Best practice paper on visual inspection to be published in September 2014


The ECA working group on visual inspection, which was founded this year, is going to publish its first document during the ECA event Particles in Parenterals and beyond. Read more.,Z-PEM_n.html

Press Announcement: Best practice paper on visual inspection to be published in September 2014

The work on this best practice paper has already started earlier this year and has been intensified since the foundation of the working group in March 2014. The goal of this paper is to harmonise the long lasting experience and knowledge from different and approved industrial practices and from presentations from previous conferences.
The paper, which is much rather supposed to be a reference than a strict requirement, will cover Manual and Automated Inspection issues in the following chapters:

  • Workplace (manual)
  • Operation (manual and automated)
  • Qualification
  • Re-Qualification
  • Re-Validation
  • Evaluation of defects
  • Batch release considerations

The paper is still in the group internal discussion phase, but it will be published in its first version during the ECA conference “Particles in Parenterals and beyond” scheduled in Copenhagen, Denmark, from 24-25 September 2014. All participants of the event will receive a copy of this document.

In the future course of this year, the group will decide whether it will be transferred to an interest group which would then allow to further discuss and supplement the content of the paper and to possibly admit further group members.
More information will be published on the group’s webpage, when available.


Handling of OOS Results in Europe


FDA’s Guidance on Out-of-Specification Results has been seen as the state of the art regarding the handling of OOS results. In the meantime, Europe – through the British MHRA and the German ZLG – has also developed requirements on that topic. Read more here about the most important regulations of the respective guidance documents.


GMP News: Handling of OOS Results in Europe,8430,Z-QCM_n.html

For some time now, information about the handling of OOS results has been put on the website of the MHRA. There, you can find a Guidance document entitled “Out of Specification Investigations”. This document was updated last year to add microbiological aspects.

It is easier to understand than the FDA Guideline on the same topic. The different Flow Charts are also helpful.

A definition of all terms – both Out-of-Specification (OOS) Results and Out of Trend (OOT) Results – is provided at the beginning as well as atypical / aberrant / anomalous results. A definition of the term “Reportable Result” is also provided as follows: “is the final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the original sample.”

Regarding averaging, it is explicitly said that it “must be specified by the test method”. Moreover, the 95% Confidence Limit must be taken into consideration when averaging is used.

Retesting may be performed if no assignable cause can be found to explain a deviating result. Retesting should be performed on the original sample not on a different sample. Regarding the number of retests required, the MHRA refers to other publications suggesting 5, 7 or 9 retests. Retest results shouldn’t be averaged with the original results which triggered the OOS investigation.

Like in the FDA Guidance, an outlier test solely can’t be considered as sufficient to justify the rejection of data.

Also the aspect of OOS and OOT results for stability testing is addressed.

For quite a long time, Germany has been using the ZLG Aide Mémoire (Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten) on the monitoring of manufacturers of medicinal products; section 6.8 also addresses the handling of OOS results. With regard to retesting, the Aide Mémoire defines that the number of retests should be set in advance in an SOP based on sound scientific judgement and should be statistically valid.

The ZLG Aide Mémoire also states that averaging is allowed: the average value must correspond to the specification, but single results must not. However, it is a condition that acceptance criteria should be defined for the variability of the single values and that these provisions are described in an SOP.

You can find more information in the MHRA Guidance Document Out-of-Specification Investigations here as well as in the ZLG Aide Mémoire on the monitoring of manufacturers of medicinal products.

FDA warns consumers: Dietary supplements cannot treat concussions

Atasteofcreole's Blog

The U.S. Food and Drug Administration is warning consumers about dietary supplements that falsely claim to prevent or cure concussions or other traumatic brain injuries. The FDA says supplements with labels that make these claims are not backed up by scientific evidence, and in a consumer alert issued Monday it urged users to beware.

Additionally, the FDA says some companies have marketed these products to military service members and veterans who have sustained combat-related traumatic brain injuries. The U.S. Department of Defense was among the first to raise concerns.

The warning comes as school is starting up again many student athletes are getting back into competitive sports that can lead to concussion and other serious injuries. The risk for head trauma from contact sports, such as football and wrestling, has provided another marketing opportunity for companies to make false claims that certain dietary supplements can help cure or prevent…

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Indian Sterile Manufacturer receives FDA Warning Letter and changes company name from Marck Biosience to Amanta Healthcare

Marck Biosciences Ltd. to “Amanta Healthcare Ltd.”, effective from June 24, 2014.

Click here to visit  website at


Indian Sterile Manufacturer receives FDA Warning Letter and changes company name from Marck Biosience to Amanta Healthcare

Marck Biosciences Limited is a producer of sterile products which has been producing sterile products for the US market. The FDA Warning Letter dated July 8, 2014 contains shocking details about the GMP situation at this facility. Read more here about the FDA Warning Letter to Marck Biosciences and about the name change to Amanta Healthcare.


Which SOPs are required by GMP?

ECA is receiving a lot of questions on SOPs (Standard Operating Procedures) needed in a GMP environment. The most interesting is the one on which SOPs are required by law. Here is an Overview.

GMP News: Which SOPs are required by GMP?

The ECA Academy is receiving a lot of questions on SOPs (Standard Operating Procedures) needed in a GMP environment. The most interesting is the one on which SOPs are required by law. Here is an Overview:

U.S. Food and Drug Administration (FDA):

A three year old Notice focusing on specific recordkeeping requirements in the Federal Register also gives a very good summary of SOPs required by 21 CFR Part 211:

“Written procedures (standard operating procedures – SOPs), are required for many Part 211 records. The current SOP requirements were initially provided in a final rule published in the Federal Register of September 29, 1978 (43 FR 45014), and are now an integral and familiar part of the drug manufacturing process.”

The 25 SOPs provisions under Part 211 include:

  • Section 211.22(d)-Responsibilities and procedures of the quality control unit;
  • Section 211.56(b)-Sanitation procedures
  • Section 211.56(c)-Use of suitable rodenticides, insecticides, fungicides, sanitizing agents;
  • Section 211.67(b)-Cleaning and maintenance of equipment;
  • Section 211.68(a)-Proper performance of automatic, mechanical, and electronic equipment;
  • Section 211.80(a)-Receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers or closures;
  • Section 211.94(d)-Standards or specifications, methods of testing, and methods of cleaning, sterilizing, and processing to remove pyrogenic properties for drug product containers and closures;
  • Section 211.100(a)-Production and process control;
  • Section 211.110(a)-Sampling and testing of in-process materials and drug products;
  • Section 211.113(a)-Prevention of objectionable microorganisms in drug products not required to be sterile;
  • Section 211.113(b)-Prevention of microbiological contamination of drug products purporting to be sterile, including validation of any sterilization process;
  • Section 211.115(a)-System for reprocessing batches that do not conform to standards or specifications, to insure that reprocessed batches conform with all established standards, specifications, and characteristics;
  • Section 211.122(a)-Receipt, identification, storage, handling, sampling, examination and/or testing of labeling and packaging materials;
  • Section 211.125(f)-Control procedures for the issuance of labeling;
  • Section 211.130-Packaging and label operations, prevention of mixup and cross contamination, identification and handling of filed drug product containers that are set aside and held in unlabeled condition, and identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch;
  • Section 211.142-Warehousing;
  • Section 211.150-Distribution of drug products;
  • Section 211.160-Laboratory controls;
  • Section 211.165(c)-Testing and release for distribution;
  • Section 211.166(a)-Stability testing;
  • Section 211.167-Special testing requirements;
  • Section 211.180(f)-Notification of responsible officials of investigations, recalls, reports of inspectional observations, and any regulatory actions relating to good manufacturing practice;
  • Section 211.198(a)-Written and oral complaint procedures, including quality involving specifications failures, and serious and unexpected adverse drug experiences;
  • Section 211.204-Holding, testing, and reprocessing of returned drug products; and
  • Section 211.208-Drug product salvaging.

