Name of Guidance
Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Postmarketing Individual Case Safety Reports
Status of Guidance
Draft guidance
Date of Guidance
June 10, 2008
Link to the Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072369.pdf
Target audience
Individuals charged with making postmarketing individual case safety reports to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA).
Laws and Regulations Referenced
21 CFR 314.98 Abbreviated new drug applications (ANDA)
21 CFR 310.305 prescription drug products marketed for human use without an approved new drug application or ANDA
21 CFR 600.80 biological products marketed for human use with biologic license applications and submission tracking numbers
21 CFR 1271.350(a) section 361 human cells, tissues, and cellular and tissue-based products
21 U.S.C. 379aa section 760 nonprescription human drug products marketed without an approved application
Summary and Rationale
Since 1997 the FDA has encouraged the use of electronic submissions for regulatory documents. Over the years, the agency has issued several guidances regarding premarketing and postmarketing submissions. These submissions become part of the the FDA’s Adverse Event Reporting System database.
The rationale for this draft guidance is to simplify FDA guidance for industry by consolidating 2 existing draft guidances. The draft Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Postmarketing Individual Case Safety Reports supersedes and consolidates draft guidances Providing Regulatory Submissions in Electronic Format – Postmarketing Expedited Safety Reports issued in May 2001 and Providing Regulatory Submissions in Electronic Format – Postmarketing Periodic Adverse Drug Experience Reports issued in June 2003.
This guidance applies to submissions of postmarketing individual case safety reports (ICSRs) of adverse events related to drugs, biologics, therapeutic vaccines, human cells, tissues, and cellular and tissue-based products that have been approved under a new drug application, abbreviated drug application, or a biologic license application, as well as nonprescription drugs marketed without FDA approval. The draft guidance explains how to submit an electronic ICSR and any attachments, which may be electronic or paper documents. It also explains when and how a report receipt will be issued and what to do if the FDA’s Electronic Submission Gateway is temporarily unavailable.
Resulting Recommendations
1. Each adverse events experienced by a patient should be reported to the CDER as an invidudual case report. Any relevant documents should be submitted separately as attachments. This means that if a report has attachments, 2 submissions should be made: 1 for the report and 1 for the attachments. The information required in a report can be found on FDA form 3500A.
2. Each report should have its own identification number that would allow the CDER to match follow-up reports with the original report. All reports with the same identification number will be linked in the adverse event database. If the initial report is an electronic submission and follow-up reports are made on paper, the paper reports should have the same identification number as the original report. If the identification number is the manufacturer’s control number, follow-up reports should use that number as well.
3. Data elements and electronic transport format can be found in the FDA guidance document, Specifications for Preparing and Submitting Electronic ICSRs and ICSR Attachements.
4. Before submitting your first electronic ICSR, contact the FDA’s Adverse Event Reporting System coordinator by e-mail in order to send a test file. This only needs to be done before the first submission.
5. Electronic ICSRs should be sent through the FDA’s Electronic Submission Gateway because it’s the most efficient way for the CDER to process submissions. The ICSR should be sent first, followed by any attachments in subsequent dispatches. When the electronic gateway recognizes the message, the gateway will send a receipt, which will serve as the FDA receipt date of the report and its attachments.
6. If you do not receive a receipt of a submission within 24 hours, check the Web site (www.fda.gov/esg/default.htm) to see if the system is temporarily unavailable. If the system is available, contact the system coordinator by e-mail. If the system is down and you decide to send the report and attachments on paper, do not resend the report later as an electronic submission. For paper submissions, the date the paper documents arrive at CDER will be the FDA receipt date.
Impact
Individuals who submit ICSRs electronically should have good working knowledge of the format for submission as well as the protocols for sending the submissions electronically. They will need to be familiar with the guidance Specifications for Preparing and Submitting Electronic ICSRs and ICSR Attachments in order to include all the needed information in the proper format. Once the electronic submission is prepared, the submitter should have good knowledge of how to use the Electronic Submission Gateway, how to create a identification number for the case, and what to do if the electronic gateway is not working. In order to achieve this, drug firms, research institutions, hospitals, investigative sites, and contract research organizations should have appropriate training courses.
Saturday, April 10, 2010
Kent's #4 Blog Post
Name of Guidance
Draft Guidance for Industry and FDA Staff: Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation
Status of Guidance
Draft Guidance
When was the Guidance released?
14 September, 2009
Link to Guidance
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM182017.pdf
Target audience
Ablation device manufacturers, clinicians, and other research personnel involved in designing, recruiting, and carrying out clinical studies for ablation devices used for treating atrial fibrillation.
Laws and Regulations Referenced
21 CFR 878.4350 GEH Cryosurgical unit and accessories
21 CFR 878.4400 Electrosurgical cutting and coagulation devices and accessories
21 CFR 878.4810 Powered surgical laser instrument
21 CFR 878.4810 Cardiac ablation percutaneous catheter
21 CFR 812.2 Investigational device exemptions
21 CFR 812.42 Institutional review board approval
21 CFR part 50 Informed consent
Summary and Rationale
Atrial fibrillation is a fairly common disease caused by abnormalities in the electrical system of the heart. Dysrhythmic firings of the electrical impulses that control the contraction and release of the atrium and the ventricles cause an irregular heartbeat and compromised bloodflow in the heart and throughout the body. Atrial fibrillation can be caused by several factors. Most importantly it is caused by the wear and tear of aging, as well as abnormalities of the heart valves, thyroid disease, and many unknown factors, according to the Society of Thoracic Surgeons.
Atrial fibrillation can be treated with drugs, catheterization, or in more extreme cases by the Maze procedure, which has becoming more popular since it was first described in the late 1980s. During this open heart procedure, a series of incisions are made in the atrium in order to disrupt the electrical circuits in the heart. The incisions cut the electric pathway so that the electrical impulse can only follow a single path that in most cases will not allow to the heart to beat irregularly. The incisions are made with ablation devices that use electricity, extreme cold, microwaves, ultrasound, or a laser to cut the heart tissue.
As more medical devices are created to be used in the Maze procedure, as well as related procedures that have evolved from it, the FDA feels that there should be guidance for device manufacturers and clinicians who will be performing pre- and post-marketing clinical studies to establish the safety and effectiveness of these ablation devices. The FDA believes that the design of clinical studies should be different for patients with longstanding persistent atrial fibrillation and patients with sudden or recurrent atrial fibrillation and that effectiveness evaluation should reflect the proposed indications for the devices in everyday surgical practice.
The draft guidance addresses randomized control trials, alternative study designs, control group considerations, indications for ablation devices, study endpoints, and evaluation of the effectiveness of these devices.
Resulting Recommendations
1. Randomized controlled trial (RCT) should be the first choice of study design because it is the least burdensome method of gathering scientific evidence and evaluating it. Any RTC should have an appropriate control group based on the type of therapy or indication under study and any other surgical procedures or pre-existing diseases or conditions that patients may have.
2. Alternative study designs that are not RCTs should be scientifically sound and allow for as little bias and other confounders as possible. Study design should match subjects as closely as possible.
3. Studies with historical control groups that have already received treatment should include a thorough analysis of the relevant medical literature. Whenever possible, historical data should include patient level data, rather than data from publications.
4. The study design should reflect the proposed indication for an ablation device such as the type of atrial fibrillation to be treated, the surgical approach used, and any procedures that will be performed at the same time of surgery. The hypothesis of a clinical study should be related to the proposed indication for the device.
5. Study endpoints for the evaluation of effectiveness should differ depending on the type of atrial fibrillation of the patients. For patients with longstanding persistent atrial fibrillation, the primary effectiveness endpoint should be 6 months without atrial fibrillation. For patients with persistant atrial fibrillation, the primary effectiveness endpoint should be 9 months without atrial fibrillation.
Impact
When designing clinical studies for ablation devices for treating atrial fibrillation, the FDA believes that it’s important that the studies compare “apples to apples”. The people involved in designing these studies will need to make sure that they use the rigorous scientific methodology. They will have to make special efforts to gather similar patients into control and treatment groups. For researchers, this may mean conducting a wider search for patients suitable to participation in the studies and conducting the study in multiple investigational sites.
When the control group is based on historical data, the researchers will have to perform an exhaustive literature analysis to support their arguments that the historical data is a valid control group. For evaluating the effectiveness of treatment, the follow up will have to be longer for certain patient groups, such as patients with persistant atrial fibrillation, who will need to be followed for at least 9 months. In the end, the results of the study should reflect the how the ablation device will be used if approved and how well the device actually works in specific situations.
Draft Guidance for Industry and FDA Staff: Clinical Study Designs for Surgical Ablation Devices for Treatment of Atrial Fibrillation
Status of Guidance
Draft Guidance
When was the Guidance released?
