Guidance for Industry: Chronic Obstructive Pulmonary Disease: Developing Drugs for Treatment

Theresa Seiverd
BW706-Blog 2
1. Name: Chronic Obstructive Pulmonary Disease (COPD): Developing Drugs for Treatment
2. Status: Draft Guidance
3. Release Date: November 2007
4. Link to Guidance: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071575.pdf
5. Target Audience: Pharmaceutical companies that design, plan, and sponsor clinical trials
6. Laws and regulations referenced:
21 CFR 300.50-Fixed-combination prescription drugs for humans
7. Summary:
COPD is characterized by the presence of air flow obstruction due to chronic bronchitis or emphysema. Therapies for COPD may cover a wide range of targets such as: improving airflow obstruction; providing symptom relief for a chronic cough or shortness of breath; reducing or preventing exacerbations; altering the disease progression; and modifying the lung structure.
One of the major goals of this guidance is to assist drug companies in the design of clinical trials for new molecular entities in the treatment of COPD. One of the first considerations when developing a clinical trial is to consider the spectrum of patients with COPD since a drug may benefit some patients and not others. Another important consideration is to consider the type of drug under development and its target therapy since this will have impact on the efficacy endpoints measured. The emphasis of this guidance is on the evaluation of efficacy parameters that are discussed in detail to provide the sponsor with many outcome measurements to consider when designing a clinical trial. The guidance groups the endpoints into 3 broad categories of descriptions.
The first category describes physiological assessments. The physiological assessments include the pulmonary function test to determine the extent of airflow obstruction. This assessment can be easily obtained with a spirometry test that measures forced expiratory volume in 1 second (FEV1). Exercise capacity is another common assessment that determines the reduced capacity for exercise due to airflow obstruction. It can be easily obtained by measuring the duration of activity on the treadmill or stationary bike.
The secondary category describes patient or evaluator outcome measures. These assessments include symptom scores, activity scales, and health-related quality of life instruments. Symptom scores were based on a patient’s own self assessment of their health status. The measure may be based on a categorical, visual, or numerical scale. The activity scales can be used as supportive measures to show efficacy of the drug since they are not always reliable and have limitations. For instance, the scales require patients to recall prior symptoms and make comparisons that is hard to measure and can be subjective.
The third category describes surrogate and biomarker endpoints. Surrogates and biomarkers can be used in consideration as supportive assessments of the drug’s mechanism of action. FEV1 that was described above can be used as a surrogate marker to obtain the status of the disease. One commonly used biomarker is the high resolution chest computed tomography to assess the lung tissue structure, to determine the disease state, or to show evidence of whether the lung tissue is functional.
For Phase 3 studies, primary and secondary endpoints need to be chosen based on the drug’s mechanism of action on the target therapy. For instance, if the target therapy of the drug is to improve airflow obstruction then the primary endpoint or assessment would be to compare pre‑dose and post-dose FEV1 measurements to show the beneficial effect with the drug over time.
8. Rationale: The rationale for putting out a guidance specific to COPD is to provide companies with a basis of the FDA’s (ie, the agency) expectations of primary and secondary endpoints that should be considered for a particular indication on the drug label when planning for pivotal Phase 3 studies. It is also important to design the study with the expected duration depending on the label claim that is being sought.
9. Resulting recommendation: The main considerations for this guidance are built around efficacy endpoints that need to be addressed when considering a drug’s specific indication (or claim) such as indicated below.
a. For the indication, improving airflow obstruction, if the drug being studied is a bronchodilator then the endpoint change in post-dose FEV1 should be evaluated. For non-bronchodilator’s, the change in pre-dose FEV1 should be considered.
b. For the indication, providing symptom relief, the endpoint should be clinically meaningful, and the magnitude should be clinically relevant.
c. For the indication, modifying or preventing exacerbations, the endpoint should be clinically meaningful for measuring exacerbations. For example, some measurements that can be considered for exacerbations are: duration, severity, delay in occurrence of an exacerbation, or reduction of frequency of an exacerbation.
d. For the indication, altering disease progression, the preferred efficacy endpoint that should be considered is the serial measurement of FEV1 over time.
e. For the indication, modifying lung structure, a radiological assessment of lung structure should be considered along with evidence that the regenerated lung tissue is beneficial and benefit’s patients. The latter part may involve a physiological assessment such as FEV1 to show evidence of improvement of airflow obstruction.
The duration of the study is important and also must be taken into consideration when planning the design of the study. Depending on the claim, the recommended study duration can range from 3 months to three years to show evidence of efficacy. Longer durations may be necessary to adequately address safety factors too. The number of studies recommended depends on the drug and claim that is being evaluated. Typically, 2 confirmatory studies are done for Phase 3 trials. For indications such as altering disease progression or modifying lung structure, 1 study may be acceptable provided the design is acceptable and results are clinically significant and robust. In order to demonstrate efficacy, the design of the study should include 1 primary endpoint and with more than 1 secondary endpoints. This should be considered up front in the design.
10. Impact: This guidance offers companies a roadmap on how to design their clinical trials to provide meaningful benefit for patients with COPD. Once the company has defined its therapeutic target, it will have a better understanding of the benefits or claims that may potentially be put on the label. With this knowledge, choosing the primary and secondary endpoints to evaluate becomes more clear, and the development of the Phase 3 clinical program can be further defined.