European Union:

SOPs required by EU-GMP are mainly defined in the EU Guidelines to Good Manufacturing Practice of Eudralex Vol. 4 (EU-GMP Guide). There is no comprehensive list provided but Chapter 4 of Part 1 (Documentation) of the Guide gives some examples:

“There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples:

  • Validation and qualification of processes, equipment and systems;
  • Equipment assembly and calibration;
  • Technology transfer;
  • Maintenance, cleaning and sanitation;
  • Personnel matters including signature lists, training in GMP and technical matters, clothing and hygiene and verification of the effectiveness of training.
  • Environmental monitoring;
  • Pest control;
  • Complaints;
  • Recalls;
  • Returns;
  • Change control;
  • Investigations into deviations and non-conformances;
  • Internal quality/GMP compliance audits;
  • Summaries of records where appropriate (e.g. product quality review);
  • Supplier audits.”

Chapter 4.30 requires that operating procedures “should be available for major items of manufacturing and test equipment.”

World Health Organisation (WHO)

A very comprehensive list can be found in the WHO guide to good manufacturing practice (GMP) requirements, Part 1: Standard operating procedures and master formulae. Although written as part of the Global Programme for Vaccines and Immunization, Vaccine Supply and Quality, this overview gives valuable guidance also for other pharmaceutical companies.

More than 75 SOPs are listed from the following areas in Appendix 1 (“List of Document Requirements”):

  • Raw Materials
  • Biological Starting Materials
  • Facility
  • Equipment (Production and QC)
  • Production
  • Labelling and Packaging
  • Quality Control
  • Quality Assurance

The examples from FDA, EU and WHO provided above are not a finite list. Some topics might be split in a number of SOPs for the sake of practicality. Some other company or quality system specific processes might be defined in SOPs as well.

Wednesday, 20 August 2014 Glenmark enters Oncology with the Discovery and the Initiation of IND enabling Studies of an innovative bispecific Antibody

New Drug Approvals

August20, 2014: Glenmark Pharmaceuticals S.A. (GPSA), a wholly owned subsidiary of Glenmark Pharmaceuticals Limited India (GPL), announces the discovery and initiation of IND enabling studies of a novel clinical development candidate, GBR 1302, a HER2xCD3 bispecific antibody. GBR 1302 was discovered and developed by the Glenmark Biologics Research Centre located in La Chaux-de-Fonds, Switzerland. GBR 1302 is based on Glenmark’s innovative BEAT antibody technology platform which facilitates the efficient development and manufacture of antibodies with dual specificities, so-called bispecific antibodies. GBR 1302 is the first clinical development candidate based on the BEAT technology. Glenmark expects to obtain approval for the initiation of clinical studies during this financial year.


·GBR 1302 is the first bispecific antibody based on Glenmark’s proprietary BEAT platform

  • GBR 1302 is Glenmark’s first clinical candidate targeting oncology indications

    Glenmark Pharmaceuticals announced the discovery and initiation of IND enabling studies of a novel clinical development candidate…

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Turkish man pleads guilty to importing illegal cancer drugs


August 15, 2014


Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.

Akman pleaded guilty in the U.S. District Court for the Eastern District of Missouri, in St. Louis, Missouri, where he initially shipped his illegal drugs. The drugs did not meet the FDA’s standards and had not been approved for distribution in the United States.

The FDA’s Office of Criminal Investigations coordinated a complex, multi-layered international investigation that led to Akman’s arrest in Puerto Rico in January 2014. The investigation identified Akman and his company as a source of Altuzan, the Turkish version of the cancer treatment drug Avastin.

“These criminals exploited our most vulnerable patients when they arranged for their illicit drugs to be brought into the United States and used to treat cancer patients. We will continue to investigate and bring to justice those who prey on our ill, susceptible patients,” said Philip J. Walsky, acting director of the FDA’s Office of Criminal Investigations. “We commend our colleagues – international, national, state, and local – whose contributions helped bring this case to a successful conclusion.”

Akman, along with his employee, Ozkan Semizoglu, obtained the illicit drugs and then used shipping labels to conceal the illegal nature of the shipments, including customs declarations falsely describing the contents as gifts. They also broke large drug shipments into several smaller packages to reduce the likelihood of seizures by U.S. Customs and Border Protection authorities.

Along with the FDA and Europol, the international operation involved several German government offices: the Bonn prosecutor; the Federal Criminal Police, the Dusseldorf police, and the German State Criminal Police.  Special agents of the U.S. Department of State’s Diplomatic Security Service assigned to the U.S. Embassy’s Regional Security Office in Ankara, Turkey, and the U.S. Consulate General’s Overseas Criminal Investigations Branch in Istanbul, Turkey also played key roles in the successful resolution of this case.

Road map to 2015, The European Medicines Agency’s contribution to science, medicines and health

One of the European Medicines Agency’s long-term strategic goals is to foster researchand the uptake of innovative methods in the development of medicines.

READ………….Road map to 2015

The European Medicines Agency’s
contribution to science, medicines and health……………..

This helps the Agency to meet its objective of making safe and effective medicines available to patients in a timely manner, following evaluation using state-of-the-art methods.

The Agency also supports the development of new therapies and technologies by working with interested parties in the European Union (EU).

Activities at the Agency

In 2004, the Agency set up the European Medicines Agency/Committee for Medicinal Products for Human Use (CHMP) Think-Tank Group on Innovative Drug Development.

This group included Agency staff and members of the CHMP and its working parties. Its work focused on identifying scientific bottlenecks and emerging science in the development of medicines, both in industry research and development and in academia, and on generating recommendations for future activities at the Agency:

In 2008 the EMA and its Scientific Committees integrated the recommendations made by the Think Tank in its strategy for supporting innovative medicines developments. Key areas of action included the strengthening of the EU scientific network model, emphasis on communication during the lifecycle of medicinal products development and international activities. Overview of measures implemented in the period 2008-2010.

The recently published Road Map to 2015 further expands on the role the Agency plays to promote innovation in pharmaceuticals.

The Agency also contributes to the Innovative Medicines InitiativeExternal link icon (IMI). This is a public-private initiative that aims to speed up the development of better and safer medicines for patients:

Support for business

The Agency provides support for business on issues related to innovative medicines:

WHO issues draft proposal for biosimilar naming

biosimilar ladder WHO issues draft proposal for biosimilar naming

A long debate is ongoing about biosimilar naming around the world. Although EU accepted the same INN system years ago, with the latest developments around the world, biosimilar naming uncertainty is still ongoing.

The global INN (International Non-Proprietary Name) system is managed by the World Health Organization. They have held several meetings to solve this long debate and finally released a proposal for biosimilars naming.

