Michelle Keyvani BW706 Blog #4

Name of Guidance:
Exception from Informed Consent Requirements for Emergency Research

Status of Guidance:
Draft Guidance

Guidance Release Date:
This Guidance was released July 2006

Link to Guidance: http://www.fda.gov/RegulatoryInformation/Guidances/ucm127625.htm

Target Audience:
Sponsors, clinical investigators, and Institutional Review Boards (IRBs)

Laws and Regulations:
21 CFR 50.24 and the conforming amendments contained in 21 CFR Parts 56, 312, 314, 601, 812, and 814 provide an exception from the requirement to obtain informed consent from each subject, or the subject's legally authorized representative, prior to enrollment in a clinical investigation.

Summary:
An exception from the requirement to obtain informed consent applies to emergency research for which: (1) an Investigational New Drug Application (IND) or Investigational Device Exemption (IDE) is required, (2) that involves human subjects who have a life-threatening medical condition for which available treatments are unproven or unsatisfactory, (3) that involves subjects who because of their condition (e.g., incoherent) cannot give informed consent and (4) where the intervention must be administered before informed consent from the subjects' legally authorized representative is feasible.

"Studies involving an exception from the informed consent requirements may proceed only after a sponsor has received prior written authorization from FDA and the IRB has found and documented that specific conditions have been met."

Rationale:
The reason why this guidance is so important is because the emergency research permitted under 21 CFR 50.24 involves a particularly vulnerable population (persons with life-threatening conditions who can neither give informed consent nor actively refuse enrollment). This lack of autonomy creates a special need for FDA, sponsors, IRBs and clinical investigators to work closely together to protect the interests of this vulnerable population of subjects. At the same time, FDA needs to consider the unmet medical needs of such subjects and the potential for them to benefit from new therapies for such conditions.

Resulting Recommendations:
Under 21 CFR 50.24(a)(3), the IRB must find and document that participation in emergency research studies holds out the prospect of direct benefit to the subjects because: (1) the subjects are in a life-threatening situation that necessitates intervention, (2) appropriate animal and other preclinical studies support the potential for the intervention to provide a direct benefit and (3) the risks associated with the investigation are reasonable in relation to what is know about the medical condition of the potential class of subjects, the risks and benefits of standard therapy, if any, and what is known about the risks and benefits of the proposed intervention or activity.

Impact:
Being able to conduct emergency research without informed consent can facilitate the unmet medical needs of subjects and enable them the potential to benefit from new therapies for their conditions.

BW706 Blog #4

Theresa Seiverd
Blog #4
1. Name of Guidance: E2F: Development Safety Update Report

2. Status of Guidance: Draft

3. Release Date: 05 June 2008

4. Link to Guidance: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129284.pdf

5. Target Audience: Pharmaceutical companies (sponsors)

6: Laws and Regulations Referenced: 21 CFR312.33: Investigational New Drug (IND) Application Annual Reports and EU Directive 2001/20/EC on Clinical Trials

7: Summary: The Development Safety Update Report (DSUR) is annual summary of safety information for investigational drugs (ie, drugs that are administered in clinical trials). It is considered critical information for the ongoing assessment of the risk to trial participants during the clinical development of a new drug. The goal for developing the DSUR is to create a common standard among the International Conference of Harmonization (ICH) regions for reporting annual safety information that will promote a consistent approach to reporting, and also make the current reporting structure more efficient. The intent is to have the DSUR replace the US IND Annual Report and the EU Annual Safety Report (ASR).

8. Rationale: It makes sense to consolidate similar reports required by different regions into 1 report that would satisfy all regions. The DSUR is also the complimentary document to the Periodic Safety Update Report (PSUR). Both the DSUR and PSUR will have some overlap, but the DSUR focuses on pre‑approval conditions and the PSUR focuses on post-approval conditions Therefore, the development of the DSUR made sense from a transitioning standpoint for the development of a n integrated life-cycle approach between the 2 documents in transitioning from preclinical to post approval stage.