Regulatory Blog Post #2 - Providing Regulatory Submissions in Electronic Format (General Considerations)

Laura Salomon
September 19, 2010

Name of Guidance:
Guidance for Industry: Providing Regulatory Submissions in Electronic Format – General Considerations

Status of Guidance/Release Date:
Providing Regulatory Submissions in Electronic Format – General Considerations is a draft guidance. It was first issued in January, 1999 and revised in October, 2003.

Link to the Guidance:
The guidance can be found at the following location:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm124751.pdf

Target Audience:
General Considerations 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:
62 FR 13430 Federal Register of March 20, 1997
21 CFR, Part 11 Electronic Records; Electronic Signatures – Scope and Application

Summary:
One of the main goals of the updated draft of General Considerations is to incorporate electronic submission information in all centers of the FDA, including

• CBER – Center for Biologics Evaluation and Research
• CDER – Center for Drug Evaluation and Research
• CDRH – Center for Devices and Radiological Health
• CFSAN – Center for Food Safety and Applied Nutrition, and
• CVM – Center for Veterinary Medicine.

Additional changes from the previous draft include a description relating electronic submissions to the Code of Federal Regulations (21, part 11) and recommendations for formatting PDF documents with specific font types. Finally, the latest version of the guidance introduces new file formats such as XML (extensible markup language) and SGML (standard generalized markup language).

Electronic Submissions and the Relationship to 21 CFR Part 11
Following suit of the March 20, 1997 Federal Register, which allowed sponsors to submit records in electronic format without accompanying paper copies, CDER and CBER finalized a joint guidance document on general considerations for electronic submissions in January, 1999. The revised draft results from a working group with CBER, CDER, CDRH, CVM, and CFSAN, which formed to coordinate electronic submissions across all FDA centers. The goal of electronic submission standards complies with Section 11.2(b) of 21 CFR, which states that records submitted to the Agency may be electronic as long as the Agency is technologically able to accept them (as identified in public docket No. 92S-0251).

The guidances on electronic submissions describe general characteristics of electronic documents from the user’s perspective; based on these characteristics, PDF is the accepted format, and the user should be able to view a legible copy of the information, print specific pages of each document while maintaining its integrity (font, page orientation, etc.), navigate through the submission using a table of contents, and copy text, images, and data to other common software formats.

General Considerations also discusses detailed specifications for electronic documents, including acceptable PDF versions, fonts, page orientations and margins, hypertext linking and bookmarks, naming conventions, and several other technical standards.