WHO issues draft proposal for biosimilar naming: A long debate is ongoing about biosimilar naming around the world. Although EU accepted the same INN system years ago, with the latest developments around the world, biosimilar naming uncertainty is still… READ MORE

Regulatory Considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs)



A sponsor of an Abbreviated New Drug Application (ANDA) must have information to show that the proposed generic product and the innovator product are both pharmaceutically equivalent and bioequivalent, and therefore, therapeutically equivalent. Many pharmaceutical solids exist in several crystalline forms and thus exhibit polymorphism. Polymorphism may result in differences in the physico-chemical properties of the active ingredient and variations in these properties may render a generic drug product to be bioinequivalent to the innovator brand. For this reason, in ANDAs, careful attention is paid to the effect of polymorphism in the context of generic drug product equivalency. This review discusses the impact of polymorphism on drug product manufacturability, quality, and performance. Conclusions from this analysis demonstrate that pharmaceutical solid polymorphism has no relevance to the determination of drug substance “sameness” in ANDAs. Three decision trees for solid oral dosage forms or liquid suspensions are provided for evaluating when and how polymorphs of drug substances should be monitored and controlled in ANDA submissions. Case studies from ANDAs are provided which demonstrate the irrelevance of polymorphism to the determination of drug substance “sameness”. These case studies also illustrate the conceptual framework from these decision trees and illustrate how their general principles are sufficient to assure both the quality and the therapeutic equivalence of marketed generic drug products.


  • Polymorphism;
  • Polymorph;
  • Abbreviated New Drug Application (ANDA);
  • Drug substance;
  • Drug product;
  • Pharmaceutical solid

The pharmacovigilance system in the European Union (EU)


The pharmacovigilance system in the European Union (EU) operates with the management and involvement of regulatory authorities in Member States, the European Commission and the European Medicines Agency. In some Member States, regional centres are in place under the coordination of the national competent authority.

Within this system, the Agency’s role is to coordinate the EU pharmacovigilance system and to ensure the provision of advice for the safe and effective use of medicines.

More information




Pharmacovigilance (PV or PhV), also known as Drug Safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention ofadverse effects with pharmaceutical products.[1] The etymological roots for the word “pharmacovigilance” are: pharmakon (Greek for drug) and vigilare (Latin for to keep watch). As such, pharmacovigilance heavily focuses on adverse drug reactions, or ADRs, which are defined as any response to a drug which is noxious and unintended, including lack of efficacy. (The condition, that this definition only applies with the doses normally used for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological disorder function was excluded with the latest amendment of the applicable legislation.) Medication errors such as overdose, and misuse and abuse of a drug as well as drug exposure during pregnancy and breastfeeding, are also of interest (even without adverse event itself), because they may result in an ADR.[2]

Information received from patients and healthcare providers via pharmacovigilance agreements (PVAs), as well as other sources such as the medical literature, plays a critical role in providing the data necessary for pharmacovigilance to take place. In fact, in order to market or to test a pharmaceutical product in most countries, adverse event data received by the license holder (usually a pharmaceutical company) must be submitted to the local drug regulatory authority. (See Adverse Event Reporting below.)

Ultimately, pharmacovigilance is concerned with identifying the hazards associated with pharmaceutical products and with minimizing the risk of any harm that may come to patients.

Terms commonly used in drug safety

Pharmacovigilance has its own unique terminology that is important to understand. Most of the following terms are used within this article and are peculiar to drug safety, although some are used by other disciplines within the pharmaceutical sciences as well.

  • Adverse Drug Reaction is a side effect (non intended reaction to the drug) occurring with a drug where a positive (direct) causal relationship between the event and the drug is thought, or has been proven, to exist.
  • Adverse event (AE) is a side effect occurring with a drug. By definition, the causal relationship between the AE and the drug is unknown.
  • Benefits are commonly expressed as the proven therapeutic good of a product but should also include the patient’s subjective assessment of its effects.
  • Causal relationship is said to exist when a drug is thought to have caused or contributed to the occurrence of an adverse drug reaction.
  • Clinical trial (or study) refers to an organised program to determine the safety and/or efficacy of a drug (or drugs) in patients. The design of a clinical trial will depend on the drug and the phase of its development.
  • Control group is a group (or cohort) of individual patients that is used as a standard of comparison within a clinical trial. The control group may be taking a placebo (where no active drug is given) or where a different active drug is given as a comparator.
  • Dechallenge and Rechallenge refer to a drug being stopped and restarted in a patient, respectively. A positive dechallenge has occurred, for example, when an adverse event abates or resolves completely following the drug’s discontinuation. A positive rechallenge has occurred when the adverse event re-occurs after the drug is restarted. Dechallenge and rechallenge play an important role in determining whether a causal relationship between an event and a drug exists.
  • Effectiveness is the extent to which a drug works under real world circumstances, i.e., clinical practice.
  • Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical trials.
  • Event refers an adverse event (AE).
  • Harm is the nature and extent of the actual damage that could be or has been caused.
  • Implied causality refers to spontaneously reported AE cases where the causality is always presumed to be positive unless the reporter states otherwise.
  • Individual Case Study Report (ICSR) is an adverse event report for an individual patient.
  • Life-threatening refers to an adverse event that places a patient at the immediate risk of death.
  • Phase refers to the four phases of development: I – small safety trials early on in a drug’s development; II – medium-sized trials for both safety and efficacy; III – large trials, which includes key (or so-called “pivotal”) trials; IV – large, post-marketing trials, typically for safety reasons. There are also intermediate phases designated by an “a” or “b”, e.g. Phase IIb.
  • Risk is the probability of harm being caused, usually expressed as a percent or ratio of the treated population.
  • Risk factor is an attribute of a patient that may predispose, or increase the risk, of that patient developing an event that may or may not be drug-related. For instance, obesity is considered a risk factor for a number of different diseases and, potentially, ADRs. Others would be high blood pressure, diabetes, possessing a specific mutated gene, for example, mutations in the BRCA1 and BRCA2 genes increase propensity to develop breast cancer.
  • Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a post-marketing trial to study the issue.
  • Temporal relationship is said to exist when an adverse event occurs when a patient is taking a given drug. Although a temporal relationship is absolutely necessary in order to establish a causal relationship between the drug and the AE, a temporal relationship does not necessarily in and of itself prove that the event was caused by the drug.
  • Triage refers to the process of placing a potential adverse event report into one of three categories: 1) non-serious case; 2) serious case; or 3) no case (minimum criteria for an AE case are not fulfilled).

Adverse Event Reporting

The activity that is most commonly associated with Pharmacovigilance (PV), and which consumes a significant amount of resources for drug regulatory authorities (or similar government agencies) and drug safety departments in pharmaceutical companies, is that of adverse event reporting. Adverse event (AE) reporting involves the receipt, triage, data entering, assessment, distribution, reporting (if appropriate), and archiving of AE data and documentation. The source of AE reports may include: spontaneous reports from healthcare professionals or patients (or other intermediaries); solicited reports from patient support programs; reports from clinical or post-marketing studies; reports from literature sources; reports from the media (including social media and websites); and reports reported to drug regulatory authorities themselves. For pharmaceutical companies, AE reporting is a regulatory requirement in most countries. AE reporting also provides data to these companies and drug regulatory authorities that play a key role in assessing the risk-benefit profile of a given drug. The following are several facets of AE reporting:

The “4 Elements” of an AE case

One of the fundamental principles of adverse event reporting is the determination of what constitutes an adverse event case. During the triage phase of a potential adverse event report, the triager must determine if the “four elements” of an AE case are present: (1) an identifiable patient, (2) an identifiable reporter, (3) a suspect drug, and (4) an adverse event.

