Pharmacovigilance and Drug Safety

Pharmacovigilance: Key Applications Of Epidemiology and Pharmacoepidemiology

PrimeVigilance have provided a new page which provides some background summaries of the various definitions of epidemiology and pharmacoepidemiology and some key applications within contemporary drug saftey work. This page provides some further background to the topic by providing defintions from relevant organisations and  a bullet point summary of key applications within contemporary drug saftey.

Further  Contemporary Definitions Of Epidemiology

Epidemiology is often summarised as considering the “who, where, what and why” of how a particular disease arises and develops within a pre-determined real life population. The European Network of Centres for  Pharmacoepidemiology and Pharmacovigilance (co-ordinated by the European Medicines Agency) provide the following brief definition (which can be found at http://www.encepp.eu/glossary.html ) :

“Epidemiology is the study of factors affecting the health and illness of populations, and serves as the foundation and logic of interventions made in the interest of public health and preventive medicine.”¹

Investigations involve larger-scale ‘real life’ populations, meaning patients within particular pre-defined communities, cities, areas, countries, continents, etc. There may be reference to individual details for one particular patient; however, this branch of science concerns itself with studies conducted on a macro-scale.

Further Contemporary Definitions Of Pharmacoepidemiology

This science also concerns itself with macro-scale studies of ‘real life’ populations – they key characteristic being that the population will be one taking a particular medicinal product (or products). The International Society for Pharmacoepidemiology provides a definition which futher notes key characteristics as:

• “the study of the utilization and effects of drugs in large numbers of people.”
• “a bridge science spanning both pharmacology and epidemiology”
• “the application of epidemiological methods to pharmacological issues”².

Key Applications Within Pharmacovigilance

It should be noted that the types of studies and methodology found within which epidemiology and pharmacoepidemiology are not likely to form part of the routine day to day workload of pharmacovigilance services. However, there are times when the data generated by the former disciplines is vital for the latter:

• Epidemiology data informs the “Safety Specification” for each new medicine (which forms part of the Risk Management Plan prepared by drug safety services)
• Pharmacoepidemiology studies are helpful to follow up patients and determine their progess over longer periods of time
• Pharmacoepidemiology studies may also aid investigations into new saftey signals arising during the post-marketing phase

References

1. The European Network of Pharmacoepidemiology and Pharmacovigilance Centres (ENCePP). 2012. Glossary Of Terms. [online]. Available from: http://www.encepp.eu/glossary.html [Accessed 19th April 2012]

2. International Society For Pharmacoepidemiology. (undated). About Pharmacoepidem[online]. Available from:  http://www.pharmacoepi.org/about/index.cfm [Accessed 19th April 2012]

The Concept Of Risk Within Pharmacovigilance

Both the science and practice of pharmacovigilance are centered around the minimisation and management of risk wherever humanly possible. The definition of risk as it applies to drug safety can be understood in a number of ways. This page provides information on universal definitions of risk; definitions within the industry; the use of the term ‘safe’; and some obligations for pharmaceutical companies

Global Concepts Of Risk

In our everyday lives, we expose ourselves to innumerable risks because we can see an end benefit for doing so, and we feel the level of risk is acceptable to us. For example, when we take the train to work, there is always the small possibility that there could be an accident – yet we know that rail accidents are relatively rare events, thus we do not feel our journey is somehow unusually or inadvisably dangerous. There are also situations that obviously present us with unacceptably high levels of risk – for example, very few people would feel entirely comfortable walking along a narrow footpath next to a busy motorway. There are many definitions of loss in everyday life, which usually involve the concept that something or someone will be lost, harmed, damaged or a situation made worse as a direct (or sometimes indirect) result of following a particular course of action or exposure to a particular object or situation.

Concepts Of Risk Within Pharmacovigilance Work

Risk here relates to the possibility of an adverse reaction or harmful toxic effect provoked by taking a particular medicinal drug.

