Blog 1

Name of Guidance: E2B(R) Revision of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports

Status of Guidance: Draft Guidance

When was the Guidance released?
This guideline was originally signed off July 17, 1997 and modified as E2B(M) guideline in November 2000. The E2B(R) was released 12 May 2005.

Link to the Guidance http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073096.pdf

Target audience: pharmaceutical companies, regulatory authorities, ethics committees

Laws and Regulations Referenced (and what each law states in relevant part}
World Health Organization – Collaborating Center for International Drug Monitoring
ICH E2A and E2D guidelines for life-threatening and other medically important conditions

Summary
This guidance objective is to standardize data elements for transmission of individual safety reports, by identifying and defining elements for the transmission of all individual safety reports, regardless of source and destination. This guidance includes the standards for data elements of safety reports for both pre and post approval periods and covers adverse drug reaction and adverse event reports.

Rationale
To standardize safety reporting.

Resulting Recommendations
This guidance will be followed for all safety reporting.

Impact
Clarifies reporting format
Provides standards for data transmission format
This standard allows for information to be transmitted in an encoded format.

Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials

Name: Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials


Status of Guidance: Final Guidance

Guidance Released: September 2007

Link to Guidance:
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm074775.htm#TableofContents

Target Audience: Sponsors (eg, pharmaceutical companies), monitors (eg, clinical research associates), investigators (eg, research physicians), and Institutional Review Boards (IRBs) of vaccine trials

Laws and Regulations Referenced:
1. Section 351 of the Public Health Service Act (42 U.S.C. 262) by which the Office
of Vaccines Research and Review, Center for Biologics Evaluation and Research,
regulates preventive vaccines
2. The Federal Food, Drug, and Cosmetic Act, eg, Title 21 Code of Federal Regulations (CFR) Parts 312, 600, and 601, which address investigational new drug applications (INDs) and biologics license applications (BLAs)
3. 21 CFR 312.32, 312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 312.64, and 312.66 which present the regulations involved with the recording, monitoring, and reporting of adverse events (AEs) in clinical trials

Summary: The Office of Vaccines Research and Review (of the Center for Biologics Evaluation and Research [CBER] of the Food and Drug Administration [FDA] of the US Department of Health and Human Services [HHS]) follows established rules to control the study of preventive vaccines. Preventive vaccines are most often developed to prevent disease in healthy people. When healthy people are enrolled in clinical trials, there is a very low tolerance for risk of AEs for the volunteer. The vaccine’s benefits should greatly outweigh its risks of harming a healthy volunteer.

To consistently evaluate the risk of AEs that healthy adult and adolescent volunteers undergo in preventive vaccine clinical trials, recommendations for the assessment of the severity of clinical and laboratory abnormalities are presented. The authors of this guidance recommend that these appropriate and uniform criteria be incorporated into the vaccine’s investigational plan (study protocol), case report forms, and study reports. That said, they also recommend that the clinical and laboratory parameters being monitored be tailored to the needs of each study vaccine. By this they mean that additional parameters might be added in a clinical study of a vaccine based on one or more of the following: safety signals detected in pre-clinical toxicology studies, the theoretical possibility of the occurrence of certain AEs, or prior experience with a similar licensed vaccine.

Rationale: If all sponsors of vaccine trials use uniform criteria for categorizing toxicities in healthy volunteers, comparisons of safety data among groups within the same study and also between different studies will be improved.

Resulting Recommendations: The following criteria should be assessed in all preventive vaccine clinical trials conducted in healthy adult and adolescent volunteers:

· Clinical: vital signs, local (injection site) reactions, and general (systemic) reactions
· Laboratory: results of serum chemistry assays, whole blood hematology tests, and urinalysis

When these criteria are outside of the normal range of results, they should be graded either Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3) or Potentially Life Threatening (Grade 4) according to the measurements listed in the Tables for Clinical Abnormalities and Tables for Laboratory Abnormalities of the guidance.