9. Recommendation: It is recommended that the DSUR be adopted by industry as the common global standard for reporting safety data for clinical trials for a single drug product during a standard reporting period on an annual. If a sponsor has more than 1 drug in clinical trials than it is recommended that a DSUR be prepared with a single data lock for all trials. Submission of the DSUR should be no later than 60 calendar days after the data lock point. Once a drug receives marketing approval the data lock point must align with the International Birth Date (IBD) so the DSUR and PSUR can be synchronized. The guidance provides a template of sections that the DSUR should contain. The sections are outlined below and should be written as concise as possible. If there is no information to report for a certain section, this should be stated below the header to keep it organized and follow the template provided.

• Introduction: The introduction should include the dates of the reporting period, a brief description, its mode of action, route of administration, and formulation. It should provide the active trials during the reporting period, the indication(s) being studied and the population.
• Worldwide Marketing Authorization Status: If a marketing application has been submitted in 1 or more countries or regions then this section should be completed, and a status update for each country or region provided. The PSUR has a similar section and the format for that section can be followed here.
• Update on Actions Taken in the Reporting Period for Safety Reasons: A description of any significant safety related actions taken by the sponsor, regulator, or safety monitoring board’s needs to be disclosed and reported in the section. It applies to both the clinical development and marketing product if a product a drug has received approval.
• Changes to Reference Safety Information: Any safety related changes to the investigator brochure during the reporting period is required.
• Status of Clinical Trials Ongoing and Completed During the Reporting Period: This section typically has a table for each ongoing and completed trials of the reporting period. It includes information that describes the trial, dose regimen, countries with active sites, enrollment numbers, exposure numbers, and other pertinent information of the trial.
• Estimated Exposure: This section describes the method used to estimate subject exposure during the reporting period. Data should be presented by indication if available.
• Presentation of Safety Data from Clinical Trials: This section should include general information about the line listings of all serious adverse events for each clinical study and the criteria used for inclusion. It should reference the reader to the appropriate appendices.
• Significant Findings from Clinical Trials during the Reporting Period: This includes ongoing and completed trials during the reporting period. If any significant safety information becomes available for any trial than it needs to be included.
• Relevant Finding s from Non-interventional Studies: This section takes into account information that is learned from observational studies whereby the sponsor is not responsible for providing the drug (or intervention) to the subject. Non-interventional studies would include the Phase 4 registry studies, surveillance programs, or epidemiological studies.
• Relevant Findings from Other Sources: This may include results from meta-analyses or trials with vaccines.
• Safety Findings from Marketing Experience: If an investigational drug is approved in any country a concise summary of key findings should be reported. Especially if the findings resulted in changes to the label or risk management plan.
• Other Information: If there are any safety findings from non-clinical in vivo or in vitro studies then it needs to be reported. Or, if there is new safety information on drugs of the same class then this information should also be included.
• Late-breaking Information: This would include any safety information that becomes available after the data lock point. It could be from a case study or information from a safety board or regulatory authority that becomes available.
• Overall Safety Assessment: This section should provide an interpretation of the information provided, and its implications to the subjects in the clinical trial population. It is important that certain categories (withdrawals, pregnancies, deaths, overdoses, laboratory evidence, drug-drug interactions) be monitored to identify a potential risk to the safety of the subject.
• Summary of Important Risks: A summary of any risks identified and how they will be managed needs to be provided in this section.
• Appendices to the DSUR: Line Listings of Serious Adverse Reactions for each study, and Aa cumulative tabulation of SAEs is recommended and would probably accompany a DSUR report.
  10. Impact: The concept of creating the DSUR is to reduce the number of similar documents that are submitted through separate regional health authorities, and create one document that will contain all information and meet all the regional health authority requirements. By accomplishing this goal of creating 1 document, it will make resourcing more efficient since the same people will not have to do multiple documents and can focus on 1 document. From the Regulatory side, it may also reduce review time since multiple documents with similar information will not have to be reviewed.

