Pharmacovigilance Drug Safety Essay

IM:

• To present an overview on the pharmacovigilance practice and realize the significance of pharmacovigilance in envisaging drug safety and efficacy

• To decisively appraise the pharmacovigilance findings of the anti-diabetic drug Avandia

INTRODUCTION AND BACKGROUND INFORMATION:

The World Health Organization defines pharmacovigilance as

“The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”.⁹

THE NEED FOR PHARMACOVIGILANCE:

Primarily let us understand the need for pharmacovigilance. It has been long debated that the data from animal experiments is not completely 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 within species to species as well. Pharmacovigilance Drug Safety Essay. Extrapolating such statistics from animals to humans though necessary is not foolproof.

Additionally, the clinical trial environment is extremely controlled. The patient population, however large, is not a good representative of the general global population. The number of patients is limited. Owing to these facts, an adverse effect, which would occur in one in ten thousand or so, is very unlikely to arise within the restrictions of the clinical trial atmosphere. Moreover, in a real life situation the patients using the drug are likely to have other diseases, consuming other drugs and with different genetic make-ups.

Accordingly arises the urgent need for better pharmacovigilance practices. The importance of identifying rare and serious adverse effects of drugs that have remained secret during the course of the clinical trial cannot be ignored.

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THE STEPS IN PHARMACOVIGILANCE:

• Spontaneous reporting and prescription event monitoring:

Spontaneous reports and prescription event monitoring include reports of adverse effects of drugs to sponsors, CROs or regulatory authorities, reported by patients, nurses, doctors and other healthcare professionals and consumers. The above process is streamlined with the help of global and countrywide structured programs to accelerate the practice and facilitate consumers to testify 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 reported. An incoming report is called as a case report. FDA has defined certain characteristics of a good case report. They are as follows:

“1. Description of the adverse events or disease experience, including time to onset of signs

or symptoms;

2. Suspected and concomitant product therapy details (i.e., dose, lot number, schedule,

dates, duration), including over-the-counter medications, dietary supplements, and

recently discontinued medications;

3. Patient characteristics, including demographic information (e.g., age, race, sex), baseline

medical condition prior to product therapy, co-morbid conditions, use of concomitant

medications, relevant family history of disease, and presence of other risk factors;

4. Documentation of the diagnosis of the events, including methods used to make the

diagnosis;

5. Clinical course of the event and patient outcomes (e.g., hospitalization or death);5

6. Relevant therapeutic measures and laboratory data at baseline, during therapy, and

subsequent to therapy, including blood levels, as appropriate;

7. Information about response to dechallenge and rechallenge; and

8. Any other relevant information (e.g., other details relating to the event or information on

benefits received by the patient, if important to the assessment of the event).”⁶

• Signal generation:

A signal is reported information of the possible causal relationship between an adverse event and the drug, which has been reported more than 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. Pharmacovigilance Drug Safety Essay.

• Signal follow-up and strengthening:

Signal follow-up and strengthening consists of identifying similar cases in different countries, mining the literature for evidence 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 scrutiny has to be done in order to assess the ingenuity of the signal. The report could have been due to the patients illness history, concomitant medication, disease state or any other reason not related to the use of drug. Even then, such confounded reports should be analyzed promptly. Signal follow-up ensures authenticity of the reports.

• Causality assessment:

Determining whether the adverse event has a causal relationship with the drug or not, and if it has, the degree to which the association exists is called as causality assessment. The WHO has defined six degrees of relationship, namely: certain, probable, possible, unlikely, conditional/unclassified and unassessable/unclassifiable with lowering intensity of causality.

• Action:

Action is taken once it is well established that there exists a causal relationship in between the drug and the adverse event. Depending on the severity of the adverse event, action taken can be in the form of withdrawal of marketing approval, change in package insert, additional trials to confirm causality and dissemination of information globally.

