Blog Post #5: Brief Summary: Disclosing Risk Information in Consumer-Directed Print Advertisements

Rosalyn Finlayson

Name of Guidance:

Brief Summary: Disclosing Risk Information in Consumer-Directed Print Advertisements

Status of Guidance

Draft Guidance

Date of Guidance

January 2004

Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm069984.pdf

Target audience

Manufacturers of prescription drug products and the advertising industry

Laws An Regulations Referenced

Section 502(n) of the Act (21 U.S.C. 352(n)) Federal Food, Drug, and Cosmetic Act (the Act)

21 CFR 202.1(e)(1): Requires that an advertisement contain a true statement of information in brief summary relating to side effects, contraindications and effectiveness.

21 CFR 202.1(e)(3)(iii)): Requires disclosure of each specific side effect and contraindication.

Summary

This draft guidance replaces the April 2001 guidance on Using FDA-Approved Patient Labeling in Consumer-Directed Print Advertisements. Provided in this January 2004 draft guidance are revised recommendations on the disclosure of risk information in print advertisement for prescription drug products marketed to the general public. The guidance encourages the use of consumer-friendly language in all advertising materials created specifically for the consumer. The focus of this guidance is on the content of the FDA brief summary requirement for the true statement and disclosure of side effects.

Rationale

This draft guidance is proposing revisions to the manner in which risk factors of prescription drugs are presented in print media directed towards consumers. The FDA has taken the stance that the approved professional labeling guidelines are inappropriate for consumer-directed print advertisements because many consumers do not have the technical background to understand the information presented. Under FDA guidelines, advertisements for prescription drugs must contain the product's established name, quantitative composition and a "true statement" including information in brief summary relating to side effects, contraindications, and effectiveness. In order to fulfill the brief summary requirement, consumer-directed print advertisements frequently include all of the risk-related sections of the FDA approved professional labeling. Although the agency has drafted guidance discouraging this practice many consumer directed advertisements continue to contain the FDA approved professional labeling, which is written with highly technical medical terminology, contains extensive lists and printed in small type.

Resulting Recommendations

The FDA is making the following recommendations for consumer-directed print advertisements. All information intended for the general public consumer should be presented in language that can be fully understood by a lay reader and presented in an easily readable format. An easily readable format is defined as a format consisting of larger easy to read type and a manageable volume of material. Utilizing a smaller volume of material related to the major risk factors is recommended rather than extensive lists containing all of the major and minor risk factors. Including extensive lists of minor risk factors makes it difficult for the consumer to comprehend and retain the more important information about the major risk factors.

The FDA is also encouraging the use of Highlights for consumer-directed print advertisements. Highlights are to be written in a language that is easy to understand by the general public consumer. The guidance provides the following example of a Highlight for industry to follow. Instead of using the term “contraindications” in the Highlight the FDA recommends using phrasing that the general public is more than likely to understand. For example: “You should not take drug X if you….”

Impact

Compliance with this guidance will assist drug manufacturers and the advertising industry in creating materials that are easily understood by the ordinary general public consumer under normal conditions. The general public will be able to receive materials in layman’s terms about the risk factors associated with prescription drugs.

ICH Harmonized Tripartite Guideline: Guideline on the Need for Carcinogenicity Studies if Pharmaceuticals, S1A

Status of Guidance: Step 4

Release Date: 29 November 1995

Link: http://www.ich.org/LOB/media/MEDIA489.pdf

Target Audience: Individuals/companies developing non-clinical safety evaluation plans for drug products expected for chronic use in humans.

Laws and Regulations Referenced: No laws or regulations are referenced in this guidance.

Summary: Carcinogenicity studies assess the potential for new drugs to induce tumors can and can be an important part of non clinical safety evaluations. The old rationale required carcinogenicity tests to be performed before drugs were administered to humans. However, this requirement no longer applies to all classes of drugs. Drugs intended for short term use, use in terminally ill or deep salvage patients, or those that do not induce systemic exposure may not need carcinogenicity studies performed. Data collected from in vivo and in vitro genotoxicity tests, repeat dose toxicity tests, and chronic toxicity tests can be used to evaluate the need for resource and time intensive carcinogenicity tests.

Rationale: Carcinogenicity studies assess the potential for new drugs to induce tumors can and can be an important part of non clinical safety evaluations. However, these studies are time consuming and resource intensive and may not be beneficial to the overall safety assessment if there is no prior concern for carcinogenetic effects.

