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Draft Guidance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This draft guidance replaces the April 2001 guidance on Using FDA-Approved Patient Labeling in Consumer-Directed Print Advertisements. Provided in this January 2004 draft guidance are revised recommendations on the disclosure of risk information in print advertisement for prescription drug products marketed to the general public.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This draft guidance is proposing revisions to the manner in which risk factors of prescription drugs are presented in print media directed towards consumers.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.