study; and
5. Significant payments of other sorts, which are payments that have a cumulative monetary value of $25,000 or more made by the sponsor of a covered study to the investigator or the investigators’ institution to support activities of the investigator exclusive of the costs of conducting the clinical study or other clinical studies, (e.g., a grant to fund ongoing research, compensation in the form of equipment or retainers for ongoing consultation or honoraria) during the time the clinical investigator is carrying out the study and for 1 year following completion of the study. This requirement applies to payments made on or after February 2, 1999.
Q31: Please list the Financial Disclosure Requirements of the FDA?
Answer:
Under the applicable regulations (21 CFR Parts 54, 312, 314, 320, 330, 601, 807, 812, 814, and 860), an applicant is required to submit to FDA a list of clinical investigators who conducted covered clinical studies and certify and/or disclose certain financial arrangements as follows:
1. Certification that no financial arrangements with an investigator have been made where study outcome could affect compensation; that the investigator has no proprietary interest in the tested product; that the investigator does not have a significant equity interest in the sponsor of the covered study; and that the investigator has not received significant payments of other sorts; and/or
2. Disclosure of specified financial arrangements and any steps taken to minimize the potential for bias.
Disclosable Financial Arrangements:
1. Compensation made to the investigator in which the value of compensation could be affected by study outcome. This requirement applies to all covered studies, whether ongoing or completed as of February 2, 1999.
2. A proprietary interest in the tested product, including, but not limited to, a patent, trademark, copyright or licensing agreement. This requirement applies to all covered studies, whether ongoing or completed as of February 2, 1999.
3. Any equity interest in the sponsor of a covered study, i.e., any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices. This requirement applies to all covered studies, whether ongoing or completed;
4. Any equity interest in a publicly held company that exceeds $50,000 in value. These must be disclosed only for covered clinical studies that are ongoing on or after February 2, 1999. The requirement applies to interests held during the time the clinical investigator is carrying out the study and for 1 year following completion of the study; and
5. Significant payments of other sorts, which are payments that have a cumulative monetary value of $25,000 or more made by the sponsor of a covered study to the investigator or the investigators’ institution to support activities of the investigator exclusive of the costs of conducting the clinical study or other clinical studies, (e.g., a grant to fund ongoing research, compensation in the form of equipment or retainers for ongoing consultation or honoraria) during the time the clinical investigator is carrying out the study and for 1 year following completion of the study. This requirement applies to payments made on or after February 2, 1999.
Q:Find (in the literature or on Internet) a story on clinical trials fraud. What factors could have played a significant roll in order to detect fraud in your story? Answer:
Fraud in breast cancer study;
Doctor lied on data for decade.
Chicago Tribune, 13 March 1994
A 1989 New England Journal of Medicine article on breast cancer therapy presented findings from a study directed by Fisher. Recurrence rates for cancer after lumpectomy and radiation were compared with rates following mastectomy.
The study involved 5,000 patients at nearly 500 medical centers. The recurrence rates were found to be essentially the same, leading many women to opt for the less disfiguring lumpectomy and radiation treatment.
This article reported that Federal investigators discovered that one of the principal collaborators, Dr.
Roger Poisson at the University of Montreal, enrolled at least 100 of his cancer patients who were not eligible for the study and falsified their records to make them appear eligible.
It is suggested that Poisson was not trying to affect the outcome but only wanted to appear good at
recruiting patients, in order to improve his chances for continued financial support. Poisson contributed about 16% of the patients to the 1989 study.
The organizers of the study privately assured investigators nearly two years ago that the fraud did
not affect the results of any of their findings. Fisher promised to publish a re-analysis of the data.
Later news articles reported that Federal health officials have commissioned three statisticians to
analyze the study independently and to give their report in two weeks. Fisher is now expected to give his own analysis to the New England Journal of Medicine within the next two weeks.
Factors that played a significant role in order to detect fraud:
1) Checking the patient ID cards and papers played a vital role in catching the fraud.
2)The dates of prohibited medication use altered or suppressed. The subject was treated, but it was not put in chart or on the CRF. So interviewing the patients thoroughly payed an important role in identifying patients who had antibiotic treatments but not reported in CRF.
Q1: Please list regular inspection activities during a Clinical Trial? Answer:.
