Blog Post #4: Product Name Placement, Size, and Prominence in Advertising and Promotional Labeling

Rosalyn Finlayson

November 20, 2010

Name of Guidance:

Product Name Placement, Size, and Prominence in Advertising and Promotional Labeling

Status of Guidance

Draft Guidance

Date of Guidance

January 1999

Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070076.pdf

Target audience

Industry, governing agencies and drug manufacturers

Laws An Regulations Referenced

21 CFR 201.10(g) and (h), 202.1(b): addresses products containing two or more active ingredients.

21 CFR 201.10 (c)): addresses the placement of one active ingredient in relation to the prominence of the proprietary and established names for human and animal prescription drug products

21 CFR 610.62: specifies that regulations for biological products apply only to the container and package labels.

Summary

This guidance is intended to clarify the requirements for product name placement on human and animal prescription drugs. Outlined are the specific requirements for the text size and prominence of the proprietary name and the established trade name on prescription products. The regulations and recommendations address products with one active ingredient as well as products with two or more active ingredients.

Rationale

The recommendations in this guidance were developed to help ensure the safe and effective use of prescription drugs and to assist the following agencies that deal with violations and inquiries about the placement, size, and prominence of the proprietary name and established trade name in promotional materials: The Division of Drug Marketing, Advertising, and Communications (DDMAC), Center for Drug Evaluation and Research (CDER), the Division of Epidemiology and Surveillance (DES), Center for Veterinary Medicine (CVM), and the Advertising and Promotional Labeling Staff (APLS), Center for Biologics Evaluation and Research (CBER). The violations and inquiries frequently addressed by these agencies are the visual contrasting effect of the proprietary and established trade names in relation to certain graphic presentations and problems that stem from the vague presentation of or minimizing disclosure of the established trade name.

Resulting Recommendations

The following recommendations are suggested for products containing one active ingredient:

The Placement of the Proprietary Name and the Established Trade Name

• The text for the proprietary name or established trade name will not be separated by a logo, trademark or other graphic designs.
• The text for the established trade name will be placed to the right of or directly under the proprietary name.
• There are to be no items pertaining to the graphic matter (text, logo or visual graphic) that de-emphasize the product name or interfere in a way that would cause the proprietary name or established trade name to become unclear or unintelligible to the consumer.

Print Size of Proprietary and Established Trade Names

• The proprietary name and established trade names are to be presented in the same size type within the running text of advertisements and promotional labeling,
• The established trade name is be printed in letters that are at least half as large as the letters used for the proprietary name when the proprietary name is used in headlines or has a type size larger than the established trade name in the running text of the promotional materials.
• The print size requirement refers to the actual size of the letters not the point size.
• The print size is independent of whether or not the established trade name is printed in upper or lower-case letters.

Prominence of Proprietary and Established Trade Names in Printed Materials

• The established trade name will have a position equal to that of the proprietary name in terms of the typography, layout, and contrast.

Proprietary and Established Trade Names in Audio-Visual and Broadcast Advertisements and Promotional Labeling

• Audio-visual and broadcast advertisements, and promotional labeling are to utilize the same requirements for printed materials in regards to printing features such as typography, layout, and contrast.
• During audio-visual promotional labeling and broadcast advertisements, the established trade name is to be displayed at the same time as the proprietary name. The size and prominence of the text will follow all of the requirements listed under Print Size of Proprietary and Established Trade Names.
• The established trade name and the proprietary name are to have the same amount of exposure time within the broadcast.

Proprietary and Established Trade Names in the Running Text of Electronic and Computer-based Advertisements and Promotional Labeling

Although electronic and computer based media do not contain text pages in the same manner as print media, sponsors can meet the requirements by using one of the following approaches:

• Present the established trade name along with the proprietary name each time the proprietary name is used in the running text of the promotional materials.
• Present the established trade name along with the proprietary name once in each paragraph of the promotional materials.
• Present the established trade name along with the proprietary name in regular intervals such as every fifth paragraph throughout the running text of promotional materials.
• Present the established trade name along with the proprietary name at the beginning, middle or end of the running text of promotional materials.
• Present the established trade name at least once along side the proprietary name and in type size that is at least half as large as the type used for the most noticeable position of the proprietary name when the proprietary name in the running text has a larger type size than the established trade name.