14 September, 2009
Link to Guidance
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM182017.pdf
Target audience
Ablation device manufacturers, clinicians, and other research personnel involved in designing, recruiting, and carrying out clinical studies for ablation devices used for treating atrial fibrillation.
Laws and Regulations Referenced
21 CFR 878.4350 GEH Cryosurgical unit and accessories
21 CFR 878.4400 Electrosurgical cutting and coagulation devices and accessories
21 CFR 878.4810 Powered surgical laser instrument
21 CFR 878.4810 Cardiac ablation percutaneous catheter
21 CFR 812.2 Investigational device exemptions
21 CFR 812.42 Institutional review board approval
21 CFR part 50 Informed consent
Summary and Rationale
Atrial fibrillation is a fairly common disease caused by abnormalities in the electrical system of the heart. Dysrhythmic firings of the electrical impulses that control the contraction and release of the atrium and the ventricles cause an irregular heartbeat and compromised bloodflow in the heart and throughout the body. Atrial fibrillation can be caused by several factors. Most importantly it is caused by the wear and tear of aging, as well as abnormalities of the heart valves, thyroid disease, and many unknown factors, according to the Society of Thoracic Surgeons.
Atrial fibrillation can be treated with drugs, catheterization, or in more extreme cases by the Maze procedure, which has becoming more popular since it was first described in the late 1980s. During this open heart procedure, a series of incisions are made in the atrium in order to disrupt the electrical circuits in the heart. The incisions cut the electric pathway so that the electrical impulse can only follow a single path that in most cases will not allow to the heart to beat irregularly. The incisions are made with ablation devices that use electricity, extreme cold, microwaves, ultrasound, or a laser to cut the heart tissue.
As more medical devices are created to be used in the Maze procedure, as well as related procedures that have evolved from it, the FDA feels that there should be guidance for device manufacturers and clinicians who will be performing pre- and post-marketing clinical studies to establish the safety and effectiveness of these ablation devices. The FDA believes that the design of clinical studies should be different for patients with longstanding persistent atrial fibrillation and patients with sudden or recurrent atrial fibrillation and that effectiveness evaluation should reflect the proposed indications for the devices in everyday surgical practice.
The draft guidance addresses randomized control trials, alternative study designs, control group considerations, indications for ablation devices, study endpoints, and evaluation of the effectiveness of these devices.
Resulting Recommendations
1. Randomized controlled trial (RCT) should be the first choice of study design because it is the least burdensome method of gathering scientific evidence and evaluating it. Any RTC should have an appropriate control group based on the type of therapy or indication under study and any other surgical procedures or pre-existing diseases or conditions that patients may have.
2. Alternative study designs that are not RCTs should be scientifically sound and allow for as little bias and other confounders as possible. Study design should match subjects as closely as possible.
3. Studies with historical control groups that have already received treatment should include a thorough analysis of the relevant medical literature. Whenever possible, historical data should include patient level data, rather than data from publications.
4. The study design should reflect the proposed indication for an ablation device such as the type of atrial fibrillation to be treated, the surgical approach used, and any procedures that will be performed at the same time of surgery. The hypothesis of a clinical study should be related to the proposed indication for the device.
5. Study endpoints for the evaluation of effectiveness should differ depending on the type of atrial fibrillation of the patients. For patients with longstanding persistent atrial fibrillation, the primary effectiveness endpoint should be 6 months without atrial fibrillation. For patients with persistant atrial fibrillation, the primary effectiveness endpoint should be 9 months without atrial fibrillation.
Impact
When designing clinical studies for ablation devices for treating atrial fibrillation, the FDA believes that it’s important that the studies compare “apples to apples”. The people involved in designing these studies will need to make sure that they use the rigorous scientific methodology. They will have to make special efforts to gather similar patients into control and treatment groups. For researchers, this may mean conducting a wider search for patients suitable to participation in the studies and conducting the study in multiple investigational sites.
When the control group is based on historical data, the researchers will have to perform an exhaustive literature analysis to support their arguments that the historical data is a valid control group. For evaluating the effectiveness of treatment, the follow up will have to be longer for certain patient groups, such as patients with persistant atrial fibrillation, who will need to be followed for at least 9 months. In the end, the results of the study should reflect the how the ablation device will be used if approved and how well the device actually works in specific situations.
Thursday, April 8, 2010
Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device
Thursday April 8, 2010
Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable
Name: Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable
Status of Guidance: Final Guidance
Guidance Released: April 25, 2006
Link to Guidance: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM071265.pdf
Audience: This guidance was created for in vitro diagnostic manufacturing companies (sponsors), institutional review boards (IRBs), clinical investigators, and the staff of the US Food and Drug Administration (FDA).
Definition of Terms Used in this Guidance:
Agency: The FDA.
In vitro: This refers to tests performed outside of the patient’s body, for example, tests that are performed on a patient’s blood in a laboratory.
In vitro diagnostic products: These are the reagents (chemicals), instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, lessen the severity of, treat, or prevent disease or its negative after-effects. In vitro diagnostic products are intended for use in the collection, preparation, and examination of specimens taken from the human body.
Leftover specimen: This is the remaining portion of a human specimen collected for routine clinical care or analysis that would otherwise have been discarded.
Not individually identifiable: A specimen is considered not individually identifiable when the identity of the subject is not known to or may not readily be ascertained by the investigator or any other individuals associated with the investigation, including the sponsor.
Specimen repository: This is a common site for storage of collections of human biological specimens available for study.
Laws and Regulations Referenced:
1. 21 CFR 10.115: Good guidance practices
2. 21 CFR part 50: Protection of human subjects
3. 21 CFR 50.23(a): Exception from general requirements of informed consent of human subjects
4. 21 CFR 50.24: Exception from informed consent requirements for emergency research
5. 21 CFR part 56: Institutional Review Boards
6. 21 CFR 809.3(a): In vitro diagnostic products for human use definition
7. 21 CFR 812.2(c)(3): Exempted investigations of diagnostic devices
8. 21 CFR 812.3(p): Definition of “subject”
9. Section 520(g) of Federal Food, Drug, and Cosmetic Act (the Act), 21 USC 360j(g): Exemption for devices for investigational use
10. 44 USC 3501-3520: Paperwork Reduction Act
Rationale: The FDA issued this guidance to notify in vitro diagnostic manufacturing companies (sponsors), IRBs, clinical investigators, and agency staff that under certain circumstances it intends to exercise enforcement discretion with respect to its current regulations governing the requirement for informed consent when human specimens are used for FDA-regulated in vitro diagnostic (IVD) device investigations. The FDA requires that informed consent be obtained from human subjects, except in limited emergency circumstances specified in the regulations (see 21 CFR 50.23(a) and 50.24), before specimens can be used in FDA-regulated research. The regulations requiring informed consent when human specimens are used for IVD device research have created confusion and difficulty for persons developing IVD devices. In fact, many clinicians, research hospitals, and IVD device companies have viewed the FDA requirement for informed consent for IVD device studies using leftover specimens as unnecessary for the protection of human subjects as well as an overly burdensome and costly requirement.
Summary: This guidance applies only to those IVD device studies that use leftover specimens that are not individually identifiable, are regulated by the FDA, and are exempt from most requirements of the Investigational Device Exemptions (IDE) regulation. The FDA believes that it is possible in certain circumstances for IVD device studies to be conducted using leftover specimens obtained without informed consent while protecting the human subjects who are the source of such specimens. The IVD device studies do not pose new medical risks to subjects because the specimens have already been collected from the subjects. Additionally, no risks from erroneous test results are presented because the results of the testing in the IVD device studies are not used for clinical management of the subject. Finally, privacy risks are mitigated by limiting the applicability of this guidance to specimens that are not identifiable.
Resulting Recommendations:
The FDA will exercise human subject informed consent enforcement discretion when an IVD device investigation is performed and all of the following are true:
1. The study meets the IDE criteria presented in 21 CFR 812.2(c)(3).
2. The study uses any of the following types of specimens: leftover specimens, specimens obtained from specimen repositories, or leftover specimens that were previously collected for other research purposes.
3. The specimen is not individually identifiable. This means that the identity of the subject is not known and may not easily be determined by the investigator or any other person associated with the study, including the sponsor.
4. It is permissible for the specimens to be accompanied by clinical information as long as the clinical information does not make the identity of the subject available to the investigator or any other person associated with the study, including the sponsor.
5. The people conducting the study are not the same people who are caring for the patients and those people caring for the patients do not share information about the patients with the people who are conducting the study.
6. The specimens are provided to the investigator without any information that would identify the subjects who provided the specimens. The supplier of the specimens must have established policies and procedures to prevent the release of the subjects’ personal information.
