WHAT IS PHARMACOVIGILANCE?

This section provides information on some of the major concepts within pharmacovigilance related to pharmaceutical products for human use.

Pharmacovigilance has been defined by the World Health Organisation as “The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problem”

Adverse Events & Adverse Reactions

The ICH E2A guideline describes Adverse Events as any “untoward medical occurrence” which happens to either a patient or a subject in a clinical investigation when a pharmaceutical product has been given to that person¹. This encompasses any signs which are unfavourable and unexpected for the patient or subject, including any abnormal laboratory findings. These could be symptoms or a diseases temporally associated with the use of a medicinal product, and do not have to have been previously associated with that product. Neither do they have to have a known causal relationship with the course of treatment.

ICH E2A characterises Adverse Reactions according to the stage of the medicinal product’s life cycle. If the product has not yet been marketed, Adverse Reactions are any “noxious and unintended responses”¹ to the product at any dose. The effect of this classification is to reasonably establish that a relationship between the product and the reaction “cannot be ruled out”¹. Once the product has been placed on the market, “Adverse Reactions” encompass responses which are again “noxious and unintended” but occur at the established routine dosages which have been defined for use in humans to prevent, diagnose, or treat disease or modify “physiological function”¹. However, some more recent definitions include responses to doses and uses outside those recommended.

Serious Adverse Events (SAEs)
As the names implies, these are “any untoward medical occurrence” that:
 Is fatal
 Is a threat to life   
Results in inpatient hospitalisation  
Prolongs an existing hospital stay        
Results in persistent or significant disability or incapacity  
Results in a congenital anomaly or birth defect
Events that require intervention to prevent the patient or subject experiencing any of the outcomes listed above or otherwise jeopardise the patient are also to be classed as serious, depending on their nature. In some cases expedited reporting will clearly be appropriate. In the EU, suspected transmission of an infectious agent also constitutes a serious adverse event.
Suspected Adverse Drug Reaction (ADRs)
This term is discussed in ICH E2A and ICH E2D, it covers those events where there is the reasonable possibility the event is a direct result of taking the product. Inevitably most serious drug reactions are treated as being “suspected” rather than “confirmed” since they would need some kind of additional evidence, such as “dechallenge and rechallenge” in order to be confirmed. This would mean the patient would take the drug, have the reaction, recover after the drug is withdrawn, and then take the drug again to confirm the reaction. Given the serious nature of such reactions, rechallenge as a test may be unethical, but it may happen in clinical practice.

Suspected Unexpected Serious Adverse Reactions (SUSARs) and Expected Drug Reactions

Before a product is marketed, a Suspected Unexpected Serious Adverse Reaction is any suspected adverse reaction which is serious and is not consistent with the information on adverse reactions made available in the current investigator brochure¹. Once a product is marketed, unexpected reactions are are those whose nature or severity is not consistent with the undesirable effects included in the standard product information (Package Insert or Summary of Product Characteristics), although the investigator brochure could also be the reference document for post-marketing studies.

The goal of pharmacovigilance is to protect patients and the public wherever possible and to disseminate knowledge among the relevant professional communities and to patients in order to minimise risk. The information here is provided as a general introduction to the topics and in no way constitutes legal, safety or any other form of professional advice.

CIOMS is an abbreviation for the “Council for International Organizations of Medical Sciences”, which plays an important role within contemporary pharmacovigilance practice. This page provides information on the composition and activities of the organisation, which is hosted at The World Health Organisation, Geneva, Switzerland.

What Is CIOMS?

The organisation was founded by the WHO and UNESCO, the United Nations Educational, Scientific and Cultural Organisation, in 1949. It is an independent not-for-profit body which is not affiliated to, or funded by, any single government or nation. The organisation brings together representatives from the “biomedical scientific community” worldwide, aiming to encourage and facilitate international biomedical scientific activities whilst maintaining a relationship with the United Nations organisation (particularly WHO and UNESCO)

What Does It Do?

CIOMS coordinates programmes devised to run for many years to address the following key areas of biomedicine:

·         Bioethics

·         Health Policy, Ethics and Human Values – An International Dialogue

·         Drug Development and Use

·         International Nomenclature of Diseases

Why Is It Important Within Pharmacovigilance Work?