1. The definition can be understood in terms of those undesirable effects caused by ‘intrinsic’’ factors:

i) The active chemical or chemicals within a particular medicinal product (the ‘drug itself;)

2. Or in terms of those caused by ‘extrinsic’ factors:

i) The excipients used alongside those active chemical components to provide form, colour, texture, shape etc to a particular medicinal product

ii) The packaging for the medicinal product as supplied to professionals (and therefore eventually to their patients)

iii) The method and rate of delivery of the drug to the body

iv) Dosage including underdoses and overdoses

v)The influence of non-compliance (meaning when a patient does not take the drug according to the instructions of the health care professional who prescribed it/ the pharmacist/ the product labelling, etc)

3. There are then further extrinsic factors to consider for each individual patient, including:

i) Their general physiological condition (including age, sex and weight)

ii) Any previous known exposure to the medicine

iii) Any allergies

iv) Any other medicines that they are already taking, stop taking or start taking  during the course of treatment with the drug in question

v)Any other diseases they have in addition to the one the drug is intended to treat

Drug Safety: ‘Safe’ Cannot Mean ‘Risk-Free’

Within the field, there has been an intensified focus on risk assessment and management over the previous two decades. Numerous publications from regulatory bodies within the EU, the USA and around the world have all addressed these themes as their primary priority. The  concept of the term “safe” has been extensively re-examined in relation to pharmaceutical drugs, to clarify the position that “safe” indicates the benefits of a particular drug are considered to outweigh the corresponding potential harmful events or side effects. It is important to note that this definition therefore does not mean that the drug carries no level of risk at all. It is also very important to note that where a drug may be described as effective, this does not mean regardless of the manner of use nor without any risks in every possible scenario.

Responsibilities For Producers

Pharmaceutical companies are required by EU and national regulators to ensure they report relevant information about potential risks related to each individual drug before and after it reaches the market. They must do so within a specified time period and using a strictly controlled reporting format or face substantial penalties from the regulatory bodies.  Please note this page cannot constitute any form of professional advice since risk assessment, management and reporting is a highly complex specialist professional area. Pharmacovigilance services support timely and accurate risk reporting to ensure that companies consistently fulfil their legal obligations and avoid such costly penalties for non-compliance.

Reference and suggested further lay reading

1. Barton L.Cobert, MD. (2007). Manual of Drug Safety and Pharmacovigilance.
Massachusetts: Jones and Bartlett.

2. Barton Cobert & Pierre Burton. (2009). Practical Drug Safety From A to Z.
Massachusetts: Jones and Bartlett.

Pharmacovigilance: Key Applications Of Epidemiology and Pharmacoepidemiology

In light of a new page which provides some background summaries of the various definitions of epidemiology and pharmacoepidemiology and some key applications within contemporary drug saftey work, this page provides some further background to the topic by providing defintions from relevant organisations and a bullet point summary of key applications within contemporary drug saftey.

Further Contemporary Definitions Of Epidemiology

Epidemiology is often summarised as considering the “who, where, what and why” of how a particular disease arises and develops within a pre-determined real life population. The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (co-ordinated by the European Medicines Agency) provide the following brief definition (which can be found at http://www.encepp.eu/glossary.html):

“Epidemiology is the study of factors affecting the health and illness of populations, and serves as the foundation and logic of interventions made in the interest of public health and preventive medicine.”^[1]

Investigations involve larger-scale ‘real life’ populations, meaning patients within particular pre-defined communities, cities, areas, countries, continents, etc. There may be reference to individual details for one particular patient; however, this branch of science concerns itself with studies conducted on a macro-scale.

Further Contemporary Definitions Of Pharmacoepidemiology

This science also concerns itself with macro-scale studies of ‘real life’ populations – they key characteristic being that the population will be one taking a particular medicinal product (or products). The International Society for Pharmacoepidemiology provides a definition which futher notes key characteristics as:

• “the study of the utilization and effects of drugs in large numbers of people.”
• “a bridge science spanning both pharmacology and epidemiology”
• “the application of epidemiological methods to pharmacological issues”^[2].

