Name of Guidance: Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products – Content and Format
Final version released in January, 2006.
Link to Guidance: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127534.pdf
Laws Referenced:
• Title 21 of Code of Federal Regulations (21 CFR), Part 201.56
• 21 CFR 201.57
• 21 CFR 202.1
Target Audience: Applicants responsible for preparing the CLINICAL STUDIES section of a label.
Rationale: The FDA would like doctors (or prescribers) to be able to make informed decisions concerning the safe and effective use of a drug for their patients based on the information contained in the package insert. In addition, the FDA would prefer that a class of drugs would have similar organization and information in the CLINICAL STUDIES section of a label.
Summary: This guidance document serves as an instructional manual to help applicants decide what would be appropriate to include in the CLINICAL STUDIES section of a label.
Resulting Recommendations: When considering what to include in the CLINICAL STUDIES section of a label, the guidance recommends the following:
• Include studies that describe how effective the drug is.
• Provide a description of the methods section including the study design, who participated in the study (study population), and measures of effectiveness (endpoints). Did any of the subjects take concomitant medications while participating in the study?
• Include a description of the patient disposition characteristics (eg, age, gender, race) and analysis results that are relevant to the study objective and endpoints. Do not include data that would not add any information.
• Use tables and graphs to display results. The appendix provides examples and suggestions.
• When summarizing the results, do not make claims that are not supported by the data. Avoid vague statements. The sponsor’s marketing section may extract information from the CLINICAL STUDIES section to create promotional material.
• Ensure information in this section is consistent with other labeling sections. For example, results in the Clinical Studies section should not be presenting new information that has not been previously introduced in these other labeling sections, such as INDICATIONS AND USAGE.
• Update the CLINICAL STUDIES section when any of its content needs revision so that the information is valid.
.
Impact: The suggestions for what content to include are consistent with the methods, results, and discussion format for scientific writing. Although the recommended structure may be helpful to physicians, it would seem that the important piece in the guidance is following scientific principles in presenting claims of effectiveness that are supported by data.
Monday, March 22, 2010
Guidance for Industry: Analytical Procedures and Methods Validation
Draft guidance released August 2000. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122858.pdf
Target audience
This guidance helps applicants who submit analytical procedures (a term that herein is interchangeable with method or test procedure), validation packages, and samples to FDA to document the identity, strength, quality, purity, and potency of drug substances and drug products. Thus the guidance is relevant to those who submit new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements (collectively, applications, that are submitted by applicants or sponsors). In addition, the guidance helps those who submit Type II drug master files (DMFs). Although this guidance applies to all types of analytical procedures, it may not be suitable for certain unique analytical procedures for products like biological, biotechnological, botanical, or radiopharmaceutical drugs.
Laws, Regulations, and Related Guidances
- 21 CFR 58
- 21 CFR 211.165(e)
- 21 CFR 211.194
- 21 CFR 312.23(a)(7)
- 21 CFR 314.50(d)(1) and 314.50(e)
- 21 CFR 314.94(a)(9)(i) and 314.94(a)(10)
- 21 CFR 601.2(a) and 691.2(c)(1)(iv)
- 21 CFR 610.20
- 29 CFR 1919.1200(g)
- Food, Drug, and Cosmetic Act Section 501(b) and Section 502(e)(3)
- FDA guidances (eg, Validation of Chromatographic Methods—see References section of the guidance)
- International Conference on Harmonization (ICH) guidances
- Q2A Test on Validation of Analytical Procedures
- Q2B Validation of Analytical Procedures: Methodology
- Q3A Impurities in new Drug Substances
- Current US Pharmacopeia–National Formulary (USP–NF).
Summary
During drug discovery and development, formulation development, clinical studies, and manufacturing, applicants must ensure that they consistently control the identity, strength, quality, purity, and potency of drug substances and drug products (collectively, quality attributes). Sponsors demonstrate such attributes by reporting the results of suitable analytical procedures that can be verified in FDA laboratories using samples submitted by the applicant (and reference standards, as appropriate).
In many cases analytical procedures described in USP–NF are appropriate if they are performed on validated equipment by properly trained analysts who use samples and suitable reference standards. Alternative analytical procedures can be used only if they are shown to perform equally well or better than (“equal to or better than” in regulatory parlance) compendial (USP–NF) procedures. Applicants also must demonstrate via a stability-indicating assay that their products are stable during the period claimed on the label. That is, sponsors must submit stability-indicating assays that can detect degradation products, process impurities, and other potential impurities.
In all cases analytical procedures must be validated. As the guidance notes, “methods validation is the process of demonstrating that analytical procedures are suitable for their intended use.” Validation packages may vary depending on the nature of the application, but in all cases they must be sufficient to ensure the identity, strength, quality, purity, and potency (including bioavailability) of the drug substance and drug product. For an analytical method (compendial or noncompendial), typical validation characteristics may include:
- accuracy
- precision (repeatability, intermediate precision)
- specificity
- limit of detection
- limit of quantitation
- linearity
- range
- robustness.
These terms have specific, well-defined meanings in ICH guidances such as Q2A and Q2B.
Rationale
As noted, many factors may change during a drug’s life cycle and include modifications to drug product synthesis, formulation variables (including excipients), and manufacturing processes, among others. To ensure the quality attributes of drug substances and products, applicants perform and report the results of demonstrably suitable analytical procedures that can be repeated with similar results in different laboratories (intermediate precision). Demonstrating suitability and comparability is part of validation, the effort to show equivalence.
One aspect of equivalence is showing that the results in multiple labs with multiple analysts will yield results that are similar to a reference standard or sponsor’s drug product (including drug substance and drug product impurities). Manufacturers typically devote considerable resources to ensuring that their new drug substance is pure, consistent, and suitable for use from early tests through full-scale production following regulatory approval. Because of the effort required to quality a reference standard (see Note 1 below), manufacturers and regulators often rely on qualified reference standards from a compendial source such as USP. Reference standards from compendial sources by definition are pure, and tests performed on a sample can reliably be compared to the results obtained from the reference standard. Such comparisons involve standard statistical techniques.
Resulting Recommendations
When applicants develop drug substances and drug products, they must demonstrate the presence of suitable, predefined quality attributes. They can do so by presenting results of compendial procedures and measurements (see Note 2 below). When compendial procedures are not suitable or are not available or the applicant prefers a house method (one developed in house as opposed to taken from a compendial source), applicants can develop their own procedures. If a compendial procedure is available and the applicant submits a different method, the latter must yield results that are equivalent to or better than the results that would be obtained by compendial procedures. When reference standards are available, applicants and FDA should use them to establish equivalence. When such standards are not available, sponsors must submit highly qualified and characterized materials.
Section XI of the guidance reviews several analytical methods (chromatography, spectrophotometry, capillary electrophoresis, dissolution, and others) and makes specific recommendations about each, including validation and revalidation.
Impact
In this guidance FDA specifies the types of analytical procedures needed for submissions. To ensure drug quality and performance attributes during a drug’s life cycle, FDA expects applicants to provide an extensive body of analytical data obtained by validated procedures.
In most cases sponsors can provide data from validated USP procedures and comparison of results to compendial reference standards. When the latter are not available, sponsors rely on carefully characterized house standards. (Because house standards are available only to the sponsor and FDA, independent laboratories cannot fully test samples of the drug product, which may present public health concerns.)
Since the release of this guideline, FDA, sponsors, and USP have fine-tuned many aspects of compendial tests, and USP has published additional general chapters that outline a variety of procedures. Current regulatory research focuses on comparability and means to establish that a novel procedure is equivalent to or better than another (see Note 3 below).
Notes
1. For information about qualification of compendial reference standards, see:
Project Team 4, 2000–2005 Reference Standards Committee and Advisory Panel, USP Staff, and Council of Experts Chair. Official USP reference standards: metrology concepts, overview, and scientific issues and opportunities. J Pharm Biomed Anal. 2006;40(1):3–15.
2. If USP–NF includes the name of a drug or ingredient, manufacturers must comply with the tests, procedures, and acceptance criteria therein, whether or not the manufacturer uses the letters USP on the label. The Food, Drug, and Cosmetic Act specifies in Sec. 501 [21 USC §351] Adulterated Drugs and Devices:
A drug or device shall be deemed to be adulterated—
(b) If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium ... Whenever a drug is recognized in both the United States Pharmacopeia and the Homeopathic Pharmacopeia of the United States it shall be subject to the requirements of the United States Pharmacopeia ...