The main objectives for the inspection of clinical trials is to ensure that the generally accepted principles of good clinical practices are met, validate the quality of the data generated, and verify compliance to Division 5 of the Regulations.
Sponsors, Qualified Investigators, Contract Research Organizations and Site Management Organizations will be inspected.
The total number of inspections may vary depending on the time required for investigations.
Two types of inspections will be performed:
1. Inspection during clinical trials, and
2. Inspection after the completion of clinical trials.
The choice of inspection sites will be reviewed periodically in consultation with the Therapeutic Products Directorate (TPD) and the Biologics and Genetic Therapies Directorate (BGTD) of the HPFB and will take into consideration:
1. The level of risk to the enrolled subjects, and
2. The observations made during past inspections.
Compliance will be assessed in accordance with Division 5 of the Food and Drug Regulations, Good Clinical Practices (GCP) and other pertinent guidelines.
Following are the list regular inspection activities during a Clinical Trial:  Opening Meeting to confirm purpose of inspection, provide introductions and methodology.
 Combination of staff interviews, document review and facility visits.
 Finding missing elements,inconsistencies with protocol, Forms not updated with amendments, Poor version control, Incorrect form used and unclear process.
 Use study specific examples to demonstrate the system.
 Feedback of general findings at closing meeting.
Question28: Please, list the functions of MedDRA Maintenance and Support Services Organization. What is the main idea of MedDRA?
Main Idea:
MedDRA was developed in response to a need recognized by ICH to standardize the medical terminology used internationally to discuss the regulation of medical products. This terminology is used to share information regarding medical product registration, documentation and safety monitoring of human medical products both before and after a medical product has been authorized for sale. Functions:
MedDRA includes terminology for symptoms, signs, diseases and diagnoses. In addition, it contains the names of investigations (e.g. Liver function analyses, metabolism tests), sites (e.g. application site reactions, implant site reactions and injection site reactions), therapeutic indications, surgical and medical procedures and medical, social and family history terms.
1)The MedDRA Maintenance and Support Services Organization (MSS0) keeps, maintains and distributes MedDRA information. MedDRA users request additions and deletions to the terminology through a process described on the MSSO homepage. Updated information is regularly sent to subscribers via CD-ROM.
2)MedDRA terminology will be used to express medical concepts in certain Modules of the Common Technical Document.
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4)It will provide significant improvement over current terminologies in comprehensiveness and specificity. The data retrieval capabilities of the terminology will facilitate and simplify regulatory processes.
Question27:Â Please, list the functions of The Safety Monitoring Committee ?
Answer:
The primary functiony of the SMC is to monitor participant safety.
1)Periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and, when appropriate, efficacy, and
2) Make recommendations to DMID concerning the continuation, modification, or termination of the trial. DSMBs meet regularly and whenever any special need arises to review study conduct and cumulative study data, and to recommend whether the study should continue without change, be modified, or be terminated.. Investigators and POs should consider having at least one member of the SMC serve as an Independent Safety Monitor (see below).
3)The SMC must be able to convene on an ad hoc basis when immediate safety concerns arise. Its members may be from the investigator’s institution or other participating sites but should not be directly involved with the trial or under the investigator’s supervision..
4)The SMC considers study-specific data as well as relevant background information about the disease, test agent, and target population under study.
5)The SMC is also responsible for maintaining the confidentiality of its internal discussions and activities as well as the contents of reports provided to it.
6)The SMC should review the protocol, including the safety monitoring plan, and identify any major concerns prior to implementation. During the trial the SMC should review:
Real-time and cumulative safety data for evidence of study-related adverse events;
Adherence to the protocol;
Factors that might affect the study outcome or compromise the trial data (such as protocol violations, losses to follow-up, etc.); and,
Data relevant to proceeding to the next stage of the study, if applicable.
The SMC should conclude each review with each member’s recommendation to DMID as to whether the study should continue, be modified, or be terminated. Recommendations regarding modification of the design and conduct of the study may include corrective actions when performance is unsatisfactory, or recommendations to advance to the next dose in a dose escalation study, for example, or to the next stage in product testing.
Confidentiality must always be maintained during all phases of SMC review and deliberations. For masked studies, only members of the SMC and study biostatisticians should have access to the emerging study data.