Key Applications Within Pharmacovigilance

It should be noted that the types of studies and methodology found within which epidemiology and pharmacoepidemiology are not likely to form part of the routine day to day workload of pharmacovigilance services. However, there are times when the data generated by the former disciplines is vital for the latter:

• Epidemiology data informs the “Safety Specification” for each new medicine (which forms part of the Risk Management Plan prepared by drug safety services)
• Pharmacoepidemiology studies are helpful to follow up patients and determine their progess over longer periods of time
• Pharmacoepidemiology studies may also aid investigations into new saftey signals arising during the post-marketing phase

References

1. The European Network of Pharmacoepidemiology and Pharmacovigilance Centres (ENCePP). 2012. Glossary Of Terms. [online]. Available from: http://www.encepp.eu/glossary.html [Accessed 19th April 2012]
2. International Society For Pharmacoepidemiology. (undated). About Pharmacoepidem[online]. Available from: http://www.pharmacoepi.org/about/index.cfm [Accessed 19th April 2012]

Drug Safety Data: The Effect Of EU Regulations Protecting Data Privacy

Information outlining the need for compliance with data privacy protection laws in force throughout the EU is posted here. This page provides some further background to this important topic. All personal data within the EU must be treated in accordance with EU laws on Data Privacy. In order to protect patients’ rights to privacy, pharmacovigilance data must likewise comply with these laws. There will inevitably be clinical data which is vital to identify and analyse any adverse reactions which may be caused by taking a certain drug. While the ultimate aim of protecting patients from harm caused by any potential or actual drug safety issues, this cannot be allowed take priority over the need to protect personal privacy.

Would The 1995 EU Data Privacy Laws Stop The Flow Of Drug Safety Data?

It was in 1995 that the Directive 95/46 EC provided a framework for how all personal data should be treated within all EU member states. The Directive gave all EU member countries a period of three years to formulate and implement national laws complying with its principles. Some states chose to go further, implementing legislation which provided more stringent protection than the stipulation of the Directive originally called for. The relevant point for pharmacovigilance was that there was no exemption for any type of health care records. This means that doctors, hospitals, clinics and other health care providers must comply with national legislation – without exception. It applies to all media – whether the personal data is held on hand written forms, computerised records, captured images such as name X-Rays and scans, etc. The Directive had initially caused concerns that it could impede drug safety work by placing legal obstacles in the way of investigators who needed such clinical data to perform their professional duties.

After 1995: The Impact On Pharmacovigilance Work

In reality, these concerns proved unfounded as there are now various methods pharmaceutical companies and regulators use to balance the pressing need for data with legal compliance. It can be the case that it has become more complex to investigate (and perform the follow ups) since 1995. Nonetheless professional pharmacovigilance services can advise pharmaceutical companies on which options are open to them to fulfil their drug safety obligations without compromising their position under national data laws. When processing personal data, Regulatory agencies are also bound by additional privacy legislation (Regulation (EC) No 45/2001 Protection of Individuals). Again, in practice this has not meant that pharmacovigilance work has been impeded, rather that regulators are aware of regulations they must follow for such processing, including when data is transferred between countries, and in and out of the EU itself. As a generalised rule, it is not permitted for data which has not been rendered in an anonymous form to be exported to countries outside the EU. However, a note of caution is required regarding this last statement. National and EU wide laws are always subject to change and as such, pharmaceutical companies need accurate advice reflecting the latest legal reality within any given situation. This page therefore cannot be considered as any type of legal or other professional advice, which should be only sought from appropriately qualified persons.

Spontaneous Reporting Provokes A Host Of Statistical Pharmacovigilance Challenges

Calculating risk is a fundamental part of pharmacovigilance: when reports of an adverse reaction are received the ideal is to accurately calculate the incidence rate. www.primevigilance.com have provided a page about the complexities of calculating risk generated as a result of spontaneous reports from doctors, pharmacists, other healthcare professionals and patients themselves. This page provides further background information to the topic, including why this area is notoriously challenging for pharmaceutical companies within the EU and the broader global community.