7. The study has been reviewed by an IRB.
Impact:
This guidance will eliminate the confusion regarding the application of informed consent requirements to IVD device studies. It will also eliminate the concerns about unnecessary obstacles to IVD device product development, thereby enabling the efficient development of IVD devices in a manner consistent with the values of human subject protection.
Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable
Name: Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable
Status of Guidance: Final Guidance
Guidance Released: April 25, 2006
Link to Guidance: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM071265.pdf
Audience: This guidance was created for in vitro diagnostic manufacturing companies (sponsors), institutional review boards (IRBs), clinical investigators, and the staff of the US Food and Drug Administration (FDA).
Definition of Terms Used in this Guidance:
Agency: The FDA.
In vitro: This refers to tests performed outside of the patient’s body, for example, tests that are performed on a patient’s blood in a laboratory.
In vitro diagnostic products: These are the reagents (chemicals), instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, lessen the severity of, treat, or prevent disease or its negative after-effects. In vitro diagnostic products are intended for use in the collection, preparation, and examination of specimens taken from the human body.
Leftover specimen: This is the remaining portion of a human specimen collected for routine clinical care or analysis that would otherwise have been discarded.
Not individually identifiable: A specimen is considered not individually identifiable when the identity of the subject is not known to or may not readily be ascertained by the investigator or any other individuals associated with the investigation, including the sponsor.
Specimen repository: This is a common site for storage of collections of human biological specimens available for study.
Laws and Regulations Referenced:
1. 21 CFR 10.115: Good guidance practices
2. 21 CFR part 50: Protection of human subjects
3. 21 CFR 50.23(a): Exception from general requirements of informed consent of human subjects
4. 21 CFR 50.24: Exception from informed consent requirements for emergency research
5. 21 CFR part 56: Institutional Review Boards
6. 21 CFR 809.3(a): In vitro diagnostic products for human use definition
7. 21 CFR 812.2(c)(3): Exempted investigations of diagnostic devices
8. 21 CFR 812.3(p): Definition of “subject”
9. Section 520(g) of Federal Food, Drug, and Cosmetic Act (the Act), 21 USC 360j(g): Exemption for devices for investigational use
10. 44 USC 3501-3520: Paperwork Reduction Act
Rationale: The FDA issued this guidance to notify in vitro diagnostic manufacturing companies (sponsors), IRBs, clinical investigators, and agency staff that under certain circumstances it intends to exercise enforcement discretion with respect to its current regulations governing the requirement for informed consent when human specimens are used for FDA-regulated in vitro diagnostic (IVD) device investigations. The FDA requires that informed consent be obtained from human subjects, except in limited emergency circumstances specified in the regulations (see 21 CFR 50.23(a) and 50.24), before specimens can be used in FDA-regulated research. The regulations requiring informed consent when human specimens are used for IVD device research have created confusion and difficulty for persons developing IVD devices. In fact, many clinicians, research hospitals, and IVD device companies have viewed the FDA requirement for informed consent for IVD device studies using leftover specimens as unnecessary for the protection of human subjects as well as an overly burdensome and costly requirement.
Summary: This guidance applies only to those IVD device studies that use leftover specimens that are not individually identifiable, are regulated by the FDA, and are exempt from most requirements of the Investigational Device Exemptions (IDE) regulation. The FDA believes that it is possible in certain circumstances for IVD device studies to be conducted using leftover specimens obtained without informed consent while protecting the human subjects who are the source of such specimens. The IVD device studies do not pose new medical risks to subjects because the specimens have already been collected from the subjects. Additionally, no risks from erroneous test results are presented because the results of the testing in the IVD device studies are not used for clinical management of the subject. Finally, privacy risks are mitigated by limiting the applicability of this guidance to specimens that are not identifiable.
Resulting Recommendations:
The FDA will exercise human subject informed consent enforcement discretion when an IVD device investigation is performed and all of the following are true:
1. The study meets the IDE criteria presented in 21 CFR 812.2(c)(3).
2. The study uses any of the following types of specimens: leftover specimens, specimens obtained from specimen repositories, or leftover specimens that were previously collected for other research purposes.
3. The specimen is not individually identifiable. This means that the identity of the subject is not known and may not easily be determined by the investigator or any other person associated with the study, including the sponsor.
4. It is permissible for the specimens to be accompanied by clinical information as long as the clinical information does not make the identity of the subject available to the investigator or any other person associated with the study, including the sponsor.
5. The people conducting the study are not the same people who are caring for the patients and those people caring for the patients do not share information about the patients with the people who are conducting the study.
6. The specimens are provided to the investigator without any information that would identify the subjects who provided the specimens. The supplier of the specimens must have established policies and procedures to prevent the release of the subjects’ personal information.
7. The study has been reviewed by an IRB.
Impact:
This guidance will eliminate the confusion regarding the application of informed consent requirements to IVD device studies. It will also eliminate the concerns about unnecessary obstacles to IVD device product development, thereby enabling the efficient development of IVD devices in a manner consistent with the values of human subject protection.
Wednesday, April 7, 2010
Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names
Wednesday April 7, 2010
Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names
Name: Contents of a Complete submission for the Evaluation of Proprietary Names
Status of Guidance: Final Guidance
Guidance Released: February 2010
Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075068.pdf
Audience: This guidance was created for pharmaceutical companies as a recommendation for the submission of proposed proprietary names for their new products to the US Food and Drug Administration (FDA) for review
Definition of Terms Used in this Guidance:
Applicant or sponsor: The organization that submits a proposed proprietary name (trademark or brand name) submission for prescription drug products (including biologics) and nonprescription drug products. For example, GlaxoSmithKline (GSK) could be an applicant or a sponsor.
Complete submission: This is the information identified by the FDA that is needed by them to perform a complete review of a proposed proprietary name.
Established name: This is the official name of the drug. It is often the generic or common name and can usually be found in the United States Pharmacopeia (USP). For example, topotecan hydrochloride is the established name (generic name or common name) for Hycamtin®.
Label: A display of written, printed, or illustrated matter upon the immediate container of any drug.
Labeling: Labeling includes all labels and other written, printed, or illustrated matter that is found upon any drug or any of its containers or wrappers or that accompanies the drug. Labeling includes outside containers, wrappers, and package liners.
Medical error: The Institute of Medicine (IOM) defines medical error as “the failure of a planned action to be completed as intended or the use of a wrong plan to achieve an aim.”[1] Types of medical errors include diagnostic, treatment, preventive and other (such as communication, equipment, or system failure).[2]
Medication error: Any preventable situation that may cause or result in inappropriate medication use or harm to the patient while the medication is in the control of the health care professional, patient, or consumer. These preventable situations may be related to professional practice, health care products, procedures, and systems. These situations include prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.[3]
Medication-use system: This is the system that includes (1) prescribing by the clinician (or self-prescribing), followed by transcribing; (2) preparing and dispensing by the pharmacist; (3) administering by the provider or consumer (self-care); and (4) monitoring for therapeutic and adverse effects (by nurse, surrogate, or self). Each of these four steps includes critical control points at which decisions and actions can contribute to safety or errors.[4]
Product characteristics: The physical characteristics of the product itself and those of the environment in which the product is used. Characteristics of the product include dosage form, strength, and active ingredient. Characteristics of the environment in which the product is used include the facility, storage conditions, the person who prescribes and administers the product, and patient population.
Proprietary name: The trademark or brand name.
Laws and Regulations Referenced:
1. 21 CFR 201: Labeling
2. 21 CFR 201.6(b): Drugs; misleading statements
3. 21 CFR 201.10(c)(3): Drugs; statement of ingredients
4. 21 CFR 202.1(a)(3), (e)(5)(i), and (e)(6)(i): Prescription-drug advertisements
5. 21 CFR 299.4: Established names for drugs
6. 21 CFR 312.3: Investigational New Drug application – Definitions and interpretations
7. 21 CFR 314.105(c): Approval of an application and an abbreviated application
8. 21 CFR 314.125(b)(6) and (b)(8): Refusal to approve an application
9. 21 CFR 314.3: Applications for FDA approval to market a new drug - Definitions
10. 21 CFR 314.50: Content and format of a New Drug Application
11. 21 CFR 314.92: Drug products for which abbreviated applications may be submitted
12. 21 CFR 601.2: Applications for biologics licenses; procedures for filing
13. 21 CFR 601.4(b): Issuance and denial of [a biologics] license
14. 21 USC 321(n), 352(a) and (n): Definitions (misbranded) and Misbranded drugs and devices
15. 21 USC 352(e)(3): Designation of drugs or devices by established names
16. 21 USC 355(d)(7): Grounds for refusing application; approval of application; “substantial evidence” defined
17. 42 USC 262(a)(1)(B)(ii): Biologics license
18. 42 USC 262(b): Falsely labeling or marking a package or container; altering a label or mark of a biological product
19. Public Law 110-85 Stat 823: The Food and Drug Administration Amendments Act of 2007 (September 27, 2007; 121 Stat. 823; 156 pages) also known as an act to amend the Federal Food, Drug, and Cosmetic Act to revise and extend the user-fee programs for prescription drugs and for medical devices, to enhance the postmarket authorities of the Food and Drug Administration with respect to the safety of drugs, and for other purposes
Summary: This guidance provides US pharmaceutical companies with the information the FDA considers essential to be enabled to conduct a complete review of a proposed proprietary name. A proprietary name is a trademark or brand name. For example, Tylenol® is McNeil Consumer Healthcare’s brand name for acetaminophen. All proprietary names that are proposed for new drugs (both prescription and nonprescription) and new biologics must be evaluated by the FDA before a product is allowed to be sold on the US market.
