Significance of Pharmacovigilance for Drug Safety

moment of Pharmacovigilance for do drugs SafetyAIMTo present an overview on the pharmacovigilance practice and slang the signifi crapperce of pharmacovigilance in envisaging dose synthetic rubber and capacityTo decisively tax the pharmacovigilance findings of the anti-diabetic medicine AvandiaINTRODUCTION AND BACKGROUND INFORMATIONThe World Health presidential term defines pharmacovigilance asThe science and activities relating to the detection, assessment, under rest and pr sheathion of adverse effects or any other medicine-related problem.9THE NEED FOR PHARMACOVIGILANCEPrimarily let us understand the need for pharmacovigilance. It has been long debated that the data from animal experiments is not on the whole worth of extrapolation. The differences in their metabolic pathways, resistance to drugs and various other factors, the pharmacokinetics and dynamics of drugs tend to vary deep down species to species as swell up. Extrapolating such statistics from animals to huma ns though necessary is not foolproof.Additionally, the clinical run environment is extremely controlled. The tolerant population, however large, is not a good representative of the general spheric population. The number of patients is limited. Owing to these facts, an adverse effect, which would occur in adept in ten thousand or so, is very unlikely to arise within the restrictions of the clinical trial atmosphere. Moreover, in a real life post the patients using the drug ar likely to adopt other diseases, overpowering other drugs and with various genetic key go forth-ups.Accordingly arises the urgent need for give pharmacovigilance practices. The importance of identifying rare and serious adverse effects of drugs that fill remained clandestine during the course of the clinical trial cannot be ignored.THE STEPS IN PHARMACOVIGILANCE offhanded physical compositioning and prescription event monitoringSpontaneous reports and prescription event monitoring include reports of adverse effects of drugs to sponsors, CROs or restrictive authorities, describe by patients, nurses, doctors and other healthcare professionals and consumers. The above process is streamlined with the patron of global and countrywide structured programs to accelerate the practice and facilitate consumers to usher an adverse effect. Example the National Pharmacovigilance Program in India. All events that are serious (as defined in ICH-GCP), unexpected, unlabeled, additional efficacy and lack of efficacy should be promptly account. An incoming report is called as a carapace report. FDA has defined certain characteristics of a good possibility report. They are as follows1. Description of the adverse events or disease experience, including time to onset of signsor symptoms2. Suspected and concomitant product therapy details (i.e., dose, lot number, schedule,dates, duration), including over-the- expect medications, dietary supplements, andrecently discontinued medications3. Pat ient characteristics, including demographic entropy (e.g., age, race, sex), baseline checkup condition prior to product therapy, co-morbid conditions, use of concomitantmedications, relevant family news report of disease, and presence of other risk factors4. Documentation of the diagnosis of the events, including methods used to make thediagnosis5. clinical course of the event and patient outcomes (e.g., hospitalization or closing)56. Relevant therapeutic measures and laboratory data at baseline, during therapy, and succeeding to therapy, including blood levels, as appropriate7. Information about response to dechallenge and rechallenge and8. any other relevant information (e.g., other details relating to the event or information onbenefits received by the patient, if important to the assessment of the event).6Signal generationA signal is reported information of the possible causative relationship in the midst of an adverse event and the drug, which has been reported to a grea ter extent than at once. The frequency of reports to generate a signal depends on the seriousness of the event, drug class, disease status, authenticity of the reporter etc.Signal follow-up and beef upSignal follow-up and strengthening consists of identifying similar cases in different countries, mine the literature for examine to support the hypothesis, pre-clinical information and patient follow-up. The prospective analysis of reports of interests is crucial for a signal to generate any action. Careful exam has to be done in order to assess the ingenuity of the signal. The report could stick been due to the patients illness fib, concomitant medication, disease state or any other reason not related to the use of drug. blush then, such con ensnareed reports should be analyzed promptly. Signal follow-up ensures authenticity of the reports.Causality assessmentDetermining whether the adverse event has a causal relationship with the drug or not, and if it has, the degree to whi ch the association exists is called as reason assessment. The WHO has defined six degrees of relationship, namely certain, probable, possible, unlikely, conditional/unclassified and unassessable/unclassifiable with sound intensity of causality.ActionAction is bown once it is well realized that there exists a causal relationship in surrounded by the drug and the adverse event. Depending on