1. When an investigator receives confirmation that a study can be archived,reference should be made to the clinical trials agreement that should specify whether the investigator or sponsor is responsible for archiving the
study.
2. All documentation as defined in ICH-GCP guidelines (section 8.2, 8.3, 8.4) as ‘essential documents which individually and collectively permit the evaluation of the conduct of a study and the quality of the data produced’’ must be retained until notification from the sponsor.
3. Where electronic copies of documents exist, these should be backed up and retained alongside the paper documents.
4. Files and documents relating to a study may be held in other departments,such as Pharmacy or Clinical Radiology. These should be collated with the master site file when the study is archived.
5. One copy of each document should be kept and filed in a bankart box and stored within the clinical trials archives store.
6. All archived material should be stored in a suitable place. The archival location should be restricted to only appropriately delegated individuals,and appropriate quality checks should be in place to ensure the
preservation of the archive. This would include a Risk Assessment for fire,environmental damage, pest control, and ongoing monitoring of these risks. This store may be an internal storage area or a commercial archiving
store.
7. The Trust will nominate an archivist for Clinical trials; this will usually be the R&D Manager.
8. The master site file and other research documents will be held by the PI,or delegate, for 3 years following the last day of the patient’s active followup period.
9. Study documentation will be consolidated to ensure that only one copy of any document is held in the archive store
10. Archived documents should be packed securely in archival boxes. Staples, plastic wallets and paper clips must be removed as these will degrade the records over time.
11. Paper documents must be suitable for long term archiving. For example,faxes or ECG results should be photocopied since the inks used may be prone to fading.
12.The file should be clearly labelled with the name and reference number of the study, sponsor, investigator and date to be archived until. See Appendix A for a copy of label to be used.
13.For commercial studies it is the lead investigators role to identify the storage area. If it is the sponsor’s responsibility, arrange for them to archive study contents as soon as possible.
14. Access to the material should be restricted to the investigator, his/her delegate and the regulatory authorities.
15.Details of the archiving location should be recorded in a location register stored in the R&D Office. See Appendix B. This register should record the name and reference number of the study, Sponsor, Investigator and date to be archived until as well as where the documents are located.
16.Whenever an item is retrieved from archive, the date, item and person retrieving the item should be documented, together with the date returned to archive.
Medical Records:
17. A check should be made that all enrolled patients are flagged before the study is archived.
18. A destruction date will be recorded on the archiving box: the notes should not be destroyed until at least 20 years after the completion of the trial.
Tuesday, September 28, 2010
Archiving documents in Clinical Trials Scenario
Clinical trial documentation can be archived by the Principal investigator /designee or the Sponsor. The Principal Investigator must agree with the sponsor the exact requirements for local archiving and make or assist in making the necessary arrangements. The investigator has a responsibility to allow the sponsor and regulators access to the archived data on request. The Management of trial documentation and study file is the responsibility of the Principal Investigator however this role may be delegated to the clinical trials co-ordinator or research nurse or other member of the research team. This procedure should be carried out in accordance with local hospital policies. All data should be made available if requested by relevant authorities. The Trust Archivist will consolidate the research files and manage the clinical trials archives store. For local studies not involving investigational medicinal products it will be the responsibility of the Principal Investigator to
store the data.
Archiving occurs as soon as possible after completion of a study, typically the end of the follow-up stage for treatment and multicentre studies, and at close down of study for all other studies. Regulations state that the documentation for clinical trials involving medicinal products should be archived for at least five years after the last licence application. Patients’ medical records should be retained for a minimum of twenty years after the completion of a trial. Three years following the Principal Investigator’s close down of the study the archivist will gather all of the trial documents from all the areas across the Trust, including Pharmacy, and undertake the consolidation process.
store the data.
Archiving occurs as soon as possible after completion of a study, typically the end of the follow-up stage for treatment and multicentre studies, and at close down of study for all other studies. Regulations state that the documentation for clinical trials involving medicinal products should be archived for at least five years after the last licence application. Patients’ medical records should be retained for a minimum of twenty years after the completion of a trial. Three years following the Principal Investigator’s close down of the study the archivist will gather all of the trial documents from all the areas across the Trust, including Pharmacy, and undertake the consolidation process.
Anatomical Therapeutic Chemical Classification(ATC) - WHO DD
The Anatomical Therapeutic Chemical (ATC) Classification System is used for the classification of drugs. It is controlled by the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC), and was first published in 1976.
The classification system divides drugs into different groups according to the organ or system on which they act and/or their therapeutic and chemical characteristics. Each bottom-level ATC code stands for a pharmaceutically used substance in a single indication (or use). This means that one drug can have more than one code: acetylsalicylic acid (aspirin), for example, has A01AD05 as a drug for local oral treatment, B01AC06 as a platelet inhibitor, and N02BA01 as an analgesic and antipyretic. On the other hand, several different brands share the same code if they have the same active substance and indications.
First level
The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:
Code Contents
A Alimentary tract and metabolism
B Blood and blood forming organs
C Cardiovascular system
D Dermatologicals
G Genito-urinary system and sex hormones
H Systemic hormonal preparations, excluding sex hormones and insulins
J Antiinfectives for systemic use
L Antineoplastic and immunomodulating agents
M Musculo-skeletal system
N Nervous system
P Antiparasitic products, insecticides and repellents
R Respiratory system
S Sensory organs
V Various
Second level
The second level of the code indicates the therapeutic main group and consists of two digits.
Example: C03 Diuretics
Third level
The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.