Rationale: The FDA is committed to the efficient development of safe and effective new medications for the American public. One goal of the FDA is to reduce medication errors by ensuring that all products have clearly understandable labels. The FDA hopes to reduce medication errors by eliminating look-alike and sound-alike proprietary names, unclear label abbreviations, unclear acronyms, confusing dose designations, and poor packaging designs. As part of this goal to reduce medication errors that are related to unclear labeling, the FDA agreed to publish guidance on the contents of a complete submission package for a proposed proprietary name for a drug or biological product. Resulting Recommendations:
1. Applicants (drug/biologic manufacturers) must submit, and FDA must review, proposed proprietary names as part of New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologic License Applications (BLAs).
2. When possible, applicants may have the FDA evaluate a proposed proprietary name even earlier in the drug development process; however, the product must have successfully completed phase 2 trials prior to submission. This time period is referred to as the end of phase 2 of the Investigational New Drug (IND) process.
3. A complete submission for evaluation of proposed proprietary names includes the following:
3.1. General Information
Each submission should be identified as one of the following:
REQUEST FOR PROPRIETERY NAME REVIEW, or
AMENDMENT TO REQUEST FOR PROPRIETARY NAME REVIEW, or
REQUEST FOR RECONSIDERATION OF PROPRIETERY NAME, as appropriate.
Either FDA Form 1571 (for all products that are the subject of an IND) or FDA Form 356h (for all products that are the subject of an NDA, ANDA, or BLA) should be submitted and include:
-Proposed first choice of proprietary name
-Application number (BLA/NDA/ANDA/IND)
-Applicant or sponsor contact information
-Identification of the submission as mentioned above (in bold under Section 3.1.)
-A list of the contents of the submission
3.2. Proposed Proprietary Name
All submissions should include the following information about the proposed proprietary name:
-Primary and alternate proposed proprietary name
-Intended pronunciation of the proposed proprietary name
-Derivation of proprietary name
-Intended meaning of proprietary name modifiers (for example, the meaning of a prefix or suffix such as “ER” means extended-release)
-Pharmacologic/therapeutic category
3.3. Additional Information about the Product
Submissions should include the following depending on whether they already have proposed labels and labeling or not:
3.3.1. Submission for a product that has proposed labels and labeling is to include:
-Proposed labeling (also known as the package insert, prescribing information, or physician labeling)
-Proposed container labels and labeling (external labeling and packaging)
3.3.2. Submission for a product without proposed labeling is to include (this information is normally contained in professional labeling):
-Established name
-Prescription status
-Dosage form(s)
-Product strength(s)
-Proposed indication(s) for use
-Route(s) of administration
-Usual dosage, frequency of administration, dosing interval, maximum daily dose
-Dosing in specific populations
-Instructions for use
-Storage requirement
-How supplied and packaging configuration
3.4. Information about product dispensing and delivery
-Likely care environment(s) for dispensing and use
-Delivery system
-Measuring device
3.5 Applicant’s assessments of proprietary name, packaging, and/or labeling
Impact:
This guidance will help improve patient safety and decrease preventable adverse drug events in the US. Although an applicant (a pharmaceutical company, for example) may perform their own assessment of the proprietary name they have chosen for one of their new drug/biologic products, it is an added safety step to have the FDA evaluate proposed proprietary names. In the US, 44,000 to 98,000 deaths each year are the direct result of medical errors.[5] This statistic makes medical errors the eighth leading cause of death in the US.[6] Of these deaths due to medical errors, 7,000 deaths annually were attributed to medication errors.[7] Labeling and packaging issues are the cause of 33 percent of medication errors and 30 percent of the fatalities associated with medication errors.[8] It is no surprise that the IOM recommended that the FDA 1) develop and enforce standards for the design of drug packaging and labeling that will maximize safety in use and 2) require pharmaceutical companies to test proposed drug names to identify and remedy potential sound-alike and look-alike confusion with existing drug names. The IOM is an unbiased, independent, nonprofit organization that works outside of government to advise the nation how to improve national health.
[1] Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. Institute of Medicine, National Academies Press: Washington DC, 2000. Chapter 1, p. 1.
[2] Leape L, Lawthers AG, Brennan TA, et al. Preventing Medical Injury. Qual Rev Bull. 19(5):144-149, 1993, cited in To Err is Human, p. 1.
[3] National Coordinating Council for Medication Error Reporting and Prevention Web site, http://www.nccmerp.org/aboutMedErrors.html.
[4] Aspden P, Wolcott JA, Bootman JL, Cronenwett LR, eds. Overview of the Drug Development, Regulation, Distribution, and Use System. Preventing Medication Errors, Institute of Medicine, The National Academies Press: Washington DC, 2006. Chapter 2, p. 67.
[5] Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. Institute of Medicine, National Academies Press: Washington DC, 2000.
[6] American Hospital Association. Hospital Statistics. Chicago, 1999.
[7] Phillips, DP, Christenfeld, N, and Glynn, LM. Increase in US Medication-Error Deaths between 1983 and 1993. The Lancet. 351:643-644, 1998.
[8] Aspden P, Wolcott JA, Bootman JL, Cronenwett LR, eds. Preventing Medication Errors. Institute of Medicine, The National Academies Press: Washington DC, 2006.
Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names
Name: Contents of a Complete submission for the Evaluation of Proprietary Names
Status of Guidance: Final Guidance
Guidance Released: February 2010
Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075068.pdf
Audience: This guidance was created for pharmaceutical companies as a recommendation for the submission of proposed proprietary names for their new products to the US Food and Drug Administration (FDA) for review
Definition of Terms Used in this Guidance:
Applicant or sponsor: The organization that submits a proposed proprietary name (trademark or brand name) submission for prescription drug products (including biologics) and nonprescription drug products. For example, GlaxoSmithKline (GSK) could be an applicant or a sponsor.
Complete submission: This is the information identified by the FDA that is needed by them to perform a complete review of a proposed proprietary name.
Established name: This is the official name of the drug. It is often the generic or common name and can usually be found in the United States Pharmacopeia (USP). For example, topotecan hydrochloride is the established name (generic name or common name) for Hycamtin®.
Label: A display of written, printed, or illustrated matter upon the immediate container of any drug.
Labeling: Labeling includes all labels and other written, printed, or illustrated matter that is found upon any drug or any of its containers or wrappers or that accompanies the drug. Labeling includes outside containers, wrappers, and package liners.
Medical error: The Institute of Medicine (IOM) defines medical error as “the failure of a planned action to be completed as intended or the use of a wrong plan to achieve an aim.”[1] Types of medical errors include diagnostic, treatment, preventive and other (such as communication, equipment, or system failure).[2]
Medication error: Any preventable situation that may cause or result in inappropriate medication use or harm to the patient while the medication is in the control of the health care professional, patient, or consumer. These preventable situations may be related to professional practice, health care products, procedures, and systems. These situations include prescribing; order communication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.[3]
Medication-use system: This is the system that includes (1) prescribing by the clinician (or self-prescribing), followed by transcribing; (2) preparing and dispensing by the pharmacist; (3) administering by the provider or consumer (self-care); and (4) monitoring for therapeutic and adverse effects (by nurse, surrogate, or self). Each of these four steps includes critical control points at which decisions and actions can contribute to safety or errors.[4]
Product characteristics: The physical characteristics of the product itself and those of the environment in which the product is used. Characteristics of the product include dosage form, strength, and active ingredient. Characteristics of the environment in which the product is used include the facility, storage conditions, the person who prescribes and administers the product, and patient population.
Proprietary name: The trademark or brand name.