Impact: The use of uniform AE/toxicity criteria to evaluate the safety of vaccines in healthy volunteers will enhance our current understanding of immunization safety by improving the comparability of vaccine safety data. If this guidance is followed, many will benefit, not least of which are the current and future vaccinees. Additionally, scientists, health officials, and healthcare providers who need to make scientifically sound decisions and who need to obtain, interpret, provide, and report information on immunization safety will benefit.

My comments:
Many vaccines are administered to neonates, infants, toddlers, and children. This guidance would become complete if it also addressed toxicity grading scales for these patient populations.

The addition of language describing Serious Adverse Events (SAEs) and providing a distinction from severe AEs would also be helpful. It is not clear to me whether the Grade 4 (Potentially Life Threatening) category would be equivalent to an SAE.

Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims

Guidance for Industry – Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

In December 2009 the FDA finalized a new guidance for industry providing guidelines for the development and testing of instruments used for collecting, measuring, and assessing patient-reported outcomes (PRO) that support labeling and promotional claims. Specifically, the guideline is written to inform sponsors of how the FDA evaluates the PRO instruments developed for use in clinical trials and it outlines the FDA’s expectations of the evidence that must be submitted to verify the validity and reliability of the PRO instrument. It is the FDA’s position that a PRO instrument must be shown to be a credible measure of the claim being made. The draft guideline was initially published for public comment in February 2006.

PRO instruments are designed to capture the patients’ perspective on the effectiveness of the medical product or intervention for aspects that can only be reported by the patient. Questionnaires and diaries are examples of PRO instruments used in clinical trials. Sponsors must demonstrate that the PRO instruments used for the collection of patient-reported outcomes to support a claim of a treatment benefit have been tested and validated for both content and the design and are able to effectively measure the particular concept being tested. In selecting a PRO instrument the sponsor must evaluate whether the instrument is capable of measuring the concepts of interest in the target population. In making these evaluations, the content and design of the PRO instrument must be validated and tested to show that the results are reliable and reproducible and are able to detect change. General considerations for content and design include the type and number of questions to include, recall period (timeframe the patients are instructed to consider when answering the questions), response options (visual analog scale, Likert scale, pictorial scale, checklist), and scoring methods for items or domains.

The FDA recommends that sponsors apply the same design principles that are followed for other endpoint measures to the PRO endpoints. For example, sponsors are expected to establish procedures to ensure consistency (instructions for administration of questionnaires) and to develop methods to minimize unintentional unblinding and for handling missing data to minimize bias. The guidance also includes a section on statistical considerations for analyzing the data collected with the PRO instruments.

The impact of the guidance helps sponsor understand the expectations of the FDA for patient-reported outcome data when the data is used for labeling claims. Following the guidelines for the development of the PRO instruments provides a sponsor with greater assurances that the data collected will be acceptable to the FDA and can be used to support labeling claims.

The guidance references the FDA regulations related to record keeping, maintenance and access – 21 CFR Part 312 (for drugs and biologics) and 21 CFR Part 812 (for medical devices). Another key reference is 21 CFR Part 11 defining the regulatory requirements for use of computerized systems. When creating and using PRO instruments, sponsors must ensure the methods of collecting data are in compliance with these regulations.

Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification on What to Report

Name: Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification on What to Report

Status: final

Release date: August 1997

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071981.pdf

Target audience:

Industry required to report adverse experiences to the Food and Drug Administration, including

• Applicants of approved new drug applications, abbreviated new drug applications, and antibiotic applications
• Manufacturers (including packers and distributors) of marketed prescription drugs for humans
• Licensed manufacturers of approved biologic license applications

Laws and Regulations Referenced:

Revoking of the postmarketing safety reporting requirement to submit expedited increased frequency reports for human drugs and licensed biological products:

• Final rule in the Federal Register (62 FR 34166; June 25, 1997)

Postmarketing adverse event reporting:

• Guideline for Postmarketing Reporting of Adverse Drug Experiences (March 1992)
• Guidelines for Adverse Experience Reporting for Licensed Biological Products (October 1993)

Data to be included in a safety report:

• Code of Federal Regulations, title 21, 310.305, 314.80, 314.98, and 600.80
• International Conference on Harmonisation (ICH) E2A document
• Guideline on Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (60 FR 11284; March 1, 1995)
• International Reporting of Adverse Drug Reactions, 1990: definition of Minimum Standard of Information
• International Reporting of Periodic Drug-Safety Update Summaries, 1992: definition of CIOMS Reportable Case histories (CIOMS Report)

Summary: This guidance provides recommendations to industry on how best to do postmarketing safety reporting, including what data must be gathered before an adverse experience should be submitted to the FDA and how to handle solicited safety information from patients. This guidance also encourages the use of waiver requests for periodic safety reports for adverse experiences that are classified "nonserious and labeled" (i.e., included in the labeling for marketed products) .