3 For more information about current concepts in comparability and demonstration of equivalence, see:
Hauck WW, DeStefano AJ, Cecil TL, Abernethy DR, Koch WF, Williams RL. Acceptable, equivalent, or better: approaches for alternatives to official compendial procedures. Pharm Forum. 2009;35(3):772–778.
Small Molecules Collaborative Group, Williams RL, Abernethy RL, Koch WF, Hauck WW, Cecil TL. Performance-based monographs. Pharm Forum. 2009;35(3):765–771.
— Stefan Schuber
Providing clinical evidence of effectiveness for human drugs and biological products
Title: Guidance for Industry: Providing clinical evidence of effectiveness for human drugs and biological products
Date released: May 1998
Status: final
Target audience: industry sponsors planning to apply for a New Drug Application, Biologic License Application, or applications for supplemental indications
Laws and regulations referenced:
Date released: May 1998
Status: final
Target audience: industry sponsors planning to apply for a New Drug Application, Biologic License Application, or applications for supplemental indications
Laws and regulations referenced:
- The Federal Food, Drug, and Cosmetic Act of 1962 amended that in addition to demonstrating safety, manufacturers must also demonstrate their product's effectiveness through "adequate and well-controlled studies" to gain marketing approval.
- The Food and Drug Administration Modernization Act of 1997 for human drug and biological products (P.L. 105-115) subsection 403(b)(1) , which requires the FDA to provide guidance on conditions in published material may partially or completely support approval of a supplemental application, and subsection 403(b)(2), which requires the FDA to provide guidance on conditions in which relating existing data from the original application or other sources can be used to support approval of a supplemental application.
- The Food and Drug Administration Modernization Act of 1997 section 115(a) allows the FDA to consider "data from one adequate and well-controlled clinical investigation and confirmatory evidence" to establish effectiveness.
- The Public Health Service Act section 351 authorizes the FDA to grant marketing approval to biological products with established "continued safety, purity, and potency" (in which potency is interpreted to include effectiveness).
- 21 Code of Federal Regulations 314.126 defines proof of effectiveness as and describes the essential characteristics of "adequate and well-controlled studies".
Summary: This documents provides guidance to the target audience planning to file applications on evidence of effectiveness as well as to fulfill the requirements of subsections 403(b)(1-2) of the Modernization Act.
Rationale: The language of "adequate and well-controlled studies" has been generally interpreted as at least two adequate and well-controlled studies with confirmatory results are needed for a sponsor to demonstrate effectiveness. However, sometimes the FDA grants marketing approval based on a single adequate and well-controlled study demonstrating effectiveness if
1) it is multicenter, excellently designed, and provides highly reliable and statistically strong evidence of an important clinical benefit, e.g., prolongation of survival, and there are ethical grounds against conducting a second study;
2) other adequate and well-controlled studies of the drug in other dosages, dosage forms, disease stages, patient populations, or endpoints demonstrate effectiveness of the new use ; or
3) when alternative method adequately substantiates effectiveness, e.g., serologic response data known to be correlated with clinical effectiveness (for biologics only).
Resulting Recommendations:
Conditions/examples in which existing data may provide "independent substantiation of related claims"
- Extrapolation from existing studies (e.g., pediatric uses; bioequivalence; modified-release dosage forms; different doses, regimens, or dosage forms)
- Demonstration of effectiveness by a single study of a new use, with independent substantiation from related study data (e.g., different doses, regimens, or dosage forms; studies in other disease phases; studies in other populations; studies as monotherapy or combination therapy; studies in a closely related disease; studies in less closely related diseases but with a similar general purpose of therapy; studies of different clinical endpoints; pharmacologic/pathophysiologic endpoints
- Evidence of effectiveness from a single study (e.g., large multicenter study; consistency across study subsets; multiple studies in a single study; multiple endpoints involving different events; statistically very persuasive finding)
However, there is always a possibility of relying on an incorrect outcome from a single multicenter study, especially when the benefit is unrepeatable or inconsistency of benefit is seen with other data.
Documentation of the quality of evidence supporting an effectiveness claim
Supportive clinical studies are typically conducted in accordance with good clinical practices; with sponsors routinely monitoring all clinical sites; and the FDA having routine access to the original clinical protocols, primary data, clinical site source documents for audits, and complete study reports. However, when some of these are lacking, such as in the case of less rigorous postapproval studies for supplemental applications, sponsors may still rely on such studies to support an effectiveness claim.
Reliance on less than usual access to clinical data or detailed study reports may be supplemented by
- submission of published literature or other reports with other important information enhancing the data reliability (e.g., study protocol and protocol amendments in relation to study accrual/randomization; record of each patient's data for critical variables and baseline characteristics)
- submission of published literature reports alone (e.g., consistent findings across multiple adequately designed studies by different investigators; clearly appropriate, objective endpoints; robust results from pre-specified analyses that yield a consistent conclusion of efficacy)
Reliance on studies with alternative, less intensive quality control/on-site monitoring may be supplemented by
- Prospective plan to assure data quality
- Studies designed to prevent bias, e.g., relatively simple procedures, noncritical entry criteria, readily assessed outcomes
- Ability to sample critical data and compare with supporting records, e.g., hospital records
- Study conduct by a group with established operating procedures and a history of effectiveness implementation of such procedures
Impact: This guidance allows sponsors to plan drug development programs sufficient to demonstrate effectiveness without excessive scope. The FDA's assessment of clinical study data required to support drug effectiveness will be more consistent and predictable with this guidance as reference. The guidance provided in this document for supplemental application clarifies the requirements and may encourage more sponsors to file supplemental applications.
Sunday, March 21, 2010
Blog #3
Name of Guidance: Drug-Induced Liver Injury: Premarketing Clinical Evaluation
Final version released in July, 2009.
Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
Laws Referenced: None – the recommendations in this guidance are based on research and industry best practices.
Target Audience: Industry sponsors and investigators involved with drug development studies focused on identifying drug-induced liver injury (DILI).
Rationale: For drugs that have been approved, then withdrawn from the market are due to reports of severe liver damage. While some drugs cause liver damage (hepatotoxicity), some of the damage can be reversed. However, there are rare events where hepatotoxicity is irreversible. Although there are methods for detecting liver damage, it would be more helpful to identify the potential for liver damage earlier in drug development.
Summary: Some types of DILIs are idiosyncratic because some individuals are susceptible to DILI while others are not. When researchers looked at previously-collected data, they noticed specific signs of liver damage, such as higher aminotransferase (AT) levels (an enzyme helpful for bilirubin excretion, a process in which the liver excretes bile). Damage to liver cells (hepatocellular injury) is associated with high AT levels, specifically alanine aminotransferase (ALT) and aspartate aminotransferase (AST). However, high AT levels by themselves are not considered precursors of DILI. Rather, high AT levels and impaired bilirubin excretion that cannot be explained by other causes (eg, hepatitis) is an indication that a drug has potential to cause DILI. This observation is known as Hy’s law, in which drugs that have potential to cause severe liver damage are those that disrupt bilirubin excretion with hepatocellular injury.
An investigator conducting a clinical trial can use the following criteria as potential indicators for DILIs:
1. Treatment group has higher AT levels than the control group (>3x the upper limit for normal, or ULN).
2. More subjects in the treatment group have 5x-20xULN while few subjects in the control group do not.
3. One or more instances of high total serum bilirubin levels (>2xULN) plus hepatocellular injury with no obvious cause (eg, gall bladder, hepatitis) and criterion #1.
The criteria are not always indicators of DILI; for example, aspirin can produce higher AT levels >3ULN.
Resulting Recommendations: For investigators conducting clinical trials, the FDA guidance suggests the following:
• Subjects with stable pre-existing liver disease intended to be included in the later phases of clinical trials should be thoroughly screened first to ensure that liver function (eg, bilirubin) is not impaired.
• Periodically monitor subjects for abnormal liver symptoms (nausea, fatigue, fever, discomfort in upper right abdomen) as these may appear before the diagnostic tests identify abnormal levels of liver enzymes. Monitor subjects more frequently (including repeat tests) if the clinical trials are shorter or show results that suggest abnormal liver function.