Laws and Regulations Referenced:
1. 21 CFR 201: Labeling
2. 21 CFR 201.6(b): Drugs; misleading statements
3. 21 CFR 201.10(c)(3): Drugs; statement of ingredients
4. 21 CFR 202.1(a)(3), (e)(5)(i), and (e)(6)(i): Prescription-drug advertisements
5. 21 CFR 299.4: Established names for drugs
6. 21 CFR 312.3: Investigational New Drug application – Definitions and interpretations
7. 21 CFR 314.105(c): Approval of an application and an abbreviated application
8. 21 CFR 314.125(b)(6) and (b)(8): Refusal to approve an application
9. 21 CFR 314.3: Applications for FDA approval to market a new drug - Definitions
10. 21 CFR 314.50: Content and format of a New Drug Application
11. 21 CFR 314.92: Drug products for which abbreviated applications may be submitted
12. 21 CFR 601.2: Applications for biologics licenses; procedures for filing
13. 21 CFR 601.4(b): Issuance and denial of [a biologics] license
14. 21 USC 321(n), 352(a) and (n): Definitions (misbranded) and Misbranded drugs and devices
15. 21 USC 352(e)(3): Designation of drugs or devices by established names
16. 21 USC 355(d)(7): Grounds for refusing application; approval of application; “substantial evidence” defined
17. 42 USC 262(a)(1)(B)(ii): Biologics license
18. 42 USC 262(b): Falsely labeling or marking a package or container; altering a label or mark of a biological product
19. Public Law 110-85 Stat 823: The Food and Drug Administration Amendments Act of 2007 (September 27, 2007; 121 Stat. 823; 156 pages) also known as an act to amend the Federal Food, Drug, and Cosmetic Act to revise and extend the user-fee programs for prescription drugs and for medical devices, to enhance the postmarket authorities of the Food and Drug Administration with respect to the safety of drugs, and for other purposes
Summary: This guidance provides US pharmaceutical companies with the information the FDA considers essential to be enabled to conduct a complete review of a proposed proprietary name. A proprietary name is a trademark or brand name. For example, Tylenol® is McNeil Consumer Healthcare’s brand name for acetaminophen. All proprietary names that are proposed for new drugs (both prescription and nonprescription) and new biologics must be evaluated by the FDA before a product is allowed to be sold on the US market.
Rationale: The FDA is committed to the efficient development of safe and effective new medications for the American public. One goal of the FDA is to reduce medication errors by ensuring that all products have clearly understandable labels. The FDA hopes to reduce medication errors by eliminating look-alike and sound-alike proprietary names, unclear label abbreviations, unclear acronyms, confusing dose designations, and poor packaging designs. As part of this goal to reduce medication errors that are related to unclear labeling, the FDA agreed to publish guidance on the contents of a complete submission package for a proposed proprietary name for a drug or biological product. Resulting Recommendations:
1. Applicants (drug/biologic manufacturers) must submit, and FDA must review, proposed proprietary names as part of New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologic License Applications (BLAs).
2. When possible, applicants may have the FDA evaluate a proposed proprietary name even earlier in the drug development process; however, the product must have successfully completed phase 2 trials prior to submission. This time period is referred to as the end of phase 2 of the Investigational New Drug (IND) process.
3. A complete submission for evaluation of proposed proprietary names includes the following:
3.1. General Information
Each submission should be identified as one of the following:
REQUEST FOR PROPRIETERY NAME REVIEW, or
AMENDMENT TO REQUEST FOR PROPRIETARY NAME REVIEW, or
REQUEST FOR RECONSIDERATION OF PROPRIETERY NAME, as appropriate.
Either FDA Form 1571 (for all products that are the subject of an IND) or FDA Form 356h (for all products that are the subject of an NDA, ANDA, or BLA) should be submitted and include:
-Proposed first choice of proprietary name
-Application number (BLA/NDA/ANDA/IND)
-Applicant or sponsor contact information
-Identification of the submission as mentioned above (in bold under Section 3.1.)
-A list of the contents of the submission
3.2. Proposed Proprietary Name
All submissions should include the following information about the proposed proprietary name:
-Primary and alternate proposed proprietary name
-Intended pronunciation of the proposed proprietary name
-Derivation of proprietary name
-Intended meaning of proprietary name modifiers (for example, the meaning of a prefix or suffix such as “ER” means extended-release)
-Pharmacologic/therapeutic category
3.3. Additional Information about the Product
Submissions should include the following depending on whether they already have proposed labels and labeling or not:
3.3.1. Submission for a product that has proposed labels and labeling is to include:
-Proposed labeling (also known as the package insert, prescribing information, or physician labeling)
-Proposed container labels and labeling (external labeling and packaging)
3.3.2. Submission for a product without proposed labeling is to include (this information is normally contained in professional labeling):
-Established name
-Prescription status
-Dosage form(s)
-Product strength(s)
-Proposed indication(s) for use
-Route(s) of administration
-Usual dosage, frequency of administration, dosing interval, maximum daily dose
-Dosing in specific populations
-Instructions for use
-Storage requirement
-How supplied and packaging configuration
3.4. Information about product dispensing and delivery
-Likely care environment(s) for dispensing and use
-Delivery system
-Measuring device
3.5 Applicant’s assessments of proprietary name, packaging, and/or labeling
Impact:
This guidance will help improve patient safety and decrease preventable adverse drug events in the US. Although an applicant (a pharmaceutical company, for example) may perform their own assessment of the proprietary name they have chosen for one of their new drug/biologic products, it is an added safety step to have the FDA evaluate proposed proprietary names. In the US, 44,000 to 98,000 deaths each year are the direct result of medical errors.[5] This statistic makes medical errors the eighth leading cause of death in the US.[6] Of these deaths due to medical errors, 7,000 deaths annually were attributed to medication errors.[7] Labeling and packaging issues are the cause of 33 percent of medication errors and 30 percent of the fatalities associated with medication errors.[8] It is no surprise that the IOM recommended that the FDA 1) develop and enforce standards for the design of drug packaging and labeling that will maximize safety in use and 2) require pharmaceutical companies to test proposed drug names to identify and remedy potential sound-alike and look-alike confusion with existing drug names. The IOM is an unbiased, independent, nonprofit organization that works outside of government to advise the nation how to improve national health.
[1] Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. Institute of Medicine, National Academies Press: Washington DC, 2000. Chapter 1, p. 1.
[2] Leape L, Lawthers AG, Brennan TA, et al. Preventing Medical Injury. Qual Rev Bull. 19(5):144-149, 1993, cited in To Err is Human, p. 1.
[3] National Coordinating Council for Medication Error Reporting and Prevention Web site, http://www.nccmerp.org/aboutMedErrors.html.
[4] Aspden P, Wolcott JA, Bootman JL, Cronenwett LR, eds. Overview of the Drug Development, Regulation, Distribution, and Use System. Preventing Medication Errors, Institute of Medicine, The National Academies Press: Washington DC, 2006. Chapter 2, p. 67.
[5] Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. Institute of Medicine, National Academies Press: Washington DC, 2000.
[6] American Hospital Association. Hospital Statistics. Chicago, 1999.
[7] Phillips, DP, Christenfeld, N, and Glynn, LM. Increase in US Medication-Error Deaths between 1983 and 1993. The Lancet. 351:643-644, 1998.
[8] Aspden P, Wolcott JA, Bootman JL, Cronenwett LR, eds. Preventing Medication Errors. Institute of Medicine, The National Academies Press: Washington DC, 2006.
Monday, April 5, 2010
Blog 5 Help-Seeking and other Disease Awareness Communications
Name of the Guidance:
“Help-Seeking” and Other Disease Awareness Communications by or on Behalf of Drug and Device Firms
Status of the Guidance:
Draft guidance published in January 2004
When the Guidance was Released:
January 2004
Link to the Guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070068.pdf
Target Audience:
Sponsors of prescriptions drugs and medical devices and medical communication companies working on behalf of sponsors to develop disease awareness communications directed to consumers.
Laws and Regulations Referenced:
21 CFR Part 202.1 – Prescription Drug Advertisement regulations
21 CFR 314.50 FDA-approved labeling for drugs
21 CFR 601.2 FDA-approved labeling for biologics
21 CFR 814.2 FDA-approved labeling for devices
Summary:
Disease awareness communications include general discussions of a disease or health condition, communications that advise the target audience to “see your doctor” for diagnosis or treatment, advisements to doctors and health professionals to encourage awareness signs of a disease, or information on diagnosis of a particular disease. Disease awareness communications cannot name, suggest, or represent any particular drug or device. The FDA encourages industry-sponsored disease awareness communications because these types of communications do promote the general public health and are often sponsored and disseminated by government agencies and educational organizations. However, when sponsored by manufacturers of a drug or device, these guidelines should be followed to ensure the help-seeking communications do not go beyond the limits of help-seeking or disease awareness communications and become advertisements or promotional material for a specific drug or device.