Guidances for when a carcinogenicity study is needed for a new drug previously differed widely between Japan, the US, and Europe. The main point of contention was how long a drug was expected to be administered to patients. Other considerations for carcinogenicity studies include: other similar drugs that have previously demonstrated carcinogenic potential; molecular structure similar to those known to pose a carcinogenetic risk; pre-cancerous indications in repeat-dose toxicity studies; and long-term retention of the drug or metabolites in specific organs.

A standard battery of in vivo and in vitro genotoxicity tests can either indicate risk or limited risk for carcinogenetic potential. The life expectancy of the intended patient population should also be considered when deciding if long term carcinogenicity studies are needed. A lack of systemic exposure to dermal or ocularly adminsted drugs as established in other non clinical safety studies can also indicate that additional oral carcinogenicity studies are not needed.

Resulting Recommendations: Drugs that are expected to be chronically administered for 6 or more months or administered intermittently for chronic conditions should include carcinogenicity studies in their safety assessment plan.

Drugs that have positive findings from in vivo and in vitro genotoxicity testing and are considered to be genotoxic do not require carcinogenicity studies. However, a 1 year chronic toxicity study should be performed if these drugs are intended for chronic use in humans.

Carcinogenicity studies are not needed if the life expectancy of the intended patient population is less than 3 years. If the drug is intended to treat life threatening diseases that currently do not have an effective treatment available, carcinogenicity studies do not need to be completed until after marketing approval. Carcinogenicity studies are generally not needed for dermal or ocularly adminsitered drugs, except if there is concern for photocarcinogenic risk.
Impact: These recommendations indicate that costly and time consuming carcinogenicity studies that were previously required before the drug could be administered to humans may not be needed for all new drugs. Companies and regulating agencies can use data from other required studies to make determinations about the risk of carcinogenecity and potentially reduce the number of animals used and reduce the time drugs can reach the intended population.

Blog #5 Michelle Keyvani

Name of Guidance:
Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population

Status of Guidance:
Final Guidance

Guidance Release Date:
This Guidance was released December 2000

Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073143.pdf

Target Audience:
Medicine in the pediatric population is limited. This guidance is intended to encourage timely pediatric medicinal products internationally.

Laws and Regulations:
Other ICH documents with relevant information affecting pediatric studies include:
E2: Clinical Safety Data Management
E3: Structure and Content of Clinical Study Reports
E4: Dose-Response Information to Support Drug Registration
E5: Ethnic Factors in the Acceptability of Foreign Clinical Data
E6: Good Clinical Practice: Consolidated Guideline
E8: General Considerations for Clinical Trials
E9: Statistical Principles for Clinical Trials
E10: Choice of Control Group in Clinical Trials
M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
Q1: Stability Testing
Q2: Validation of Analytical Procedures
Q3: Impurity Testing

Summary:
The guidance provides an outline of critical issues in pediatric drug development and approaches to the safe, efficient, and ethical study of medicinal products in the pediatric population.

Issues When Initiating a Pediatric Medicinal Product Development Program - The decision to proceed with a pediatric development program for a medicinal product, and the nature of that program, involve consideration of many factors, including:
· The prevalence of the condition to be treated in the pediatric population
· The seriousness of the condition to be treated
· The availability and suitability of alternative treatments for the condition in the pediatric population, including the efficacy and the adverse event profile (including any unique pediatric safety issues) of those treatments
· Whether the medicinal product is novel or one of a class of compounds with known properties
· Whether there are unique pediatric indications for the medicinal product
· The need for the development of pediatric-specific endpoints
· The age ranges of pediatric patients likely to be treated with the medicinal product
· Unique pediatric (developmental) safety concerns with the medicinal product, including any nonclinical safety issues
· Potential need for pediatric formulation development

Of these factors, the most important is the presence of a serious or life-threatening disease for which the medicinal product represents a potentially important advance in therapy.

Pediatric Formulations -
For oral administration, different types of formulations, flavors, and colors may be more acceptable in one region than another. Several formulations, such as liquids, suspensions, and chewable tablets, may be needed or desirable for pediatric patients of different ages. Different drug concentrations in these various formulations may also be needed. Consideration should also be given to the development of alternative delivery systems.

For injectable formulations, appropriate drug concentrations should be developed to allow accurate and safe administration of the dose. For medicinal products supplied as single use vials, consideration should be given to dose-appropriate single-dose packaging.