Rationale: More and more individual safety case reports are being submitted to the FDA without sufficient data for interpretation/evaluation. "Nonserious and labeled" adverse experiences are the fastest growing type of safety report to be submitted to the FDA. Guidance is needed to improve postmarketing safety reporting and to reduce the burden of safety reporting on industry without compromising public health.

Recommendations:

The four following criteria should be obtained for each safety report, and safety reports without all of the criteria should not be submitted

1. an identifiable patient (identified by an assigned code, not name or address; with specific information, e.g., "an elderly woman")
2. an identifiable reporter
3. a suspect drug/biological product
4. an adverse event (at minimum: specific signs [including abnormal laboratory values], symptoms, or disease diagnosis)/fatal outcome (reporting required even if the adverse event is unknown)

Potential adverse experiences from planned contacts and active solicitation of information from patients (e.g., sponsored patient support programs, disease management programs) should not be submitted to the FDA unless an adverse event is classified "serious and unexpected" (see definitions for "serious adverse drug experience" and "unexpected adverse drug experience" here) and is possibly reasonably related to the human drug or biological product.

Requests to waive reporting of "nonserious and labeled" postmarketing adverse experiences are encouraged for human drugs but not for new biological products within one year of approval or blood products, plasma derivatives, or vaccines.

Impact: Submission of postmarketing safety reports with insufficient data (e.g., "some patients had anaphylaxis") and nonserious and known adverse events will be reduced. This will decrease the burden of safety reporting on industry and consequently decrease the corresponding workload of the FDA reviewers. With fewer and cleaner safety reports for the FDA to review, new and significant safety signals may be identified faster.

Tracey Blog: Guidance for Industry: Acceptance of Foreign Clinical Studies

The Guidance for Industry: Acceptance of Foreign Clinical Studies was released as a final guidance in March 2001. This guidance can be found online at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm124939.pdf.

Target Audience:

The sponsor (financial supporter, often a pharmaceutical company) of a clinical trial

Laws and Regulations Referenced:

• Title 21 of the Code of Federal Regulations, part 312 (Investigational New Drug Application [IND]); referred to as 21 CFR Part 312.
• Title 21 of the Code of Federal Regulations, part 812 (Investigational Device Exemptions [IDE]); referred to as 21 CFR Part 812.
• Title 21 of the Code of Federal Regulations Part 814 (Premarket Approval of Medical Devices)

Rationale:

In the United States prior to testing new drugs or devices on humans the FDA requires sponsors to complete an Investigational New Drug Application (IND) for drugs or an Investigational Device Exemption (IDE) for a medical device. The regulations for clinical studies conducted under an IND or IDE, including ethical standards the FDA expects to be followed during the conduct of these clinical trials, are described in Title 21 CFR Part 312 and Part 812, respectively.

In general, the international medical community adheres to the ethical principles outlined in the Declaration of Helsinki. This declaration was originally adopted by the World Medical Association’s in 1964 and has since been revised 5 times. With each new version the FDA assesses the changes and decides whether the relevant regulations should be updated. At this time, the regulation for INDs (21 CFR Part 312) incorporates language from the 1989 version of the declaration; the regulation for IDEs (21 CFR Part 814 incorporates the 1983 version of the Declaration of Helsinki.

Studies conducted outside the United States may or may not be conducted under an IND or IDE. The FDA has written Guidance for Industry: Acceptance of Foreign Clinical Studies to provide their expectations with regards to the ethical treatment of people participating in clinical studies conducted in countries other than the United States.