Example: C03C High-ceiling diuretics
Fourth level
The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.
Example: C03CA Sulfonamides
Fifth level
The fifth level of the code indicates the chemical substance and consists of two digits.
Example: C03CA01 Furosemide
The classification system divides drugs into different groups according to the organ or system on which they act and/or their therapeutic and chemical characteristics. Each bottom-level ATC code stands for a pharmaceutically used substance in a single indication (or use). This means that one drug can have more than one code: acetylsalicylic acid (aspirin), for example, has A01AD05 as a drug for local oral treatment, B01AC06 as a platelet inhibitor, and N02BA01 as an analgesic and antipyretic. On the other hand, several different brands share the same code if they have the same active substance and indications.
First level
The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:
Code Contents
A Alimentary tract and metabolism
B Blood and blood forming organs
C Cardiovascular system
D Dermatologicals
G Genito-urinary system and sex hormones
H Systemic hormonal preparations, excluding sex hormones and insulins
J Antiinfectives for systemic use
L Antineoplastic and immunomodulating agents
M Musculo-skeletal system
N Nervous system
P Antiparasitic products, insecticides and repellents
R Respiratory system
S Sensory organs
V Various
Second level
The second level of the code indicates the therapeutic main group and consists of two digits.
Example: C03 Diuretics
Third level
The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.
Example: C03C High-ceiling diuretics
Fourth level
The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.
Example: C03CA Sulfonamides
Fifth level
The fifth level of the code indicates the chemical substance and consists of two digits.
Example: C03CA01 Furosemide
Main Files in WHO-DD
1)Medicinal Products :
# This is the main file in which most information about the product is recorded. This file contains the unique identifier and the Trade name.
# It also contains information about the company responsible for the product internationally, and the company that markets the product.
2)Pharmaceutical Product :
# The WHO-DD allows for the use of a two-level structure of the product information.
# The two-level structure makes it possible to record both the Medicinal Product – the product name and the pharmaceutical products with their individual ingredient.
3)Therapeutic Group :
# Each medicinal product can be coded to one or several Therapeutic groups.
# The therapeutic grouping uses the Anatomical Therapeutic Chemical classification (ATC).
4)Ingredient :
# Each Pharmaceutical Product contains one or several Ingredients.
# Only active substances are included (no excipients, colouring agents, filling agents etc.
# This is the main file in which most information about the product is recorded. This file contains the unique identifier and the Trade name.
# It also contains information about the company responsible for the product internationally, and the company that markets the product.
2)Pharmaceutical Product :
# The WHO-DD allows for the use of a two-level structure of the product information.
# The two-level structure makes it possible to record both the Medicinal Product – the product name and the pharmaceutical products with their individual ingredient.
3)Therapeutic Group :
# Each medicinal product can be coded to one or several Therapeutic groups.
# The therapeutic grouping uses the Anatomical Therapeutic Chemical classification (ATC).
4)Ingredient :
# Each Pharmaceutical Product contains one or several Ingredients.
# Only active substances are included (no excipients, colouring agents, filling agents etc.
Drug Code in detail
# The term drug code refers to the unique numeric key in the B format of the dictionary. A drug code identifies a name, either a trade name or a generic Preferred Name.
# A Drug Code is aggregated from Drug Record Number (Drecno),Sequence number 1 and Sequence number 2.
# The code differs from the Medicinal Product ID in that it has a meaning.
# The code is not only a unique identifier of a name – it also gives information about the active ingredients and salt/ester form of the substance.
For example:
A Drecno identifies a generic identification level. In most cases the generic identification level is the one active ingredient, but it can also identify a unique combination of active
ingredients.
Sequence number 1 : It identifies the salt or the ester of the active ingredient.
Sequence number 2 : It identifies the trade names and in some cases a synonym to a generic name. Eg ; Acetaminophen as a synonym to Paracetamol.
Combination products : Products with more than one active ingredient – needs to have a separate coding
principle. It is not possible to include the names of all active ingredients in the name field, so the first trade name with the unique combination of ingredients will be the preferred name though it is not a generic name.
Use of Codes in Data analysis and Retrievals :
The identification levels are useful for querying and analysis of aggregate data.
# The Drecno can be used to identify all products with the same active ingredient(s)
# The Drecno + Sequence number 1 to identify different salts.
# The Drecno + Sequence number 1 + Sequence number 2 to identify a trade name.
# A Drug Code is aggregated from Drug Record Number (Drecno),Sequence number 1 and Sequence number 2.
# The code differs from the Medicinal Product ID in that it has a meaning.
# The code is not only a unique identifier of a name – it also gives information about the active ingredients and salt/ester form of the substance.
For example:
A Drecno identifies a generic identification level. In most cases the generic identification level is the one active ingredient, but it can also identify a unique combination of active
ingredients.
Sequence number 1 : It identifies the salt or the ester of the active ingredient.
Sequence number 2 : It identifies the trade names and in some cases a synonym to a generic name. Eg ; Acetaminophen as a synonym to Paracetamol.
Combination products : Products with more than one active ingredient – needs to have a separate coding
principle. It is not possible to include the names of all active ingredients in the name field, so the first trade name with the unique combination of ingredients will be the preferred name though it is not a generic name.
Use of Codes in Data analysis and Retrievals :
The identification levels are useful for querying and analysis of aggregate data.