Timing of Studies -
During clinical development, the timing of pediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of alternative treatments.

Types of Studies -
Pharmacokinetics, Efficacy, Safety and Postmarketing Information

Age Classification of Pediatric Patients - The following is one possible categorization. There is, however, considerable overlap in developmental (e.g., physical, cognitive, and psychosocial) issues across the age categories: · Preterm newborn infants
· Term newborn infants (0 to 27 days)
· Infants and toddlers (28 days to 23 months)
· Children (2 to 11 years)
· Adolescents (12 to 16-18 years (dependent on region))

Ethical Issues in Pediatric Studies -
The pediatric population represents a vulnerable subgroup. Therefore, special measures are needed to protect the rights of pediatric study participants and to shield them from undue risk.

Institutional Review Board/Independent Ethics Committee (IRB/IEC) is critical to the protection of study participants.

Recruitment of study participants should be free of inappropriate inducements.

Consent and Assent: Full informed consent should be obtained from the parent(s) or legal guardian.

Minimizing Risk: Every effort should be made to anticipate and reduce known hazards.

Minimizing Distress: Practical considerations to ensure that participants’ experiences in clinical studies are positive and to minimize discomfort and distress include the following:
· Personnel knowledgeable and skilled in dealing with the pediatric population and its age-appropriate needs, including skill in performing pediatric procedures
· A physical setting with furniture, play equipment, activities, and food appropriate for age
· The conduct of studies in a familiar environment such as the hospital or clinic where participants normally receive their care
· Approaches to minimize discomfort of procedures, such as (1) topical anesthesia to place IV catheters, (2) indwelling catheters rather than repeated venipunctures for blood sampling, and (3) collection of some protocol-specified blood samples when routine clinical samples are obtained.

Rationale:
The number of medicinal products currently labeled for pediatric use is limited. The reason why this guidance is so important is because it is intended to encourage and facilitate timely pediatric medicinal product development internationally. The guidance provides an outline of critical issues in pediatric drug development and approaches to the safe, efficient, and ethical study of medicinal products in the pediatric population.

Resulting Recommendations:
Pediatric patients should be given medicines that have been appropriately evaluated for their use in those populations. Safe and effective pharmacotherapy in pediatric patients requires the timely development of information on the proper use of medicinal products in pediatric patients of various ages and, often, the development of pediatric formulations of those products. Advances in formulation chemistry and in pediatric study design will help facilitate the development of medicinal products for pediatric use.

Drug development programs should usually include the pediatric patient population when a product is being developed for a disease or condition in adults and it is anticipated the product will be used in the pediatric population. Obtaining knowledge of the effects of medicinal products in pediatric patients is an important goal. However, this should be one without compromising the well-being of pediatric patients participating in clinical studies. This responsibility is shared by companies, regulatory authorities, health professionals, and society as a whole.

Impact:
Being able to provide safe and effective medicines for the pediatric population.

Blog #5 - Michael O'Donnell

Name of Guidance: Guidance for Industry - Formal Dispute Resolution: Appeals above the division level

Status of Guidance: Final

Release Date: February 2000

Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm077137.pdf

Target Audience: Healthcare industry professionals and study drug sponsors

Laws and Regulations Referenced:
• 21 CFR 10.3
• 21 CFR 10.75
• 21 CFR 312.48
• 21 CFR 314.103
• 21 CFR 312.48
• 21 CFR 312.48
• 21 U.S.C. 360bbb-1
• 63 FR 63978
• 64 FR 13591
• Prescription Drug User Fee Act (PDUFA)
• Federal Food, Drug, and Cosmetic Act (“The Act”)
• Section 351 of the Public Health Service Act (PHS)

Summary:
This guidance provides direction on what type of procedural action should be taken for resolving any disputes between healthcare industry professionals and the Food and Drug Administration (FDA) that cannot be resolved at the division level.

The procedures for study drug sponsors appealing their disputes to the appropriate Office or Center level are explained. Numerous sections of the U.S. Code of Federal Regulations (CFR) and several acts are referenced to support the position on how these procedures should be followed by the sponsor. One of the acts that influenced these procedures is the Prescription Drug User Fee Act (PDUFA). PDUFA is discussed in detail in the context of its role in dispute resolution at the Center or Office level, which is above the division level. Appeals to the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) would constitute a Center level appeal. If the dispute cannot be resolved at the Center level, it must continue through the chain of command until a resolution is reached. In extreme cases of unresolved disputes, the appeal may be escalated to the FDA Commissioner for a final ruling on the dispute. The type of dispute appealed may be scientific or procedural in nature.