It is the FDA’s position that most disease awareness communications are not labeling or advertising so there is no need for disclosure of risk information. This assessment does not necessarily apply to companies who are the only manufacturer of a commercially available product for a particular disease or condition or companies who manufacture only one commercially available product. Such companies are not necessarily excluded from disseminating help-seeking information; however, if the through the help-seeking communication a particular drug or device is implicated then the FDA may treat the communication as advertisement and require the disclosure of risk information. For communications that combine help-seeking communication and reminder advertisement, an advertisement that may mention a product and advice to see a physician, the disclosure of risk information is required or the product may be deemed to be misbranded.
The guidance also recognizes that when the timing and proximity of promotional material is close to the help-seeking communications the help-seeking communication may be mentally linked with the product being promoted. The audience may perceive the two components as one and the message will be linked.
Rationale:
The primary purpose of the guidance is to help clarify for sponsors the distinction of help-seeking and disease awareness communications and promotional advertisements for regulated products. Sometimes the combination of two communications, neither of which alone would be considered promotional, may together meet the definition of an advertisement and have to comply with the FDA regulations for advertisements of prescriptions drugs. Sponsors must ensure the help-seeking and disease awareness material are perceptually distinct in content, in timing of display or in physical proximity so there will not be a psychological link to a disease and product.
Resulting Recommendations:
The FDA recommends that sponsors consider the following factors when developing help-seeking or disease awareness communications that would be exempt from the mandated risk disclosure for promotional material for prescription drugs:
• Are the pieces perceptually distinct in use of graphic, visual, thematic, or other presentation elements?
• Are the pieces presented in close physical or temporal proximity?
Impact:
This guidance will assist sponsors in developing and planning disease awareness or help-seeking campaigns that are designed to promote use of their drug or device without violating the FDA’s regulations on the promotion of drugs and devices.
“Help-Seeking” and Other Disease Awareness Communications by or on Behalf of Drug and Device Firms
Status of the Guidance:
Draft guidance published in January 2004
When the Guidance was Released:
January 2004
Link to the Guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070068.pdf
Target Audience:
Sponsors of prescriptions drugs and medical devices and medical communication companies working on behalf of sponsors to develop disease awareness communications directed to consumers.
Laws and Regulations Referenced:
21 CFR Part 202.1 – Prescription Drug Advertisement regulations
21 CFR 314.50 FDA-approved labeling for drugs
21 CFR 601.2 FDA-approved labeling for biologics
21 CFR 814.2 FDA-approved labeling for devices
Summary:
Disease awareness communications include general discussions of a disease or health condition, communications that advise the target audience to “see your doctor” for diagnosis or treatment, advisements to doctors and health professionals to encourage awareness signs of a disease, or information on diagnosis of a particular disease. Disease awareness communications cannot name, suggest, or represent any particular drug or device. The FDA encourages industry-sponsored disease awareness communications because these types of communications do promote the general public health and are often sponsored and disseminated by government agencies and educational organizations. However, when sponsored by manufacturers of a drug or device, these guidelines should be followed to ensure the help-seeking communications do not go beyond the limits of help-seeking or disease awareness communications and become advertisements or promotional material for a specific drug or device.
It is the FDA’s position that most disease awareness communications are not labeling or advertising so there is no need for disclosure of risk information. This assessment does not necessarily apply to companies who are the only manufacturer of a commercially available product for a particular disease or condition or companies who manufacture only one commercially available product. Such companies are not necessarily excluded from disseminating help-seeking information; however, if the through the help-seeking communication a particular drug or device is implicated then the FDA may treat the communication as advertisement and require the disclosure of risk information. For communications that combine help-seeking communication and reminder advertisement, an advertisement that may mention a product and advice to see a physician, the disclosure of risk information is required or the product may be deemed to be misbranded.
The guidance also recognizes that when the timing and proximity of promotional material is close to the help-seeking communications the help-seeking communication may be mentally linked with the product being promoted. The audience may perceive the two components as one and the message will be linked.
Rationale:
The primary purpose of the guidance is to help clarify for sponsors the distinction of help-seeking and disease awareness communications and promotional advertisements for regulated products. Sometimes the combination of two communications, neither of which alone would be considered promotional, may together meet the definition of an advertisement and have to comply with the FDA regulations for advertisements of prescriptions drugs. Sponsors must ensure the help-seeking and disease awareness material are perceptually distinct in content, in timing of display or in physical proximity so there will not be a psychological link to a disease and product.
Resulting Recommendations:
The FDA recommends that sponsors consider the following factors when developing help-seeking or disease awareness communications that would be exempt from the mandated risk disclosure for promotional material for prescription drugs:
• Are the pieces perceptually distinct in use of graphic, visual, thematic, or other presentation elements?
• Are the pieces presented in close physical or temporal proximity?
Impact:
This guidance will assist sponsors in developing and planning disease awareness or help-seeking campaigns that are designed to promote use of their drug or device without violating the FDA’s regulations on the promotion of drugs and devices.
Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases and Conditions
Draft guidance released January 2004, available at:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126838.pdf
Target Audience
This guidance assists individuals including clinical trials professionals, quality assurance staff, regulatory affairs personnel, and others who submit data (collectively: sponsors) to the Clinical Trials Data Bank (http://www.clinicaltrials.gov/). The guidance also is germane to those who are responsible for implementation of the FDA Modernization Act (FDAMA) of 1997.
Laws, Regulations, and Related Guidances
Section 113 of the FDAMA, 1997
Public Law 107-109 Best Pharmaceuticals for Children Act (BPCA), 2002
Federal Food, Drug, and Cosmetic Act Section 505(i)
21 CFR [Investigational New Drugs (INDs)]
21 CFR 312 (regarding clinical trials)
21 CFR 312.81(a) (defines life-threatening diseases)
21 USC 356 (defines fast-track designation)
42 USC 282 especially Section 282(j)(3)(A)
Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases and Conditions, March 2000
Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases: Implementation Plan, June 2001
Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases and Conditions, March 2002 [NOTE: This 2002 guidance incorporated the 2 guidances just cited. The 2004 guidance updates the 2002 version.]
Guidance for Industry: Fast Track Drug Development Programs— Designation, Development, and Application Review (revision 2, January 2006)
Summary
Section 113 of FDAMA directs the Secretary of the Department of Health and Human Services, via the Director of the National Institutes of Health (NIH), to “establish, maintain, and operate a data bank of information on clinical trials for drugs to treat serious or life-threatening diseases and conditions.” The Clinical Trials Data Bank at http://www.clinicaltrials.gov is a central resource that provides information about clinical trials for individuals who have serious or life-threatening diseases or conditions. Because this is a public site, researchers, health care providers, and the public at large have access to the information. The site includes:
- information about federally and privately funded clinical trials for experimental drug and biological treatments for patients with serious or life-threatening diseases or conditions
- a description of the purpose of each experimental drug
- patient eligibility criteria
- the location of clinical trial sites
- a point of contact for patients wanting to enroll in the trial.
Sponsors must submit required information no later than 21 days after trial opens for enrollment. Every 30 days thereafter sponsors can provide supplemental information (amendments, interruptions, continuations, or completion, as well as changes in eligibility). The guidance recommends posting closings (eg, clinical holds) within 10 days or fewer from the closing. Finally, the guidance suggests that sponsors should conduct overall reviews of the posting at least semiannually to ensure all data remain current.
As the guidance notes, the term life-threatening diseases is defined as diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and, when the endpoint of the clinical trial is survival, diseases or conditions with potentially fatal outcomes. Overall, FDA’s view is that untreated patients who have life-threatening diseases will move from less-severe conditions to more-serious ones in terms of survival and day-to-day functioning. Life-threatening diseases include Human Immunodeficiency Virus, Alzheimer disease, angina pectoris, heart failure, cancer, all conditions treated by fast-track drugs, and others).
The Clinical Trials Data Bank supercedes the former AIDS Clinical Trials Information System (ACTIS) and the Physician’s Data Query (PDQ) databases and incorporates information from the Rare Diseases and National Institute of Aging Databases. Posting clinical trial information to the Data Bank does not require the approval of the trial’s institutional review board(s).
Sponsors who conduct an ex–US study under an IND must comply with this guideline.
Rationale
As the guidance notes, FDAMA section 113 “creates a public resource for information on studies of drugs, including biological drug products, to treat serious or life-threatening diseases and conditions.” Although the guidance does not address historical context, since the first (2000) version was published, Internet use in the United States expanded rapidly, and the public increasingly asked for information about drugs in development to treat serious diseases. In some cases, patients and their relatives were seeking access to advanced therapies that might offer hope to friends and family members. To others, the fact that the federal government regulated clinical trials suggested that results from these trials should be more public.1 Revocation of marketing privileges for several drugs, notably those in the COX-2 inhibitor class, involved public outcry about underreported and possibly distorted reports from clinical trials (eg, the RECORD Trials).2,3
Resulting Recommendations
The Clinical Trials Data Bank established 4 fundamental data elements for posting on http://www.clinicaltrials.gov:
- Descriptive information about the clinical trial
- Brief title (in lay language)
- Brief summary (in lay language)
- Study design/phase/type
- Condition or disease
- Intervention
- Single-patient/expanded access information (if any)
- Recruitment Information
- Status: Recruiting/Not recruiting/Completed
- Individual site status
- Location and Contact Information
- Administrative data
- Protocol ID number
- Sponsor
- Verification date.