# The Drecno can be used to identify all products with the same active ingredient(s)
# The Drecno + Sequence number 1 to identify different salts.
# The Drecno + Sequence number 1 + Sequence number 2 to identify a trade name.
Proposed Coding Rules- WHO DD
Proposed Coding Rules
# Code the drug term to the appropriate drug name level of the dictionary (generic/generic and trade/trade)
# Do not change, add, or subtract to the original verbatim in a way that modifies its original meaning or content.
# Abbreviations should be avoided at all costs.
# Misspellings are never assumed as it is dangerous. Eg; PRAZAC (prazosin hydrochloride) and PROZAC (fluoxetine hydrochloride)
# Verbatim terms with symbols – Trade marks, accent marks etc are not appropriate and should be queried and removed while coding clinical data and ignored in post marketing data.
# Verbatim terms with procedures – Code the drug regardless of procedure information.
# Code the drug term to the appropriate drug name level of the dictionary (generic/generic and trade/trade)
# Do not change, add, or subtract to the original verbatim in a way that modifies its original meaning or content.
# Abbreviations should be avoided at all costs.
# Misspellings are never assumed as it is dangerous. Eg; PRAZAC (prazosin hydrochloride) and PROZAC (fluoxetine hydrochloride)
# Verbatim terms with symbols – Trade marks, accent marks etc are not appropriate and should be queried and removed while coding clinical data and ignored in post marketing data.
# Verbatim terms with procedures – Code the drug regardless of procedure information.
WHO Drug Dictionary (WHO-DD)
Introduction
# The WHO-DD is administered and licensed by the World Health Organization’s Uppsala Monitoring Center (UMC). The UMC collaborates with regulators, researchers and other professionals from healthcare and pharmaceutical industry in practice of pharmacovigilance.
#A drug dictionary proves useful when tabulating medication usage because it classifies the same medication, often known by different names, into a single name.
#For example – Tylenol, acetaminophen and paracetamol all refer to the same active ingredient, and WHO-DD uses the ingredient name paracetamol.
CODES AND IDs
# The WHO-DD dictionary contains a large number of data fields that contain information about the Medicinal Products. This information is used to identify a product that should be coded in a database, eg.For clinical trial data or drug safety data.
#The WHO Drug Dictionary enhanced contains two types of IDs that can be used as links between the case report in the clinical trials database/Drug Safety database and the WHO-DD.
#The medicinal product ID identifies an entry in the dictionary.
Medicinal Product ID (MP ID):
The Medicinal Product ID identifies a unique entry in the WHO-DD. The ID is just a “numeric name” of the medicinal product and it has no intrinsic meaning.
The MP ID constitute:
# Medicinal Product Name (generic name)
# Drug code (drug record number + sequence 1 + sequence 2)
# Name specifier
# Market Authorization Holder
# Country
# Dosage form (available as Pharmaceutical form in pharmaceutical product table)
# Strength (available as amount and unit of active ingredients in the ingredient table)
# The WHO-DD is administered and licensed by the World Health Organization’s Uppsala Monitoring Center (UMC). The UMC collaborates with regulators, researchers and other professionals from healthcare and pharmaceutical industry in practice of pharmacovigilance.
#A drug dictionary proves useful when tabulating medication usage because it classifies the same medication, often known by different names, into a single name.
#For example – Tylenol, acetaminophen and paracetamol all refer to the same active ingredient, and WHO-DD uses the ingredient name paracetamol.
CODES AND IDs
# The WHO-DD dictionary contains a large number of data fields that contain information about the Medicinal Products. This information is used to identify a product that should be coded in a database, eg.For clinical trial data or drug safety data.
#The WHO Drug Dictionary enhanced contains two types of IDs that can be used as links between the case report in the clinical trials database/Drug Safety database and the WHO-DD.
#The medicinal product ID identifies an entry in the dictionary.
Medicinal Product ID (MP ID):
The Medicinal Product ID identifies a unique entry in the WHO-DD. The ID is just a “numeric name” of the medicinal product and it has no intrinsic meaning.
The MP ID constitute:
# Medicinal Product Name (generic name)
# Drug code (drug record number + sequence 1 + sequence 2)
# Name specifier
# Market Authorization Holder
# Country
# Dosage form (available as Pharmaceutical form in pharmaceutical product table)
# Strength (available as amount and unit of active ingredients in the ingredient table)
Drug Coding
Drug coding is the process of identifying a particular medications pharmacological classification for the intended use in adverse event evaluation, drug/drug interaction study, drug-herbal interaction study, or drug-food interaction study (hereto referred as drug-substance interaction).
# In a clinical trial, concomitant and historical/prior medications are usually recorded for this purpose.
# While data-mining and initial detection of drug-substance issues can be determined using the ATC levels, true drug-substance analysis requires active ingredient retrieval from the dictionary.
WHY IS DRUG CODING IMPORTANT ?
# Drug interactions account for 3-5% of preventable in-hospital Adverse Drug Reactions (ADRs)
# Drug interactions contribute to a number of emergency room (ER) visits and hospital admissions
# Drugs are removed/restricted from marketplace due to drug/drug interactions
Examples of drug interactions with other drugs …
Cordarone (amiodarone): FDA issued an alert in August 2008, warning patients about taking Cordarone to correct abnormal rhythms of the heart and the cholesterol-lowering drug Zocor (Simvastatin). Patients taking Zocor in doses higher than 20 mg while also taking Cordarone run the risk of developing a rare condition of muscle injury called rhabdomyolysis, which can lead to kidney failure or death. "Cordarone also can inhibit or reduce the effect of the blood thinner Coumadin (warfarin)," . "So if you're using Cordarone, you may need to reduce the amount of Coumadin you're taking."