If one or more of these four elements is missing, the case is not a valid AE report. Although there are no exceptions to this rule there may be circumstances that may require a judgment call. For example, the term “identifiable” may not always be clear-cut. If a physician reports that he/she has a patient X taking drug Y who experienced Z (an AE), but refuses to provide any specifics about patient X, the report is still a valid case even though the patient is not specifically identified. This is because the reporter has first-hand information about the patient and is identifiable (i.e. a real person) to the physician. Identifiability is important so as not only to prevent duplicate reporting of the same case, but also to permit follow-up for additional information.

The concept of identifiability also applies to the other three elements. Although uncommon, it is not unheard of for fictitious adverse event “cases” to be reported to a company by an anonymous individual (or on behalf of an anonymous patient, disgruntled employee, or former employee) trying to damage the company’s reputation or a company’s product. In these and all other situations, the source of the report should be ascertained (if possible). But anonymous reporting is also important, as whistle blower protection is not granted in all countries. In general, the drug must also be specifically named. Note that in different countries and regions of the world, drugs are sold under various tradenames. In addition, there are a large number of generics which may be mistaken for the tradeproduct. Finally, there is the problem of counterfeit drugs producing adverse events. If at all possible, it is best to try to obtain the sample which induced the adverse event, and send it to either the EMA, FDA or other government agency responsible for investigating AE reports.

If a reporter can’t recall the name of the drug they were taking when they experienced an adverse event, this would not be a valid case. This concept also applies to adverse events. If a patient states that they experienced “symptoms”, but cannot be more specific, such a report might technically be considered valid, but will be of very limited value to the pharmacovigilance department of the company or to drug regulatory authorities.[3]

Coding of Adverse Events

Adverse event coding is the process by which information from an AE reporter, called the “verbatim”, is coded using standardized terminology from a medical coding dictionary, such as MedDRA (the most commonly used medical coding dictionary). The purpose of medical coding is to convert adverse event information into terminology that can be readily identified and analyzed. For instance, Patient 1 may report that they had experienced “a very bad headache that felt like their head was being hit by a hammer” [Verbatim 1] when taking Drug X. Or, Patient 2 may report that they had experienced a “slight, throbbing headache that occurred daily at about two in the afternoon” [Verbatim 2] while taking Drug Y. Neither Verbatim 1 nor Verbatim 2 will exactly match a code in the MedDRA coding dictionary. However, both quotes describe different manifestations of a headache. As a result, in this example both quotes would be coded as PT Headache (PT = Preferred Term in MedDRA).

Seriousness Determination

Although somewhat intuitive, there are a set of criteria within pharmacovigilance that are used to distinguish a serious adverse event from a non-serious one. An adverse event is considered serious if it meets one or more of the following criteria:

  1. results in death, or is life-threatening;
  2. requires inpatient hospitalization or prolongation of existing hospitalization;
  3. results in persistent or significant disability or incapacity;
  4. results in a congenital anomaly (birth defect); or is otherwise
  5. “medically significant” —i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.[3]

Aside from death, each of these categories is subject to some interpretation. Life-threatening, as it used in the drug safety world, specifically refers to an adverse event that places the patient at an immediate risk of death, such as cardiac or respiratory arrest. By this definition, events such as myocardial infarction, which would be hypothetically life-threatening, would not be considered life-threatening unless the patient went into cardiac arrest following the MI. Defining what constitutes hospitalization can be problematic as well. Although typically straightforward, it’s possible for a hospitalization to occur even if the events being treated are not serious. By the same token, serious events may be treated without hospitalization, such as the treatment of anaphylaxis may be successfully performed with epinephrine. Significant disability and incapacity, as a concept, is also subject to debate. Whereas permanent disability following a stroke, would no doubt be serious, would “complete blindness for 30 seconds” be considered “significant disability”? For birth defects, the seriousness of the event is usually not in dispute so much as the attribution of the event to the drug. And, finally, medically significant events is a category that includes events that may be always serious, or sometimes serious, but will not fulfill any of the other criteria. Events such as cancer might always be considered serious, whereas liver disease, depending on its CTCAE (Common Terminology Criteria for Adverse Events) grade—Grades 1 or 2 are generally considered non-serious and Grades 3-5 serious—may be considered non-serious.[4]

Expedited Reporting

This refers to ICSRs that involve a serious and unlabelled event (an event not described in the drug’s labeling) that is considered related to the use of the drug. (Spontaneous reports are typically considered to have a positive causality, whereas a clinical trial case will typically be assessed for causality by the clinical trial investigator and/or the license holder.) In most countries, the timeframe for reporting expedited cases from the time a drug company receives notification (referred to as “Day 0”) of such a case is 15 calendar days. Within clinical trials such a cases is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction). If the SUSAR involves an event that is life-threatening or fatal, it may be subject to a 7-day “clock”. Cases that do not involve a serious, unlabelled event may be subject to non-expedited or periodic reporting.

Clinical Trial Reporting

Also known as SAE (Serious Adverse Event) Reporting from clinical trials, safety information from clinical studies is used to establish a drug’s safety profile in humans and is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny market authorization (market approval) for a drug. SAE reporting occurs as a result of study patients (subjects) who experience serious adverse events during the conducting of clinical trials. (Non-serious adverse events are also captured separately.) SAE information, which may also include relevant information from the patient’s medical background, are reviewed and assessed for causality by the study investigator. This information is forwarded to a sponsoring entity (typically a pharmaceutical company) that is responsible for the reporting of this information, as appropriate, to drug regulatory authorities.

Spontaneous reporting

Spontaneous reporting is the core data-generating system of international pharmacovigilance, relying on healthcare professionals (and in some countries consumers) to identify and report any adverse events to their national pharmacovigilance center, health authority (such as EMA or FDA), or to the drug manufacturer itself.[5] Spontaneous reports are, by definition, submitted voluntarily although under certain circumstances these reports may be encouraged, or “stimulated”, by media reports or articles published in medical or scientific publications, or by product lawsuits. In many parts of the world adverse event reports are submitted electronically using a defined message standard.[6][7]

One of the major weaknesses of spontaneous reporting is that of under-reporting, where, unlike in clinical trials, less than 100% of those adverse events occurring are reported. Further complicating the assessment of adverse events, AE reporting behavior varies greatly between countries and in relation to the seriousness of the events, but in general probably less than 10% (some studies suggest less than 5%) of all adverse events that occur are actually reported. The rule-of-thumb is that on a scale of 0 to 10, with 0 being least likely to be reported and 10 being the most likely to be reported, an uncomplicated non-serious event such as a mild headache will be closer to a “0” on this scale, whereas a life-threatening or fatal event will be closer to a “10” in terms of its likelihood of being reported. In view of this, medical personnel may not always see AE reporting as a priority, especially if the symptoms are not serious. And even if the symptoms are serious, the symptoms may not be recognized as a possible side effect of a particular drug or combination thereof. In addition, medical personnel may not feel compelled to report events that are viewed as expected. This is why reports from patients themselves are of high value. The confirmation of these events by a healthcare professional is typically considered to increase the value of these reports. Hence it is important not only for the patient to report the AE to his health care provider (who may neglect to report the AE), but also report the AE to both the biopharmaceutical company and the FDA, EMA, … This is especially important when one has obtained one’s pharmaceutical from a compounding pharmacy.