the severity of the adverse event, action taken can be in the form of withdrawal of selling approval, change in package insert, additional trials to confirm causality and dissemination of information globally.THE practical(a) ASPECTConsider the story of the blockbuster drug Avandia (rosiglitazone), used to continue patients with type II diabetes mellitus.Rosiglitazone (Avandia) is a thiazolidinedione indicated in the treatment of type 2 diabetes mellitusas monotherapy in patients (particularly overweight patients) inadequately controlled by dietand operate for whom metformin is inappropria te because ofcontraindications or intoleranceas duple verbal therapy in combination with metformin, in patients (particularly overweight patients) with insufficientglycaemic control notwithstanding maximal tolerated dose of monotherapy withmetformin a sulphonylurea, only in patients who show intolerance to metformin or forwhom metformin is contraindicated, with insufficient glycaemic controlpatronage monotherapy with a sulphonylureaas triple oral therapy in combination with metformin and a sulphonylurea, in patients (particularly overweight patients)with insufficient glycaemic control despite dual oral therapy4Little did the world know that a bequest was in fact a bane for a certain congregation of people with a history of cardiovascular illnesses. A meta-analysis by Nissen and Wolski et al. provided evidence thatrosiglitazone was associated with a significant change magnitude in the risk of (MI)myocardial infarction (odds ratio, 1.43 95% confidence interval CI, 1.03 to 1.98 P = 0.03) and a borderline-significant finding for death from cardiovascular causes (odds ratio, 1.64 95% CI, 0.98 to 2.74 P = 0.06).2Though the meta-analysis study had quite a few numbers of weaknesses, the increased risk of MI in patients consuming rosiglitazone has come as a rude shock to the sponsors as well as the patient community. Something, which could not be unveiled during the clinical trial process.Another study (called Antipsychotic drugs and tenderness muscle disorder in international pharmacovigilance data mining study) by David Coulter et al. used a Bayesian confidence propagation network to analyze the correlation between anti-psychotic drugs and occurrences of cardiomyopathy and myocarditis. Though the study did not prove much, it did bring up an association between use of clozapine and incidences of heart disorders. It besides scanned the WHO database and cerebrate that as compared to other anti-psychotic drugs, clozapine is more widely reported. A French phar macovigilance study (called Reports of hypoglycemia associated with the use ACE inhibitors and other drugs a case/non-case study in the French pharmacovigilance system database) by Nicholas Moore et al. set out to find any association between use of ACE inhibitors and incidences of hypoglycemia. The results authenticated that in fact there was no significant increase in the occurrences of hypoglycemia in patients on ACE inhibitors. Such pharmacovigilance approaches add to the intimacy base of drugs and related Adverse Drug Reactions. Pharmacovigilance is a vital excessivelyl. thither are various advances and approaches to good pharmacovigilance practices ranging from data mining studies to conducting global clinical trials. What approach is deemed best to yield the right results, only time ordain tell.CASE STUDY THE CHRONICLE OF DIABETES MELLITUS TYPE II, AVANDIA, HOPE AND DEATH archaeozoic in frightful 2006, Vivians mother had gone to the hospital for some spot cancer tests. However, what was supposed to be routine, did not turn out to be. The doctors found the left side of the patients body egotistic. She was admitted immediately. On admission, the doctors found her heart swollen as well. Her heart was racing. Every trick in the trade was tried to get Vivians mother under control, but nothing seemed to work. Just a few days into her admission, she died, of cardiac arrest.Till the end, the doctors failed to find out the adjudicate cause for her death. However strange it may seem, the drug which she was taking for the former(prenominal) eight years, to control her blood sugar level has been the prime umbrageous and the causative agent of edema and myocardial infarction. The name, Avandia generically known as Rosiglitazone. Vivians mother was put on Avandia since 1999, the drugs approval year. Her death occurred in august 2006. Precisely eight years of Avandia, took her life.Then in May 2007, came to slatternly a stunning NEJM study which spilled th e beans for GlaxoSmithKline. They founda significant increase 43 percentin the risk for myocardial infarction -with rosiglitazone. They excessively found a 64 percent increased risk for death from other cardiovascular causes in people taking the drug. These findings were based on analyses of 42 clinical trials of the drug.10As a response to this, but probably too late for Vivian and her mother, FDA issued a public warning about the findings of the Avandia pharmacovigilance study. Patients with a large cardiovascular history were now verbalize to revise their use of Avandia. any stop it, or lower the dose. The information directly applies to Vivians mother death. Vivian saidAt the time I didnt realize that she had any cardiac problems. hardly there is a history of heart problems in my mothers family, including