Recommendations:

Foreign studies conducted under and IND or IDE must comply with the same regulations as those conducted in the United States. However, the FDA will also accept foreign studies that were not conducted under an IND if they adhere to the ethical standards outlined in the 1989 version of the Declaration of Helsinki. Studies conducted under an IDE will be accepted if they adhere to the ethical standards outlined in the 1983 version of the Declaration of Helsinki. Both types of studies will be accepted by the FDA if they were conducted using the ethical principles of local regulatory authorities if their principles provided greater participant protection than the declaration.

Impact:

As more clinical trials are being conducted the competition for study participants is also increasing. In addition, research is being conducted on diseases that do not occur in this country. In these cases clinical studies may be conducted in the location where the disease is found. As a result, sponsors are going into countries where there may be little or no oversight regarding the ethical treatment of study participants. Therefore, this guideline is essential. Although most sponsors of drugs and devices are ethical, for those who might be motivated by money to cut corners that might but study participants at risk, the FDA is forcing them to put people first. With this guidance the FDA is making a statement: follow the guidelines or risk spending a lot of money on data that cannot be used to support approval of a drug or medical device.

The FDA guidance entitled, Guidance for IRBs, Clinical Investigators, and Sponsors, IRB Continuing Review after Clinical Investigation Approval was released in its draft form in January, 2010 (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM197347.pdf). An institutional review board (IRB) is a diverse group of people who possess the qualifications and background to review and decide whether or not a clinical study can begin. IRB review helps protect clinical study participants. IRBs can disapprove proposed clinical study activities or ask that they be modified before subsequent approval. Even after IRB approval, clinical studies require ongoing review, generally by a different IRB.

Rationale: IRBs must follow Title 21, Part 56 of the Code of Federal Regulations (21 CFR), including developing and executing procedures for continuing review of clinical studies (21 CFR 56.108(a)(1) and 56.115 (a)(2)).

Target Audience: IRBs can use this guidance to develop and execute procedures for ongoing review. The guidance is also helpful for clinical investigators and drug sponsors because both parties submit information to the IRB.

Summary: The guidance describes suggested topic areas and actions, so IRBs can develop a procedure that describes how often the IRB will meet and the communication parameters between the IRB and clinical investigator. The guidance also describes when a clinical study is eligible for expedited review, one that requires less IRB votes for approval (see http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm for more information) and when a clinical study may be suspended or terminated.

Recommendations: The procedure should describe how an IRB reviews the appropriate documents and discusses topics pertaining to the risk-benefit ratio. IRB decisions must be communicated in writing and the clinical investigator be afforded the opportunity to respond. Each meeting should be carefully documented (eg, minutes, meeting agenda, and votes) and filed as the US Food and Drug Administration (FDA) has the right to inspect such records.

• IRBs must review an ongoing clinical study at least once per year. Meeting frequency depends on the most recent study status. More risks mean more frequent reviews.

• Each IRB review should involve a risk assessment, which evaluates the potential risks a participant may encounter during the clinical study and whether those risks are acceptable in comparison to the benefits (21 CFR 56.111). IRBs review safety-related summary documents for results that impact the risk/benefit ratio, which can affect the IRB’s decision to approve continuation of a clinical study.

• IRBs should verify that the informed consent documents are correct and contain the necessary material that constitute informed consent as described in 21 CFR 50.25.

• IRBs review local issues or business-related items that can affect the safety of clinical study participants. For example, a site that has a lot of personnel turnover may disrupt the quality of the clinical study.

• IRBs evaluate how well the clinical study adheres to the protocol, a document that describes how the clinical study will be conducted. If changes are needed, the investigator must justify that such changes will not increase the risks to participants. An IRB can stop approval if the study does not follow the IRB-approved plan and/or if participants are at risk for serious harm (21 CFR 56.113).

Impact: The clinical investigator and sponsor will know when to prepare and submit clinical study-related documents for IRB review and avoid disruptions (eg, missing an IRB meeting, not submitting documents ahead of time) when such information is described in a procedure.