Two or more active ingredients

Products with two or more active ingredients may not have an established trade name equivalent to the proprietary name. In such instances the quantitative ingredient information is to be placed directly with the most prominent display of the proprietary name. The text of the ingredient information is to have a reasonable relationship to the prominence of the proprietary name in terms of text size, layout and contrast.

Impact

The implementation of the regulations of this guidance will assist the industry in the proper identification of and disclosure of established names and ingredients in the promotional labeling and advertising for all prescription human and animal drug and biological products. The effective disclosure of all product names and ingredients with help ensure safe and effective use of the product in consumer health.

Guidance for Industry and Review Staff: Recommended Approaches to Integration of Genetic Toxicology Study Results

Status of Guidance: Final

Release Date: 3 January 2006

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079257.pdf

Target Audience: Individuals/companies developing clinical safety evaluation plans and reviewers for the Center for Drug Evaluation and Research for drug products that had positive genotoxic study results.

Laws and Regulations Referenced: No laws or regulations were referenced. This guidance is considered an additional reference for genetic toxicology studies presented in the ICH guidances for industry: M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals, and S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals.

Summary: The S2B standard genotoxicity battery of genotoxicity studies are needed to provide information about the genotoxic potential of new drugs before they are used in clinical trials. A positive result from any of these studies needs to be explained or evaluated further to ensure the safety in humans. Statistically significant in vitro positive results may not be biologically and/or clinically relevant. All of the evidence collected from the core studies, additional tests, and mechanism of action should be considered together when determining the safety risk of potentially genotoxic drugs. The specific patient population should also be taken into consideration as well. Some potentially genotoxic drugs may be suitable in terminally ill patients or those with life threatening diseases but not healthy volunteers.

Rationale: The 3 core genotoxicity studies recommended before human clinical trials are performed are: bacterial gene mutation, chromosomal damage in mammalian cells, and chromosomal damage in rodent hematopoietic cells. Clinical trials can proceed if there are no positive results in any of these core studies. For positive results, it needs to be determined if the drug product is interacting directly with the DNA. If the drug is not interacting directly with DNA there may not be a significant risk for genotoxicity in living organisms. If the drug is determined to be directly damaging DNA, it may still be suitable for use in terminally ill patients or those with life-threatening disease, but not healthy volunteers.

Resulting Recommendations: There are three approaches to determining the biologic genotoxic potential of a drug if positive results are observed in any of the core genotoxicity studies.

The first is a weight of evidence approach. This approach compares the exposure levels used in the in vitro studies against the desired clinical exposure. If positive results are only seen at the highest doses studied in vitro and this dose is not to be used in vivo then the genotoxic potential may not be clinically relevant. Similarly, if positive results are seen in the in vitro studies but not in the in vivo mouse lymphoma study, there may not be clinical relevance. The level of cytotoxicity should also be considered.

A thorough understanding of the mechanism of action is another way to explain positive results and demonstrate no biological relevance. For example, some drugs that test positive in the core tests induce genotoxic effects indirectly below the biologic threshold. Also, positive results from tests with high osmolarity or low pH are not relevant to in vivo exposure due to the nonphysiologic conditions.

The third approach is to perform additional tests. Micronucleus induction can be evaluated from peripheral blood smears of mice in repeat-dose toxicity studies. Chromosomal damage can be evaluated in peripheral blood lymphocytes of rats or monkeys in repeat-dose toxicity studies. Transgenic mouse models are also a viable option for evaluating short-term carcinogenicity potential. These additional studies should be considered with all previous studies in a weight of evidence approach.

Impact: A full understanding of the genotoxic potential of a drug is important to ensure the safety of all clinical trial patients. If the drug is not intended to treat terminally ill patients or those with life threatening diseases, then unexplained positive genotoxic results from non clinical studies may provide evidence that the drug is not safe for humans. Alternatively, if positive results are not fully understood, they could not be clinically relevant and delay or prevent the availability of a potentially useful new drug.