• If an investigator suspects the abnormal test results may be possible DILI, the investigator should monitor the subject closely, gathering additional information that would help rule out other possible causes of the liver injury (eg, hepatitis, alcohol use, concomitant medications, cardiovascular diseases). If closer monitoring includes assessments not listed in the protocol, the investigator should document this information in the case report form and continue monitoring the subject until normal test results occur.
• An investigator can discontinue drug administration while continuing to monitor the subject based on the following FDA guidelines:
o ALT or AST>8xULN
o ALT or AST>5xULN for more than 2 weeks
o ALT or AST>3xULN and (TBL>2xULN or INR>1.5)
o ALT or AST>3xULN plus abnormal liver symptoms
• The decision to withdraw study drug, wait, then administer study drug again (rechallenge) depends on a risk/benefit consideration conducted by an institutional review board.
• Notify the FDA of any suspected adverse event that follows Hy’s law, even if subsequent assessment identifies another cause.
The FDA includes a recommended list of liver function tests, analyses, and means of documenting information during clinical trials that may help identify DILIs.
Impact: This guidance is useful for investigators attempting to identify signals indicative of DILI earlier in drug development, potentially avoiding the situation of having an approved drug removed from the market because of DILI. What is more interesting, though, is the research stimulated by the FDA’s Critical Path Initiative that is attempting to identify biomarkers and other factors that would help predict what types of individuals would be susceptible to DILI. Initial results appear promising (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm163067.htm); however, more research is needed.
Final version released in July, 2009.
Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
Laws Referenced: None – the recommendations in this guidance are based on research and industry best practices.
Target Audience: Industry sponsors and investigators involved with drug development studies focused on identifying drug-induced liver injury (DILI).
Rationale: For drugs that have been approved, then withdrawn from the market are due to reports of severe liver damage. While some drugs cause liver damage (hepatotoxicity), some of the damage can be reversed. However, there are rare events where hepatotoxicity is irreversible. Although there are methods for detecting liver damage, it would be more helpful to identify the potential for liver damage earlier in drug development.
Summary: Some types of DILIs are idiosyncratic because some individuals are susceptible to DILI while others are not. When researchers looked at previously-collected data, they noticed specific signs of liver damage, such as higher aminotransferase (AT) levels (an enzyme helpful for bilirubin excretion, a process in which the liver excretes bile). Damage to liver cells (hepatocellular injury) is associated with high AT levels, specifically alanine aminotransferase (ALT) and aspartate aminotransferase (AST). However, high AT levels by themselves are not considered precursors of DILI. Rather, high AT levels and impaired bilirubin excretion that cannot be explained by other causes (eg, hepatitis) is an indication that a drug has potential to cause DILI. This observation is known as Hy’s law, in which drugs that have potential to cause severe liver damage are those that disrupt bilirubin excretion with hepatocellular injury.
An investigator conducting a clinical trial can use the following criteria as potential indicators for DILIs:
1. Treatment group has higher AT levels than the control group (>3x the upper limit for normal, or ULN).
2. More subjects in the treatment group have 5x-20xULN while few subjects in the control group do not.
3. One or more instances of high total serum bilirubin levels (>2xULN) plus hepatocellular injury with no obvious cause (eg, gall bladder, hepatitis) and criterion #1.
The criteria are not always indicators of DILI; for example, aspirin can produce higher AT levels >3ULN.
Resulting Recommendations: For investigators conducting clinical trials, the FDA guidance suggests the following:
• Subjects with stable pre-existing liver disease intended to be included in the later phases of clinical trials should be thoroughly screened first to ensure that liver function (eg, bilirubin) is not impaired.
• Periodically monitor subjects for abnormal liver symptoms (nausea, fatigue, fever, discomfort in upper right abdomen) as these may appear before the diagnostic tests identify abnormal levels of liver enzymes. Monitor subjects more frequently (including repeat tests) if the clinical trials are shorter or show results that suggest abnormal liver function.
• If an investigator suspects the abnormal test results may be possible DILI, the investigator should monitor the subject closely, gathering additional information that would help rule out other possible causes of the liver injury (eg, hepatitis, alcohol use, concomitant medications, cardiovascular diseases). If closer monitoring includes assessments not listed in the protocol, the investigator should document this information in the case report form and continue monitoring the subject until normal test results occur.
• An investigator can discontinue drug administration while continuing to monitor the subject based on the following FDA guidelines:
o ALT or AST>8xULN
o ALT or AST>5xULN for more than 2 weeks
o ALT or AST>3xULN and (TBL>2xULN or INR>1.5)
o ALT or AST>3xULN plus abnormal liver symptoms
• The decision to withdraw study drug, wait, then administer study drug again (rechallenge) depends on a risk/benefit consideration conducted by an institutional review board.
• Notify the FDA of any suspected adverse event that follows Hy’s law, even if subsequent assessment identifies another cause.
The FDA includes a recommended list of liver function tests, analyses, and means of documenting information during clinical trials that may help identify DILIs.
Impact: This guidance is useful for investigators attempting to identify signals indicative of DILI earlier in drug development, potentially avoiding the situation of having an approved drug removed from the market because of DILI. What is more interesting, though, is the research stimulated by the FDA’s Critical Path Initiative that is attempting to identify biomarkers and other factors that would help predict what types of individuals would be susceptible to DILI. Initial results appear promising (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm163067.htm); however, more research is needed.
Blog 4
Blog 4
Guidance
ICH Guidance M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
Status
This guidance was approved in June 2009.
Guidance Released
December 2009.
Link to Guidance
http://www.ema.europa.eu/pdfs/human/ich/028695en.pdf
Target Audience
This guidance is targeted for regulatory authorities, marketing authorization holders, and all parties responsible for non-clinical trial and all phases of clinical trial development. In addition to all those involved in the protecting public health.
Referenced Laws and Regulations
This guidance represents the European Medicines Agency non-clinical safety studies for the conduct of human clinical trials and marketing authorization for the pharmaceutical industry.
Summary
This guidance’s purpose is to recommend international standards and promote harmonization of non clinical safety studies that are recommended to support human clinical trials and marketing authorization for pharmaceuticals. Harmonization of the guidance for nonclinical safety studies helps to define current recommendations and reduce the likelihood of substantial differences amongst regions.
This guidance facilitates the timely conduct of clinical trials, reduces the use of animals in accordance with R3 (reduction, refinement, and replacement) principles and reduces the use of other drug development resources. In addition, promotes the development of safe, ethical, and availability of new pharmaceuticals.
Rationale
This document applies situations encountered during development of pharmaceuticals and should be viewed as general guidance for drug development. Nonclinical safety studies and human clinical trials should be planned and designed scientifically and ethically appropriate.
Recommendation
The recommendations of this revised guidance, is to harmonize nonclinical safety studies to support various stages of clinical development among regions of the European Union, Japan, and the United States.
Impact
Human clinical trials investigate the efficacy and safety of an investigational pharmaceutical product. Serious adverse event clinical or nonclinical findings influence decisions of continuing clinical trials. These findings should be reviewed to determine the appropriateness of the study design of additional nonclinical and/or clinical trials. As this impact the dose-range in nonclinical and clinical trials for a compound and whether the compound will move forward in development.
Guidance
ICH Guidance M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
Status
This guidance was approved in June 2009.
Guidance Released
December 2009.
Link to Guidance
http://www.ema.europa.eu/pdfs/human/ich/028695en.pdf
Target Audience
This guidance is targeted for regulatory authorities, marketing authorization holders, and all parties responsible for non-clinical trial and all phases of clinical trial development. In addition to all those involved in the protecting public health.
Referenced Laws and Regulations
This guidance represents the European Medicines Agency non-clinical safety studies for the conduct of human clinical trials and marketing authorization for the pharmaceutical industry.
Summary
This guidance’s purpose is to recommend international standards and promote harmonization of non clinical safety studies that are recommended to support human clinical trials and marketing authorization for pharmaceuticals. Harmonization of the guidance for nonclinical safety studies helps to define current recommendations and reduce the likelihood of substantial differences amongst regions.
This guidance facilitates the timely conduct of clinical trials, reduces the use of animals in accordance with R3 (reduction, refinement, and replacement) principles and reduces the use of other drug development resources. In addition, promotes the development of safe, ethical, and availability of new pharmaceuticals.
Rationale
This document applies situations encountered during development of pharmaceuticals and should be viewed as general guidance for drug development. Nonclinical safety studies and human clinical trials should be planned and designed scientifically and ethically appropriate.