As such, spontaneous reports are a crucial element in the worldwide enterprise of pharmacovigilance and form the core of the World Health Organization Database, which includes around 4.6 million reports (January 2009),[8] growing annually by about 250,000.[9]

Aggregate Reporting

Aggregate, or periodic reporting plays a key role in the safety assessment of drugs. Aggregate reporting involves the compilation of safety data for a drug over a prolonged period of time (months or years), as opposed to single-case reporting which, by definition, involves only individual AE reports. The advantage of aggregate reporting is that it provides a broader view of the safety profile of a drug. Worldwide, the most important aggregate report is the Periodic Safety Update Report (PSUR). This is a document that is submitted to drug regulatory agencies in Europe, the US and Japan (ICH countries), as well as other countries around the world. The PSUR was updated in 2012 and is now referred to in many countries as the Periodic Benefit Risk Evaluation report (PBRER). As the title suggests, the PBRER’s focus is on the benefit-risk profile of the drug, which includes a review of relevant safety data compiled for a drug product since its development.

Other reporting methods

Some countries legally oblige spontaneous reporting by physicians. In most countries, manufacturers are required to submit, through its Qualified Person for Pharmacovigilance(QPPV), all of the reports they receive from healthcare providers to the national authority. Others have intensive, focused programmes concentrating on new drugs, or on controversial drugs, or on the prescribing habits of groups of doctors, or involving pharmacists in reporting. All of these generate potentially useful information. Such intensive schemes, however, tend to be the exception.

Risk Management

Causality Assessment[edit]Risk Management is the discipline within Pharmacovigilance that is responsible for signal detection and the monitoring of the risk-benefit profile of drugs. Other key activities within the area of Risk Management are that of the compilation of Risk Management Plans (RMPs) and aggregate reports such as the Periodic Safety Update Report (PSUR), Periodic Benefit Risk Evaluation Report (PBRER), and the Development Safety Update Report (DSUR).

One of the most important, and challenging, problems in pharmacovigilance is that of the determination of causality. Causality refers to the relationship of a given adverse event to a specific drug. Causality determination (or assessment) is often difficult because of the lack of clear-cut or reliable data. While one may assume that a positive temporal relationship might “prove” a positive causal relationship, this is not always the case. Indeed, a “bee sting” AE—where the AE can clearly be attributed to a specific cause—is by far the exception rather than the rule. This is due to the complexity of human physiology as well as that of disease and illnesses. By this reckoning, in order to determine causality between an adverse event and a drug, one must first exclude the possibility that there were other possible causes or contributing factors. In addition, if the patient is on a number of medications, it may be the combination of these drugs which causes the AE, and not anyone individually. There have been a number of recent high-profile cases where the AE led to the death of an individual. The individual(s) were not overdosed with any one of the many medications they were taking, but the combination there appeared to cause the AE. Hence it is important to include in your/one’s AE report, not only the drug being reported, but also all other drugs the patient was also taking.

For instance, if a patient were to start Drug X and then three days later were to develop an AE, one might be tempted to attribute blame Drug X. However, before that can be done, the patient’s medical history would need to be reviewed to look for possible risk factors for the AE. In other words, did the AE occur with the drug or because of the drug? This is because a patient on any drug may develop or be diagnosed with a condition that could not have possibly been caused by the drug. This is especially true for diseases, such as cancer, which develop over an extended period of time, being diagnosed in a patient who has been taken a drug for a relatively short period of time. On the other hand, certain adverse events, such as blood clots (thrombosis), can occur with certain drugs with only short-term exposure. Nevertheless, the determination of risk factors is an important step of confirming or ruling-out a causal relationship between an event and a drug.

Often the only way to confirm the existence of a causal relationship of an event to a drug is to conduct an observational study where the incidence of the event in a patient population taking the drug is compared to a control group. This may be necessary to determine if the background incidence of an event is less than that found in a group taking a drug. If the incidence of an event is statistically significantly higher in the “active” group versus the placebo group (or other control group), it is possible that a causal relationship may exist to a drug, unless other confounding factors may exist.

Signal Detection

Signal detection (SD) involves a range of techniques (CIOMS VIII). The WHO defines a safety signal as: “Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously”. Usually more than a single report is required to generate a signal, depending upon the event and quality of the information available.

Data mining pharmacovigilance databases is one approach that has become increasingly popular with the availability of extensive data sources and inexpensive computing resources. The data sources (databases) may be owned by a pharmaceutical company, a drug regulatory authority, or a large healthcare provider. Individual Case Safety Reports (ICSRs) in these databases are retrieved and converted into structured format, and statistical methods (usually a mathematical algorithm) are applied to calculate statistical measures of association. If the statistical measure crosses an arbitrarily set threshold, a signal is declared for a given drug associated with a given adverse event. All signals deemed worthy of investigation, require further analysis using all available data in an attempt to confirm or refute the signal. If the analysis is inconclusive, additional data may be needed such as a post-marketing observational trial.

SD is an essential part of drug use and safety surveillance. Ideally, the goal of SD is to identify ADRs that were previously considered unexpected and to be able to provide guidance in the product’s labeling as to how to minimize the risk of using the drug in a given patient population.

Risk Management Plans

A Risk Management Plan (RMP) is a documented plan that describes the risks (adverse drug reactions and potential adverse reactions) associated with the use of a drug and how they are being handled (warning on drug label or on packet inserts of possible side effects which if observed should cause the patient to inform/see his physician and/or pharmacist and/or the manufacturer of the drug and/or the FDA, EMA)). The overall goal of an RMP is to assure a positive risk-benefit profile once the drug is (has been) marketed. The document is required to be submitted, in a specified format, with all new market authorization requests within the European Union (EU). Although not necessarily required, RMPs may also be submitted in countries outside the EU. The risks described in an RMP fall into one of three categories: Identified Risks, Potential Risks, and Unknown Risks. Also described within an RMP are the measures that the Market Authorization Holder, usually a pharmaceutical company, will undertake to minimize the risks associated with the use of the drug. These measures are usually focused on the product’s labeling and healthcare professionals. Indeed, the risks that are documented in a pre-authorization RMP will inevitably become part of the product’s post-marketing labeling. Since a drug, once authorized, may be used in ways not originally studied in clinical trials, this potential “off-label use“, and its associated risks, is also described within the RMP. RMPs can be very lengthy documents, running in some cases hundreds of pages and, in rare instances, up to a thousand pages long.

In the US, under certain circumstances, the FDA may require a company to submit a document called a Risk Evaluation and Mitigation Strategies (REMS) for a drug that has a specific risk that FDA believes requires mitigation. While not as comprehensive as an RMP, a REMS can require a sponsor to perform certain activities or to follow a protocol, referred to as Elements to Assure Safe Use (ETASU),[10] to assure that a positive risk-benefit profile for the drug is maintained for the circumstances under which the product is marketed.