THE PRACTICAL ASPECT:

Consider the story of the blockbuster drug Avandia (rosiglitazone), used to treat patients with type II diabetes mellitus.

“Rosiglitazone (Avandia®) is a thiazolidinedione indicated in the treatment of type 2 diabetes mellitus:

as monotherapy

– in patients (particularly overweight patients) inadequately controlled by diet

and exercise for whom metformin is inappropriate because of

contraindications or intolerance

as dual oral therapy in combination with

– metformin, in patients (particularly overweight patients) with insufficient

glycaemic control despite maximal tolerated dose of monotherapy with

metformin

– a sulphonylurea, only in patients who show intolerance to metformin or for

whom metformin is contraindicated, with insufficient glycaemic control

despite monotherapy with a sulphonylurea

as triple oral therapy in combination with

– metformin and a sulphonylurea, in patients (particularly overweight patients)

with insufficient glycaemic control despite dual oral therapy”⁴

Little did the world know that a boon was in fact a bane for a certain group of people with a history of cardiovascular illnesses. A meta-analysis by Nissen and Wolski et al. provided evidence that

“rosiglitazone was associated with a significant increase 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).”²

Though 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 heart 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. Pharmacovigilance Drug Safety Essay. It also scanned the WHO database and concluded that as compared to other anti-psychotic drugs, clozapine is more widely reported. A French pharmacovigilance 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 attested that in fact there was no significant increase in the occurrences of hypoglycemia in patients on ACE inhibitors. Such pharmacovigilance approaches add to the knowledge base of drugs and related Adverse Drug Reactions. Pharmacovigilance is a vital tool. There 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 will tell.

CASE STUDY: THE CHRONICLE OF DIABETES MELLITUS TYPE II, AVANDIA, HOPE AND DEATH!

Early in august 2006, Vivian’s mother had gone to the hospital for some routine cancer tests. However, what was supposed to be routine, did not turn out to be. The doctors found the left side of the patient’s body swollen. 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 Vivian’s 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 root cause for her death. However strange it may seem, the drug which she was taking for the past eight years, to control her blood sugar level has been the prime suspect and the causative agent of edema and myocardial infarction. The name, Avandia; generically known as Rosiglitazone. Vivian’s 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 light a stunning NEJM study which spilled the beans for GlaxoSmithKline. They found

“a significant increase – 43 percent–in the risk for myocardial infarction -with rosiglitazone. They also 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.”¹⁰

As 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 bad cardiovascular history were now said to revise their use of Avandia. Either stop it, or lower the dose. The information directly applies to Vivian’s mother death. Vivian said

“At the time I didn’t realize that she had any cardiac problems. But there is a history of heart problems in my mother’s 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.”¹⁰

A CRITICAL ANALYSIS

That’s the tale of one drug and one death. But there have been many. And no noise is being made 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 turned the fortunes for Avandia. Pharmacovigilance Drug Safety Essay. But for the time being let’s spare Avandia, and concentrate our resources towards analyzing the situation of global pharmacovigilance. Does it really happen? What constitutes good pharmacovigilance practice? But one thing’s for sure, the mindsets of sponsors and regulatory authorities needs to change. Things need to get crystallized. Vigilance should be policed. Conditional approval to market the drug should follow stringent laws.

The two core issues surrounding pharmacovigilance are drug safety 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 drug safety puts millions of patients at risk. Reputation can be back, but life, once gone, never returns, and so is Vivian’s mother. Even then, the reputation of GSK seems to be untouched. Vivian’s 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 raised 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 rung the bells at the FDA. It was no doubt too late for Vivian’s 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 have 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-term 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 Progression Trial), DREAM and RECORD. The studies back Avandia’s 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 longer 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 equal 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, the death of Vivian’s mother cannot be reversed, not by me, nor by GSK nor by the FDA.

CONCLUSION

The 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. Awareness among patients has to be created for better reporting of ADRs. The current approach to drug development 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.