Michael O'Donnell - Blog Post #4

Name of Guidance: Guidance – Drug Safety Information – FDA’s Communication to the Public

Status of Guidance: Final

Release Date: March 2007

Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072281.pdf

Target Audience: Healthcare professionals, patients, and the public

Laws and Regulations Referenced:

• 21 U.S.C. 352
• 21 U.S.C. 355
• 21 CFR 201.66
• 21 CFR 202.1(e)
• 21 CFR 208.1
• 21 CFR 310.305
• 21 CFR 310.501
• 21 CFR 310.515
• 21 CFR 314.80
• 21 CFR 314.80(a)
• 21 CFR 314.98
• 21 CFR 600.80
• Docket No. 2005D-0062

Guidances and miscellaneous documents referenced:

• Guidance for industry on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment
• FDA Fact Sheet (February 15, 2005)

Summary:
The guidance is about the process of presenting drug safety issues as publicly available information, as explained by the FDA to the general public. The guidance explicates in detail when, where, how, why, and what drug safety information is communicated.

The beginning of the guidance specifically discusses the importance of making drug safety data public for the purpose of fostering informed decision-making regarding any drug treatment. This applies not just to the general public, but healthcare professionals as well that are involved in the treatment process. The goal of the FDA in communication of drug safety is to aid all parties involved in or interested in such information to make as informed decisions as possible.

In the sections following the introduction, the guidance details what exactly constitutes safety information valuable to the public. It is explained that serious adverse drug experiences are an example of one type of information that should be made public, and this is broken down into two categories: post-approval in a new setting, and frequently occurring adverse experiences in patient subpopulations. Also recommended for dissemination to the public are medication errors. The guidance points out that these are just examples of what can be communicated, and that there are no limitations on what else might be necessary to make the public aware of, in the name of safety.

The guidance mentions many considerations that the FDA must fully evaluate before making a decision on issuing a public statement about safety concerns for a drug. Some of the bulleted list in the guidance includes factors such as plausibility, degree of exposure in a patient population, risk magnitude, and the severity of adverse experiences. It is explained in the guidance that the timing of when the FDA releases the safety information to the public is normally after a complete analysis of an approved drug, but there are instances where the FDA may feel it necessary to publicly release safety data prior to finalizing a decision on what, if any regulatory action is needed.

On page 6 of the guidance, a table is included that summarizes the communication methodologies for all manner of drug safety information. The table organizes this data with brief descriptions for type of communication, content, and target audience. Each of the distinct types of data is explored in much further detail in pages 7-10 of the guidance.

The next several sections of the guidance are devoted to explication of where safety information can be found by the public, how confidentiality of contributed information is protected, and how the data is continually updated. The closing sections of the guidance focus on FDA and sponsor interaction prior to releasing data to the public, and concern about implications for promotion of prescription drugs.

Rationale:
The goal of the FDA with this guidance is to explain their thinking and organizational approach to the release of drug safety information to the general public. The guidance will address concerns or confusion from healthcare professionals and the public, about the process of making safety data publicly available.

Resulting Recommendations:
Healthcare professionals with concerns about the release of drug safety data, and how it will effect promotion of prescription drugs, should consult this guidance to be aware of the FDA methodology for what, how, when, why, and where this information will be released to the public.

Also, any member of the general public that has questions about what safety data the FDA makes available, or has concerns about dissemination of drug safety information, would benefit from reading this guidance.

Impact:
This guidance is a multi-dimensional dissection of FDA drug safety data communication to the public. It answers questions in concise detail about the FDA decision-making process, the characteristics of the safety data communicated, and the methodology behind the multi-faceted process of how, why, when, where, and what is released to the public. Understanding of the public dissemination of drug safety information is fully realized upon a review of this guidance.

Michelle Keyvani Blog Post #3

Name of Guidance:
Guidance for Industry - Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

Status of Guidance:
Final Guidance

Guidance Release Date:
This Guidance was released March 2005.

Link to the Guidance: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf

Target Audience:
Drug sponsors and Applicants.

Laws and Regulations Referenced:
There were no laws and regulations referenced in this guidance.

Summary:
This document provides guidance to industry on good pharmacovigilance practices and pharmacoepidemiologic assessment of observational data regarding drugs, including biological drug products (excluding blood and blood components). Specifically, this document provides guidance on safety signal identification, pharmacoepidemiologic assessment and safety signal interpretation, and pharmacovigilance plan development.