The guidance places an emphasis on the importance of timely dispute resolution because of the magnitude of the scientific or commercial implications of an appeal. The procedural recommendations of the guidance are intended for appeals involving either PDUFA or non-PDUFA drugs. A generic drug is considered to be a non-PDUFA drug.

Discussed are the PDUFA-recommended timeframes for settling disputes between study drug sponsors and the FDA. The way that PDUFA goals for these timeframes are evaluated is to target a percentage of acted upon appeals for each year. “Acted upon,” here means that all associated requests for information, meetings, presentations, and granting or denying the appeal has been fully completed. The recommendations for percent of acted upon appeals from a 1997 PDUFA-related letter is specifically presented in the guidance as follows:

Year 1999: 70% acted upon within 30 calendar days
Year 2000: 80% acted upon within 30 calendar days
Year 2001 and each subsequent year: 90% acted upon within 30 calendar days

During the resolution process, the sponsor has the right to request a scientific review from an advisory committee, if necessary. Also explained is that a written request must be submitted to CDER or CBER as appropriate, but only after all efforts to resolve the dispute at lower levels have been exhausted.

Non-generic drug disputes have to be submitted to the Formal Dispute Resolution Project Manager (DRPM) of CDEER. Generic drug disputes have to be submitted to the Director of the Office of Generic Drugs. CDER disputes should be sent to one of these two offices as appropriate. CBER-related disputes have to be sent to the DRPM specific to CBER.

The guidance provides a detailed overview of exactly what must be included in the supporting information that is sent with the dispute. There should be a cover sheet, application number, product name, description of dispute, original agency decision, list of necessary supported documents, statement explaining what transpired at previous level of attempted resolution, and sponsor contact information.

According to the guidance, the FDA will notify the sponsor with a written response or via telephone with the resolution of the dispute within 30 days. If more time is needed, the FDA still needs to contact the sponsor within the 30 day window to explain why they need more time to process the appeal. If an advisory committee is approved to be involved in the decision, it could take longer because the advisory committee has to be organized to evaluate the appeal, and there might be a waiting period for the next available meeting to discuss the issue.

After reaching a decision, the advisory committee notifies the FDA of their decision on the issue, and then the FDA has 30 days from that point to in turn notify the sponsor of the FDA decision. The FDA decision will not necessarily be the same as the advisory committee, but the advisory committee’s decision could still provide valuable additional information supporting or rejecting the sponsor’s position on the disputed issue.

Rationale:
This guidance aims to speed up the FDA’s dispute resolution practices for scientific and procedural issues that develop during the course of a study drug product’s development and review processes.

Resulting Recommendations:
There is a need to have as quick a turnaround on the appeals process as possible so that the study drug sponsor can proceed with the next appropriate scientific or commercial action needed, and not lose time while waiting for decisions on appeals. If the procedures recommended in this guidance are followed by study drug sponsors that need to escalate dispute resolution, the sponsors will benefit from improved timeframes.

Impact:
Scientific and procedural disputes are resolved more quickly. CDER and CBER employees at the supervisory level have a defined process to advise sponsors of if the issue is beyond their level of resolution capabilities. Study drug sponsors reviewing this guidance know what is expected from them in the process, and what they can expect from the FDA in terms of time to resolution, when a dispute is raised beyond the Division level.

FDA Guidance Blog #5 - Laura Salomon

Name of Guidance:
Guidance for Industry – Providing Submissions in Electronic Format – Receipt Date

Status of Guidance/Release Date:
Providing Regulatory Submissions in Electronic Format – Receipt Date is a draft guidance, dated June 2007.

Link to the Guidance:
The guidance can be found at the following location:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072385.pdf

Target Audience:
Receipt Date is one guidance in a series that the FDA is developing for sponsors to reference when submitting electronic applications. The target audience, therefore, includes the sponsor and any employees involved in formatting, assembling, and/or submitting electronic documents, as well as any who ensure regulatory compliance of these electronic submissions.