BIBLIOGRAPHY:

• Dhruv Kazi, Rosiglitazone and implications for pharmacovigilance, BMJ 2007;334:1233-1234 (16 June), doi:10.1136/bmj.39245.502546.BE

• Steven E. Nissen, M.D., and Kathy Wolski, M.P.H., Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes, n engl j med 356;24, vol. 356 no. 24. Pharmacovigilance Drug Safety Essay.

• Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg, M.D., Ph.D., Rosiglitazone and Cardiovascular Risk, n engl j med 356;24

• Overview of cardiac adverse drug reactions reported in association with rosiglitazone, Nederlands Bijwerkingen Centrum Lareb November 2007

• V. 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 3

• Guidance for Industry, Good 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 Medical

• David 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 VOLUME 322 19 MAY 2001, BMJ 2001;322:1207-9

• Nicholas 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 Pharmacol1997;44: 513-518, 1997 Blackwell Science Ltd.

• Data Assessment in Pharmacovigilance (powerpoint presentation), R.H.B. Meyboom

• Avandia: Meant to Help but Killed Instead March 30, 2008. By Lucy Campbell, Seed Newsvine

Every medicinal product has its own risk-benefit ratio. The products, whose benefits to the patients overweigh its risk, are approved by the Competent Authorities (CA). The approved products do not mean that they have no side effects. Actually every medicinal product has some side-effects and it’s very important to identify the side-effects throughout its lifecycle. The process of constant monitoring of the medicinal product throughout the product lifecycle is called Pharmacovigilance. Pharmacovigilance Drug Safety Essay. The aim of pharmacovigilance is to protect people by identifying, detecting, characterising, monitoring and communicating risk for rational and safe use of medicines.¹ These benefit-risk findings helps to take decision regarding safety of the medicinal product by regulators, company, physicians and patients.²

BACKGROUND

In 1961, after disaster of thalidomide, it has been brought forward that post-authorisation data was not sufficient to detect early warning signs of the drug safety.³ If Pharmacovigilance system were in place during that time; such a disaster would be minimised. To avoid any such disaster in future Marketing Authorisation Holder (MAH) & Competent Authority (CA) work together to ensure that pharmacovigilance system is maintained and patient’s safety is not compromised.

CONCEPT OF PHARMACOVIGILANCE

In general, pharmacovigilance have no boundaries and it should be performed to all medicinal products throughout its lifecycle. Rapid and effective assessment of drug safety is achieved by early information of any unintended effect. Innovative and generic companies have to follow the same requirements with regards to updating the safety specification.⁴

Currently, the pharmacovigilance system is set as per guidance,

• Regulation EC/726/2004
• Directive 2004/27/EC.
• Volume 9A and
• ICH guidelines

PHARMACOVIGILANCE RESPONSIBILITY

• Marketing Authorisation Holder (MAH):

In current situation, it’s very difficult to identify a new product and new product application is expensive and time-consuming process. To make a blockbuster product; MAH focus thoroughly on Pharmacovigilance system to avoid any disappointment at the later stage of the product lifecycle as it’s very essential for survival of the company. Pharmacovigilance Drug Safety Essay. The importance of Pharmacovigilance is that if successful product fails to detect early signals, company also fails to protect its brand identity.

The first step initiated by MAH is to ensure that proper pharmacovigilance system is set up to detect signal of any adverse effect and risk management plans should be in place to minimise its impact.³

To perform above activities, MAH appoints a QPPV who is responsible for,⁵

• Collecting and collating all suspected adverse effects globally and establish benefit-risk balance to submit to CA.
• Preparing and submitting Periodic Safety Update Review (PSUR), Individual Case Safety Review (ICSR), pre & post-authorisation studies to the CA through electronic reporting.
• Reviewing safety issues and product defects.
• Conducting internal audit of pharmacovigilance system and ensure management of database.