The Difference Between Spontaneous Reports and Data From Clinical Trials

Spontaneous reports arise when healthcare professionals and patients around the world report a suspicion that an untoward medical event has an association with taking a particular prescribed drug. During the post marketing phase, the volume of reports can be affected by two known effects. The Webber Effect describes an increased volume of reports for new drugs within their first two years on sale. The Secular Effect describes increased reporting when a drug becomes subject to media exposure because it has been taken by a well known figure or a warning has been issued by a regulatory authority. These two considerations aside, the quality and integrity of data can still be entirely variable within spontaneous reports. Crucial areas may be incomplete, for example, scant information on the health status of the patient. There may be little or no information on whether any other medications were being taken at the same time. Busy healthcare personnel may be difficult to contact to complete the follow up. Patients may feel uncomfortable divulging sensitive information. Furthermore, pharmaceutical companies provide researchers with just the quantity of kilograms manufactured for each drug. Specialist firms then provide services attempting to quantity patient exposure to it. From this data, an approximation of demographical analysis and prescribing trends would then be made. For these reasons alone, it is not possible to draw any meaningful conclusions from spontaneous reports; yet they are still considered to be vitally important within drug safety. It would be impossible to launch clinical trials on a scale which mirrored real life prescribing for each individual drug; hence spontaneous reporting retains its function.

Epidemiological and clinical studies typically present more complete and uniformly compiled data. Since the data will be submitted to the regulatory authorities, it should be presented in standard formats. It is therefore likely to be adequately defined, including adequate descriptions of statistical methodology. Efficacy and safety analysis are also likely to be well documented and carefully controlled. The patient samples studied should be well described. Regular periodical subject or patient monitoring should be conducted specifically aimed at uncovering any Adverse Reactions by the appropriate professional teams. Using placebos or other comparators provides a clearer basis for evaluating risk using confidence intervals and significance values. As a result, the data from such studies is considered to be meaningful, with the likelihood that any problems will have been detected.

Data Mining And Statistical Analysis

There are various methods of statistical analysis which may be employed to evaluate the results of spontaneous reporting. Collectively termed ‘data mining’, these methods are typically used to generate signals, which can be crudely characterised as indications that further study may be required. Signal screening requires analysis of large amounts of data. The aim is to identify any clear anomalies, which may then be subjected to clinical investigation. However, the results of Signal Screening may still not be sufficiently robust to be considered particularly meaningful.

Proportionality methods are sometimes also called ‘disproportionality methods’. As a rather broad summary, these methods compare the proportion of reports received for a particular Adverse Reaction to those received for other drugs using data held within the same database. The aim is a comparison with other drugs rather than the examination of exposure data for the drug under evaluation. Limitations include smaller sample sizes; compounding factors such as any issues of polypharmacy; a lack of suitable comparative data; demographic variations within the patient group; and any variations in coding. The results again may not be sufficiently robust to generate any meaningful drug safety conclusions.

Bayesian methods may also be referred to as ‘probabilistic causality’. The aim is to analyse causality in terms of conditional probability, the data from which will be routinely modified as fresh information is obtained. One of the limitations is that within the EU (and other markets) the numbers of untoward medical events which occur in real life dwarf the numbers which are actually reported. Studies since the 1980s have proved that this factor means that again, this method is not always produce the desired drug safety conclusion, i.e., a meaningful final causality prediction.

The issues involved are invariably complex. No matter which statistical methodology is employed, pharmaceutical companies and regulators find themselves faced with discrepancies between the quality and/ or quantity of reports. The challenges they face require highly senior pharmacovigilance services personnel to produce results which are likely to satisfy both the operational needs of pharmaceutical companies and fully comply with the relevant EU drug safety regulations.

Three Examples Of Pharmacovigilance For ‘Long Latency’ Adverse Reactions

Adverse reactions may not present only immediately after the release of a new drug onto the market; on the contrary, they are entirely possible even decades after the drug was first prescribed. Information on fundamental aspects of pharmacovigilance for complex untoward medical events can be found on a page at www.primevigilance.com This page provides three examples of complex reactions where establishing the true drug safety profile proved more challenging to detect.

It is tempting to reason that through the combination of premarketing clinical trials and post marketing spontaneous reporting, safety concerns could be expected to be resolved within several years of a new drug being placed onto the market. The time period elapsed after taking the drug and the reaction is termed the ‘latency period’. It is important to note that there have been many well established drugs which have provoked reactions following a latency period of years or even decades. The time elapse and confounding issues means that such reactions are more difficult to detect, whereas those with a short latency period are likely to arouse a higher level of suspicion.