Recommendation
The recommendations of this revised guidance, is to harmonize nonclinical safety studies to support various stages of clinical development among regions of the European Union, Japan, and the United States.
Impact
Human clinical trials investigate the efficacy and safety of an investigational pharmaceutical product. Serious adverse event clinical or nonclinical findings influence decisions of continuing clinical trials. These findings should be reviewed to determine the appropriateness of the study design of additional nonclinical and/or clinical trials. As this impact the dose-range in nonclinical and clinical trials for a compound and whether the compound will move forward in development.
Blog 3
Blog 3
Guidance
ICH Guidance E2C Clinical Safety Data Management Periodic Safety Update Report for Marketed Drugs
Status
This final guidance addendum is intended for preparation of the periodic safety update report recommended in the ICH guidance E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs. The guidance was published by the FDA in May 1977 and updated February 2004.
Link to Guidance
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129455.pdf
Target Audience
This guidance is targeted for regulatory authorities, marketing authorization holders, and all parties protecting public health. This guidance is implemented in some but not all ICH countries.
Laws & Regulations
This guidance represents the Food and Drug Administration current thinking on safety update reporting. It is also the ICH safety update reporting Guidance for the industry.
Summary
The PSUR is a practical and achievable way for summarizing interval safety data for periods of 6 months and/or 1 year and the overall safety evaluation of the compound. Marketing authorization holders use the PSUR to conduct analyses of safety data on an ongoing basis. The PSUR should include updates on major signal detection and evaluation addressed in other documents and emerging or urgent safety issues.
The PSURs are valuable to all parties protecting public health. The guidance was developed to harmonize PSUR submission to regulatory authorities for content and format and to introduce the concept of international birth date.
The original guidance was misinterpreted by marketing authorization holders and regulatory authorities. Therefore, the Counsel for International Organizations of Medical Science (CIOMS) Working Group V made recommendations and developed concepts to harmonize the practice for PSUR preparation. This addendum should always be used in conjunction with the E2C guidance.
Rationale
This is an ICH requirement for a practical achievable method for summarizing interval safety data on marketed drugs.
Resulting Recommendations
The recommendation is for a single PSUR, information on indication, dosage forms, and regimens for active substance should be included, with a single data lock point for all aspects of product use. Having consistent broad-based examination of safety information for active substance(s) in a single document is recommended. Data relevant to a particular indication, dosage form, or dosing regimen should be presented separately within the body of the PSUR with safety issues addressed accordingly.
Impact
This guidance harmonizes safety reporting in most countries. Periodic Safety Update Reports have a great impact on the timely safety reporting of marketed drugs and the protection of public health.
Guidance
ICH Guidance E2C Clinical Safety Data Management Periodic Safety Update Report for Marketed Drugs
Status
This final guidance addendum is intended for preparation of the periodic safety update report recommended in the ICH guidance E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs. The guidance was published by the FDA in May 1977 and updated February 2004.
Link to Guidance
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129455.pdf
Target Audience
This guidance is targeted for regulatory authorities, marketing authorization holders, and all parties protecting public health. This guidance is implemented in some but not all ICH countries.
Laws & Regulations
This guidance represents the Food and Drug Administration current thinking on safety update reporting. It is also the ICH safety update reporting Guidance for the industry.
Summary
The PSUR is a practical and achievable way for summarizing interval safety data for periods of 6 months and/or 1 year and the overall safety evaluation of the compound. Marketing authorization holders use the PSUR to conduct analyses of safety data on an ongoing basis. The PSUR should include updates on major signal detection and evaluation addressed in other documents and emerging or urgent safety issues.
The PSURs are valuable to all parties protecting public health. The guidance was developed to harmonize PSUR submission to regulatory authorities for content and format and to introduce the concept of international birth date.
The original guidance was misinterpreted by marketing authorization holders and regulatory authorities. Therefore, the Counsel for International Organizations of Medical Science (CIOMS) Working Group V made recommendations and developed concepts to harmonize the practice for PSUR preparation. This addendum should always be used in conjunction with the E2C guidance.
Rationale
This is an ICH requirement for a practical achievable method for summarizing interval safety data on marketed drugs.
Resulting Recommendations
The recommendation is for a single PSUR, information on indication, dosage forms, and regimens for active substance should be included, with a single data lock point for all aspects of product use. Having consistent broad-based examination of safety information for active substance(s) in a single document is recommended. Data relevant to a particular indication, dosage form, or dosing regimen should be presented separately within the body of the PSUR with safety issues addressed accordingly.
Impact
This guidance harmonizes safety reporting in most countries. Periodic Safety Update Reports have a great impact on the timely safety reporting of marketed drugs and the protection of public health.
Saturday, March 13, 2010
Kent’s #3 Blog Post: Guidance for Industry and FDA Staff: Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers
Name of Guidance
Guidance for Industry and FDA Staff: Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers
Status of Guidance
Supersedes “Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers” (September 30, 1997)
Release Date
September 9, 2008
Link to Guidance
www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM070911.pdf
Target Audience
Manufacturers of diagnostic ultrasound devices, non-OEM replacement transducers, reprocessors of single-use transducers, and personnel designing cleaning and disinfecting protocols for transducers.
Laws and Regulations Referenced
21 U.S.C 21 360 Registration of Producers of Drugs and Devices
21 CFR 807.87 Section 402(j)(5)(B) of the Public Health Service Act
21 CFR 892.1550 Ultrasonic Pulsed Doppler Imaging System
21 CFR 892.1560 Ultrasonic Pulsed Echo Imaging System
21 CFR 892.1570 Diagnostic Ultrasound Transducer
21 CFR 876.1500 Endoscope and Accessories
21 CFR 870.1200 Diagnostic Intravascular Catheter
21 CFR884.2660 Fetal Doppler Ultrasound
21 CFR 884.2660 Echocardiograph
21 CFR870.2330 Cardiovascular Blood Flowmeter
21 CFR870.2100 Intravascular Ultrasound Catheter
21 CFR 1020.10 Performance Standard for Ionizing Radiation Emitting Products
21 CFR 1002.20 Reporting of Accidental Radiation Occurrences
21 CFR Part 1003 Notification of Defects or Failure to Comply
21 CFR Part 1004 Repurchase, Repairs, or Replacement of Electronic Products
Summary
In September 2008 the FDA updated guidelines related to applying for marketing clearance for diagnostic devices using ultrasonic waves. These devices include imaging systems for visualizing fetuses, tissues, nerves, anatomic structures, and bloodflow below the skin surface. Ultrasonic diagnostic devices are commonly used in obstetrics, cardiac care, regional anesthesia, orthopedic surgery, and general surgery.
This guidance is aimed at manufacturers who plan to apply for marketing approval for diagnostic ultrasound devices. When applying for marketing clearance, manufacturers must submit a 510 (K) application, as for all medical devices. However, several technical issues apply specifically to ultrasonic diagnostic devices. The updated guidance addresses these issues as they relate to 501 (K) submissions.
The most substantial changes in this guidance are included in 3 appendices. First, the manufacturer no longer needs to submit a 510(K) Special Report related to acoustic output measurements and labeling records if this information is included the Design History File of the 510 (K) application.
Secondly, the guidance stresses that ultrasonic transducers made by companies that are not original equipment manufacturers (OEMs) that are designed to replace those provided with new equipment should be considered new medical devices, and therefore are required to have 510 (K) pre-market approval. The 510(K) application should include comparison between the replacement transducer and the non-OEM transducer using the OEM generator. The application should also include acoustic output comparisons of the OEM and replacement transducers in the various modes, including the Doppler setting, which defines the flow direction of fluids. If the outputs between the 2 products do not agree, then the non-OEM transducers should be referred to as “similar to” and not “replacement” transducers.
Finally, tranducers that are sold originally as “single-use” devices but have been reprocessed by the OEM, a third party, or a hospital are also considered “new devices” by the FDA. Therefore, the reprocessor must submit a 510 (K). The application should include data that shows that the reprocessed device has the characteristics and output quality as the new devices. The test methodology for gathering this data must be well described. Each reprocessed transducer should be tested at the end of the reprocessing cycle.