Mechanical Calibration of Dissolution Apparatus—Stefan

Version:1.0 StartHTML:0000000258 EndHTML:0000008734 StartFragment:0000002842 EndFragment:0000008698 SourceURL:file://localhost/Users/Stefan/%20Univ%20Sci%20Phila/2010-01-21%20Ethics%20Law%20BW706/2010-01-31%20Blogs/2010-02-04%20Mech%20Calib%20Blog.doc

Dissolution testing was developed by pharmaceutical scientists to ensure that oral solid dosage forms do in fact dissolve and that one batch of tablets or capsules dissolves at the same rate as previous, approved batches. Dissolution testing helps ensure that tablets and capsules do not pass through the gastrointestinal (GI) tract intact without releasing the drug, and it also helps show that the dosage form is equivalent from batch to batch.

The 2 most common dissolution testers consist of temperature-controlled U-shaped glass vessels that are filled with liquid (usually purified water brought to acidity similar to that of the human stomach). In Apparatus 1 tablets or capsules are placed inside a rotating mesh basket that is lowered into the vessel. In Apparatus 2, a paddle is lowered into the fluid and the dosage is placed into the vessel, where the paddle rotates above it. The turning of the basket or the paddle inside the acidic liquid mimics the conditions in the stomach and GI tract.

At specified intervals analysts withdraw samples of the liquid and measure the amount of drug released from the tablets or capsules. Each drug has a specific drug-release profile, and by measuring this release and comparing it with established profiles analysts can measure dissolution profiles. In the US dissolution testing is performed according to the specifications in US Pharmacopeia (USP) General Chapter Dissolution <711> (http://www.usp.org/pdf/EN/USPNF/chapter711.pdf accessed 04 February 2010).

Studies have shown that dissolution profiles can be affected by several factors, including the temperature in the U-shaped vessel, vibration, irregularities in the interior walls of the vessels, variations in the alignment or speed of the basket or paddle rotation, and many others. These variables can significantly alter dissolution profiles and have sparked a debate about the relative values of mechanical calibration vs use of reference standards Basically, the question is: Can physical measurements of the dissolution apparatus ensure consistent results, or do analysts need to use certified reference standards (USP Prednisone Reference Standard Tablets) to determine if their equipment meets standards?

To address these questions the Food and Drug Administration (FDA) released its Guidance for industry: the use of mechanical calibration of dissolution apparatus 1 and 2—current good manufacturing practice (CGMP) in January 2010 (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198649.pdf accessed 04 February 2010). This guidance will help analysts, regulatory affairs professionals, and compendial scientists to conduct dissolution testing accurately and consistently.

FDA’s cGMP regulations for dissolution testing [21 CFR 211.160(b)(4) and 211.68] are satisfied by demonstrated compliance with <711>. At issue in FDA’s recent guidance is whether mechanical calibration is sufficient or whether analysts must compare the results of their equipment with USP Reference Standard tablets. The guidance recognizes the utility of both approaches and concludes “Either the Apparatus Suitability procedure in <711> [involving USP Reference Standard tablets] or an appropriately enhanced [mechanical calibration] method executed according to a written procedure will satisfy the CGMP requirement for calibration ...”

The guidance reviews recent publications about the relative merits of USP Reference Standards and calibration, citing several articles that draw attention to both the use of Reference Standards and some limitations of mechanical calibration. The guidance notes that an industry group advises manufacturers to use “enhanced mechanical calibration.” The final guidance avoids either extreme of mechanical calibration without use of Reference Standards or exclusive reliance on the latter without mechanical calibration. FDA also notes that neither approach is “as comprehensive or as stringent as those in the enhanced [mechanical calibration] procedure recommended in this guidance (for detailed specifications about enhanced mechanical calibration, see http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM142492.pdf accessed 04 February 2010). Finally, the guidance recommends that manufacturers pay particular attention to 3 aspects of mechanical calibration during dissolution testing: dissolved gases (which can cause bubbles to form on tablet or capsule surfaces) in the dissolution liquid, vibration, and vessel dimensions.

Overall, the guidance will give industry additional tools and increased confidence that the results of dissolution testing are accurate and reliable.

Stefan Schuber