File Formats for Datasets and Electronic Submission Procedures
While the original guidance document described datasets in SAS System XPORT transport format (Version 5 SAS transport file) as acceptable, the updated draft includes information on XML and SGML. XML files are read by internet browsers through use of style sheets. They form a dynamic hierarchical structure as individual files (elements) are related to one another. The FDA currently uses XML version 1.0, which is recommended by the World Wide Web Consortium (W3C). SGML, also developed by W3C, is similar to XML and has many similar features. It was developed to organize and transmit information in digital format.

The FDA has identified three methods for sending electronic submissions: via electronic data interchange (EDI), through web-based transmission, and by secure email. Additional information is provided for various transmission methods depending on specific submission types. For example, electronic submissions can also be provided on physical media formats such as floppy disks, CD-ROM, and digital linear tape.

Rationale:
An update to the original General Considerations document was required to provide information on font specifications and new acceptable file types, which was not included in January, 1999 draft. Furthermore, aligning with the Agency’s goal to address electronic submissions to all centers in one common document, this updated draft includes information on submitting to CHRH, CVM, and CFSAM, as well as CDER and CBER. As submissions are increasingly transitioning from paper to electronic, it benefits the Agency to have one document that sponsors can reference for specifications for any center or submission type.

Resulting Recommendations:
The Agency recommends that sponsors adhere to the guidance to ensure general compliance of their electronic submissions with established regulations and technical standards. General Considerations should be referenced for electronic submissions to any center in the Agency.

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, since large documents no longer require printing, binding, and boxing. In particular, eCTD (electronic common technical document) structures are becoming the standard, and they allow for document reuse; this structure makes the submission and review process more efficient. Considering what it takes to send hundreds of volumes of a large NDA on a truck to FDA headquarters, electronic submissions save money, space, and manual labor.

The Agency’s series of guidances on electronic submissions is impactful because industry can refer to a single group of documents for all processes and specifications that characterize this submission format. Particularly important are the updates to this draft of General Considerations, because sponsors now have information regarding submissions to any of the Agency’s centers. The FDA’s goal of increased efficiency in the review process has coincided with movement toward standardization. These standard procedures have helped to clarify the electronic submission process for all involved.

Single Dose Acute Toxicity Testing For Pharmaceuticals

1. Name of Guidance

Guidance for Industry: Single dose acute toxicity testing for pharmaceuticals

2. Status of Guidance: Draft/ Final Guidance

Final

3. When was the Guidance released?

August 1996

4. Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079270.pdf

5. Target audience

Companies designing their non-clinical safety plan.

6. Laws and Regulations Referenced (and what each Law states in relevant part)

No laws or regulations are referenced in this guidance. It does reference the guidance for how many animals should be used in these studies (Federal Register of

October 11, 1988, 53 FR 39650). This guidance, which was updated since the release of the FDA guidance document, provides alternative methods to the LD50 test that was used to find the dose that killed 50% (n>/=20) of animals within 14 days of a single dose.

7. Summary

Acute toxicology studies are preliminary drug development studies that provide information about target organs of toxicity, delayed toxicity, and appropriate doses for future studies. The study consists of a single dose (or multiple doses within a 24 hour period if a single dose is not feasible) of test article by 2 different routes of administration (unless the intended human administration route is intravenous, then only the IV route needs to be used in acute toxicity studies). The study should include a rodent and non-rodent species. Only 3-5 rodents should be used for the rodent study. Fewer non-rodents may be used. Animals are observed for 14 days following test article administration for signs of acute toxicity, dose response relationships, pharmacokinetics, clinical pathology, and histopathology.

8. Rationale

Acute toxicity studies provide basic safety information about an investigational chemical product early in the development process. The data generated are used to determine the maximally tolerated dose and design further non-clinical and clinical studies. The small number of animals used reduces the number of animals subjected to potential overt toxicities while still obtaining the necessary information.

9. Resulting Recommendations

Acute toxicology studies should be performed in a rodent and non-rodent species (n=3-5) early in development. LD50 calculations are no longer recommended.