a history of heart murmurs. And my brother has a congenital heart defect, my mother was also on at least 13 drugs at the time she went to hospital.10A CRITICAL ANALYSISTh ats the tale of one drug and one death. exclusively there have been many. And no noise is being make about it. What approach is the right approach for pharmacovigilance is still to be stereotyped. But so far, the structured ADR reporting systems and data mining seems to have false the fortunes for Avandia. But for the time being lets spare Avandia, and concentrate our resources towards analyzing the situation of global pharmacovigilance. Does it really happen? What constitutes good pharmacovigilance practice? But one things for sure, the mindsets of sponsors and regulatory authorities necessarily to change. Things need to get crystallized. Vigilance should be policed. conditional approval to market the drug should follow stringent laws.The two burden issues surrounding pharmacovigilance are drug asylum and the reputation of pharmaceuticals. Which one of those needs to be sacrificed does the time arise, is a million dollar question. The reputation, it should be. Compromising dru g safety puts millions of patients at risk. Reputation can be back, but life, once gone, never returns, and so is Vivians mother. Even then, the reputation of GSK seems to be untouched. Vivians mother did have a history of cardiovascular illnesses, but still she was on the death drug for over eight years. Such an issue was never elevated during any of the trials of Avandia. It is thanks to pharmacovigilance that the root cause analysis was performed and the association between Avandia and edema and myocardial infarction was established. If not completely, at least it has bout the bells at the FDA. It was no doubt too late for Vivians mother, but the information has the potential to save millions of life, now that the correlation has been ascertained.However, some issues in the meta-analysis also need to be addressed. The study combined data of 42 different clinical trials. Trials with different outcomes, disease states, patients, duration and many other differentiating factors hav e been combined to pool in the data. The data from varying trials can be sometimes conflicting. GSK argues, the most reliable way to assess the long safety of the trial is to conduct a long-term safety trial. Three long-term safety trials of Avandia have been conducted by GSK. Namely ADOPT (A Diabetes Outcome forward motion Trial), DREAM and RECORD. The studies back Avandias safety profile. No more than a minimalist increase in risk has been noted in one of the studies. Again, as Avandia is known to control the blood sugar level for a long time, it said to have benefits outweighing the risks.The conflict will always remain. However, in such a scenario, the safety of patients should not in any way take a back seat. Sponsors and regulatory authorities along with consumers and healthcare professionals commensurate should take serious and committed steps to improve pharmacovigilance. The authenticity of the safety profile of Avandia will be demonstrated over time. But in any case, t he death of Vivians mother cannot be reversed, not by me, nor by GSK nor by the FDA.CONCLUSIONThe coming years are bound to be very interesting on the pharmacovigilance front. The techniques regulatory agencies mandate to make PV more stringent will be worth waiting for. Sponsors will have to invest more money to establish the safety profile of the drug. cognizance among patients has to be created for better reporting of ADRs. The current approach to drug ripening focuses an intensive, strong and time-consuming pre approval process, but a similar standing is required post approval also. The transition from research to marketing has to be more governed with the research step not stopping at the marketing juncture.BIBLIOGRAPHYDhruv Kazi, Rosiglitazone and implications for pharmacovigilance, BMJ 20073341233-1234 (16 June), doi10.1136/bmj.39245.502546.BESteven E. Nissen, M.D., and Kathy Wolski, M.P.H., Effect of Rosiglitazone on the Risk of Myocardial Infarction and expiry from cardi ovascular Causes, n engl j med 35624, vol. 356 no. 24Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg, M.D., Ph.D., Rosiglitazone and Cardiovascular Risk, n engl j med 35624Overview of cardiac adverse drug reactions reported in association with rosiglitazone, Nederlands Bijwerkingen Centrum Lareb November 2007V. Thawani1, S. Sharma2, K. Gharpure1, Pharmacovigilance Is it possible if bannable medicines are available over the counter?, Indian J Pharmacol June 2005 Vol 37 Issue 3Guidance for Industry, correct Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), March 2005, Clinical MedicalDavid M Coulter, Andrew Bate, Ronald H B Meyboom, Marie Lindquist, I Ralph Edwards, Antipsychotic drugs and heart muscle disorder in international pharmacovigilance data mining study, BMJ script 322 19 MAY 200 1, BMJ 20013221207-9Nicholas Moore et al., Reports of hypoglycemia associated with the use of ACE inhibitors and other drugs a case/non-case study in French pharmacovigilance sysyem database, Br J Clin Pharmacol199744 513-518, 1997 Blackwell Science Ltd.Data Assessment in Pharmacovigilance (powerpoint presentation), R.H.B. MeyboomAvandia Meant to Help but Killed kinda March 30, 2008. By Lucy Campbell, Seed Newsvine