Risk/Benefit Profile of Drugs

Pharmaceutical companies are required by law in most countries to perform clinical trials, testing new drugs on people before they are made generally available. This occurs after a drug has been pre-screened for toxicity, sometimes using animals for testing. The manufacturers or their agents usually select a representative sample of patients for whom the drug is designed – at most a few thousand – along with a comparable control group. The control group may receive a placebo and/or another drug, often a so-called “gold standard” that is “best” drug marketed for the disease.

The purpose of clinical trials is to determine:

  • if a drug works and how well it works
  • if it has any harmful effects, and
  • if it does more good than harm, and how much more? If it has a potential for harm, how probable and how serious is the harm?

Clinical trials do, in general, tell a good deal about how well a drug works and what potential harm it may cause. They provide information that should be reliable for larger populations with the same characteristics as the trial group – age, gender, state of health, ethnic origin, and so on.

The variables in a clinical trial are specified and controlled, but a clinical trial can never tell you the whole story of the effects of a drug in all situations. In fact, nothing could tell you the whole story, but a clinical trial must tell you enough; “enough” being determined by legislation and by contemporary judgements about the acceptable balance of benefit and harm. Ultimately, when a drug is marketed it may be used in patient populations that were not studied during clinical trials (children, the elderly, pregnant women, patients with co-morbidities not found in the clinical trial population, etc.) and a different set of warnings, precautions or contraindications (where the drug should not be used at all) for the product’s labeling may be necessary in order to maintain a positive risk/benefit profile in all known populations using the drug.


Pharmacogenetics and PharmacogenomicsPharmacoepidemiology is the study of the incidence of adverse drug reactions in patient populations using drug agents.[citation needed]

Although often used interchangeably, there are subtle differences between the two disciplines. Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation that gives rise to differing responses to drugs, including adverse drug reactions. It is hoped that pharmacogenetics will eventually provide information as to which genetic profiles in patients will place those patients at greatest risk, or provide the greatest benefit, for using a particular drug or drugs. Pharmacogenomics, on the other hand, is the broader application of genomic technologies to new drug discovery and further characterization of older drugs.

International collaboration on pharmacovigilance

The World Health Organization (WHO)
[edit]The following organizations play a key collaborative role in the global oversight of pharmacovigilance.

The principle of international collaboration in the field of pharmacovigilance is the basis for the WHO International Drug Monitoring Programme, through which over 100 member nations have systems in place that encourage healthcare personnel to record and report adverse effects of drugs in their patients,[citation needed] reports that are assessed locally and may lead to action within the country. Member countries send their reports to the Uppsala Monitoring Centre where they are processed, evaluated and entered into the WHO International Database; through membership in the WHO Programme one country can know if similar reports are being made elsewhere.[citation needed] When there are several reports of adverse reactions to a particular drug, this process may lead to the detection of a signal, and an alert about a possible hazard communicated to members countries after detailed evaluation and expert review.[citation needed]

The International Conference on Harmonization (ICH)

The ICH is a global organization with members from the European Union, the United States and Japan; its goal is to recommend global standards for drug companies and drug regulatory authorities around the world, with the ICH Steering Committee (SC) overseeing harmonization activities. Established in 1990, each of its six co-sponsors—the EU, the European Federation of Pharmaceutical Industries and Associations (EFPIA), Japan’s Ministry of Health, Labor and Welfare (MHLW), the Japanese Pharmaceutical Manufacturers Association (JPMA), the U.S. Food and Drug Administration (FDA), and the Pharmaceutical Research and Manufacturers of America (PhRMA)—have two seats on the SC. Other parties have a significant interest in ICH and have been invited to nominate Observers to the SC; three current observers[when?] are the WHO, Health Canada, and the European Free Trade Association (EFTA), with the International Federation of Pharmaceutical Manufacturers Association (IFPMA) participating as a non-voting member of the SC.[11][12]

The Council for International Organizations of Medical Sciences (CIOMS)

The CIOMS, a part of the WHO, is a globally oriented think tank that provides guidance on drug safety related topics through its Working Groups.[citation needed] The CIOMS prepares reports that are used as a reference for developing future drug regulatory policy and procedures, and over the years, many of CIOMS’ proposed policies have been adopted.[citation needed] Examples of topics these reports have covered include: Current Challenges in Pharmacovigilance: Pragmatic Approaches (CIOMS V); Management of Safety Information from Clinical Trials (CIOMS VI); the Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials (CIOMS VII); and Practical Aspects of Signal Detection in Pharmacovigilance: Report of CIOMS Working Group (CIOMS VIII).[citation needed]

The International Society of Pharmacovigilance (ISoP)

The ISoP is an international non-profit scientific organization, which aims to foster pharmacovigilance both scientifically and educationally, and enhance all aspects of the safe and proper use of medicines, in all countries.[13] It was established in 1992 as the European Society of Pharmacovigilance.[14]

Pharmacovigilance regulatory authorities

United StatesDrug regulatory authorities play a key role in national or regional oversight of pharmacovigilance. Some of the agencies involved are listed below (in order of 2011 spending on pharmaceuticals, from the IMS Institute for Healthcare Informatics).[15]

In the U.S., with about a third of all global 2011 pharmaceutical expenditures,[15] the drug industry is regulated by the FDA, the largest national drug regulatory authority in the world.[citation needed] FDA authority is exercised through enforcement of regulations derived from legislation, as published in the U.S. Code of Federal Regulations (CFR); the principal drug safety regulations are found in 21 CFR Part 312 (IND regulations) and 21 CFR Part 314 (NDA regulations).[citation needed] Pharmaceutical manufacturers and academic/non-profit organizations such as RADAR and Public Citizen also play a role in pharmacovigilance in the US.[citation needed] The post-legislative rule-making process of the U.S. federal government provides for significant input from both the legislative and executive branches, which also play specific, distinct roles in determining FDA policy.[citation needed]

Emerging economies, including Latin America

The “pharmerging”, or emerging pharmaceutical market economies, which include Brazil, India, Russia, Argentina, Egypt, Indonesia, Mexico, Pakistan, Poland, Romania, South Africa, Thailand, Turkey, Ukraine, Venezuela, and Vietnam, accrued one fifth of global 2011 pharmaceutical expenditures; in future, aggregated data for this set will include China as well.[15]

China’s economy is anticipated to pass Japan to become second in the ranking of individual countries’ in pharmaceutical purchases by 2015, and so its PV regulation will become increasing important; China’s regulation of PV is through its National Center for Adverse Drug Reaction (ADR) Monitoring, under China’s Ministry of Health.[16]

As JE Sackman notes, as of April 2013 “there is no Latin American equivalent of the European Medicines Agency—no common body with the power to facilitate greater consistency across countries”.[17] For simplicity, and per sources, 17 smaller economies are discussed alongside the 4 pharmemerging large economies of Argentina, Brazil, Mexico and Venzuala—Bolivia, Chile, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, El Salvador, Guatemala, Haiti, Honduras, Nicaragua, Panama, Paraguay, Peru, Suriname, and Uruguay.[18] As of June 2012, 16 of this total of 21 countries have systems for immediate reporting and 9 have systems for periodic reporting of adverse events for on-market agents, while 10 and 8, respectively, have systems for immediate and periodic reporting of adverse events during clinical trials; most of these have PV requirements that rank as “high or medium… in line with international standards” (ibid.). The WHO’s Pan American Network for Drug Regulatory Harmonization[19] seeks to assist Latin American countries in develop harmonized PV regulations.[18]