10. Impact

This guidance changed the way in which acute toxicology studies were performed. It recommends the use a very small number of animals early in non-clinical development so future studies can try to avoid overt toxicities while providing valuable information about the toxicology of the test article.

Blog #1: Submission of Abbreviated Reports and Synopses in Support of Marketing Applications

Name of Guidance
Guidance for Industry: Submission of Abbreviated Reports and Synopses in Support of Marketing Applications

Status of Guidance
Final

Release Date
August 1999

Link to the Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078761.pdf

Target Audience
NDA or BLA applicants

Laws and Regulations Referenced (and what each Law states in relevant part)
• Food and Drug Administration Modernization Act (FDAMA) of 1997, Section 118 (states FDA must issue guidance on when abbreviated study reports may be submitted instead of full reports)
• Federal Food, Drug, and Cosmetic Act, Section 505(b)(1) (requires reports of studies demonstrating safety and effectiveness be submitted in an NDA)
• 21 CFR 601.2(a) and (c)(1)(i) (requires reports demonstrating safety, purity, and potency be submitted in a BLA)
• 21 CFR 314.50(d)(5) (requires description and analysis of each controlled clinical study be submitted in an NDA)

Other Guidances Referenced
• Guidance for Industry: Format and Content of the Clinical and Statistical Sections of an Application (http://www.docstoc.com/docs/536075/Format-and-Content-of-the-Clinical-and-Statistical-Sections-of-an-Application)
• ICH E3: Structure and Content of Clinical Study Reports (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073113.pdf)

Summary
This guidance provides FDA recommendations for when submitting safety and/or effectiveness data as a full clinical study report, an abbreviated study report, or a synopsis is appropriate. Recommendations for the format of abbreviated study reports and synopses are also provided.

Rationale
In 1988, the FDA issued a guidance (Format and Content of the Clinical and Statistical Sections of an Application) recommending that full study reports were only required when a study provided both safety and effectiveness data. If the study was not intended to evaluate effectiveness for the proposed indication, or to support labeling information, then a less-than-full report could be submitted. Applicants, however, often continued to submit full reports because of the difficulty in interpreting the requirements.
One of the key goals of the FDA’s Modernization Act (FDAMA) in 1997 was to improve efficiency of the regulatory review process.1 To this end, in 1999 the FDA issued a new guidance that offers clearer instructions detailing formats for alternative reports that could be submitted in lieu of full reports. The guidance also provides explanations and examples of when such alternatives, called “abbreviated reports” and “synopses,” are appropriate.

Resulting Recommendations
Full study reports should be submitted for all studies that contribute data affecting a product’s labeling information, including studies that evaluate the product’s effectiveness for the proposed indication.
Examples of clinical studies requiring full reports include the following:
• Dose-finding studies
• Pivotal studies
• Controlled studies supporting effectiveness
• Controlled studies demonstrating comparativeness
• Controlled studies of different indications or dosage forms or regimens if they are intended to support approval of the proposed indication,
• Controlled studies designed to evaluate effectiveness that fail to show an effect
The format for a full report is described in ICH E3.

Abbreviated reports require the same amount of safety information as would be included in a full report, but less effectiveness information. These reports should be submitted for studies that are not designed to evaluate product effectiveness or describe clinical pharmacology, but for which the reviewer needs enough information to see that the study results do not contradict effectiveness claims or clinical pharmacology profiles determined in other studies.
Examples of clinical studies requiring abbreviated reports include:
• Studies not designed as efficacy studies but that provide significant safety information
• Studies that do not provide the primary or substantiating evidence of effectiveness (results must be consistent with the substantiating studies)
• Studies of indications not intended for marketing but which are related to the proposed indication
• Studies of doses or dosage forms not intended for marketing
• Controlled safety studies
The format for an abbreviated report includes the following sections from ICH E3: 1, 2, 3, 4, 9.1, 9.8, 10.1, 12, 13, 14, 16.1.1, 16.1.2, 16.3.1, and 16.4. A summary of efficacy results (such as described in ICH E3 Section 11.4.1, if appropriate) should also be included.