To enable clinical trial sponsors to provide this information, FDA established the Protocol Registration System (http://prsinfo.clinicaltrials.gov/). This tool allows sponsors to submit necessary information. Importantly, the Protocol Registration System sends FDA a receipt after the sponsor submits the information package.
Impact
The first version of the Clinical Trials Data Bank was posted publicly on 29 Feb 2000. The site reports that it now contains 87,850 trials sponsored by the National Institutes of Health, other federal agencies, and private industry. It includes trials in all 50 states and in 172 countries and receives more than 50 million page views per month and 65,000 visitors daily. Public posting of clinical trials can be seen as a step toward the disclosure of the results of all clinical studies.
Note that sponsors are required to post information to the Clinical Trials Data Bank unless the sponsor provides a detailed certification to FDA that disclosure would “substantially interfere with the timely enrollment of subjects” in the trial. But at line 341 (p 9) the guidance notes that FDA has received no comments that attempted to justify not posting to the Clinical Trials Data Bank.
Note
The Food and Drug Administration Amendment Act (FDAAA) of September 2007 requires sponsors of all clinical trials registered at www.clinicaltrials.gov (excepting Phase I trials) to report key outcomes no later than 12 months after they receive data for the last patient. As noted, this requirement results from public and Congressional pressure to ensure that outcomes of all trials are available in the public record.
References
1. Although the movement toward public access of NIH-funded research and open access in general are peripheral to this blog, the guidance discussed here is part of the context in which several medical journals refused to publish results from trials that were not registered at, eg, clinicaltrials.gov. See: DeAngelis CD, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medicl Journal Editors. JAMA. 2004;292:1363–1364.
2. Nissen SE. Setting the RECORD straight. JAMA. 2010;303(12):1194–1195. This study obviously follows FDAMA, but it helpfully frames some of the issues that were under debate when FDAMA was enacted. Note references herein.
3. DeAngelis CD, Fontanarosa PB. Ensuring integrity in industry-sponsored research. JAMA. 2010;202(12):1196–1198. This editorial by JAMA editors shows some results of the apparent lack of transparency in the conduct and reporting of clinical trials. Note references herein.
Sunday, April 4, 2010
Blog #5
Name of Guidance: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications.
Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf
Draft guidance released in September, 2009.
Laws Referenced:
• Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA)
• Section 505(b) of the FDCA
• Section 505(j) of FDCA
• Section 351 of the Public Health Service Act (PHS Act)
• Title IX, Subtitle A, section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public Law 110-85)
• Sections 909(b)(1) through 909(b)(3) of FDAAA
• Title 21 of the Code of Federal Regulations (21 CFR), sections 314.520 and 601.42
• 21 CFR, part 208
Target Audience: Industry sponsors and applicants
Rationale: Some drug or biological products, despite having a product label that describes the benefits and risks associated with the product, may require additional information that describes how to use the product in such a way that the risks are minimized. The guidance describes the purpose of the risk evaluation and mitigation strategy (REMS), a plan that describes what a sponsor is doing to provide current safety-related information that contributes to the benefit portion of the risk-benefit ratio (ie, the drug or biological product has more benefits than risks). The guidance also describes what to include in a REMS and recommended sponsor-FDA communication strategies so that the FDA has current safety-related information for drug or biological products that support the risk-benefit ratio.
Summary: Under a 2007 statute of FDAAA, the FDA can require a drug sponsor to submit a REMS for certain drug or biological products in situations where the FDA determines that additional supporting information is necessary for appropriate use of the drug. Examples of such information include, but are not limited to, instructions to the pharmacist, recommending a particular lab test result before starting the drug or biological treatment, or providing additional risk-related information to healthcare professionals (eg, information sheets) so they can make an informed decision about treatment. The FDA also has the authority to require a sponsor to revise the label and/or the REMS based on the information provided in it. In addition, the FDA may require a sponsor to show how it is achieving its objectives; for example, a sponsor may need to evaluate the effectiveness of its information sheet that encourages safe use of the product by monitoring how many healthcare professionals are using the information sheet.
Resulting Recommendations: A REMS generally includes the following elements, although some may not be applicable:
• Product name and information
• Objectives
• A schedule that describes when assessments are submitted to the FDA
• Medication guide
• Patient package insert
• Recommendations for healthcare providers in using the drug or biological product as intended to minimize risks
• Other information that encourages appropriate use of the drug or biological product in order to minimize risk (elements to assure safe use).
A REMS template is found on the FDA Web site (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm).
A REMS is subdivided into 2 parts – a proposed REMS (what the sponsor promises to do) and a REMS supporting document (background and information that supports the proposed REMS). The first type is important because the FDA will enforce the content contained in the proposed REMS. Failure to provide a REMS when required by the FDA has consequences, such as financial penalties, having the drug or biological product labeled misbranded, and/or prohibiting shipment across state lines.
Impact: This statute from FDAAA fits in nicely with the FDA’s goal of making drug or biological product information more accessible to the public. It also is another way of periodically monitoring safety. The use of REMS may prevent a drug or biological product that is beneficial to a small subset of the population from being withdrawn because of adverse effects.
Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf
Draft guidance released in September, 2009.
Laws Referenced:
• Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA)
• Section 505(b) of the FDCA
• Section 505(j) of FDCA
• Section 351 of the Public Health Service Act (PHS Act)
• Title IX, Subtitle A, section 901 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public Law 110-85)
• Sections 909(b)(1) through 909(b)(3) of FDAAA
• Title 21 of the Code of Federal Regulations (21 CFR), sections 314.520 and 601.42
• 21 CFR, part 208
Target Audience: Industry sponsors and applicants
Rationale: Some drug or biological products, despite having a product label that describes the benefits and risks associated with the product, may require additional information that describes how to use the product in such a way that the risks are minimized. The guidance describes the purpose of the risk evaluation and mitigation strategy (REMS), a plan that describes what a sponsor is doing to provide current safety-related information that contributes to the benefit portion of the risk-benefit ratio (ie, the drug or biological product has more benefits than risks). The guidance also describes what to include in a REMS and recommended sponsor-FDA communication strategies so that the FDA has current safety-related information for drug or biological products that support the risk-benefit ratio.
Summary: Under a 2007 statute of FDAAA, the FDA can require a drug sponsor to submit a REMS for certain drug or biological products in situations where the FDA determines that additional supporting information is necessary for appropriate use of the drug. Examples of such information include, but are not limited to, instructions to the pharmacist, recommending a particular lab test result before starting the drug or biological treatment, or providing additional risk-related information to healthcare professionals (eg, information sheets) so they can make an informed decision about treatment. The FDA also has the authority to require a sponsor to revise the label and/or the REMS based on the information provided in it. In addition, the FDA may require a sponsor to show how it is achieving its objectives; for example, a sponsor may need to evaluate the effectiveness of its information sheet that encourages safe use of the product by monitoring how many healthcare professionals are using the information sheet.
Resulting Recommendations: A REMS generally includes the following elements, although some may not be applicable:
• Product name and information
• Objectives
• A schedule that describes when assessments are submitted to the FDA
• Medication guide
• Patient package insert
• Recommendations for healthcare providers in using the drug or biological product as intended to minimize risks
• Other information that encourages appropriate use of the drug or biological product in order to minimize risk (elements to assure safe use).
A REMS template is found on the FDA Web site (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/default.htm).
A REMS is subdivided into 2 parts – a proposed REMS (what the sponsor promises to do) and a REMS supporting document (background and information that supports the proposed REMS). The first type is important because the FDA will enforce the content contained in the proposed REMS. Failure to provide a REMS when required by the FDA has consequences, such as financial penalties, having the drug or biological product labeled misbranded, and/or prohibiting shipment across state lines.
Impact: This statute from FDAAA fits in nicely with the FDA’s goal of making drug or biological product information more accessible to the public. It also is another way of periodically monitoring safety. The use of REMS may prevent a drug or biological product that is beneficial to a small subset of the population from being withdrawn because of adverse effects.
Saturday, April 3, 2010
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics
Title: Guidance for Industry--Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics
Release date: May 2007
Status: Final
Target audience: Pharmaceutical and biotechnology companies planning to submit clinical trials of products to treat cancer to support the claim of effectiveness in a marketing application to the FDA.