Some further PV regulatory examples from the pharmerging nations are as follows. In India, the PV regulatory authority is the Indian Pharmacopoeia Commission, with a National Coordination Centre under the Pharmacovigilance Program of India, in the Ministry of Health and Family Welfare.[20][21] Scientists working on pharmacovigilance share their experiences, findings, innovative ideas and researches during the annual meeting of Society of Pharmacovigilance, India.[citation needed] In Egypt, PV is regulated by the Egyptian Pharmacovigilance Center of the Egyptian Ministry of Health.[citation needed]

European Union

The EU5 (France, Germany, Italy, Spain, United Kingdom) accrued ~17% of global 2011 pharmaceutical expenditures.[15] PV efforts in the EU are coordinated by the European Medicines Agency (EMA) and are conducted by the national competent authorities (NCAs).[citation needed] The main responsibility of the EMA is to maintain and develop the pharmacovigilance database consisting of all suspected serious adverse reactions to medicines observed in the European Community; the data processing network and management system is called EudraVigilance and contains separate but similar databases of human and veterinary reactions.[citation needed] The EMA requires the individual marketing authorization holders to submit all received adverse reactions in electronic form, except in exceptional circumstances; the reporting obligations of the various stakeholders are defined by EEC legislation, namely Regulation (EC) No 726/2004, and for human medicines, European Union Directive 2001/83/EC as amended and Directive 2001/20/EC.[citation needed] In 2002, Heads of Medicines Agencies[22] agreed on a mandate for an ad hoc Working Group on establishing a European risk management strategy; the Working Group considered the conduct of a high level survey of EU pharmacovigilance resources to promote the utilization of expertise and encourage collaborative working.[citation needed]

In conjunction with this oversight, individual countries maintain their distinct regulatory agencies with PV responsibility. For instance, in Spain, PV is regulated by the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), a legal entity that retains the right to suspend or withdraw the authorization of pharmaceuticals already on-market if the evidence shows that safety (or quality or efficacy) of an agent are unsatisfactory.[23]

Rest of Europe, including non-EU

[The remaining EU and non-EU countries out side the EU5 accrued ~7% of global 2011 pharmaceutical expenditures.[15] Regulation of those outside the EU being managed by specific governmental agencies. For instance, in Switzerland, PV “inspections” for clinical trials of medicinal products are conducted by the Swiss Agency for Therapeutic Products.[24]

In Japan, with ~12% of all global 2011 pharmaceutical expenditures,[15] PV matters are regulated by the Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labour, and Welfare MHLW.[

South Korea
[edit]In Canada, with ~2% of all global 2011 pharmaceutical expenditures,[15] PV is regulated by the Marketed Health Products Directorate of the Health Products and Food Branch (Health Canada).

Rest of world (ROW)
The Republic of Korea, with ~1% of all global 2011 pharmaceutical expenditures,[15] PV matters are regulated in South Korea by the Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labour, and Welfare MHLW.

ROW accrued ~7% of global 2011 pharmaceutical expenditures.[15] Some examples of PV regulatory agencies in ROW are as follows. In Iraq, PV is regulated by the Iraqi Pharmacovigilance Center of the Iraqi Ministry of Health. In Kenya, PV is regulated by the Pharmacy and Poisons Board.[25] In Uganda, PV is regulated by the National Drug Authority.

Ecopharmacovigilance (EPV; pharmacoenvironmentology)

Despite attention from the FDA and regulatory agencies of the European Union, procedures for monitoring drug concentrations and adverse effects in the environment are lacking.[citation needed] Pharmaceuticals, their metabolites, and related substances may enter the environment after patient excretion, after direct release to waste streams during manufacturing or administration, or via terrestrial deposits (e.g., from waste sludges or leachates).[26] A concept combining pharmacovigilance and environmental pharmacology, intended to focus attention on this area, was introduced first as ecopharmacology and later as ecopharmacovigilance (EPV) by Velo et al., with further concurrent and later terms for the same concept (pharmacoenvironmentology, environmental pharmacology, ecopharmacostewardship).[26][27][28][29]

The first of these routes to the environment, elimination through living organisms subsequent to pharmacotherapy, is suggested as the principal source of environmental contamination (apart from cases where norms for treatment of manufacturing and other wastes are violated), and EPV is intended to deal specifically with this impact of pharmacological agents on the environment.[26][30]

Activities of EPV have been suggested to include:

  • Increasing, generally, the availability of environmental data on medicinal products;
  • Tracking emerging data on environmental exposure, effects and risks after product launch;
  • Using Environmental Risk Management Plans (ERMPs) to manage risk throughout a drug’s life cycle;
  • Following risk identification, promoting further research and environmental monitoring, and
  • In general, promoting a global perspective on EPV issues.[26]

Pharmacovigilance related to medical devices

Given the inherent difference between medicinal products and medical products, the pharmacovigilance of medical devices is also different from that of medicinal products. To reflect this difference, a classification system has been adopted in some countries to stratify the risk of failure with the different classes of devices. The classes of devices typically run on a 1-3 or 1-4 scale, with Class 1 being the least likely to cause significant harm with device failure versus Classes 3 or 4 being the most likely to cause significant harm with device failure. An example of a device in the “low risk” category would be contact lenses. An example of a device in the “high risk” category would be cardiac pacemakers.A medical device is an instrument, apparatus, implant, in vitro reagent, or similar or related article that is used to diagnose, prevent, or treat disease or other conditions, and does not achieve its purposes through chemical action within or on the body (which would make it a drug). Whereas medicinal products (also called pharmaceuticals) achieve their principal action by pharmacological, metabolic or immunological means, medical devices act by physical, mechanical, or thermal means. Medical devices vary greatly in complexity and application. Examples range from simple devices such as tongue depressors, medical thermometers, and disposable gloves to advanced devices such as medical robots,cardiac pacemakers, and neuroprosthetics.

Medical device reporting (MDR), which is the reporting of adverse events with medical devices, is similar to that with medicinal products, although there are differences. For instance, in the US user-facilities such as hospitals and nursing homes are legally required to report suspected medical device-related deaths to both FDA and the manufacturer, if known, and serious injuries to the manufacturer or to FDA, if the manufacturer is unknown.[31] This is in contrast to the voluntary reporting of AEs with medicinal products.