Lanoxin (digoxin): "Lanoxin has a narrow therapeutic range. So other drugs, such as Norvir (ritonvair), can elevate the level of Lanoxin,". "And an increased level of Lanoxin can cause irregular heart rhythms." Norvir is a protease inhibitor used to treat HIV, the virus that causes AIDS.
Antihistamines: Over-the-counter (OTC) antihistamines are drugs that temporarily relieve a runny nose, or reduce sneezing, itching of the nose or throat, and itchy watery eyes. If you are taking sedatives, tranquilizers, or a prescription drug for high blood pressure or depression, you should check with a doctor or pharmacist before you start using antihistimines. Some antihistamines can increase the depressant effects (such as sleepiness) of a sedative or tranquilizer. The sedating effect of some antihistamines combined with a sedating antidepressant could strongly affect your concentration level. Operating a car or any other machinery could be particularly dangerous if your ability to focus is impaired. Antihistamines taken in conjunction with blood pressure medication may cause a person's blood pressure to increase and may also speed up the heart rate.
Reference: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm096386.htm
Will discuss more about the WHO DD in my next post.So keep blogging.
# In a clinical trial, concomitant and historical/prior medications are usually recorded for this purpose.
# While data-mining and initial detection of drug-substance issues can be determined using the ATC levels, true drug-substance analysis requires active ingredient retrieval from the dictionary.
WHY IS DRUG CODING IMPORTANT ?
# Drug interactions account for 3-5% of preventable in-hospital Adverse Drug Reactions (ADRs)
# Drug interactions contribute to a number of emergency room (ER) visits and hospital admissions
# Drugs are removed/restricted from marketplace due to drug/drug interactions
Examples of drug interactions with other drugs …
Cordarone (amiodarone): FDA issued an alert in August 2008, warning patients about taking Cordarone to correct abnormal rhythms of the heart and the cholesterol-lowering drug Zocor (Simvastatin). Patients taking Zocor in doses higher than 20 mg while also taking Cordarone run the risk of developing a rare condition of muscle injury called rhabdomyolysis, which can lead to kidney failure or death. "Cordarone also can inhibit or reduce the effect of the blood thinner Coumadin (warfarin)," . "So if you're using Cordarone, you may need to reduce the amount of Coumadin you're taking."
Lanoxin (digoxin): "Lanoxin has a narrow therapeutic range. So other drugs, such as Norvir (ritonvair), can elevate the level of Lanoxin,". "And an increased level of Lanoxin can cause irregular heart rhythms." Norvir is a protease inhibitor used to treat HIV, the virus that causes AIDS.
Antihistamines: Over-the-counter (OTC) antihistamines are drugs that temporarily relieve a runny nose, or reduce sneezing, itching of the nose or throat, and itchy watery eyes. If you are taking sedatives, tranquilizers, or a prescription drug for high blood pressure or depression, you should check with a doctor or pharmacist before you start using antihistimines. Some antihistamines can increase the depressant effects (such as sleepiness) of a sedative or tranquilizer. The sedating effect of some antihistamines combined with a sedating antidepressant could strongly affect your concentration level. Operating a car or any other machinery could be particularly dangerous if your ability to focus is impaired. Antihistamines taken in conjunction with blood pressure medication may cause a person's blood pressure to increase and may also speed up the heart rate.
Reference: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm096386.htm
Will discuss more about the WHO DD in my next post.So keep blogging.
Medication guide- Product Labeling
A Medication Guide or other patient labeling may be required for certain medicines. This printed document contains FDA-approved information that may be included at the end of the PI, but must be made available separately.
A Medication Guide or other patient labeling may provide:
• Certain information that is necessary to prevent serious side effects.
• Information about a known serious side effect with a medicine to help patients to make an informed decision about whether the benefits of taking the medicine outweigh the risks.
• Directions for the use of a product that are essential to its effectiveness.
Refer this site: http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm
A Medication Guide or other patient labeling may provide:
• Certain information that is necessary to prevent serious side effects.
• Information about a known serious side effect with a medicine to help patients to make an informed decision about whether the benefits of taking the medicine outweigh the risks.
• Directions for the use of a product that are essential to its effectiveness.
Refer this site: http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm
Precautions and Information for patients/patient counseling information- Product Labeling
Precautions:
Actions required to make sure a medicine is properly and safely used are included under Precautions if not covered in other sections of the PI (for example, under Warnings, Dosage and Administration,Indications and Usage, or Contraindications).Precautions for health care professionals are covered separately from precautions for patients. For example, health care professionals might be instructed to ensure that certain preexisting medical
conditions are treated prior to using the medicine because of the risk of the medicine exacerbating those conditions, or to test the levels of certain enzymes in the patient that might affect the activity of the medicine.
This section also may include information for the prescriber concerning certain laboratory tests that may be necessary or helpful to the practitioner to ensure the medication is being used safely or to help predict when possible adverse reactions might occur.
[Note: The Information for Patients subsection, within the Precautions section under the old labeling rules, has been deleted under the new PI labeling format. It may still appear in older labels, but not in the newer labels. That section has been replaced by the Patient Counseling Information section (see
below).]
Information for patients/patient counseling information:
This section explains to health care professionals the information about the medicine that they should discuss with their patients. Such information might include precautions about operating machinery when using the medicine, or instructions on when to take the medicine relative to mealtimes.Note that this section may have different titles and locations within the product label according to when the medicine and/or its labeling was approved. Whether in the newer or older format, however, the same types of information are provided.