Laws and Regulations Referenced:
21 CFR 312 Investigational New Drug Application

Prescription Drug User Fee Act of 1992 (PDUFA) – allows the Agency to collect fees from companies that manufacture certain human drug and biological products

Summary:
The purpose of this guidance is to clarify what the FDA considers the receipt date for electronic submissions, which include eCTD (electronic common technical document), non-eCTD electronic submissions, and hybrid submissions to CBER and CDER. The receipt date of a submission is often used by the FDA to determine regulatory milestones, such as the 30-day safety review cycle for an IND or a review performance goal date for an NDA or BLA.

For a completely electronic submission, such as a submission on CD-ROM or in eCTD format, the official receipt date is the date the submission arrives at the appropriate document room or transmits through the electronic submission gateway (ESG). For a two-part submission, in which part is in paper and part is electronic, the receipt date is determined separately according to when each part is received.

The FDA asserts that occasional technical problems (e.g. defects in media, improper sequence numbering, presence of a virus, etc) that prevent reviewers from opening, processing, or archiving information will often interfere with and delay submission review; it cannot begin until all technical issues are resolved.

The FDA changed its policy to encourage technically valid electronic submissions: the Agency will consider a technically deficient application not received until all problems are corrected and the application properly resubmitted. Any submission must pass a technical validation to ensure it can be opened, processed, and archived before the receipt date is confirmed. Once a submission passes this validation process, the assigned receipt date is the business day on which it arrives at the appropriate document room or is received through the ESG.

Rationale:
The FDA changed its policy on receipt date to encourage applicants to ensure that their electronic submissions are free from technical issues. Technically sound submissions allow the FDA to begin the review process promptly and without problems.

Resulting Recommendations:
The FDA recommends that sponsors become familiar with the technical specifications an electronic submission must pass; these specifications are posted on the Agency website, and they describe the validation checks performed on each type of submission in electronic format. Sponsors and applicants who are inexperienced in submitting electronic applications should request technical assistance.


Impact:
The transition from paper to electronic submissions has had a major impact in industry. In general, electronic submissions are both created and reviewed faster, and they are quickly becoming the standard format in the United States and worldwide. Because this guidance attempts to guarantee technically sound electronic submissions and establish clear definitions of receipt date, sponsors should be more confident that their submissions are received and important regulatory milestones can align with company-established timelines.

Blog # 5 Guidance for Industry: Residual Drug in Transdermal and Related Drug Delivery Systems

Theresa Seiverd
Blog #5

Name of Guidance: Residual Drug in Transdermal and Related Drug Delivery Systems

Status of Guidance: Draft

Release Date: August 2010

Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM220796.pdf

Target Audience: Pharmaceutical Industry, specifically developers and manufacturers of drug and device combination products

Laws and Regulations Referenced: None

Summary: The transdermal drug delivery system (TDDS), transmucosal drug delivery system (TDMS), and topical patches contains an excess amount of drug substance beyond what is needed to be delivered to the patient. The excess amount is needed to make sure the patient is getting the intended amount of drug. The excess amount of drug in the product has a significant potential to impact the product’s quality, safety, and efficacy. The goal of this guidance is to ensure that the sponsor is applying a risk base approach to the design and manufacture to the TDDS, TDMS, and similar delivery systems.

Rationale: The excess amount of drug that is retained in the TDDS, TDMS, and topical patches raises a potential safety issue not only to the patient, but also to other family members, caregivers, children, and pets. There have been adverse events reported that are related to prolonged drug exposure because the patient did not remove the TDDS or related device. In fact, some children have died from inadvertent exposure to a discarded TDDS.

Recommendation: The FDA recommends that a quality by design approach be implemented in the in the design, development, and manufacture for TDDS, TMDS, and topical patches. The quality by design approach is the subject of the International Conference on Harmonization (ICH) Guidance for industry: Q8(R2) Pharmaceutical Development. It is a risk-based approach to design and development of the product. This approach leads to better understanding of the product and takes into account the patient needs and post use considerations of the product.

The FDA also recommends that a scientific justification to support the amount do residual drug in the TDDS, TDMS, and topical patches to be included in an application. The discussion of this justification can be provided in section 3.2.P.2 (Pharmaceutical Development) of the Common Technical Document. The justification should be sufficient to demonstrate product and process understanding and to ensure that the risks were considered to minimize the amount of residual drug post use to the lowest possible level.

Impact: By applying the quality by design approach to the development of transdermal and similar delivery systems an added benefit is achieved through a higher level of understanding of the product and manufacturing process. Also quality attributes, the product’s characteristics, and patient use are considered very early in the development process and has the result of a better quality product.

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.