Synopses should be submitted for studies that provide no relevant evaluation of effectiveness or clinical pharmacology. Safety data from such studies must still be provided for review.
Examples of clinical studies requiring synopses include:
• Studies of indications not intended for marketing and which are unrelated to the proposed indication
• Studies evaluating routes of administration not intended for marketing
• Incomplete studies (ie, enrolling fewer than one-third of intended patients), unless stopped due to safety or failure to show efficacy
• Uncontrolled studies not specifically identified as needing abbreviated or full reports
• Early general phase-1 safety-tolerance studies, but not specific, required toxicity studies
The format for an abbreviated report includes the following sections from ICH E3: 2, 12, 16.1.1.

Impact
After the guidance was implemented in 1999, FDA Commissioner Jane Henney described it as a process improvement. “This guidance not only provides clarity,” she stated, “it should also ensure that industry is not submitting more information than is required by the Agency.”1 Reducing the amount of information required saves applicants and reviewers time.

________________________________________
1. Henney JE. Testimony by the FDA Commissioner before the Senate Committee on Health, Education, Labor and Pensions, October 21, 1999. Available at: http://www.fda.gov/NewsEvents/Testimony/ucm115036.htm . Accessed on September 12, 2010.

Blog Post #1: Presenting Risk Information in Prescription Drug and Medical Device Promotion

Rosalyn Finlayson

September 12, 2010

Name of Guidance:

Presenting Risk Information in Prescription Drug and Medical Device Promotion

Status of Guidance

Draft

Date of Guidance

May 2009

Link to the Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM155480.pdf

Target audience

Manufacturers, advertisers, and sponsors who produce promotional materials for prescription drugs and medical devices.

Laws An Regulations Referenced

21 CFR 1.3 Defines label and specifications for the labeling of products in interstate commerce.

21 CFR 202.1 Contains the statutes and regulations regarding truth in advertising.

21 CFR 314.50 Stipulates that the manufacturers draft of a label is subject to review and approval by FDA as part of the new drug application.

103 F.T.C. 110 Federal Trade Commission Policy Statement on Deception, (Oct. 14, 1983)

21 U.S.C. 321 Defines label and specifies that labels failing to reveal material facts will be considered misleading.

21 U.S.C. 352 Stipulates that the manufacturing, sale and distribution of drugs and devices in the United States is regulated by the FDA under the authority of the Federal Food, Drug, and Cosmetic Act.

Kordel v. United States, 335 U.S. 345, 350 (1948) Stipulates that supplemental materials of an article do not require physical attachment but must have a textual relationship.

Summary

The FDA recommendations in this guidance apply to all forms of print, audio and video advertising for prescription drugs and medical devices, including promotional materials produced for the healthcare industry and general public consumers. In formulating compliance recommendations the FDA relied on social science principles and data from cognitive science research studies regarding how the human brain processes visual and auditory information.

Contained within the guidance are clear directives and concrete examples of the factors considered by the FDA in assessing the degree of compliance. The concrete examples provided demonstrate how to present benefit and risk factors as well as the overall presentation of the product. In assessing the overall impression of a promotional piece, the FDA relies on the Federal Trade Commission’s interpretation of social science principles for net-impression to determine if any aspect of the promotional material could be determined as misleading.

Rationale

The FDA seeks to guide manufacturers of prescription drugs and medical devices in the overall design of promotional advertising materials in order to ensure that accurate, truthful and adequate information is being given to consumers and health care professionals.

The FDA provides information from cognitive science studies to encourage the producers of promotional materials to design materials that are compatible with the manner in which a human brain processes visual and auditory information.

Resulting Recommendations

The FDA recommends the following guidelines for drug and medical device promotional materials.

• Language and Terminology: Manufacturers of promotional materials need to use language appropriate for the intended audience by using medical terminology with healthcare professionals and laymen’s terms with general public consumers.