Risk assessment and risk minimization form what FDA calls risk management. Risk management is the process of assessing a product's benefit-risk balance, developing and implementing tools to minimize its risks while preserving its benefits, evaluating tool effectiveness and reassessing the benefit-risk balance, and making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance. This four part process should be continuous throughout a product's life-cycle, with the results of risk assessment informing the sponsor's decisions regarding risk minimization.

Rationale:
Risk assessment during product development should be conducted thoroughly, however, it is impossible to identify all safety concerns during clinical trials. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with co-morbid conditions and those being treated with concomitant medical products. Therefore, post-marketing safety data collection and risk assessment based on observational data are critical for evaluating and characterizing a product's risk and for making informed decisions on risk minimization.

This guidance document focuses on pharmacovigilance activities in the post-approval period. This guidance uses the term pharmacovigilance to mean all scientific and data gathering activities relating to the detection, assessment, and understanding of adverse events. This includes the use of pharmacoepidemiologic studies. The goal being to identify adverse events and understanding, where possible, their nature, frequency, and potential risk factors.

Pharmacovigilance involves the identification and evaluation of safety signals. In this guidance safety signal refers to a concern about an excess of adverse events compared to what would be expected to be associated with a product's use.

Safety signals warranting additional investigation can be further evaluated through carefully designed non-randomized observational studies of the product's use in the "real world". Pharmacoepidemiologic studies are often initiated when a safety signal has been identified after approval. The results of these studies may be used to characterize one or more safety signals associated with a product, or may examine the natural history of a disease or drug utilization patterns. Sponsors can initiate pharmacoepidemiologic studies at any time.

Resulting Recommendations: (Developing a Pharmacovigilance Plan)
In certain limited instances, unusual safety risks may become evident after a product is marketed that could suggest that consideration by the sponsor of a pharmacovigilance plan may be appropriate. A pharmacovigilance plan is a plan developed by a sponsor that is focused on detecting new safety risks and/or evaluating already identified safety risks. The development of such a plan may be useful at the time of product launch or when a safety risk is identified during product marketing.

Impact:
Pharmacovigilance plans have proven appropriate for products with which serious safety risks have been identified pre or post approval, or for at-risk populations that have not been adequately studied.

Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

Blog #3

Name of Guidance: Guidance for Industry and Review Staff: Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route

Status of Guidance: Draft

Release Date: 7 March 2008

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079245.pdf

Target Audience: Individuals/companies developing non-clinical safety evaluation plans for currently approved drug products reformulated for a new, unapproved, route of administration.

Laws and Regulations Referenced: Good Laboratory Practices (21 CFR part 58). GLPs are the general regulations that apply to the conduct of all nonclinical studies to be submitted for evaluation by the FDA. GLPs set standards for operations, animal care and use, documentation, key personnel, and quality assurance.

Summary: This guidance provides recommendations for nonclinical safety evaluations on approved drug products reformulated for a new, unapproved, route of administration. Regardless of the change in formulation, acute and repeat dose toxicity studies should be performed in at least one appropriate species using the new route of administration. These studies should also include pathology. New formulation methods that dramatically alter the route (for example, oral instead of IV) and/or duration of dosing require more additional nonclinical safety evaluations than less significant reformulations.

The guidance assumes that the drug product has a previously established safety profile. If deficiencies are found in the previous assessments, more studies may be needed.

Rationale: Although a complete nonclinical safety package would have been completed for the original drug formulation, it cannot be assumed the safety profile would remain the same if delivered into the body differently. Alternate routes of administration can change exposure profiles. Therefore, nonclinical evaluations should focus on establishing the pharmacokinetics and absorption, distribution, metabolism, and elimination of the drug in the new formulation.

Differences in the bioavailability and excretion between routes of administration can also have effects on the toxicological profile of the drug, which need to be evaluated. Target organs of toxicity and local tolerance should be evaluated for each new route of administration before performing clinical trials to have a clear understanding of the new impacts of the new route.

