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. 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.
THE STEPS IN PHARMACOVIGILANCE:
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
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
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
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.
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.
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 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:
– 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
– 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. 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. 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.
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.