There may be any number of reasons for this phenomenon:

• Greater access to medical records with a shorter latency period
• Greater clarity of patient recollection regarding how and when they took the medication
• A more immediate association between the known pharmacologic or biologic effects of the drug and a particular Adverse Reaction
• The rarity of the rate of occurrence of the reaction
• Unusual aspects of the clinical manifestation

However, this does not mean that detecting those reactions with a longer latency period is impossible. There have been some notable cases where vital drug safety conclusions have been reached even though the adverse reactions affected the patient’s children and grandchildren rather than the patients themselves. Epidemiologic studies may prove vital in detecting drug safety problems long after the product launch.

‘Late Onset’ Reactions Can Happen – Long After Patients Start Taking The Drug

Just as it is a fallacy to assume that problems will be detected within a short time of launch, the clinical severity of the disease being treated is no indicator of whether there can be late onset problems. The following three examples illustrate these concepts.

Nitrofurantoin is an example of a drug which has been known to cause mild to extremely serious problems within weeks of taking it – and after at least 6 months therapy. It is an antibiotic used for prophylaxis in cases of recurrent urinary tract infections or the treatment of such current infections. There have been reports of early onset reactions, within 3 weeks of starting to take the drug. Problems have been documented to range from a multisystem hypersensitivity reaction to fatal cases of suspected pulmonary fibrosis. Late onset reactions have also been documented at least six months after starting to take the drug, featuring compromised lung function, sometimes due to pulmonary fibrosis and infiltration, and a small number of fatalities.

Minocycline is a medication to combat acne vulgaris which has been documented as causing late onset effects as late as two years after commencing therapy in at least one case. Reactions have been reported when the drug was administered in combination with other typical acne medications. When an Adverse Reaction is relatively rare, this factor which can contribute to the complexity of detecting problems. It is of note that this medication had been prescribed for at least 30 years when a doctor initiated literature review identified a series of rarer reactions characterised by such polypharmacy.

Diethylstilbestrol (DES) is a drug was widely prescribed in the USA, Europe and further afield aiming to prevent miscarriage. A period of some thirty years elapsed before suspicions were raised. The issue lay with the fact that the drug was found to cause serious adverse reactions not within the original patient group, but within their children (and even their grandchildren). Cases studied in the early 1970s included structural abnormalities of reproductive organs; rare vaginal cancers usually prevalent in patients at least 56 to 48 years older; and higher instances of ectopic pregnancies, spontaneous abortions and preterm births.

This brief list of products which have been associated with late onset reactions is by no means exhaustive. Instead it is provided as a simple illustration of how even well established drugs have been found to provoke mild to serious reactions. Drug safety problems may be more difficult to detect not only due to the longer latency period, but due to a rare occurrence rate or a highly unconventional manifestation within clinical practice. The need for robust pharmacovigilance services remains of paramount importance at every stage of a products life cycle, no matter how widely prescribed the product, nor how long lived its life cycle.

Why Pharmaceutical Companies Need Post-Marketing Pharmacovigilance For New Drugs

This page expands on the overview of post-marketing pharmacovigilance provided at www.primevigilance.com, giving further details on the types of pharmacovigilance activities required to ensure post-marketing drug safety activities typically conducted after a drug has been released onto the market within the EU. All new drugs must successfully complete each of Phases I, II and III of clinical trials before being launched onto the market. However, after the regulators have granted a Marketing Authorisation, there are still some regulatory requirements for continued studies. There may also still be other studies which the pharmaceutical company chooses to initiate.

Limitations Of Clinical Trials

As discussed, one of the major limitations of pre-marketing clinical trials is the logistics of scale. Even though there could have been some 10,000 patients participating in a trial, these numbers are still not sufficient to detect less common and rare Adverse Reactions. For example, statistically speaking an Adverse Event which has a 1 in 10,000 incidence rate might produce 100 cases when the drug is used by 1,000,000 patients. However the incidence rate means it is entirely possible that this hypothetical Adverse Event would not be detected at all during an initial study of 10,000 patients. Indeed to guarantee with 95% certainty that the adverse event would be seen, one would have to do a study of 30,000 patients. This doesn’t make sense initially (the rate is 1 in 10,000 after all), but not all people are the same and with a reaction occuring as rarely as 1 in 10,000 – really you need a sample of 30,000 – 50,000. In 30,000 you might see 1 – 5 reactions – in a sample of 50,000 you might see 2 – 7 or 8 reactions. Even 50,000 would only give you 98% statistical certainty of seeing a “1 in 10,000″ reaction.