Along with Pharmacovigilance team, company also build Risk Management Team or Crisis Management Team who plays a vital role in minimising the impact of any adverse reactions on the product and the company.

• Competent Authorities (CA)

Along with MAH, CA also develop their Pharmacovigilance team who performs studies like MAH to evaluate the safety performance of the medicinal product. It is also the responsibility of MAH to provide timely and correct information of any signal detected to the CA. CA also evaluate Pharmacovigilance system of the MAH by routine inspections conducted by national authorities to check the system and facilities are in accordance as mentioned in Detailed Description of Pharmacovigilance System (DDPS)⁶. Apart from routine inspections, certain factors that triggers the inspections are,⁵

• Delays in carry out safety reporting
• Incomplete or poor quality reporting
• Inconsistency between reports
• Changes in benefit-risk balance and failure to communicate to CA.

Hence considering the importance of Pharmacovigilance, both MAH and CA take joint responsibility to safeguard public health. Pharmacovigilance Drug Safety Essay.

KEY STEPS IN PHARMACOVIGILANCE

Once the MAH Pharmacovigilance system is set, the key factors are,

• Signal detection

Signal detection is initiated by MAH as well as CA. At any stage during the product lifecycle, if unintended effect is detected, it prompts to evaluate the reason for its happening. Generally MAH should be first to detect any signal, but if is detected by CA, it means that MAH pharmacovigilance system is not efficient and inspections are required to verify the pharmacovigilance set up.

The adverse effect signal can be detected by:

• Constant monitoring in-house studies conducted by MAH.
• Spontaneous ADR reporting: where a healthcare professional reports any adverse effect to the MAH or CA from patients experiences as well as from his own studies.⁵  

MAH evaluates if a casual or suspected relationship is determined between adverse reaction and medicinal product. Once it is confirmed that relationship exists, MAH should inform CA within 15 days of the occurring of the adverse reaction.⁵

For cases where patient contacts the MAH directly regarding any adverse reaction, MAH should advice the patient to contact the healthcare professional. Once the adverse reactions are confirmed by healthcare professional, it should be documented by MAH as spontaneous adverse reactions.

• Prescription Event Monitoring (PEM): It is a hybrid method of data collection from surveillance as well as spontaneous adverse effects. Here all the prescriptions when dispensed are collected and analysed to give an idea of which patients are exposed to which medicines, time of exposure and any signal detected during their therapy.³
• Worldwide reports published for ICSR published on Medline or Embase etc helps MAH to be aware of the incidents and can get prepared for such adverse reaction incidents.⁵ Such literature or internet references should be reviewed atleast once or twice fortnight.

If the product is authorised by CP, it should be reported to Eudravigilance, but if the product is authorised through MRP or DCP, CA of the RMS should be reported. Here RMS takes the leading role and contacts respective CMS regarding of reporting any such adverse reaction.²⁵

All the regional wise signals detected are collected by local affiliates and then they are reported to the main office The MAH collects this information globally through local affiliates and reporting to the central office as well as collecting information through websites.

• Benefit-risk Assessment

Once the signal is detected, benefits of medicinal product are assessed on the information of cure or improve rate of the symptoms, the response rate and quality of life. Pharmacovigilance Drug Safety Essay. The risk involved is assessed as spontaneous adverse reactions, frequency and presence of risk factors, epidemiological data as well as overdose, misuse or medication errors.⁵ MAH should try to improve the benefit-risk balance to optimise safe use of the medicines.

To effectively monitor the safety performance of the medicine by the CA, it is decided to report periodically which is known as Periodic Safety Update Review (PSUR).

Pharmacovigilance during pre-authorisation

From drug discovery till the application is submitted, MAH performs several non-clinical and clinical studies to establish benefit-risk balance. Once the product is in application but not granted, if any unintended effect is seen, MAH evaluate the impact of unintended effect and inform to the CA. But there are several limitations to pre-authorisation stages like, ⁵

• limited people population,
• limited time of exposure of medicine,
• limited age & sex, geographical, ethnicity people &
• limited scope of interactions with other medicines.