• Signal Clues: The use of signal clues guides the audience’s attention to key components of information. With print materials use a change of graphic or visual context clues as a signal. When producing video, broadcast, and audio mediums use changes in the announcer, voice characteristics, background music, graphics and visual context clues as a signal.

• Framing of Information: Consistently use the drugs name, numerically state the risks statistics, and present the benefit and risk factors with equal tone.

• Hierarchy of Risk Information: Risk factors need to be listed in order of severity taking into consideration the research on cognitive processing. Place the most important risks at the beginning and end of the list when using broadcast and auditory mediums. For print materials place the most important risks first on the list.

• Material Facts: All material facts must present the essential qualities of the products benefits and risks in an accurate and truthful manner. This includes relevant properties about the product such as the appropriateness for use within certain consumer demographics as well as the type of feedback that needs to be communicated between the consumer using the product and their healthcare provider.

• Appearance and Format: Follow cognitive processing principles by using statements in bold type for categories, keep paragraph and sentence length brief, colors and background should enhance readability, use easy to read font size and style, keep non-print superimpositions in video and broadcast on the screen long enough to be read and understood, quality of speech in audio needs to be presented at a pace that can be understood by the target audience, and use background music that has a suitable tone for the type of product.

• Net Impression: Ensure that the overall promotional material conveys a message that is appropriate for the targeted audience.

Impact:

Well-enforced compliance with this guidance will hold the manufacturers of promotional materials accountable for truth in advertising of their product. Responsible advertising and promotion can serve to educate individuals about the variety of drugs and devices available to treat a specific medical condition. Consumers are able to become better self-advocates for their medical treatment when they have truthful and adequate information. Healthcare providers and consumers are ensured of receiving the type of information that will help them understand the benefits and risks of a particular prescription drug or medical device when all of the recommendations presented by the FDA are followed.

Blog #1: Emergency Use Authorization of Medical Products

Michael W. O'Donnell

Name of Guidance: Emergency Use Authorization of Medical Products

Status of Guidance: Final

Release Date: July 2007

Link to Guidance: http://www.fda.gov/RegulatoryInformation/Guidances/ucm125127.htm

Target Audience: Health Care Industry, government agencies, and FDA staff

Laws and Regulations Referenced:
• Sections 502, 505, 510(k), 515, 564, and 903 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360bbb-3)
• Project BioShield Act of 2004 (Public Law 108-276)
• Sections 319, 351 of the Public Health Service Act (PHS Act)
• Good Laboratory Practice requirements in 21 Code of Federal Regulations (CFR) part 58
• Informed consent under part 50 of FDA regulations (21 CFR part 50)
• Medtronic v. Lohr, 518 U.S. 470, 503 (1996); id. at 510
• Cipollone v. Liggett Group, Inc., 505 U.S. 504, 521 (1992) (plurality opinion); id. at 548-49
• English v. General Electric Co., 496 U.S. 72, 79 (1990)
• Florida Lime & Avocado Growers, Inc., 373 U.S. 132, 142-43 (1963)
• Hines v. Davidowitz, 312 U.S. 52, 67 (1941)
• Federal Employees' Compensation Act (5 U.S.C. 8101 et seq.)
• Federal Tort Claims Act (28 U.S.C. 1346(b))
• Smallpox Emergency Personnel Protection Act of 2003 (42 U.S.C. 233(p))
• National Vaccine Injury Compensation Program (42 U.S.C. 300aa-10 et seq.)
• Support Anti-terrorism by Fostering Effective Technologies Act of 2002 (SAFETY Act)
• Public Readiness and Emergency Preparedness Act of 2005 (Pub. L. 109-148)
• 21 CFR 312.34(b)(3)(A)
• 21 CFR 314.610(a)(2) and (3)

Summary:
FDA guidance for the administration and use of unapproved medical products in the event of a state of emergency. These emergency health care measures are intended to protect and treat the public from biological attack, or as a declared emergency preventative action due to heightened risk, or as a response to various acts of bio terrorism that threaten US national security.