• Information for Patients is found in PIs for older medicines. You will find it as a subsection under the Precautions section near the middle of the PI.
• Patient Counseling Information, on the other hand, is a separate section at the very end of the PIs for newer medicines.
If a medication has information designed specifically for patients (Patient Package Insert or Medication Guides), that information would be contained in a separate document that may be printed at the end of the PI, or provided separately. That kind of labeling is not always necessary or required, so not all medications will have such a document
Actions required to make sure a medicine is properly and safely used are included under Precautions if not covered in other sections of the PI (for example, under Warnings, Dosage and Administration,Indications and Usage, or Contraindications).Precautions for health care professionals are covered separately from precautions for patients. For example, health care professionals might be instructed to ensure that certain preexisting medical
conditions are treated prior to using the medicine because of the risk of the medicine exacerbating those conditions, or to test the levels of certain enzymes in the patient that might affect the activity of the medicine.
This section also may include information for the prescriber concerning certain laboratory tests that may be necessary or helpful to the practitioner to ensure the medication is being used safely or to help predict when possible adverse reactions might occur.
[Note: The Information for Patients subsection, within the Precautions section under the old labeling rules, has been deleted under the new PI labeling format. It may still appear in older labels, but not in the newer labels. That section has been replaced by the Patient Counseling Information section (see
below).]
Information for patients/patient counseling information:
This section explains to health care professionals the information about the medicine that they should discuss with their patients. Such information might include precautions about operating machinery when using the medicine, or instructions on when to take the medicine relative to mealtimes.Note that this section may have different titles and locations within the product label according to when the medicine and/or its labeling was approved. Whether in the newer or older format, however, the same types of information are provided.
• Information for Patients is found in PIs for older medicines. You will find it as a subsection under the Precautions section near the middle of the PI.
• Patient Counseling Information, on the other hand, is a separate section at the very end of the PIs for newer medicines.
If a medication has information designed specifically for patients (Patient Package Insert or Medication Guides), that information would be contained in a separate document that may be printed at the end of the PI, or provided separately. That kind of labeling is not always necessary or required, so not all medications will have such a document
Boxed warning- Product Labeling
This term refers to a specially formatted warning that is the strongest level of safety warning that may be required by FDA for an approved medicine. Specifically, a boxed warning gives a brief explanation of any contraindications or serious warnings that may be associated with death or serious injury, with a cross-reference to more detailed information covered in the Warnings and/or
Contraindications sections of the PI. If a boxed warning is required, it will be found at the beginning of the PI, with the text surrounded by a thick black border, with the heading WARNING. For this reason, it is often referred to as a “black box” or “black box warning.”
Contraindications sections of the PI. If a boxed warning is required, it will be found at the beginning of the PI, with the text surrounded by a thick black border, with the heading WARNING. For this reason, it is often referred to as a “black box” or “black box warning.”
Warnings- Product Labeling
Information about a medicine’s important side effects and what to do about them is provided in the Warnings section. Clinically significant adverse events are described, along with other potential safety hazards, limitations in the medicine’s use due to those reactions and hazards, and steps to take if they occur. The defining criterion for inclusion under Warnings is that a reasonable association must have been established between the adverse event or risk and the medicine—although a definitive causal relationship need not be established.
The Warnings section may also provide information about nonapproved uses of the medicine. This would be the case if the medicine either has been commonly used for a condition, or there is a common belief that the medicine is effective for a condition, but the preponderance of evidence demonstrates that the medicine is not effective and this usage of the medicine is associated with a clinically significant risk or hazard. Note that, because such situations involve nonapproved uses of the medicine, they would not be covered in other sections of the PI such as Indications and Usage or Contraindications.
The Warnings section may also provide information about nonapproved uses of the medicine. This would be the case if the medicine either has been commonly used for a condition, or there is a common belief that the medicine is effective for a condition, but the preponderance of evidence demonstrates that the medicine is not effective and this usage of the medicine is associated with a clinically significant risk or hazard. Note that, because such situations involve nonapproved uses of the medicine, they would not be covered in other sections of the PI such as Indications and Usage or Contraindications.
Contraindication- Product Label
By contrast, a “contraindication” for a medicine refers to a specific situation in which the medicine should NOT be taken or administered—defined as circumstances under which using the medicine entails a substantial risk of harm that clearly outweighs any possible therapeutic benefit. To put this another way, the Contraindications section describes the kinds of cases where patients would have a substantial risk of being harmed by a medicine without the potential for sufficient benefit to make that risk acceptable. The Warnings section of the PI will also include a brief mention of any contraindications (with cross-references to this section), and will provide more detail about any
specific adverse reaction that is involved.
Various criteria can be considered for determining when a medicine is contraindicated:
• Patient age (especially infants or young children, or elderly individuals, for whom the demonstrated effectiveness might be less, or the risk of harmful adverse reactions greater,than for other ages).
• Patient gender (a risk may be higher, or the effectiveness of the medicine less, for male versus female individuals).
• Concomitant therapy (other medicines or treatments already being taken might lead to harmful adverse reactions if this medicine were taken at the same time).
• Disease state (the risk-benefit relationship might be different for different severities or stages of the disease to be treated).
• Other condition (a specific coexisting disease or the general condition of a patient might make use of a medicine potentially more hazardous, or less effective against a disease).
• Patient hypersensitivity to the medicine.