Rational
The rational behind this stems from 2 developments. First, ultrasound diagnostic devices are becoming smaller, more portable and have better imaging capabilities. As a result, clinicians are developing more uses for these devices. In return, more products are in development for these new applications. Also, many of these devices have disposable transducers and other parts that can be expensive. As a result, an “aftermarket” of less expensive non-OEM products and reprocessed used products has evolved. The FDA issued the guidance to clarify how manufacturers of new OEM, non-OEM, and reprocessed devices must apply for marketing clearance.
Resulting Recommendations
1. Manufacturers of all new ultrasonic diagnostic devices must submit a 501 (K) application.
2. Non-OEM transducers require the same 501(K) application and must be tested to assure that they are interchangeable with the OEM products.
3. All reprocessed single-use transducers require the same 501(K) application as new products and must be tested after each reprocessing to assure that they are the same quality as new products.
Impact
As ultrasound diagnostic devices become more common, a market for non-OEM and reprocessed transducers have grown. These guidelines clarify that non-OEM replacement transducers and reprocessed transducers are subject to the same marketing approval standards as new OEM products.
Kent Steinriede
Name of Guidance
Guidance for Industry and FDA Staff: Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers
Status of Guidance
Supersedes “Information for Manufacturers Seeking Marketing Clearance of Diagnostic Ultrasound Systems and Transducers” (September 30, 1997)
Release Date
September 9, 2008
Link to Guidance
www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM070911.pdf
Target Audience
Manufacturers of diagnostic ultrasound devices, non-OEM replacement transducers, reprocessors of single-use transducers, and personnel designing cleaning and disinfecting protocols for transducers.
Laws and Regulations Referenced
21 U.S.C 21 360 Registration of Producers of Drugs and Devices
21 CFR 807.87 Section 402(j)(5)(B) of the Public Health Service Act
21 CFR 892.1550 Ultrasonic Pulsed Doppler Imaging System
21 CFR 892.1560 Ultrasonic Pulsed Echo Imaging System
21 CFR 892.1570 Diagnostic Ultrasound Transducer
21 CFR 876.1500 Endoscope and Accessories
21 CFR 870.1200 Diagnostic Intravascular Catheter
21 CFR884.2660 Fetal Doppler Ultrasound
21 CFR 884.2660 Echocardiograph
21 CFR870.2330 Cardiovascular Blood Flowmeter
21 CFR870.2100 Intravascular Ultrasound Catheter
21 CFR 1020.10 Performance Standard for Ionizing Radiation Emitting Products
21 CFR 1002.20 Reporting of Accidental Radiation Occurrences
21 CFR Part 1003 Notification of Defects or Failure to Comply
21 CFR Part 1004 Repurchase, Repairs, or Replacement of Electronic Products
Summary
In September 2008 the FDA updated guidelines related to applying for marketing clearance for diagnostic devices using ultrasonic waves. These devices include imaging systems for visualizing fetuses, tissues, nerves, anatomic structures, and bloodflow below the skin surface. Ultrasonic diagnostic devices are commonly used in obstetrics, cardiac care, regional anesthesia, orthopedic surgery, and general surgery.
This guidance is aimed at manufacturers who plan to apply for marketing approval for diagnostic ultrasound devices. When applying for marketing clearance, manufacturers must submit a 510 (K) application, as for all medical devices. However, several technical issues apply specifically to ultrasonic diagnostic devices. The updated guidance addresses these issues as they relate to 501 (K) submissions.
The most substantial changes in this guidance are included in 3 appendices. First, the manufacturer no longer needs to submit a 510(K) Special Report related to acoustic output measurements and labeling records if this information is included the Design History File of the 510 (K) application.
Secondly, the guidance stresses that ultrasonic transducers made by companies that are not original equipment manufacturers (OEMs) that are designed to replace those provided with new equipment should be considered new medical devices, and therefore are required to have 510 (K) pre-market approval. The 510(K) application should include comparison between the replacement transducer and the non-OEM transducer using the OEM generator. The application should also include acoustic output comparisons of the OEM and replacement transducers in the various modes, including the Doppler setting, which defines the flow direction of fluids. If the outputs between the 2 products do not agree, then the non-OEM transducers should be referred to as “similar to” and not “replacement” transducers.
Finally, tranducers that are sold originally as “single-use” devices but have been reprocessed by the OEM, a third party, or a hospital are also considered “new devices” by the FDA. Therefore, the reprocessor must submit a 510 (K). The application should include data that shows that the reprocessed device has the characteristics and output quality as the new devices. The test methodology for gathering this data must be well described. Each reprocessed transducer should be tested at the end of the reprocessing cycle.
Rational
The rational behind this stems from 2 developments. First, ultrasound diagnostic devices are becoming smaller, more portable and have better imaging capabilities. As a result, clinicians are developing more uses for these devices. In return, more products are in development for these new applications. Also, many of these devices have disposable transducers and other parts that can be expensive. As a result, an “aftermarket” of less expensive non-OEM products and reprocessed used products has evolved. The FDA issued the guidance to clarify how manufacturers of new OEM, non-OEM, and reprocessed devices must apply for marketing clearance.
Resulting Recommendations
1. Manufacturers of all new ultrasonic diagnostic devices must submit a 501 (K) application.
2. Non-OEM transducers require the same 501(K) application and must be tested to assure that they are interchangeable with the OEM products.
3. All reprocessed single-use transducers require the same 501(K) application as new products and must be tested after each reprocessing to assure that they are the same quality as new products.
Impact
As ultrasound diagnostic devices become more common, a market for non-OEM and reprocessed transducers have grown. These guidelines clarify that non-OEM replacement transducers and reprocessed transducers are subject to the same marketing approval standards as new OEM products.
Kent Steinriede
Tuesday, March 9, 2010
Guidance for Industry: “Lookback” for Hepatitis C Virus (HCV)
Name: “Lookback” for Hepatitis C Virus (HCV): Product Quarantine, Consignee Notification, Further Testing, Product Disposition, and Notification of Transfusion Recipients Based on Donor Test Results Indicating Infection with HCV
Status of Guidance: Final Guidance
Guidance Released: August 24, 2007
Link to Guidance: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm073170.htmTarget
Audience: Blood establishments, hospitals, and organizations that collect blood from people. Blood establishments are facilities that manufacture whole blood and blood components intended for use in transfusion as well as whole blood and blood components that are intended for further processing, for example, to be used in the creation of diagnostic tests for the clinical laboratory.
Definition of Terms Used in this Guidance:
anti-HCV: Antibodies to the hepatitis C virus. Anti-HCV are produced by your body when it is infected by the hepatitis C virus (HCV). A doctor can tell if you are infected with the hepatitis C virus by testing your blood for anti-HCV. All blood donations in the US are tested for anti-HCV.
Lookback: This is the name of a process used when blood from one donor is found to test positive for anti-HCV. To perform a “lookback” means to locate all prior donations of blood from the person who recently tested positive for anti-HCV.
Lookback Donations: These blood donations are the prior donations from one blood donor.
Lookback actions: After an anti-HCV-positive blood donor is identified and his/her prior blood donations are located after a historical review of blood donation records, possible actions include:
Laws and Regulations Referenced:
This guidance provides blood establishments, hospitals, and organizations that collect blood from people with recommendations of the US Food and Drug Administration (FDA) regarding procedures to follow once blood from a donor tests positive for anti-HCV.
Rationale:
Hepatitis C virus (HCV) is one of many viruses that can cause chronic inflammation of the liver. HCV is a major health problem in the US. HCV is transmitted primarily by exposure to blood, serum-derived body fluids and body fluids that are visibly contaminated with blood. Often, a person who is infected with HCV does not even know that he or she has the disease until his or her liver is seriously damaged. This feature of HCV infection means that infected people are usually unaware of their disease. HCV infections that are transmitted by blood transfusion account for a very small number of HCV infections; however, it is important to try to prevent all transmission of HCV by blood transfusion.
The risk of transmitting HCV through blood transfusion is reduced by asking the blood donor health habit questions before donation and by testing the blood donor’s blood for anti-HCV. Antibody tests for HCV became available in the US in 1990. It is possible, however, that a person may donate blood during the early part of their HCV infection. During this period, the viral marker, in this case anti-HCV, cannot be detected by a blood test even though HCV is present in the donor’s blood. The period of time during early HCV infection when HCV is present in the donor’s blood but cannot be detected by the current blood tests available, is called the “window period”. Further complicating the situation is the fact that in up to 25% of HCV infections, the anti-HCV may only be detected intermittently. Thus, recommendations regarding procedures that must be followed after a donor’s blood tests positive for anti-HCV are necessary.