It is possible that this hypothetical Adverse Event could range from mild cases, such as loose stools, to the very serious end of the spectrum of untoward medical events, for example, a heart attack. Since all Adverse Reactions warrant timely and diligent investigation, pharmaceutical companies need to have established and pre-implemented a robust system of post-marketing pharmacovigilance in place long before the product reaches the market. The demonstration of adequate systems to process reports of Adverse Events after a drug has completed pre-marketing tests is an essential part of any application for a Marketing Authorisation. There is no sense of any type of ‘routine rubber stamp’ exercise at this juncture: if the regulators are not satisfied that provisions for this post-marketing phase are sufficient, the application will fail.

Patient Groups, Polypharmacy And Food Issues

Phases I, II, and III studies may not have included all the possible groups of patients for whom the drug may be prescribed in order to treat a particular disease or indication. Clinical trials may study responses in subjects and patients aged between 18 and 60 years old, yet when the drug reaches the market it could be prescribed to more elderly patients. This is important to note since this demographic group can present heightened sensitivities, for example to certain types of psychotropic medication. There could also be the issue of whether patients are receiving a regular diet, which again could present as a problem for this group, for example, a dementia patient receiving care at home may not always eat at regular intervals. The possibility of an interaction between different foods, different meal timing and the drug under such circumstances could not be investigated within clinical trials. The same group are also a group example of the difficulty in assessing the effects of polypharmacy. This group of patients could be being prescribed multiple medications, the variety and extent of which again could not be replicated for study within clinical trials.

Although trials aim to establish the safety profile of a drug before it goes on general sale, the above examples illustrate why the initial stages of its release are still so crucial in terms of pharmacovigilance. Doctors, nurses and other health care practitioners report Adverse Events within the EU via country-specific spontaneous reporting systems such as the MHRA’s yellow card scheme, as part of their routine clinical duties. Where a pharmaceutical company receives a report, they must in turn report it in the correct format to the regulatory authorities within a 15 day timescale.

It is important to note that this brief illustration of some of the key issues for this postmarketing pharmaceutical safety is not any form of professional advice; readers must therefore only consult a qualified person for all drug safety or medical enquiries.

Why pharmaceutical companies Need post marketing Pharmacovigilance for well-established drugs

Information is posted at www.primevigilance.com which puts forward some of the key reasons why pharmacovigilance is essential during the post marketing phase even for those drugs which have a long history within EU markets. This page provides some further background for this timely topic, including why the products which are used as ‘fillers’ in the finished tablets, capsules, syrups and so on are of note, plus why generics still require close scrutiny.

Excipients Have Been Known To Cause Problems

The correct term for those ‘fillers’ which help to give the final drug its distinctive shape, colour, texture and any flavour is ‘excipient’. These are substances which in theory should exert no significant effects, and they are added to the chemically active component of the product, i.e. the drug, simply to render it in a convenient and/or palatable form. The problem is that there have been instances when such ‘inactive’ ingredients have been found to cause Adverse Events, for example, diarrhoea caused by a formulation containing lactose. One of the most serious instances of excipients causing Serious Adverse Events occurred in the USA during the 1930’s. The incident was of such magnitude that is has been since credited with helping to bring about some of the earliest American drug safety legislation. Dyetheline glycol was used to dilute a sulfonamide product. This ‘excipient’ is more commonly known as an ‘anti-freeze’ and tragically over 100 people died as a result of taking the product.

It can be difficult to detect Adverse Reactions due to a number of factors. Different formulations from the same manufacturer can contain different excipients. For example, even though it contains the same active (drug) ingredient, the 200mg capsule of a product might contain less excipients by volume than the 500mg size simply because the 500mg size is marketed as a much larger capsule. Or it might contain different excipient altogether, perhaps because it is marketed as a different coloured capsule to the larger dose version. A robust pharmacovigilance system is therefore essential to ensure that any problems related to excipients are properly reported and any further necessary steps are taken in a timely manner.