A contraindication is a judgment by regulators—after reviewing the available medical evidence—about the benefit-risk relationship of using that medicine under specific circumstances. For example,
a medicine may be approved for treatment of advanced stages of a life-threatening disease, despite
a known risk of serious adverse reactions, if a sufficient level of effectiveness has been demonstrated and no safer effective treatment options exist. In contrast, that same medicine may be contraindicated for patients in whom the same treated disease is less advanced, if it can be treated with other medicines that are equally effective but have a lower risk of serious side effects. It is important to remember that whether a medicine is right for you, at the right time, and for your condition, is always a decision ultimately made by you and your doctor. Note that, according to FDA regulations,contraindications are issued regarding medicine hazards that are known—because they have been demonstrated in studies and/or clinical experience—not for hazards that are simply theoretically possible.
specific adverse reaction that is involved.
Various criteria can be considered for determining when a medicine is contraindicated:
• Patient age (especially infants or young children, or elderly individuals, for whom the demonstrated effectiveness might be less, or the risk of harmful adverse reactions greater,than for other ages).
• Patient gender (a risk may be higher, or the effectiveness of the medicine less, for male versus female individuals).
• Concomitant therapy (other medicines or treatments already being taken might lead to harmful adverse reactions if this medicine were taken at the same time).
• Disease state (the risk-benefit relationship might be different for different severities or stages of the disease to be treated).
• Other condition (a specific coexisting disease or the general condition of a patient might make use of a medicine potentially more hazardous, or less effective against a disease).
• Patient hypersensitivity to the medicine.
A contraindication is a judgment by regulators—after reviewing the available medical evidence—about the benefit-risk relationship of using that medicine under specific circumstances. For example,
a medicine may be approved for treatment of advanced stages of a life-threatening disease, despite
a known risk of serious adverse reactions, if a sufficient level of effectiveness has been demonstrated and no safer effective treatment options exist. In contrast, that same medicine may be contraindicated for patients in whom the same treated disease is less advanced, if it can be treated with other medicines that are equally effective but have a lower risk of serious side effects. It is important to remember that whether a medicine is right for you, at the right time, and for your condition, is always a decision ultimately made by you and your doctor. Note that, according to FDA regulations,contraindications are issued regarding medicine hazards that are known—because they have been demonstrated in studies and/or clinical experience—not for hazards that are simply theoretically possible.
Product Label :Medicines Approved in U.S. After June 2006
Highlights of Prescribing Information:
• Product Names, Other Required Information
• Boxed Warning
• Recent Major Changes
• Indications and Usage
• Dosage and Administration
• Dosage Forms and Strengths
• Contraindications
• Warnings and Precautions
• Adverse Reactions
• Drug Interactions
• Use in Specific Populations
Full Prescribing Information:
Boxed Warning (if required)
1. Indications and Usage
2. Dosage and Administration
3. Dosage Forms and Strengths
4. Contraindications
5. Warnings and Precautions
6. Adverse Reactions
7. Drug Interactions
8. Use in Specific Populations
− 8.1 Pregnancy
− 8.2 Labor and delivery
− 8.3 Nursing mothers
− 8.4 Pediatric use
− 8.5 Geriatric use
9. Medicine Abuse and Dependence
− 9.1 Controlled substance
− 9.2 Abuse
− 9.3 Dependence
10. Overdosage
11. Description
12. Clinical Pharmacology
− 12.1 Mechanism of action
− 12.2 Pharmacodynamics
− 12.3 Pharmacokinetics
13. Nonclinical Toxicology
− 13.1 Carcinogenesis, mutagenesis, impairment of fertility
− 13.2 Animal toxicology and/or pharmacology
14. Clinical Studies
15. References
16. How Supplied/Storage and Handling
17. Patient Counseling Information
• Product Names, Other Required Information
• Boxed Warning
• Recent Major Changes
• Indications and Usage
• Dosage and Administration
• Dosage Forms and Strengths
• Contraindications
• Warnings and Precautions
• Adverse Reactions
• Drug Interactions
• Use in Specific Populations
Full Prescribing Information:
Boxed Warning (if required)
1. Indications and Usage
2. Dosage and Administration
3. Dosage Forms and Strengths
4. Contraindications
5. Warnings and Precautions
6. Adverse Reactions
7. Drug Interactions
8. Use in Specific Populations
− 8.1 Pregnancy
− 8.2 Labor and delivery
− 8.3 Nursing mothers
− 8.4 Pediatric use
− 8.5 Geriatric use
9. Medicine Abuse and Dependence
− 9.1 Controlled substance
− 9.2 Abuse
− 9.3 Dependence
10. Overdosage
11. Description
12. Clinical Pharmacology
− 12.1 Mechanism of action
− 12.2 Pharmacodynamics
− 12.3 Pharmacokinetics
13. Nonclinical Toxicology
− 13.1 Carcinogenesis, mutagenesis, impairment of fertility
− 13.2 Animal toxicology and/or pharmacology
14. Clinical Studies
15. References
16. How Supplied/Storage and Handling
17. Patient Counseling Information
Indications in Prescribing Information - Product Label
It states what diseases or conditions a medicine should be used for, by which patients, and under what situations.
An indication will specify:
• The recognized disease or condition for which the medicine’s use is approved, or the important manifestation of a disease or condition, such as:
i. Hypertension.
ii. Edema in patients with congestive heart failure.