Pharmacovigilance during post-authorisation

But when the product is authorised, it is widely prescribed in different class of patients. This gives more opportunity to identify any unintended risk or potential risk which was not identified during pre-authorisation studies. Hence post-authorisation studies are very essential to detect any such changes in benefit-risk balance and its reporting is through PSUR.

To make the post-authorisation robust, MAH maintains the list of information regarding safety, indications, dosing and pharmacology which is called Company Core Data Sheet (CCDS). CCDS proves as a reference to evaluate the change in benefit-risk balance. If any new adverse reaction is reported, CCDS data is updated to reflect changes.²⁷

PHARMACOVIGILANCE REPORTING

Periodic Safety Update Reports (PSUR)

PSUR is intended to review worldwide safety profile of the product and ensure that SmPC, labelling and leaflet are up-to-date. It is performed to evaluate the data of latest safety reports and to conclude that safety benefit-risk balance is not changed. If there is any change in safety data, appropriate actions should be taken for amendments of current information through increased market surveillance.⁷  Single PSUR is required to be submitted per MA which include all indications, dosage forms and route of administration.

The main contents of PSUR are,⁵

• Executive summary
• Introduction
• Worldwide market authorisation status
• Update to regulatory authority
• Changes to reference safety information
• Patient exposure
• Individual case histories
• Overall safety evaluation
• Conclusion
• Appendix: company core data

PSUR reporting to CA is derived from the date of birth of the medicinal product. The date when the medicinal product was approved is call International Birth Date (IBD).⁵

Considering IBD, PSUR is submitted,

• Every six months from authorisation until it is placed in the market
• Every six months for first two years
• Annually for next two years and thereafter every 3 years
• Product submitted for renewal

In certain cases, where PSUR is not submitted on time, additional 30 days are allowed to submit PSUR. For generic and well established product, PSUR submission dates can be amended depending on the benefit-risk profile of the product. But in all cases, prior permission should be taken from CA.⁵

During renewal submission, the PSUR report should cover 4 years and 4 months. Renewal can be submitted before 6 months.⁵  As PSUR submission is calculated as per IBD, renewal should not be affect by PSUR reporting and similar reporting cycle should be followed.

RISK MANAGEMENT PLAN (RMP)

As all actual or potential side-effects are not identified during studies, so along with pharmacovigilance activities which detect any unintended effects, there should also be Risk Management Plan (RMP) to minimise the impact of any such unintended effects.

RMP identifies the risk, clarifies the safety profile and decide alternative ways to minimise risk to the patients.¹⁵ As every product has different pharmacological actions and differ in safety profiles, separate RMP should be designed for each product. RMP should also identify multiple risks. RMP comprised of 4 steps:⁵

• Risk detection
• Risk assessment
• Risk minimisation
• Risk communication

EU Risk Management Plan

All products authorised within the EU should have approved EU-RMP maintained throughout the product lifecycle. EU RMP contains,

• Safety Specification – These are certain data which are not clearly addressed during non-clinical and clinical trials like toxicity, drug interactions, pharmacology & pharmacological class, population not studied, epidemiology and adverse events. Pharmacovigilance Drug Safety Essay.