Placebos Have Been Linked To Adverse Reactions Within Clinical Trials

Placebos also present a complicated picture, in that again in theory they should be inactive substances. However, untoward responses to placebos have been noted within clinical trails¹. This is noteworthy for post marketing clinical trials since the wording of EU Clinical Trial Directive (2001/20/EC, April 4, 2001) includes placebos within those substances deemed as “an investigational medicinal product”¹. Timely advice on reporting is therefore essential within any post marketing studies that use them.

Generic Formulas Vary Between Pharmaceutical Companies

Although generics might appear as more ‘straightforward’ since the drug has a well established safety profile, the reality is that different manufacturers can use different formulations for excipients. Adverse Event reporting needs to be processed with the greatest of care. With rival generics on the market, it is absolutely vital to establish that the company receiving the report is the one who manufactured the suspected product featured in that report. It is the company who manufactured the exact product who should report to the regulators in a timely and accurate manner. It is also worth noting that the responsibility does not lie with the company who held the patented formula for the original product the generic formulations were later derived from if their product is not suspected in the Adverse Event report¹.

Reference

1. Barton L. Cobert, MD. (2007). Manual of Drug Safety and Pharmacovigilance.

Massachusetts: Jones and Bartlett.

Pharmacovigilance: The Four Phases Of Clinical Trials

Pharmacovigilance regulations require any medicinal product to successfully complete each of three carefully controlled phases in ordered succession from I to III before being granted a Marketing Authorisation to allow it to go on sale. Following the granting of a marketing authorisation a fourth phase of trials is often also required. Information on the nature of the four different phases of human clinical trials can be found on the  what are clinical trials page on www.primevigilance.com. The page below provides further details of each of the phases; their participants; and the professionals who typically conduct them.

Phase I

The first steps in testing in humans, these trials are concerned primarily with drug safety rather than efficacy. They examine any beneficial or adverse effects; drug metabolism; formulation; and dosage. It is common to find phase I trials constituting a single dose trial with a small group of volunteers. A group of twelve men could be typical, avoiding the possibility of pregnancy on safety grounds. If the drug is tolerated, it may be studied using a multiple dose or rising dose trial. It is possible to conduct drug interaction studies during phase I or phase II. There can be times when drugs have a known toxicity or predictable and severe adverse reactions. In such cases, phase I trials may be conducted for ethical reasons, among patients who already have the disease the drug may treat (for example, chemotherapy drugs for cancer). Since there is no benefit for the subjects of a Phase I trial, volunteers may be paid for their participation and are often accommodated in clinical research centres.

Phase II

These trials aim to determine at which dose the maximal benefit may be delivered with the minimal level of risk. They can also further investigate metabolism and provide the basis for safety and efficacy markers for subsequent phases. The participants are patients who already have the disease for which the drug may be able to offer a new treatment. During this phase severe and unexpected toxicity can mean the trial must be immediately halted, or at the very least, the protocol will be altered to avoid repetition. Consequently effective pharmacovigilance systems are required for the whole clinical trial process. It is not common for Phase II participants to receive compensation.

Phase III

These trials are conducted on a far larger scale (from the hundreds to the thousands of patients) with the final aim of obtaining a Marketing Authorisation for the drug. This phase may be subdivided into IIIA and IIIB trials, with each individual trial conducted at multiple sites, possibly located in more than one continent, lasting from several to 12 or more months.  Since this is a far more lengthy phase, sponsors may continue to trial to investigate issues such as comparison to other drugs already on the market, cost effectiveness, etc. The results of the first (IIIA) studies may prompt design and protocol changes to the second (IIIB).

Phase IV

These are studies which occur after the Marketing Authorisation has been granted, and the drug placed onto the market. Studies  during this phase can include:

• marketing research or pharmaeconomic studies in relation to competitor drugs to assist sales

• investigation into subgroups  within the approved patient group and drug indications

• particular children’s studies

• to investigate a specific AE or unexpected signal occurring during post-marketing

These clinical trials could be small open-label trials or massive scale multicentre double blind trials involving a comparator. Patients may be compensated for their participation.