Resulting Recommendations: For the subcutaneous, intramuscular, oral, and rectal routes, only the acute and repeat dose toxicity studies should be needed. The repeat dose toxicity studies should be conducted for at least the term expected in clinical use. The following routes of administration should include the acute and repeat dose toxicity studies as well as what is additionally noted. The photoirritation and photocarcinogenic potential of dermal patches and ointments should be evaluated. If use is intended to treat a chronic condition, carcinogenicity studies may also be needed. Dermal irritation and delayed contact hypersensitivity should be evaluated for the otic, dermal, vaginal, and intra-oral routes. Reproductive and developmental toxicity studies should be performed for the itracavernosal, intraurethral, intravesicular, and vaginal routes. If the drug is to be delivered by inhalation or intranasally, inhalation studies should be conducted as well as carcinogenicity studies of intended for chronic exposure. The ocular route should be evaluated for ocular and systemic pharmacokinetics. The effects of the drug on the inner ear should be evaluated for otic drugs. Epidurals should be carefully evaluated in at least 2 species for neurotoxicity and pharmacokinetics of the cerebral spinal fluid.

Impact: Reformulations can greatly increase the profitability of a currently approved drug. However, depending on the intended route of administration, the nonclinical evaluations needed to assess the safety of the new route can be costly and extensive. These evaluations are essential for assessing the toxicological potential of the drug when it is delivered in a new way. The extent of the evaluations need to be carefully considered prior to and during the development of the new delivery method.

Michael O'Donnell - Blog Post #3

Name of Guidance: Guidance for Industry Part 11, Electronic Records; Electronic
Signatures — Scope and Application

Status of Guidance: Final

Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072322.pdf

Release Date: 09/03/03

Target Audience: Health care industry and regulatory publishing professionals

Laws and Regulations Referenced:

• 21 CFR Part 11, Electronic records and electronic signatures regulation
  
• 21 CFR Part 58, Good Laboratory Practice for nonclinical laboratory studies regulation
  
• 21 CFR Part 211, Good Manufacturing Practice regulation
  
• 21 CFR Part 820, Quality system regulation

Summary:
Unlike the Food and Drug Administration’s (FDA) Guidances for Industry, “Providing Regulatory Submissions in Electronic Format - General Considerations," and “Providing Regulatory Submissions in Electronic Format - Receipt Date,” the subject of this 12-page guidance is specifically the scope of electronic records regulation of record-keeping practices and electronic signatures. The guidance emphasizes the need for being compliant with procedures for record copying, validation, record retention, and audit trail design in accordance with part 11 of Title 21 of the Code of Federal
Regulations (21 CFR part 11).

The FDA warns in this guidance that in fulfillment of 21 CFR part 11, companies should guard against unecessary measures in electronic submission development. The vast language of part 11 can lead a company into misinterpretation of the record-keeping process recommended for an electronic submission. If part 11 is incorrectly applied by a regulatory department to an electronic submission process, then the company could incur higher cost and lost time.

Recognizing that the subject matter of 21 CFR part 11 is too open to wide-ranging interpretation, this guidance aims to better focus what exactly this part 11 information means to the healthcare industry. Within the industry, the FDA is specifically targeting this guidance to the individuals responsible for publishing regulatory data to the FDA for review.

The key points identified by the guidance for regulatory professionals to consider:

1. By correct identification of data, reduce the amount of records that are subject to 21 CFR part 11, so that the regulation can be more narrow in focus

2. For records that are subject of part 11, the FDA can enforce the regulation at it’s own discretion, but there is a “grandfather clause,” in which older pre-1997 records systems included in a review have some degree of flexibility due to the limitation of the record systems from that era

3. FDA enforces all predicate rules and requirements

Rationale:
With this guidance, the frequently referenced part 11 can be better understood. By narrowing the focus of 21 CFR part 11, The FDA is hoping to instill greater refinement of the overall process of electronic record handling, improved communication with regulatory professionals, and increased data integrity.