Resulting Recommendations:
Status of Guidance: Final Guidance
Guidance Released: August 24, 2007
Link to Guidance: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm073170.htmTarget
Audience: Blood establishments, hospitals, and organizations that collect blood from people. Blood establishments are facilities that manufacture whole blood and blood components intended for use in transfusion as well as whole blood and blood components that are intended for further processing, for example, to be used in the creation of diagnostic tests for the clinical laboratory.
Definition of Terms Used in this Guidance:
anti-HCV: Antibodies to the hepatitis C virus. Anti-HCV are produced by your body when it is infected by the hepatitis C virus (HCV). A doctor can tell if you are infected with the hepatitis C virus by testing your blood for anti-HCV. All blood donations in the US are tested for anti-HCV.
Lookback: This is the name of a process used when blood from one donor is found to test positive for anti-HCV. To perform a “lookback” means to locate all prior donations of blood from the person who recently tested positive for anti-HCV.
Lookback Donations: These blood donations are the prior donations from one blood donor.
Lookback actions: After an anti-HCV-positive blood donor is identified and his/her prior blood donations are located after a historical review of blood donation records, possible actions include:
- Quarantine the blood taken from this donor in previous blood draws. Even though the past donations from this donor did not test positive for anti-HCV, this person’s blood should not be used.
- Notify organizations, for example hospitals, that have been recipients of this blood donor’s blood or blood products.
- Perform additional blood testing on the donor.
- Destroy blood from this donor that has the potential to transmit HCV to recipients of this blood.
- Notify all people who have already received a transfusion of this donor’s blood.
Laws and Regulations Referenced:
- 21 CFR 606.121: Title 21 - Food And Drugs Chapter I - Food And Drug Administration, Department Of Health And Human Services Subchapter F – Biologics Part 606 - Current Good Manufacturing Practice For Blood And Blood Components Subpart G - Finished Product Control 606.121 - Container label.
- 21 CFR 610.40(h): Title 21 - Food and Drugs Chapter I - Food and Drug Administration, Department Of Health And Human Services Subchapter F – Biologics Part 610 - General Biological Products Standards Subpart E - Testing Requirements for Communicable Disease Agents 610.40 - Test requirements.
- 21 CFR 610.47: Title 21 - Food And Drugs Chapter I - Food And Drug Administration, Department Of Health And Human Services Subchapter F – Biologics Part 610 - General Biological Products Standards Subpart E - Testing Requirements For Communicable Disease Agents 610.47 - “Lookback” notification requirements for transfusion services.
- 21 CFR 610.48: Title 21 - Food And Drugs Chapter I - Food And Drug Administration, Department Of Health And Human Services Subchapter F – Biologics Part 610 - General Biological Products Standards Subpart E - Testing Requirements For Communicable Disease Agents 610.48 - Hepatitis C virus (HCV) ‘‘lookback’’ requirements based on review of historical testing records.
- 21 CFR 640.70: Title 21 - Food And Drugs Chapter I - Food And Drug Administration, Department Of Health And Human Services Subchapter F – Biologics Part 640 - Additional Standards For Human Blood And Blood Products Subpart G - Source Plasma 640.70 - Labeling.
- 42 CFR part 493: Clinical Laboratory Improvement Amendment (CLIA) Regulations – Laboratory Requirements.
This guidance provides blood establishments, hospitals, and organizations that collect blood from people with recommendations of the US Food and Drug Administration (FDA) regarding procedures to follow once blood from a donor tests positive for anti-HCV.
Rationale:
Hepatitis C virus (HCV) is one of many viruses that can cause chronic inflammation of the liver. HCV is a major health problem in the US. HCV is transmitted primarily by exposure to blood, serum-derived body fluids and body fluids that are visibly contaminated with blood. Often, a person who is infected with HCV does not even know that he or she has the disease until his or her liver is seriously damaged. This feature of HCV infection means that infected people are usually unaware of their disease. HCV infections that are transmitted by blood transfusion account for a very small number of HCV infections; however, it is important to try to prevent all transmission of HCV by blood transfusion.
The risk of transmitting HCV through blood transfusion is reduced by asking the blood donor health habit questions before donation and by testing the blood donor’s blood for anti-HCV. Antibody tests for HCV became available in the US in 1990. It is possible, however, that a person may donate blood during the early part of their HCV infection. During this period, the viral marker, in this case anti-HCV, cannot be detected by a blood test even though HCV is present in the donor’s blood. The period of time during early HCV infection when HCV is present in the donor’s blood but cannot be detected by the current blood tests available, is called the “window period”. Further complicating the situation is the fact that in up to 25% of HCV infections, the anti-HCV may only be detected intermittently. Thus, recommendations regarding procedures that must be followed after a donor’s blood tests positive for anti-HCV are necessary.
Resulting Recommendations:
- Product quarantine: Within 3 days of a donor testing positive for anti-HCV, blood establishments must review all records to identify blood and blood components previously donated by this infected donor. All blood from this donor that is in inventory at the blood establishment or transfusion service must be quarantined and not transfused into any patients.
- Consignee notification: Blood establishments must notify all organizations, such as transfusion services, to which they have sold blood or blood products that the blood and blood products previously donated by a donor who now tests positive for anti-HCV must be quarantined.
- Further testing: To confirm the presence of anti-HCV in the collected blood, blood establishments should perform an additional, more specific anti-HCV blood test on the first sample of blood that tested anti-HCV positive by a screening method from the infected donor. Afterwards, blood establishments must notify the transfusion services who received blood from the infected donor of the results of this confirmatory test.
- Product disposition: Blood establishments and transfusion services and hospitals are to destroy or relabel the blood that was previously collected from the infected donor, even though that blood did not test positive for anti-HCV. This potentially infectious blood can be used in scientific research or for further manufacture into laboratory testing reagents. If the decision is made to relabel the blood, the blood must be relabeled as “Biohazard” plus “Collected from a donor who subsequently tested reactive for anti-HCV or HCV RNA. An increased risk of transmission of HCV is present.” and either “Caution: For Further Manufacturing Into In Vitro Diagnostic Reagents For Which there Are No Alternative sources” or “For Laboratory Research Use Only.”
- Notification of transfusion recipients: Blood transfusion services and hospitals must notify the people who received blood from a donor who is later found to be infected with HCV.
Monday, March 8, 2010
Reporting Race and Ethnicity Data from Clinical Trials
Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials
This guidance was released in September 2005 and is available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm126340.htm.
This guidance follows a directive issued by the Office of Management and Budget (OMB) and was developed by an FDA working group that included the Office of the Commissioner (OC), the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiologic Health (CDRH).
Target audience
This guidance is relevant to medical–clinical staff who conduct, support, and report Investigational New Drug applications (INDs), New Drug Applications (NDAs), Biological License Applications (BLAs), Abbreviated New Drug Applications (ANDAs), and, for certain devices, Investigational Device Exemptions (IDEs) and Premarket Approval applications (PMAs) or Premarket Notifications (510K applications).
Laws and regulations referenced
• OMB Statistical Policy Directive 15, Race and Ethnic Standards for Federal Statistics and Administrative Reporting, 1997, reprinted in Appendix 2 of the guideline, available at http://www.whitehouse.gov/omb/fedreg_directive_15/
• OMB Provisional Guidance on the Implementation of the 1997 Standards for Federal Data on Race and Ethnicity, 2000, available at
http://www.whitehouse.gov/omb/bulletins/b00-02.html
• 63 FR 6854, codified at 21 CFR 312.33(a)(2) and 21 CFR 314.50(d)(5)(v) and (vi)(a)
• 21 CFR 312.120
• 21 CFR 314.106(b) and 601.2
• International Conference on Harmonization, M4 Common Technical Document for the Registration of Pharmaceuticals for Human Use
• Guidances for Industry and other documents (see Bibliography).
Summary
The background for this guidance is summarized in Appendix 1, History of Federal Efforts in Data Collection on Race, Ethnicity, and Other Subpopulations. In order to standardize data reporting across US government agencies, in 1997 OMB issued Statistical Policy Directive 15, Race and Ethnic Standards for Federal Statistics and Administrative Reporting. This guidance brings FDA into compliance and establishes 2 general goals:
• standardize the recommended OMB categories to ensure consistency in demographic subset analyses in applications submitted to FDA and
• make demographic subset analysis more useful by enabling analysts to evaluate potential variations in the safety and efficacy of pharmaceutical products among population subgroups.