Laws and regulations referenced:
Rationale: Drugs and biologics are required to demonstrate benefit in efficacy outcomes in adequate and well-controlled trials in order to gain the FDA's approval for marketing. See my fourth blog entry for more details about this requirement. There are various advantages and disadvantages to the endpoints that cancer clinical trials have used in the past to support a claim for clinical benefit.
Summary: This guidance gives the applicants of New Drug Applications and Biologic License Applications recommendations on the efficacy endpoints an oncology clinical trial should have to support marketing approval or labeling claims. These recommended endpoints are presented with their advantages and disadvantages.
Resulting recommendations:
Recommended efficacy endpoints:
1. Overall survival: time from randomization until death from any cause in the intent-to-treat population in randomized controlled trials. This is the conventional efficacy endpoint for cancer trials.
2. Tumor assessments:
a. Disease-free survival: time from randomization until recurrence of tumor or death from any cause. This is an important endpoint in cancers with a high rate of survival, making a survival endpoint impractical.
b. Objective response rate: the proportion of patients with a predefined amount of reduction in tumor size for a predefined minimum time period, typically from time of initial complete or partial tumor response to documented tumor progression. This can be evaluated in a single-arm trial.
c. Progression-free survival: time from randomization until tumor progression or death. This can be a primary endpoint for marketing approval.
d. Time to progression: time from randomization until tumor progression. This is considered inferior to progression-free survival because it does not include deaths, but as been used as a primary endpoint for marketing approval.
3. Symptom Assessments
a. Time to progression: time from randomization until symptomatic progression. These assessments, e.g., weight gain, decreased effusion, have been used as primary efficacy endpoints for marketing approval.
4. Biomarkers: changes in the levels of tumor biomarker. Improvement in biomarker levels can be part of a composite efficacy endpoint for marketing approval.
Impact: This guidance clarifies many issues regarding clinical trial endpoint design that traditionally would have had to be communicated individually to each trial sponsor and may have led to non-approval for applicants who did not discuss these issues with the FDA before initiating their clinical trials. This clarification will allow sponsors of drugs and biologics targeted for cancer treatment to design better clinical trials to support an application for FDA marketing approval, which may increase the likelihood of the success for clinical development programs in general.
Release date: May 2007
Status: Final
Target audience: Pharmaceutical and biotechnology companies planning to submit clinical trials of products to treat cancer to support the claim of effectiveness in a marketing application to the FDA.
Laws and regulations referenced:
- The Federal Food, Drug, and Cosmetic Act: requires a drug to demonstrate substantial evidence of effectiveness as seen from important clinical outcomes or established surrogate endpoints in adequate and well-controlled clinical trials
- The Public Health Service Act: requires a biological product to be potent, safe, and pure as seen from important clinical outcomes or established surrogate endpoints
- Code of Federal Regulations 21 part 314(H) and part 601(E): allows investigational drugs and biologics to show effectiveness in benefiting less-established surrogate endpoints in order to gain fast-track marketing approval (see my third blog entry for more details)
- The Food and Drug Administration Modernization Act of 1997: describes the evidence essential for supporting marketing approval
- International Conference on Harmonisation guidance for industry "E9 Statistical Principles for Clinical Trials": describes issues related to the proper analysis of efficacy endpoints
Rationale: Drugs and biologics are required to demonstrate benefit in efficacy outcomes in adequate and well-controlled trials in order to gain the FDA's approval for marketing. See my fourth blog entry for more details about this requirement. There are various advantages and disadvantages to the endpoints that cancer clinical trials have used in the past to support a claim for clinical benefit.
Summary: This guidance gives the applicants of New Drug Applications and Biologic License Applications recommendations on the efficacy endpoints an oncology clinical trial should have to support marketing approval or labeling claims. These recommended endpoints are presented with their advantages and disadvantages.
Resulting recommendations:
Recommended efficacy endpoints:
1. Overall survival: time from randomization until death from any cause in the intent-to-treat population in randomized controlled trials. This is the conventional efficacy endpoint for cancer trials.
2. Tumor assessments:
a. Disease-free survival: time from randomization until recurrence of tumor or death from any cause. This is an important endpoint in cancers with a high rate of survival, making a survival endpoint impractical.
b. Objective response rate: the proportion of patients with a predefined amount of reduction in tumor size for a predefined minimum time period, typically from time of initial complete or partial tumor response to documented tumor progression. This can be evaluated in a single-arm trial.
c. Progression-free survival: time from randomization until tumor progression or death. This can be a primary endpoint for marketing approval.
d. Time to progression: time from randomization until tumor progression. This is considered inferior to progression-free survival because it does not include deaths, but as been used as a primary endpoint for marketing approval.
3. Symptom Assessments
a. Time to progression: time from randomization until symptomatic progression. These assessments, e.g., weight gain, decreased effusion, have been used as primary efficacy endpoints for marketing approval.
4. Biomarkers: changes in the levels of tumor biomarker. Improvement in biomarker levels can be part of a composite efficacy endpoint for marketing approval.
Impact: This guidance clarifies many issues regarding clinical trial endpoint design that traditionally would have had to be communicated individually to each trial sponsor and may have led to non-approval for applicants who did not discuss these issues with the FDA before initiating their clinical trials. This clarification will allow sponsors of drugs and biologics targeted for cancer treatment to design better clinical trials to support an application for FDA marketing approval, which may increase the likelihood of the success for clinical development programs in general.
Friday, April 2, 2010
Blog 5
Guidance
Drug Induced Liver Injury: Premarketing Clinical Evaluation
Status: Final
Link to Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
Release date: July 2009
Target Audience
Pharmaceutical industry; investigators conduction research in new drug development; Healthcare providers, nurses, physicians, pharmacist, clinical researchers, medical writers, and anyone dealing with the care and safety and welfare of patients
Laws & Regulations
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
U.S. Department of Health and Human Services
FDA
Summary
The guidance provides an approach for the pharmaceutical industry and research study doctors that can be used to identify signals of drug induced liver injury (DILI). This guidance does not address issues of preclinical evaluation for signals of DILI, nor the detection and assessment of DILI after drug approval and marketing. Evaluations for DILI are infrequent. Evidence or signals of a drug’s potential for severe DILI are identified and logged into a new drug development database. DILI has been the single most frequent cause of safety-related drug marketing withdrawals over the past 50 years. In some cases liver toxicity or liver failure has been discovered after the approval of some marketed drug. Use of these drugs, are limited and approval in other countries have been banned due to reported liver toxic side effects. The type of liver injury that leads to severe DILI is a mainly liver cells injury. Liver cell injury is indicated by the significant rise in the liver enzymes in the blood.
Rationale
This guidance intended for people involved in new drug development compounds in assessing the potential for drug induced liver injury. The guidance explains how lab measurements that signal the potential for drug induces liver injury can be obtained and evaluated during the drug development.
Resulting Recommendations
This guidance is an important reference in early phase drug development. Appropriate testing and analysis in premarketing clinical trials can detect drugs that can provide signals for severe liver cell injury.
Impact
This guidance has a major impact on whether the compound will be terminated based on findings with liver cell injury in early development and a major impact on or patient safety.
Drug Induced Liver Injury: Premarketing Clinical Evaluation
Status: Final
Link to Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
Release date: July 2009
Target Audience
Pharmaceutical industry; investigators conduction research in new drug development; Healthcare providers, nurses, physicians, pharmacist, clinical researchers, medical writers, and anyone dealing with the care and safety and welfare of patients
Laws & Regulations
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
U.S. Department of Health and Human Services
FDA
Summary
The guidance provides an approach for the pharmaceutical industry and research study doctors that can be used to identify signals of drug induced liver injury (DILI). This guidance does not address issues of preclinical evaluation for signals of DILI, nor the detection and assessment of DILI after drug approval and marketing. Evaluations for DILI are infrequent. Evidence or signals of a drug’s potential for severe DILI are identified and logged into a new drug development database. DILI has been the single most frequent cause of safety-related drug marketing withdrawals over the past 50 years. In some cases liver toxicity or liver failure has been discovered after the approval of some marketed drug. Use of these drugs, are limited and approval in other countries have been banned due to reported liver toxic side effects. The type of liver injury that leads to severe DILI is a mainly liver cells injury. Liver cell injury is indicated by the significant rise in the liver enzymes in the blood.
Rationale
This guidance intended for people involved in new drug development compounds in assessing the potential for drug induced liver injury. The guidance explains how lab measurements that signal the potential for drug induces liver injury can be obtained and evaluated during the drug development.
Resulting Recommendations
This guidance is an important reference in early phase drug development. Appropriate testing and analysis in premarketing clinical trials can detect drugs that can provide signals for severe liver cell injury.
Impact
This guidance has a major impact on whether the compound will be terminated based on findings with liver cell injury in early development and a major impact on or patient safety.
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