Resulting Recommendations:
Companies that are submitting regulatory documents to the FDA for review should follow this guidance to ensure a navigable audit trail and more accurate submission document record-keeping. This guidance should be utilized as a tool for better understanding of 21 CFR part 11 as it pertains to records, electronic signatures, records access and records control.

Impact:
Understanding what the FDA expects of handlers, controllers, or publishers of electronic regulatory documents is better understood with this guidance. Researching an audit trail of all phases of document development is easier. The accuracy of the signature process of parties responsible for different documentation in a regulatory submission is improved. The broad scope of 21 CFR part 11 is narrowed to a level that is more easier understood and better applicable at the regulatory professional level of implementation.

Blog Post #3: Direct to Consumer Prescription Drug Advertisements

Rosalyn Finlayson

October 30, 2010

Name of Guidance:

Direct-to-Consumer Prescription Drug Advertisements: Presentation of the Major Statement in Television and Radio Advertisements in a Clear, Conspicuous, and Neutral Manner

Status of Guidance

Proposed Rule

Date of Guidance

March 29, 2010

Link to the Guidance

http://edocket.access.gpo.gov/2010/pdf/2010-6996.pdf

Target audience

Manufacturers of prescription drugs, advertising agencies and the general public.

Laws An Regulations Referenced

21 USC 352 Section 502n: stipulations for “true statements” in advertising

21 CFR 202.1: describes requirements for print and broadcast advertising

58 FR 42364: outlines “clear and conspicuous” disclosure in advertising

63 FR 24996: outlines “clear and conspicuous” disclosure in audio advertisements

Public Law 102-556: Telephone Disclosure & Dispute Resolution Act of 1992

Public Law 110-85 Section 901: Food Drug Administration Amendments Act of 2007

Public Law 106-102: Gramm Leach Bliley Act

Summary

This proposed rule is a follow up to the Food & Drug Administrations May 2009 guideline for Presenting Risk Information in Prescription Drug and Medical Device Promotion. Under this proposed rule the authority of the FDA would expand from making recommendations to having legal authority to enforce compliance. The proposed rule clarifies terminology of the following terms; neutral, major statement, and clear and conspicuous nature. Discussed in this proposal are the Eastern Research Groups findings of peer-reviewed literature on direct to consumer advertising published from 2004 through 2008. The proposed rule also discusses the FDA’s decision to adhere to standards that are consistent with previous regulations adopted by a number of other federal agencies. The proposed effective date of this particular rule will be 90 days after publication in the Federal Register. The FDA solicits public comment on several segments of this proposed rule.

Rationale

This proposed rule was developed because of the growing body of research indicating that there is an influence of direct to consumer advertising on public health. The FDA has taken into consideration the research findings of the Eastern Research Group and revised some of the recommendations contained in the May 2009 guideline Presenting Risk Information in Prescription Drug and Medical Device Promotion. The FDA has revised its previous recommendations in order to be aligned with the disclosure regulations and standards presented by other federal agencies. This proposed rule could potentially have a positive effect on the health outcomes of the general public through better communication of risk information in prescription drug television and radio advertisements.

Resulting Recommendations

Based on the regulations of a number of other federal agencies and the findings presented by the Eastern Research Group the FDA is presenting the following regulations in this proposed rule.

All risk factors, major side effects and any contraindications of prescriptions drugs must be presented in a neutral, clear and conspicuous manner regardless of how the benefit is presented.

Communication of risk information in major statements in consumer-directed prescription drug advertisements must be presented so that the consumer receives a fair and accurate impression of the drug being promoted.

The major statement in television advertisements must be included in both the audio and visual parts of the presentation.

Advertisements for prescription drugs must follow FTC regulations for the ease of comprehension of the language as well as the formatting and location of textual information in the disclosure.

Advertisements for prescription drugs must follow FTC regulations for the audio components of advertisements such as pacing, volume and quality of speech.

Impact

The implementation of this proposed rule would further regulate the manner in which manufacturers of prescription drugs would be able to present drug information in directly to consumer advertisements. This proposed rule is designed to ensure information about a prescription drug is clearly presented in advertisements targeting the general public.