Investigator Initiated Trials

These  studies aim to investigate novel uses or routes or administration for existing drugs which are well established on the market. They are typically proposed by academic researchers or the pharmaceutical company which manufactures the drug, often in liaison with academic research department staff. The costs and time-scales involved tend to be relatively small, allowing for the development of knowledge around the drug and potential new benefits to patients.

Phase I studies tend to be operated by pharmacologists (PhDs, PharmDs) and physicians and may be outsourced to Clinical Research Organisations (CROs). Phase II and III trials commonly physician led, conducted in-house at pharmaceutical companies or outsourced again in part or in whole to CROs or academic clinical research units. They also often involve specialist physicians (for example, oncologists, etc). Phase IV investigations may be conducted by those professionals who completed the Phase II and or III studies or separate operators. Please note this brief introduction to clinical trials is for educational purposes only and is not any type of professional pharmacovigilance, medical, legal or other formal advice.

Expected And Unexpected Events Within Pharmacovigilance

This page provides further information to supplement the introductory page, ‘What Is Pharmacovigilance?” located at http://www.primevigilance.com. That page provides brief definitions of Adverse Events & Adverse Reactions, Serious Adverse Events (SAEs) and Suspected Adverse Drug Reactions according to guidelines from the ICH. This page examines the question of whether any untoward medical event should be considered as ‘unexpected’ or ‘expected’ when it may be related to a medicinal product.

Product Life Cycle and Expected or Unexpected Classifications

The question of whether a Serious Adverse Event is expected or unexpected relates to the stage of the life cycle of the medicinal product. Before it reaches the market, adverse events are considered in reference to the investigators brochure. If the event does not precisely match the information within the existing available risk information, it is classified as unexpected. It could be that this information was not required or that it was not available. Or it could be that the event constitutes a mores specific risk than had been described. For example, if there was a case of cerebral thromboemobilsm and the existing risk information had described cerebral vascular accident; cerebral thromboemobilsm would be unexpected.  It is also possible for events to be deemed unexpected due to higher severity. A good example could be the stated risk of elevated liver enzymes eclipsed by the occurrence of hepatic necrosis.

Once a medicinal product has been marketed, the current product labelling becomes the reference document. This could be the packaging insert or the summary of product characteristics. Unexpected events here include those that are already detailed within that labelling, but again, carry a higher level of severity or present with greater specificity.

Class Related Adverse Events (AEs)

This refers to AEs which are apparently a risk for all the medicinal products within a particular class of drugs, and are included in the investigators brochure (pre-marketing phase) current product labelling (post-marketing phase).  If the AE is not already specifically described within those documents, it too will constitute an unexpected event.

Seriousness and Unexpectedness

An untoward event should not need to be considered of higher severity before being classed as unexpected.  The primary consideration must instead always be the precise wording of the brochure or product labelling.

Unexpected Events in Clinical Trials

For medicinal products within clinical trials it may be the case that there has been little or no human exposure to the product to date. This can be particularly true in the case of pre-marketed drugs and during the first human studies or the first phase II studies. The investigators brochure will therefore not contain any AEs. In these cases, all events are unprecedented and therefore automatically unexpected by nature.  This includes events which could be reasonably anticipated according to the pharmacologic properties of the medicinal product. When these occur within a patient, they should be reported and included within the brochure.

Variations in administration, dosage or indication

There may be different AEs described for different routes of administration; or different doses; or different indications the product is being evaluated for. For example, the product may be expected to produce certain AEs via oral administration, and a distinct set of other AEs via topical administration. The precise wording of the brochure or product labelling therefore becomes critical in assessing whether the event is expected or not.

It is not necessary for an adverse event to be serious to be classified as unexpected; and to classify as unexpected in cases where doubts remain as to whether unexpected or expected would be the most appropriate option.  This information is provided as an introductory overview and does not constitute any form of professional pharmacovigilance, medical or legal advice.

Reference and suggested further lay reading:

Barton L.Cobert, MD. (2007). Manual of Drug Safety and Pharmacovigilance. Massachusetts: Jones and Bartlett.