In other words, standardized categories facilitate meaningful and potentially significant comparisons among populations and subpopulations of patients.
Rationale
This guidance attempts to standardize OMB categories for race and ethnicity and to facilitate comparisons of populations and subpopulations across studies. FDA notes that some population subgroups may respond differently to medications, but data regarding these responses cannot be meaningfully compared unless they are collected according to a standard. When data are captured by standardized instruments, FDA and others can more accurately analyze trends and enhance patient safety. As the guidance notes, the categories are not anthropologic or scientific but instead reflect sociocultural constructs (see Note below).
The guidance provides some flexibility by allowing investigators to drill down (eg, White can reflect origins in Europe, the Middle East, or North Africa, and Asian can reflect origins ranging from India to Japan).
Resulting recommendations
This guidance makes 5 recommendations:
1. Use a two-question format (1 question regarding race, 1 question regarding ethnicity; see Appendix 2). The ethnicity question should appear first.
2. Study participants should self-report race and ethnicity information whenever possible and should be allowed to report a multiracial identity. If the patient cannot answer these questions, ask a first-degree relative or other knowledgeable source.
3. To identify ethnicity, choose at minimum between the following:
• Hispanic or Latino
• Not Hispanic or Latino.
4. To identify race choose at minimum among the following:
• American Indian or Alaska Native
• Asian (nb broken out as a separate category and separated from Pacific Islander, which is a departure from earlier assessments)
• Black or African American
• Native Hawaiian or Other Pacific Islander.
• White
5. If the study requires more detailed race and ethnicity information, follow OMB Directive 15. Also available are Health Level Seven’s Reference Information Model Structural Vocabulary Tables. Health Level Seven (HL7) is accredited by the American National Standards Institute (more information is available at http:/hl7.org).
If sponsors use the electronic Common Technical Document from ICH E4, they can refer to section 2.7.4.1.3 and table 2.7.4.2, but FDA prefers its descriptors of race and ethnicity. FDA points out that this guidance does not address levels of enrollment necessary to show statistical significance. Finally, the agency notes that the guidance can be used in CDRH applications as appropriate.
Note
Race and ethnicity are fraught with misconceptions and historical baggage. The guidance notes that in June 2005 FDA approved a fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride (BiDil) to treat heart failure in African American patients. The agency also notes that subgroups respond differently to some medical products. Certain “intrinsic factors” (eg, genetics, metabolism, elimination) and “extrinsic factors” (eg, diet, environmental exposure, sociocultural issues) may be responsible and are subject to confounding. Others have reported that Asians and African Americans respond poorly to some antidepressants, antipsychotics, and beta blockers, possibly because they have low levels of an important metabolic enzyme (CYP 2D6). Advances in genomics may make racial and ethnic descriptors less and less important.
These and related issues are discussed in: Winker MA. Measuring race and ethnicity: why and how? JAMA. 2004;292(13):1612–1614.
This guidance was released in September 2005 and is available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm126340.htm.
This guidance follows a directive issued by the Office of Management and Budget (OMB) and was developed by an FDA working group that included the Office of the Commissioner (OC), the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiologic Health (CDRH).
Target audience
This guidance is relevant to medical–clinical staff who conduct, support, and report Investigational New Drug applications (INDs), New Drug Applications (NDAs), Biological License Applications (BLAs), Abbreviated New Drug Applications (ANDAs), and, for certain devices, Investigational Device Exemptions (IDEs) and Premarket Approval applications (PMAs) or Premarket Notifications (510K applications).
Laws and regulations referenced
• OMB Statistical Policy Directive 15, Race and Ethnic Standards for Federal Statistics and Administrative Reporting, 1997, reprinted in Appendix 2 of the guideline, available at http://www.whitehouse.gov/omb/fedreg_directive_15/
• OMB Provisional Guidance on the Implementation of the 1997 Standards for Federal Data on Race and Ethnicity, 2000, available at
http://www.whitehouse.gov/omb/bulletins/b00-02.html
• 63 FR 6854, codified at 21 CFR 312.33(a)(2) and 21 CFR 314.50(d)(5)(v) and (vi)(a)
• 21 CFR 312.120
• 21 CFR 314.106(b) and 601.2
• International Conference on Harmonization, M4 Common Technical Document for the Registration of Pharmaceuticals for Human Use
• Guidances for Industry and other documents (see Bibliography).
Summary
The background for this guidance is summarized in Appendix 1, History of Federal Efforts in Data Collection on Race, Ethnicity, and Other Subpopulations. In order to standardize data reporting across US government agencies, in 1997 OMB issued Statistical Policy Directive 15, Race and Ethnic Standards for Federal Statistics and Administrative Reporting. This guidance brings FDA into compliance and establishes 2 general goals:
• standardize the recommended OMB categories to ensure consistency in demographic subset analyses in applications submitted to FDA and
• make demographic subset analysis more useful by enabling analysts to evaluate potential variations in the safety and efficacy of pharmaceutical products among population subgroups.
In other words, standardized categories facilitate meaningful and potentially significant comparisons among populations and subpopulations of patients.
Rationale
This guidance attempts to standardize OMB categories for race and ethnicity and to facilitate comparisons of populations and subpopulations across studies. FDA notes that some population subgroups may respond differently to medications, but data regarding these responses cannot be meaningfully compared unless they are collected according to a standard. When data are captured by standardized instruments, FDA and others can more accurately analyze trends and enhance patient safety. As the guidance notes, the categories are not anthropologic or scientific but instead reflect sociocultural constructs (see Note below).
The guidance provides some flexibility by allowing investigators to drill down (eg, White can reflect origins in Europe, the Middle East, or North Africa, and Asian can reflect origins ranging from India to Japan).
Resulting recommendations
This guidance makes 5 recommendations:
1. Use a two-question format (1 question regarding race, 1 question regarding ethnicity; see Appendix 2). The ethnicity question should appear first.
2. Study participants should self-report race and ethnicity information whenever possible and should be allowed to report a multiracial identity. If the patient cannot answer these questions, ask a first-degree relative or other knowledgeable source.
3. To identify ethnicity, choose at minimum between the following:
• Hispanic or Latino
• Not Hispanic or Latino.
4. To identify race choose at minimum among the following:
• American Indian or Alaska Native
• Asian (nb broken out as a separate category and separated from Pacific Islander, which is a departure from earlier assessments)
• Black or African American
• Native Hawaiian or Other Pacific Islander.
• White
5. If the study requires more detailed race and ethnicity information, follow OMB Directive 15. Also available are Health Level Seven’s Reference Information Model Structural Vocabulary Tables. Health Level Seven (HL7) is accredited by the American National Standards Institute (more information is available at http:/hl7.org).
If sponsors use the electronic Common Technical Document from ICH E4, they can refer to section 2.7.4.1.3 and table 2.7.4.2, but FDA prefers its descriptors of race and ethnicity. FDA points out that this guidance does not address levels of enrollment necessary to show statistical significance. Finally, the agency notes that the guidance can be used in CDRH applications as appropriate.
Note
Race and ethnicity are fraught with misconceptions and historical baggage. The guidance notes that in June 2005 FDA approved a fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride (BiDil) to treat heart failure in African American patients. The agency also notes that subgroups respond differently to some medical products. Certain “intrinsic factors” (eg, genetics, metabolism, elimination) and “extrinsic factors” (eg, diet, environmental exposure, sociocultural issues) may be responsible and are subject to confounding. Others have reported that Asians and African Americans respond poorly to some antidepressants, antipsychotics, and beta blockers, possibly because they have low levels of an important metabolic enzyme (CYP 2D6). Advances in genomics may make racial and ethnic descriptors less and less important.
These and related issues are discussed in: Winker MA. Measuring race and ethnicity: why and how? JAMA. 2004;292(13):1612–1614.
Sunday, March 7, 2010
Fast Track Drug Development Programs
Title: Fast Track Drug Development Programs--Designation, Development, and Application Review
Date released: January 2006
Status: Final
Target audience: Industry sponsors (i.e., pharmaceutical and biotechnology companies)
Summary: New drugs or biological products for the prevention, diagnosis, or treatment of serious or life-threatening conditions with an unmet medical need may qualify for accelerated development and FDA review through the FDA's fast track programs. This guidance describes the regulations, policies, and procedures for the FDA's fast track programs.