CIOMS has run a program focusing on drug safety since the early 1980s which incorporates distinct working groups. These groups have published many guidelines for practice, including:

·         Definition and Application of Terms for Vaccine Pharmacovigilance Safety

·         Current Challenges in Pharmacovigilance: Pragmatic Approaches (CIOMS V)

·         Development and Rational Use of Standardised MedDRA Queries (SMQs)

·         Management of Safety Information from Clinical Trials (CIOMS VI)

·         Development Safety Update Reports (CIOMS VII)

·         Practical Aspects of Signal Detection in Pharmacovigilance (CIOMS VIII)

·         Benefit-risk balance for marketed drugs (CIOMS IV)

·         International Reporting of Periodic Drug Safety Update Summaries (CIOMS II)

·         Guideline for Preparing Core Clinical Safety Information on Drugs (CIOMS III).

In addition, CIOMS was involved in publishing an initiative to standardise the use of medical terms associated with adverse drug reactions. However, this has not been widely accepted in pharmacovigilance practice.

The CIOMS guidelines are individually published in paper-back book form, available on payment to CIOMS in Geneva. Some have become obsolete or superseded by other published guidelines (e.g. CIOMS II, CIOMS VII); others have helped crystallise subsequent more definitive guidance from other bodies, such as the International Conference on Harmonisation (e.g. CIOMS VII). Some of the CIOMS guidelines, such as CIOMS III,  CIOMS V and CIOMS VIII, have been hugely influential in formulating the direction in which pharmacovigilance practice worldwide has evolved, and continue to be used in their own right.

It is important to note that, although influential, CIOMS guidelines have no legal or regulatory mandate: they reflect the (then) current thinking of a self-selected group of industry and regulatory experts but cannot be considered as consensus documents, or as legally binding.

The CIOMS I Form

As well as work on pharmacovigilance and other guidelines, several years ago CIOMS developed the CIOMS Form I. This form provides a standardised format for the reporting of suspected adverse reactions to any particular medical product.  It has proved of enduring value in practice since the 1980s and continues to be widely used (although often significantly expanded from the original one page summary).

ICH is an abbreviation for the “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use”.

It is an international Standards Development Organisation (SDO) that exists to promote the harmonisation of requirements for the registration and and on-going regulation of pharmaceuticals across the major global regions (EU Japan and USA). This page provides an introduction to ICH and some of its key publications.

What Is ICH?

ICH brings together regulators and Industry professionals from the global regions to participate in scientific debate on pharmacovigilance methodologies and procedures to be used to monitor and ensure the safety, quality and efficacy of medicines intended to treat humans.
The rationale behind its formation was the growing understanding within scientific communities that the goals of pharmacovigilance services would be better met if there existed a greater degree of uniformity regarding testing and safety regulations across the different regions. ICH was therefore established in 1990 and has since facilitated professionals from the three global regions to formulate appropriate practice guidelines. Participants in ICH are organised as working groups, including regulatory authority and pharmaceutical industry representatives from each of the three regions, together with representatives of World Health Organisation and other bodies acting as observers.
It is important to note that ICH guidelines in themselves have no regulatory or legal mandate, but the later versions of the guidelines (‘Step 4’ in the stepwise consensus-building process) are intended for adoption and implementation by regulators in the 3 regions.  Indeed, ‘step 5’ is reached when an ICH guideline has been incorporated in regulation in the constituent regions.

The “E Series”: Important Published Standards For EU Drug Safety Work

The ICH has published a number of documents setting standards for safety, both clinical and pre-clinical. Pre-clinical guidelines have an “S” designation e.g. S1, S2 etc.  It should be noted that the clinical safety guidelines are designated as “E”, standing for “Efficacy”, which is confusing for the uninitiated, as there are also E guidelines that concern efficacy only. Each of the following clinical safety guidelines reached step 4 status. Each has an identifying code, and during the lifetime of the ICH the codes have already been revised to reflect the development and evolution of those standards documents:

·         E1 The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions

·         E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting

·         E2B (R2) Maintenance of the Clinical Safety Data Management including Data Elements for Transmission of Individual Case Safety Reports