• Whether the medicine is approved to treat, prevent, or diagnose the disease or condition, or to relieve the symptoms associated with a disease or syndrome, such as:
i.Penicillin is indicated for the treatment of pneumonia due to susceptible pneumococci.
ii.Chlorpheniramine is indicated for the symptomatic relief of nasal congestion in patients with vasomotor rhinitis.
• Whether the medicine may be used by itself (often referred to as “monotherapy”), should be used as the primary therapy (ie, without first trying another medicine) versus secondary/tertiary therapy (ie, used only if another medicine has been found not to be sufficiently effective or to have unacceptable side effects), or in conjunction with another mode of therapy (such as surgery, diet, etc—often referred to as “adjunctive therapy”) or in combination with another medicine.
• Whether the medicine is only approved for certain subgroups of patients with the disease or
symptom, such as:
i. Patients with mild disease.
ii. Patients in certain age groups.
iii.
• Whether use of the medicine should be reserved for certain situations, such as:
i.Cases where other therapy has not been effective (often referred to as “refractory” to other therapy).
ii.Patients who are not able to tolerate the adverse effects they experience with another therapy or medicine.
You will get more information about the Prescribing Information including Highlights of Prescribing Information and Full Prescribing Information in my next post.
An indication will specify:
• The recognized disease or condition for which the medicine’s use is approved, or the important manifestation of a disease or condition, such as:
i. Hypertension.
ii. Edema in patients with congestive heart failure.
• Whether the medicine is approved to treat, prevent, or diagnose the disease or condition, or to relieve the symptoms associated with a disease or syndrome, such as:
i.Penicillin is indicated for the treatment of pneumonia due to susceptible pneumococci.
ii.Chlorpheniramine is indicated for the symptomatic relief of nasal congestion in patients with vasomotor rhinitis.
• Whether the medicine may be used by itself (often referred to as “monotherapy”), should be used as the primary therapy (ie, without first trying another medicine) versus secondary/tertiary therapy (ie, used only if another medicine has been found not to be sufficiently effective or to have unacceptable side effects), or in conjunction with another mode of therapy (such as surgery, diet, etc—often referred to as “adjunctive therapy”) or in combination with another medicine.
• Whether the medicine is only approved for certain subgroups of patients with the disease or
symptom, such as:
i. Patients with mild disease.
ii. Patients in certain age groups.
iii.
• Whether use of the medicine should be reserved for certain situations, such as:
i.Cases where other therapy has not been effective (often referred to as “refractory” to other therapy).
ii.Patients who are not able to tolerate the adverse effects they experience with another therapy or medicine.
You will get more information about the Prescribing Information including Highlights of Prescribing Information and Full Prescribing Information in my next post.
Prescribing information (PI)
This document includes a great deal of technical medical detail intended to inform health care professionals who might prescribe or dispense a medicine. The PI of any approved medicine is publicly available and anybody may obtain it (from the manufacturer or from FDA, for example), but a PI is written for a professional audience. Whatever your level of scientific and/or mathematical
training, reading the PI cannot substitute for a discussion with a health care professional regarding the risks and benefits and appropriateness of a medicine in your individual circumstances.
Manufacturers typically make the PIs of their medicines available on the Web, and must include the PI as a printed “package insert” with any medicine that is sold in a box or other type of package. Note that a package insert may also include other material in addition to the PI (although you may see the
terms “package insert” and “prescribing information” referred to interchangeably in general discussion).
Given the large amount of information to be provided, newer medicines must now have a two-part PI to make it easier to find and review the information. The first part, titled Highlights of the Prescribing Information, usually takes up less than one page, but may be longer, depending on the complexity and extent of the relevant information. This section excludes much of the technical detail,
charts/graphs, and less broadly applicable information about the medicine. The second part is the full PI, with specifically labeled and numbered sections.
Although PIs for the older products cover the same types of information as for new products, some of the sections are arranged and labeled a bit differently. For instance, in PIs of older medicines, the topics Medicine Interactions, Use in Special Populations, and Patient Counseling Information are subsections of a separate Precautions section. In PIs of newer medicines, each of these three topics is presented as a separate section, and Precautions is part of a combined Warnings and Precautions section, rather than being its own section.
Some of the more important sections of the PI relating to the safe and effective use of a medicine are:
a)Indications
b)Contraindications
c)Warnings
d)Boxed Warning
e)Precautions
f)Information for patients/patient counseling information
g)Medication Guide
training, reading the PI cannot substitute for a discussion with a health care professional regarding the risks and benefits and appropriateness of a medicine in your individual circumstances.
Manufacturers typically make the PIs of their medicines available on the Web, and must include the PI as a printed “package insert” with any medicine that is sold in a box or other type of package. Note that a package insert may also include other material in addition to the PI (although you may see the
terms “package insert” and “prescribing information” referred to interchangeably in general discussion).
Given the large amount of information to be provided, newer medicines must now have a two-part PI to make it easier to find and review the information. The first part, titled Highlights of the Prescribing Information, usually takes up less than one page, but may be longer, depending on the complexity and extent of the relevant information. This section excludes much of the technical detail,
charts/graphs, and less broadly applicable information about the medicine. The second part is the full PI, with specifically labeled and numbered sections.
Although PIs for the older products cover the same types of information as for new products, some of the sections are arranged and labeled a bit differently. For instance, in PIs of older medicines, the topics Medicine Interactions, Use in Special Populations, and Patient Counseling Information are subsections of a separate Precautions section. In PIs of newer medicines, each of these three topics is presented as a separate section, and Precautions is part of a combined Warnings and Precautions section, rather than being its own section.