Regulatory Blog Post #4 - Laura Salomon

FDA GUIDANCE BLOG #4

Laura Salomon

Name of Guidance:
Guidance for Industry – IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer

Status of Guidance/Release Date:
The current, final version of this guidance is dated January, 2004; it replaces the original version that was published in September, 2003.

Link to the Guidance:
The guidance can be found at the following location:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071717.pdf

Target Audience:
This guidance is targeted to sponsors whose pharmaceutical portfolios include studies of marketed drugs or biological products for treatment of cancer.

Laws and Regulations Referenced:
52 FR 8634 Federal Register of March 19, 1987
21 CFR 312 Investigational New Drug Application (IND)

CBER Office of Communication, Training and Manufacturer Assistance - Reinventing the Regulation of Cancer Drugs – Accelerating Approval and Expanding Access

Background:
Generally, the FDA requires a sponsor to submit an IND before studying a drug or biological product in humans, but certain studies, such as those investigating drugs for cancer, can be exempt if specific criteria are met. An applicant can determine that a study may be exempt if 5 criteria are met:

1. The study is not intended to support approval of a new indication or major labeling change.
2. The study is not intended to support a significant change in the product’s advertising.
3. The study does not involve any factor (dosage, route of administration, etc.) that greatly increases risk associated with product use.
4. The study complies with IRB and informed consent regulations (21 CFR parts 56 and 60).
5. The study complies with accepted regulations for investigational drug promotion and charging.

The FDA has attempted to clarify its policy on IND exemptions since 1996, when it launched the Reinventing the Regulation of Cancer Drugs initiative. At that time, sponsors were often submitting INDs for off-label indications, which were unnecessary. Sponsors and manufacturers incorrectly thought that if they provided study drug at no cost, the Agency would view this as promotional activity. As a result, the policy was further clarified, and the FDA stated that it was the investigator’s duty, rather than the IRB’s or manufacturer’s, to determine if an IND was necessary for a certain study. However, the Agency has since found that many cancer drug INDs were still being submitted when not required.

The staff at the FDA performs an initial brief review of an application it receives to determine whether or not it is exempt by focusing on parts of the protocol describing dose, schedule, route of administration, and patient population. If the Agency determines that the protocol is exempt from the requirement for an IND, a letter is sent to notify the sponsor, and there is no further review.

In cancer studies, changes in dosing recommendations are common, and oncologists need to carefully consider the probability of a major increase in risk (criterion 3 for IND exemption). The FDA recognizes that oncology drugs are associated with significant risk from known toxicity and that off-label therapy is common; these characteristics make oncology studies a specific class of investigations that may be exempt from IND submission.

Rationale:
The original version of this guidance was designed to clarify types of studies that could be exempt from the Agency’s IND requirements because many sponsors were submitting applications unnecessarily. To correct this issue, the guidance listed criteria that could allow for exemption as well as examples of oncology protocols that generally are and are not exempt. The Agency believes that explicit examples and criteria will help prevent sponsors from submitting studies that would be considered exempt under its regulations.

The guidance has since been updated. In the original version, the Agency stated that most randomized studies large enough to support a labeling supplement would probably not be exempt from IND regulation. Because this wording was often been misinterpreted to mean that the size of a study alone could lead to its exemption, the guidance was revised and the statement removed.

Resulting Recommendations:
The Agency stresses that it is the investigator’s role to determine whether or not a study is exempt from IND regulations. The investigator should be particularly aware of details of study design and purpose in oncology trials, because drugs for cancer are often used off-label and dosed differently than other drug classes. As a result, a thorough risk/benefit analysis is recommended.

Impact:
One major impact of this guidance is clear: fewer studies that qualify for exemption are submitted to the Agency erroneously, since it defines criteria and lists examples. This guidance also ensures that most of the responsibility for determining IND exemption lies with the sponsors and not with the IRBs or drug manufacturers. The sponsors should therefore be aware of these recommendations so that they are more able to make a correct determination. Sponsors who limit the number of unnecessary IND submissions would be able to promptly begin the investigations that are so important to the drug development and marketing process.

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.