·         E2B (R3) Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports

·         E2C (R1) Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs

·         E2C (R2) Periodic Benefit-Risk Evaluation Report

·         E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting

·         E2E Pharmacovigilance Planning

·         E2F Development Safety Update Report

These documents provide a high degree of detail about the expected manner, method, timing, frequency and circumstances in which pharmaceutical companies and other relevant parties need to report suspected adverse reactions and other vital clinical data to the regulatory authorities. As well as the clinical safety guidelines above, the ICH also focuses on other distinct areas. It has contributed a tremendous volume of guidelines for medicinal product Efficacy, and Quality. There is also a series of ‘Multidisciplinary’ guidelines, meaning topics which have the inevitable overlap between at least two categories from Safety, Efficacy or Quality. These include the widely used M1 guideline, which in fact is the MedDRA medical terminology (Medical Dictionary for Regulatory Activities) and the M2 guideline, which specifies the technical framework used for the electronic transmission of safety information, as well as guidelines setting standards for other key elements of pharmaceutical regulatory activities, such as data elements for drugs dictionaries and the Common Technical Document comprising the registration dossier for new medicines.

Please note that this page cannot provide detail on the full scope of the ICH guidelines and the interested reader is referred instead to the source material which can be found online at the ICH website, detailed in the references below. Please note that this page should not be considered as professional pharmacovigilance advice.

The need for Pharmacovigilance activities continue long after the initial pre-marketing clinical trials, with post-marketing studies forming an important part of the confirmation of the safety and efficacy profile of each new medicinal product.

Prior to release onto the market, all new medicines must have completed a series of clinical trials with patients. These trials will have aimed to establish the safety and efficacy of the drug for the treatment of a particular disease within a selected sample of the population. This page provides a brief insight into the need for Pharmacovigilance post marketing activities.

Why Is There A Need for Pharmacovigilance Even After Clinical Trials?

Pre-marketing trials could have been conducted on a large scale, involving up to 10,000 subjects, or they could have been relatively small. In small trials, the study size could have ranged from only dozens to perhaps hundreds of patients, as can be the case for ‘orphan drugs’ (meaning drugs intended to treat rare diseases).

However, even after having completed rigorous pre-marketing trials, the limitations of the scale of the studies mean that the less common and rare adverse reactions (ADRs) are statistically unlikely to have been detected. For example, for a study of 10,000 patients, the absence of a report of a particular ADR occurring in the study programme means that we can be confident (at the 5% probability level) that the true rate of occurrence is less than 1 in 3,333. A statistical probability level of 1% would require a zero occurrence rate in 46,000 patients. Therefore, uncommon AEs or those with less commons rate of occurrence cannot be detected with any certainty given the limitations of sample size during the pre-marketing phase.

Patient Groups, Polypharmacy And Food Issues
Pre-marketing studies of a drug may also exclude certain groups of patients, although in real-life clinical practice, the drug may be prescribed for patients from those groups. For example, clinical trials may have included patients aged 18 to 60 years old. However, the drug may then be prescribed to more elderly patients. The elderly are a population who are more sensitive to a range of adverse reactions to medicines for various reasons, including differences in metabolism and in body mass index compared with a younger population as well as a higher likelihood of non-compliance with medication and of polypharmacy. Additionally, clinical trials may exclude subjects with co-morbidities such as renal or cardiac impairment, immunodeficiency, or blood pressure anomalies etc. These conditions may put such patients at increased risk of certain ADRs and may eventually lead to the medicine being contraindicated or requiring close monitoring when used under these circumstances.

Polypharmacy is another issue which may not have been possible to adequately address during pre-marketing studies. There could have been some drug interaction studies including drug-drug interactions and investigation into the effects of food intake, but information is likely to be limited and patients taking several classes of concomitant medicines may have been excluded from the study programme, whilst such patients could be exposed to these drugs after marketing.

The initial 500,000 to 1,000,000 patients who are the first to take the new drug after it has been released onto the market represent the first large scale safety test. A robust pharmacovigilance system is clearly of pivotal importance during this particular stage of the products life cycle. Pharmacists, doctors and nurses report suspected adverse drug reactions each working day around the globe; this is known as spontaneous reporting. They may report to regulatory agencies, national or regional pharmacovigilance centres or to pharmaceutical companies. Should pharmaceutical companies receive a report of a serious suspected adverse reaction for one of their products on the market, they must report it (generally within 15 days) to the regulatory authorities according to national and international laws.