Laws and regulations referenced:
Impact: Sponsors are taking advantage of the fast track programs for their developing new drugs and biological products. Under the fast track programs, approved new drugs and biological products become available faster to the public. Unmet medical needs for the conditions addressed by these new drugs/biological products are being met faster.
Date released: January 2006
Status: Final
Target audience: Industry sponsors (i.e., pharmaceutical and biotechnology companies)
Summary: New drugs or biological products for the prevention, diagnosis, or treatment of serious or life-threatening conditions with an unmet medical need may qualify for accelerated development and FDA review through the FDA's fast track programs. This guidance describes the regulations, policies, and procedures for the FDA's fast track programs.
Laws and regulations referenced:
- Section 112 of the FDA Modernization Act of 1997 (P.L. 105-115) (see Appendix 1 in this guidance) allows the FDA to 1) approve a marketing application for a product that has an effect on a clinical endpoint or a surrogate endpoint reasonably likely to predict clinical benefit and 2) review portions of a marketing application before receiving the complete application
- Section 506 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356), which authorizes the FDA to facilitate the development and expedite the review of fast track products or drugs/biological products for serious and life-threatening conditions.
- 1988 interim rule "Procedures for Drugs Intended to Treat Life-Threatening and Severely Debilitating Illnesses" (21 CFR 312.80 through 312.88 (Subpart E)) describes procedures to facilitate the development of fast track drugs/biological products
- Center for Biologics Evaluation and Research SOPP 8405, which describes the procedures for the FDA's complete review and decision notification for fast-track new biological products
- Center for Drug Evaluation and Research MaPP 6020.3, which describes the FDA's priority review policy for fast-track new drugs
Rationale: To make new drugs/biological products for serious or life-threatening conditions available faster to the public. To do this, the FDA makes the drug development and review process easier for applicants of fast-track drugs.
Resulting recommendations:
A sponsor can apply for the fast track designation from the submission of the Investigational New Drug application (IND; this FDA approval is needed to begin clinical testing of a new drug/biological product) to before the submission of the New Drug Application (NDA) or Biological License Application (BLA) (these FDA approvals are needed to begin marketing of the new drug/biological product).
A sponsor must demonstrate that the new drug/biological product in development- is for a serious or life-threatening condition, i.e., a condition that causes a substantial impact on day-to-day functioning either by itself (e.g., cancer) or by its associated outcomes (e.g., depression)
- is intended to treat a serious or life-threatening condition, i.e, has a preventive, diagnostic, or therapeutic effect on either the serious or life-threatening condition, a serious side effect of that condition, or a serious side effect(s) of currently available therapies for that condition [note: a nonserious condition that has rare/distant serious sequelae (e.g., duodenal ulcer) may qualify]
- can address an unmet medical need for a serious or life-threatening condition by being the only available therapy or by improving upon either the safety or efficacy of currently available therapies
A sponsor must request a fast track designation and provide documentation for the serious or life-threatening condition and unmet medical needs, a basis for the new drug's potential to address the unmet medical needs, and the development plan for trials designed to evaluate the new drug's potential.
The FDA will respond within 60 days with a designation letter (approval) or nondesignation letter (disapproval, for which the sponsor can submit a subsequent request for fast track designation that the FDA will respond to within 60 days of receipt). During drug development, a sponsor must show the new drug/biological product's potential to continue receiving the fast track designation.
Once given a fast track designation,- The FDA will schedule additional meetings with a sponsor to aid the drug development program by discussing trial design, content of application submissions, etc.
- The FDA will provide a sponsor with timely comments on the design of the trials proposed by the sponsor to show the fast track product's safety and efficacy, and end of phase 1/2 letters commenting on the adequacy of a sponsor's phase 2/3 development plans
- The FDA will a) give priority review of NDA or BLA, b) allow a sponsor to submit portions of an NDA or BLA, and c) give accelerated approval (approval based on a not well-established surrogate endpoint that is reasonably likely to predict clinical benefit [e.g., improved exercise in refractory heart failure], although the FDA usually requires postmarketing studies for approvals based on surrogate endpoints or clinical endpoints other than survival/irreversible morbidity)
Impact: Sponsors are taking advantage of the fast track programs for their developing new drugs and biological products. Under the fast track programs, approved new drugs and biological products become available faster to the public. Unmet medical needs for the conditions addressed by these new drugs/biological products are being met faster.
Guidance for Industry: Investigator Responsibilities –Protecting the Rights, Safety, and Welfare of Study Subjects
This guidance was released as a final guidance in October 2009. It can be found online at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM187772.pdf
TARGET AUDIENCE
- The sponsor of the clinical trial: the sponsor is usually a pharmaceutical company who develops prescription drugs, including biological drug products.
- The clinical investigator: the clinical investigator is generally a physician contracted by the sponsor to recruit trial subjects and conduct procedures outlined in a clinical protocol.
FDA LAWS AND REGULATIONS REFERENCED
- Title 21 of the Code of Federal Regulations, Part 11 (Electronic Records; Electronic Signatures Validation); referred to as 21 CFR Part 11; http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm124946.pdf
- Title 21 of the Code of Federal Regulations, Part 50 (Protection of Human Subjects); referred to as 21 CFR Part 50; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=50
- Title 21 of the Code of Federal Regulations, Part 54 (Financial Disclosure by Clinical Investigators); referred to as 21 CFR Part 54; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=54
- Title 21 of the Code of Federal Regulations, Part 56 (Institutional Review Boards); referred to as 21 CFR Part 56; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312&showFR=1&subpartNode=21:5.0.1.1.3.4
- Title 21 of the Code of Federal Regulations, part 312 (Investigational New Drug Application [IND]); referred to as 21 CFR Part 312; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=312
- Title 21 of the Code of Federal Regulations, part 812 (Investigational Device Exemptions [IDE]); referred to as 21 CFR Part 812; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?cfrpart=812
OTHER GUIDANCES REFERENCED
Guidance for Industry: E6 Good Clinical practice: Consolidation Guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf)
RATIONALE
Within this guidance are the FDA’s thoughts regarding the investigator’s supervisory role during the conduct of a drug, biologic, or device clinical trial at his or her clinical site. It also addresses the investigator’s role in protecting the rights, welfare and safety of the human subject. The description of the responsibilities is high level; the guidance directs the investigator and sponsor to 21 CFR 312 and 21 CFR 812 for more detailed descriptions of the investigator responsibilities during the conduct of a drug/biologic or device clinical trial, respectively.
RECOMMENDATIONS
Supervision of Trial Conduct:
- Only 1 person at a site should have supervisory responsibilities and this person is the primary investigator. Responsibilities include developing an investigative plan and monitoring all trial activities.
- The investigator may delegate trial-related tasks to others. The investigator must keep an accurate record of who the responsibility is assigned to and their qualifications.
- The investigator must ensure those performing the trial-related tasks are (1) trained to perform the tasks (2) understand the purpose of the trial, (2) understand the protocol and specific details within the protocol, (3) be aware of changes to the protocol during the conduct of the trial, and (4) understand the regulatory requirements of conducting a clinical trial in human subjects.
- In some cases the site staff may not be directly employed by the investigator (ie, they are employed by a site management organization hired to perform trial-related procedures). In these cases the investigator is still responsible for ensuring the staff is qualified. If issues arise that the investigator cannot quickly resolve, it is the investigator’s responsibility to notify the sponsor.
Study Subject Protection
- Many of a protocols inclusion and exclusion criteria are there for the protection of the human subject (ie, pregnant women are excluded from the study; subjects with a medical history of Sjogren's Syndrome must not be enrolled). The investigator is responsible for making sure a person meets the protocol-defined inclusion and exclusion criteria.
- If the subject agrees, the investigator should let the subject’s primary care physician know that the person if participating in a clinical trial.
- The investigator is responsible for ensuring the subject receives reasonable medical care for any trial related adverse events.
- The investigator must be available to the trial subject to discuss trial-related procedures and concerns.
IMPACT
Overall this guidance is helpful for giving the investigator and the sponsor a high level description of the investigators’ clinical trial responsibilities. However, I found the title of this guidance misleading since based on the title this guidance is for industry. Within this guidance it specifically states the purpose is to help the investigator understand their responsibilities. If one were to only read the title this guidance would not be read by the appropriate target audience.
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