Pharmacovigilance for herbal medicines

The safety of herbal medicines has become a major concern to both national health authorities and the general public.[32][full citation needed] The use of herbs as traditional medicines continues to expand rapidly[vague] across the world; many people[vague] now take herbal medicines or herbal products for their health care in different national health-care settings.[vague][citation needed] However, mass media reports[which?] of adverse events with herbal medicines can be incomplete and therefore misleading.[citation needed]Moreover, it can be difficult to identify the causes of herbal medicine-associated adverse events since the amount of data on each event is generally less than for pharmaceuticals formally regulated as drugs (since the requirements for adverse event reporting are either non-existent or are less stringent for herbal supplements and medications).[33]

Industry associations

Adverse drug reaction

See also


  1. Jump up^ Source: The Importance of Pharmacovigilance, WHO 2002
  2. Jump up^ WHO Technical Report No 498 (1972)
  3. ^ Jump up to:a b Current Challenges in Pharmacovigilance: Pragmatic Approaches (Report of CIOMS Working Group V), 2001 Geneva.
  4. Jump up^
  5. Jump up^ Lindquist M. Vigibase, the WHO Global ICSR Database System: Basic Facts. Drug Information Journal, 2008, 42:409-419.
  6. Jump up^ The ICH E2B Standard E2B(R3)
  7. Jump up^ Data Elements for Transmission of Individual Case Safety Reports ICH E2B Standard
  8. Jump up^, accessed 10 February 2009.
  9. Jump up^ Pharmacovigilance. Mann RD, Andrews EB, eds. John Wiley & Sons Ltd, Chichester, 2002. spontaneous reports are very useful.
  10. Jump up^
  11. Jump up^ “Organisation of ICH”
  12. Jump up^ “Steering Committee”
  13. Jump up^
  14. Jump up^ Chapter 2 – A Short History of Involvement in Drug Safety Monitoring by WHO “ The Importance of Pharmacovigilance – Safety Monitoring of Medicinal Products
  15. ^ Jump up to:a b c d e f g h i M. Herper, 2012, Why Big Pharma Won’t Get Its Piece Of The $1.2 Trillion Global Drug Market,, accessed March 28, 2014.
  16. Jump up^ Sara Gambrill, 2011, China’s Pharmacovigilance System: The Hunger For Safety Insights, Clinical Leader, December 7, 2011 accessed March 28, 2014
  17. Jump up^ Sackman, JE, 2013, Navigating Emerging Markets — Latin America: Latin America’s diverse growing market seeks regulatory harmonization. BioPharm International 26(4), 60-63. accessed March 28, 2014.
  18. ^ Jump up to:a b Hoffmann E, Fouretier A, Vergne C, et al. (2012). “Pharmacovigilance Regulatory Requirements in Latin America”. Pharm Med 26 (3): 153–164.doi:10.1007/bf03262389.
  19. Jump up^ See, accessed March 28, 2014.
  20. Jump up^
  21. Jump up^
  22. Jump up^ Heads of Medicines Agencies: Home
  23. Jump up^
  24. Jump up^, accessed March 28, 2014.
  25. Jump up^
  26. ^ Jump up to:a b c d G Holm, JR Snape, R Murray-Smith, J Talbot, D Taylor, and P Sörme, 2013, Implementing Ecopharmacovigilance in Practice: Challenges and Potential Opportunities, Drug Safety, 36(7): 533–546. [doi: 10.1007/s40264-013-0049-3,, accessed March 25, 2014]
  27. Jump up^ Rahman, SZ; Khan, RA (Dec 2006). “Environmental pharmacology: A new discipline”. Indian J Pharmacol. 38 (4): 229–30. doi:10.4103/0253-7613.27017.
  28. Jump up^ Rahman, SZ; Khan RA; Gupta V; Misbah Uddin (2008). “Chapter 2: Pharmacoenvironmentology – Ahead of Pharmacovigilance”. In Rahman SZ, Shahid M & Gupta A. An Introduction to Environmental Pharmacology (1st ed.). Aligarh: Ibn Sina Academy. pp. 35–52. ISBN 978-81-906070-4-9.
  29. Jump up^ IS Ruhoy and CG Daughton, 2008, Beyond the medicine cabinet: An analysis of where and why medications accumulate. Environment International, 34 (8): 1157-1169.
  30. Jump up^ Rahman, SZ; Khan, RA; Gupta, V; Uddin, Misbah (July 2007).“Pharmacoenvironmentology – A Component of Pharmacovigilance”. Environmental Health 6 (20). doi:10.1186/1476-069X-6-20. PMC 1947975. PMID 17650313.
  31. Jump up^
  32. Jump up^ WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems, World Health Organization, Geneva, 2004
  33. Jump up^ S Z Rahman & K C Singhal, Problems in pharmacovigilance of medicinal products of herbal origin and means to minimize them, Uppsala Reports, WHO Collaborating Center for ADR monitoring, Uppsala Monitoring Centre, Sweden, Issue 17 January 2002: 1-4 (Supplement)

External links[edit]

World Hepatitis Day – European Medicines Agency uses regulatory tools to facilitate patient access to innovative medicines


World Hepatitis Day – European Medicines Agency uses regulatory tools to facilitate patient access to innovative medicines

According to the World Health OrganizationExternal link icon (WHO), viral hepatitis kills 1.4 million people worldwide every year. That is as many as are killed by AIDS/HIV infections.

Viral hepatitis is caused by five different types of hepatitis viruses, hepatitis A, B, C, D and E, which can lead to the development of acute or chronic inflammation of the liver.

In Europe, hepatitis C virus (HCV) infection is a major public-health challenge. It occurs in between 0.4% and 3.5% of the population in different European Union (EU) Member States and is the most common reason for liver transplantation in the EU.

The treatment paradigm for chronic hepatitis C is currently shifting rapidly with the development of several new classes of direct-acting antivirals. These new medicines display high efficacy rates allowing patients with chronic HCV infection to be cured without the need for co-administration of interferon. Interferon-based therapies are associated with poor tolerability and potentially serious side effects, which can be difficult to manage and rule out a considerable proportion of HCV patients for therapy. In addition, not all patients respond to these treatments.

Over the past eight months, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing authorisation for three new medicines for the treatment of chronic HCV infection, two of which are the first representatives of new classes of direct-acting antivirals.




The EMA fosters innovation and is using all the regulatory tools available to facilitate early access for patients to a range of innovative therapeutic options. The CHMP’s positive opinion is the first step towards a new medicine becoming available to patients. Once a marketing authorisation has been granted by the European Commission, decisions about pricing and reimbursement are taken at the level of each Member State.



The CHMP assessed the benefits and risks of the first two candidates in this new wave of innovative medicines for chronic HCV infection through an accelerated assessment procedure. The EMA’s accelerated assessment mechanism aims to speed up the assessment of medicines that are expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

The first medicine, Sovaldi (sofosbuvir), was authorised for marketing authorisationin January 2014 following a CHMP recommendation in November 2013, and the second medicine, Daklinza (daclatasvir), was recommended for marketing authorisation by the CHMP in June 2014.

The CHMP is also currently using this mechanism in the assessment of three new applications for innovative HCV infection medicines.

In addition, over the past eight months, the CHMP gave an opinion on the use of three medicines or combinations of medicines for the treatment of chronic HCV infection in compassionate use programmes. These programmes are intended to give patients with a life-threatening, long-lasting or seriously disabling disease access to treatments that are still under development.

The use of these tools ultimately contributes to a wider range of therapeutic options available to patients allowing the needs of more patients to be met.

The EMA supports World Hepatitis DayExternal link icon, which is taking place on Monday 28 July 2014.

World Hepatitis Day is held every year on 28 July to provide international focus for patient groups and people living with chronic hepatitis B and C. It aims to raise awareness and influence change in disease prevention and access to testing and treatment.

The World Hepatitis AllianceExternal link icon first launched World Hepatitis Day in 2008. The Alliance is a non-governmental organisation that represents hepatitis B and C patient groups from around the world. World Hepatitis Day is organised in partnership with the WHO.