Pharmacovigilance is essential during the post-marketing phase, even for medicinal products which have been on the market for a number of years.

 Although such products will have completed the pre-marketing clinical trials, been awarded Marketing Authorisations by the regulators and been taken by perhaps hundreds of thousands or even millions of patients in real life clinical practice, there are nonetheless circumstances in which unanticipated adverse reactions can arise.

Medicinal Products May Contain Excipients which invoke a reaction

The active pharmaceutical or biological component of a medicinal product as it is received by the patient (for example as a capsule or infused solution) may sometimes only form a small fraction of the total volume of the product. The remaining volume constitutes excipients which are in theory ingredients without any effects that are simply added for consistency, stability, bulk or form. They may also be present to add flavour; as a preservative; to act as a diluent, adjuvant or lubricant; to provide a certain colour to the medication, and so on.
Excipients can vary in composition between both formulations and dose strengths of the same drug. It could be that a higher dose formulation of the same drug is manufactured as a larger tablet, for example, and therefore simply contains more excipients than the lower dose formulation. The pharmaceutical industry has placed hundreds of thousands of products on the market, all containing various excipients in varying quantities. They may change formulations and/ or excipient suppliers. Adverse reactions can occur with the excipients – for example allergies, lactose intolerance, effects of sugar in diabetic patients – and these may be difficult to detect. In the past, there have also been relative overdoses caused by new formulations of old products increasing the amount of drug that is absorbed into the body.

Adverse Reactions Suspected To Be Associated With Taking Placebos
It is also of note that clinical trial participants (subjects or patients) have been known to experience Adverse Reactions to placebos. Within the EU, the Clinical Trial Directive (2001/20/EC, April 4, 2001) includes the word ‘placebo’ within the list of substances with the status of “an investigational medicinal product”. Therefore timely reporting of any Adverse Events applies to those found to occur after taking placebos in clinical trials conducted as post-marketing activities, if it is suspected that the reaction was caused by the placebo. Placebo reactions usually occur because of allergy to an excipient in the placebo – in the same way that excipients in medication with active ingredients can also cause allergic reactions.

Problems With Generic Drugs From Different Pharmaceutical Companies

Once a drug has been marketed for sufficient time to qualify for manufacture as a generic product, it is not sufficient that only the original manufacturer (innovator) of the patented drug should engage in reporting of suspected adverse reactions. Regulations require that surveillance takes place and that reports should be submitted and evaluated by whichever pharmaceutical companies made the particular generic version of the formerly patented product. Due to the types of issues with excipients stated above, there may be cases arising with suspected associations with formulation or other aspects of manufacture.

New Problems with Old Products
There are many examples where it has taken many years for even very serious adverse effects of products to be identified. This may be because of the rarity of their occurrence, or because the circumstances in the individual patients did not raise a suspicion that the medicine concerned was causing the problem. Examples include the identification of heart valve disease with some drugs used to treat obesity, and the occurrence of heart rhythm disturbances with some non-sedating antihistamines. In other instances, it may take many years or even decades for an adverse effect of a medicinal product to develop – for example if a drug causes cancer. In one example – stilboestrol, a synthetic female sex hormone – the adverse reaction concerned was a rare type of cancer which only manifested itself in the grown-up daughters of the women who took the drug in pregnancy. In another example, there was a change in the manufacturing process after many years on the market for a medicine used to treat depression. This change led to a toxic by-product of manufacture causing serious problems in the blood, muscles and lungs of patients receiving that make of the product, but patients receiving the original version were unaffected. Finally, as new medicines continuously come on to the market, these may have interactions with well-established use products presenting new risks to the patient previously not seen.

Clinical trial safety is an important component of pharmacovigilance. Every medicinal product must have satisfactorily completed a clinical trial programme establishing acceptable evidence of safety and efficacy before being placed onto the market.