Some of the more important sections of the PI relating to the safe and effective use of a medicine are:
a)Indications
b)Contraindications
c)Warnings
d)Boxed Warning
e)Precautions
f)Information for patients/patient counseling information
g)Medication Guide
Product label
The product label is developed during the formal process of review and approval by regulatory agencies of any medicine or medical product. There are specific regulations concerning what must be included in a medicine label regarding its content, and how it works, as well as its proper administration and handling, its side effects, and its proven effectiveness and safety. The content and
presentation of any medicine’s specific labeling—originally drafted and submitted by the manufacturer—are reviewed and approved by regulatory agencies, which may require changes or additions to the label before approving the use of the medicine.
In the U.S., the complete label of a prescription medicine is made up of several documents that are approved and required by FDA—some professionally oriented and some intended for patients and consumers. The first and most comprehensive of these documents is always the professional Prescribing Information. Others may include Patient Counseling Information and a patient-oriented Medication Guide.
presentation of any medicine’s specific labeling—originally drafted and submitted by the manufacturer—are reviewed and approved by regulatory agencies, which may require changes or additions to the label before approving the use of the medicine.
In the U.S., the complete label of a prescription medicine is made up of several documents that are approved and required by FDA—some professionally oriented and some intended for patients and consumers. The first and most comprehensive of these documents is always the professional Prescribing Information. Others may include Patient Counseling Information and a patient-oriented Medication Guide.
Development Safety Update Report( DSUR)
The main focus of the DSUR is data from interventional clinical trials (referred to in this document as “clinical trials”) of investigational drugs including biologicals, with or without a marketing approval, whether conducted by commercial or non-commercial sponsors.It presents an annual review and evaluation of pertinent safety information collected during the reporting period to:
1)summarise the current understanding and management of identified and potential risks;
2)describe new safety issues that could have an impact on the protection of clinical trial subjects;
3)examine whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the product’s safety; and
4)provide an update on the status of the clinical investigation/development programme. This guideline defines the content and format of a DSUR and provides an outline of points to be considered in its preparation and submission.
DSUR cannot be considered as:
a)An evaluation of the benefit-risk relationship for the product
b)An interim integrated safety summary (ISS) as submitted for marketing applications
c)A repository or discussion of individual adverse experience cases, unless by exception
d)A signal detection tool
e)An “expert report”
Reference: E2F
1)summarise the current understanding and management of identified and potential risks;
2)describe new safety issues that could have an impact on the protection of clinical trial subjects;
3)examine whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the product’s safety; and
4)provide an update on the status of the clinical investigation/development programme. This guideline defines the content and format of a DSUR and provides an outline of points to be considered in its preparation and submission.
DSUR cannot be considered as:
a)An evaluation of the benefit-risk relationship for the product
b)An interim integrated safety summary (ISS) as submitted for marketing applications
c)A repository or discussion of individual adverse experience cases, unless by exception
d)A signal detection tool
e)An “expert report”
Reference: E2F
Differences between IND Annual Report and Annual Safety Report
IND ANNUAL REPORT :
purpose- progress report
Timing- IND anniversary date
Frequency- annual
Recipients- FDA
Content- study data and summary information
Feedback by may be requested regulators: may be requested
Short term end of study report safety report within trials end of study report safety report within trials for all trials within 90 days 1 year of end
Adverse events included: all serious ± associated± expected
Format and Summary: Content, Tabular summary of most frequent and most serious AEs by body system. Summary of all IND expedited reports for the period. Lists of deaths (w/ cause) and dropouts. List of completed non-clinical studies and result summary.
Annual Safety Report:
Purpose-benefit-risk assessment
Timing- Date of 1st authorization of a clinical trial of IMP by authority in member state
Frequency-annual, or on request
Recipients- EMEA, Member States, Ethics Committees
Content- benefit-risk assessment;
Content- supporting tables
Feedback by may be requested regulators:not mentioned
Short term end of study report safety report within trials: safety report within trials for all trials within 90 days
Adverse events included SUSARs; serious,associated; ± expected
Format and Summary Content: Concise global analysis; benefit-risk evaluation; implications for trial subjects; proposed measures to minimize risk; rationale for updates of study documents and procedures; supporting results of non-clinical studies; other considerations
purpose- progress report
Timing- IND anniversary date
Frequency- annual
Recipients- FDA
Content- study data and summary information
Feedback by may be requested regulators: may be requested
Short term end of study report safety report within trials end of study report safety report within trials for all trials within 90 days 1 year of end
Adverse events included: all serious ± associated± expected
Format and Summary: Content, Tabular summary of most frequent and most serious AEs by body system. Summary of all IND expedited reports for the period. Lists of deaths (w/ cause) and dropouts. List of completed non-clinical studies and result summary.
Annual Safety Report:
Purpose-benefit-risk assessment
Timing- Date of 1st authorization of a clinical trial of IMP by authority in member state
Frequency-annual, or on request
Recipients- EMEA, Member States, Ethics Committees
Content- benefit-risk assessment;
Content- supporting tables
Feedback by may be requested regulators:not mentioned
Short term end of study report safety report within trials: safety report within trials for all trials within 90 days
Adverse events included SUSARs; serious,associated; ± expected
Format and Summary Content: Concise global analysis; benefit-risk evaluation; implications for trial subjects; proposed measures to minimize risk; rationale for updates of study documents and procedures; supporting results of non-clinical studies; other considerations
Subscribe to:
Posts (Atom)