Hence it is the summary of important identified risks, potential risk and some missing information.¹³ It should also highlight the population at risk and highlights the requirement for further study. The safety specification is itself a stand-along document along with pharmacovigilance plan and the specific elements are incorporated in CTD.⁵

• A Pharmacovigilance Plan – It is based as per safety specifications. For certain products where less risk is expected, routine Pharmacovigilance plan is designed. For certain product which involves more complexity and were less safety specifications are available, additional steps are taken to ensure that any signal detected is evaluated in early stages. Action plans are prepared depending on the safety issue. The main points for action plan are safety issue, objective of proposed action, action proposed, rational for proposed action, monitoring and finally evaluating & reporting.⁵
• Risk minimisation activities – It can be achieved through knowledge of Safety Specifications by restricting adding suitable warning on the labelling and package leaflet. Medication errors should also be considered with respect to brand names, presentations & instructions for use.⁵ Appropriate warning should also be mentioned if it can be life-threatening due to improper use of route of administration or due to mixing of different strength. Risk can be minimised through additional studies, legal status of medicines, control at pharmacy level and prescription size and validity.
• Risk communication – Risk communication is a much appreciated step for risk minimisation. Risk should be communicated to healthcare professionals through literatures, educational trainings and informative internet sources so that they can take corrective steps while prescribing to the patient and can minimise the risk.⁵

EU-RMP is required to be submitted for,⁵

• Application for new active substance, paediatric product, biological product or generic product where more information is required for reference medicinal product.
• Application for significant change in MA like new dosage forms, route of administration or change in manufacturing process
• On request of CA or if any safety issue arises of the product.

EU-RMP plan is submitted in Module 1.8.2 for evaluation by pharmacovigilance and risk management experts.⁵

PHARMACOVIGILANCE PENALTIES

Every MAH has to adhere to pharmacovigilance system. Non-compliance in the UK will have fine upto £5000 or if it is conviction it is unlimited fine and imprisonment for upto 2 years to QPPV or company management.

As per EU laws, if non-compliance is intentional or negligent, the fine is upto 5% of the annual sales or 2.5% per day average or if it is failure to co-operate or providing misleading information, the fine is upto 0.5% of total annual or per day average sales. Apart from fine, it gives a signal that company is not looking about patient’s safety, putting their profits first and an embarrassment in the industry.

EUDRAVIGILANCE

From November 2005, electronic reporting became mandatory. The reporting of European pharmacovigilance activities is supported by software called Eudravigilance. Eudravigilance maintains the database of adverse reactions reported for any medicinal product which are subject to clinical trials.⁸ Eudravigilance provides access of adverse reactions to CA, healthcare professionals, patients as well as pharmaceutical industry. It also maintains the data of ICSR and other suspected adverse reactions. While reviewing the pharmacovigilance system, it helps to identify adverse events to the rapporteur by creating regular overview of adverse events throughout the lifecycle of medicinal product. Also Eudravigilance interfaces with EU-RMP in providing systemic description of risk in terms as defined by MEDdra.⁸ It is found that 40% of safety issues can be detected earlier if Eudravigilance is used in addition to other PV sources.⁹ The typical flow of information from  PV and EU risk management strategy implication are,

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PRACTICAL APPROACH TO PHARMACOVIGILANCE

• Pharmacovigilance system is dependent on reporting and analysis of unintended effects. But all the side effects cannot be classified as unintended effects.Pharmacovigilance Drug Safety Essay.  Hence its MAH decision to classify which they consider as serious unintended effects.
• As physician did not get any feedback of their reporting of unintended effect which ends up in reluctance to report to the MAH.¹⁰
• In the EU as the products are granted through different procedures, the requirements for labelling are different which makes it difficult to understand benefit-risk balance which pose a risk to public health.¹⁰
• MAH along with manufacturers should responsible for overall detecting and evaluating the adverse effects of the medicinal product.
• Duplication of work is involved for reporting by both generic and innovator companies for same medicinal product and lack of communication between them.¹⁰
• Important safety information should be treated as priority instead of documenting, validating, evaluating and reporting all experiences with the same degree of urgency.
• PSUR reporting is complex as it involves different presentations, different approval times and country specific labelling.¹⁰

As per innovation in healthcare technology, Pharmacovigilance system should be developed to identify the potential association of side effect with a comparison of patient who was given medicine v/s patient who has not taken the medicine.¹⁰     Pharmacovigilance Drug Safety Essay.