In the EU, clinical trials have a regulatory definition: “Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the objective of ascertaining its (their) safety and/or efficacy”.
The exact nature of these pre-registration trials will depend on a number of factors including the drug itself; the particular disease or indication it has the potential to treat; and the patient group studied.
Trials may be segmented into four distinct phases although there is commonly some overlap between them. The terminology for participants reflects the particular phase: Phase 1 typically uses healthy volunteers (‘subjects’) while later phases involve volunteers who have the disease in question (hence ‘patients’, or ‘patient volunteers’ in some cases). This page provides a brief overview of Phase I, II, III and IV trials and why they sometimes overlap.

Phase I

Phase I represents the first use in humans, with studies involving healthy volunteer humans as opposed to animal models. The aim is to begin to establish the safety profile of the drug in question, determining the potential for both beneficial and adverse effects. The studies examine the pathways through which the drug is absorbed, distributed in the body, metabolised and eliminated and the maximum tolerable dose. They can also study proposed formulas and dosage (frequency and scheduling) for further trials.  The primary focus is on safety rather than efficacy, with studies usually lasting only a few days or a few weeks. Phase I studies might typically require 12 months to complete and involve comparatively few subjects. Serious Adverse Events (SAEs) are relatively rare and every effort is made to minimise any risk to the participants. For some drugs known to be toxic (such as those used in the treatment of cancer) Phase I studies in healthy volunteers may not be possible for ethical reasons.

Phase II

These trials aim to study the drug as administered to patients who already have the disease which the drug may have the potential to treat. The objective is to determine the optimal dose and dosing regimen, one which delivers maximal efficiency alongside acceptable adverse effects. Phase II trials may also investigate metabolism and excretion in more depth and establish safety and efficacy markers for subsequent trials. The scale is larger, running up to hundreds of patients, lasting several weeks or months and often uses a double blind design where a standard of care comparator product or placebo is used to benchmark the investigation product’s safety and efficacy.

Phase III

This phase usually involves hundreds or even thousands of patients and may require several years for completion. The ultimate aim is to gain statistically significant scientific proof of a positive benefit-risk profile of the medicinal product which is required for regulatory approval and often the favoured design is again double blind with randomised allocation of patients to receive active drug or placebo or active comparator treatment. It will depend on the drug and disease as to whether the current standard therapy is used as a comparator for the results, or whether they are compared to a placebo. If a serious disease for which there is already an effective treatment is being studied, the new drug may be given in addition to the established treatment, to determine if it can increase the effectiveness, compared to patients receiving placebo in addition to the established therapy. There is no guarantee that any trial in this phase will result in a Marketing Authorisation (MA) and naturally the oversight of an effective pre- and post-marketing pharmacovigilance system is a critical component of any application for an MA.

Phase IV

Different types of studies can be included in phase IV, which is conducted following the granting of a Marketing Authorisation (MA). The drug has often been placed onto the market (although there are cases this does not always happen directly after authorisation). However, regulators do often require some type of Phase IV studies (or in EU parlance, “post-authorisation studies”) to be conducted within a timely manner once a drug does go on sale. This may be to clarify issues which were not resolved during Phase III but that regulators did not classify as a cause to delay marketing. Size and designs can vary, sometimes consisting of classical clinical trials, sometimes epidemiological studies studying large populations using databases or registries of treated patients.

Overlap Between Phases

In practice, classic Phase I studies may investigate far beyond the initial dose findings, with escalation studies over several years taking place during the ensuing phases. Or, in certain cases, a company will apply for approval to mount a combined Phase II – III trial, should the results from initial larger scale Phase II trials prove suitable.

From a pharmacovigilance perspective, larger scale studies are preferable to more fully establish the safety profile of any particular drug. However, there are inevitable limitations to a pre-registration clinical trial programme. Thus, for example, the studies do not usually include sufficient patients to identify uncommon or rare adverse reactions; the close monitoring that occurs in a clinical study, with careful attention to inclusion and exclusion criteria and co-administered medicines, does not mirror real life post-marketing; the frailest patients and various populations (e.g. women, ethnic minorities) may be under-represented; and the duration of treatment may be limited. Thus there is a need for pharmacovigilance after a medicine is marketed – comprising spontaneous reporting and review of suspected adverse reactions but also increasingly, a requirement for post-authorisation safety studies (PASS) and other post-authorisation studies. In the EU, PASS are defined as: “Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures”.