The guidance specifically explains the powers initiated by the Emergency Use Authorization (EUA) to be used in the event of an emergency, in order to provide diagnosis, prevention, and treatment during biological, chemical, radiological, and nuclear attacks. The guidance states that enacting the implementation of unapproved medical products is only permitted when there are no available approved forms of prevention and treatment.

Using section 564(b)(1) of the FD&C Act to support its position, the FDA defines what constitutes declaration of an emergency. After the emergency is declared, then an EUA can be issued. The guidance follows this with EUA eligibility criteria, which include but are not limited to, life threatening disease, efficacy hypotheses of potential treatment, risk vs benefit, and availability of alternative treatment.

Procedures for the drug sponsor on how to request their drug be considered as an EUA candidate product are explained. This is vital to efficient emergency management due to time constraints and limitations of the process; the FDA Secretary must first officially declare an emergency, then an EUA can be issued. The guidance discusses recommended steps for overcoming these time limitations by utilizing pre-emergency activities, while the emergency is still in the process of being officially declared, and an EUA has not been issued yet.

Data to be included in the request for a study drug to be considered for an EUA is similar to that of non-emergency drug submissions, which would include safety, efficacy, chemical, and scientific data. Where the EUA drug candidate submission process differs from Investigational New Drug (IND) and New Drug Applications (NDA) is that there will be far less information available to submit, so the guidance explains that it may be necessary to include interim study reports to make up for this shortcoming, and speed along the process due to the expediency an emergency mandates.

The guidance explicates how an EUA is processed, including conditional criteria for emergency use of an unapproved product, and for use of an approved product for an unapproved use. This section of the guidance also explains that Good Manufacturing Practice (GMP) requirements can be waived or limited as the FDA Commissioner sees fit based on the conditions of the emergency. As with clinical trials, adverse events must be reported.

Compared to clinical trials, though, there are some fundamental differences regarding the administration of an EUA treatment product vs a non-emergency test article. One of the primary differences in the administration process of an EUA treatment product is that informed consent is not required. This guidance proclaims, “informed consent under part 50 of FDA regulations (21 CFR part 50) is not required for administration of an EUA product and the information dissemination requirements of section 564 are mandatory only to the extent conditions establishing such requirements are practicable.” However, the guidance also recommends that, “recipients be given as much appropriate information as possible given the nature of the emergency and the conditions of the authorization.” Although informed consent is not necessary, the guidance states that it is required that patients be informed that an emergency use of the product has been authorized by the FDA, and also explained that the benefits and risks involved are unknown.

This guidance also includes recommendations on preemption, EUA termination, liability protection, and possible compensation issues. Appendices are included that feature fact sheets for both health care providers and treatment recipients. As with other FDA guidance, it is emphasized that these methods of emergency response are not legally enforced but strictly recommendations based on, “the Agency’s current thinking.” However, there is extensive legislation cited in this guidance that adequately supports the FDA’s recommendations for the entire EUA process.

Rationale:
This guidance clarifies how the EUA supports the legal distribution of unapproved medical products in the event of an emergency for the health care industry, FDA staff, US government agencies and emergency management professionals. This guidance can help said professionals to develop emergency management plans for bio terrorism and similar emergency scenarios. The numerous laws and regulations referenced can help establish the legal framework for protecting these government and industry professionals from liabilities encountered in an emergency situation.

Resulting Recommendations:
The FDA recommends that patients be informed as much as the situational conditions of the emergency will allow, and that candidate treatment sponsors have a pre-emergency plan to ensure that EUA treatment can become available as soon as possible, for timely public safety.

Impact:
This is a very important FDA guidance that should be understood and utilized by health care providers, local and state government agencies, and FDA regulatory reviewers. The instruction and recommendations are practical considerations to fulfill the goal of reacting to a state of emergency in a timely fashion, in order to protect the public from harm as best as possible.

Michelle Keyvani Blog #1

Name of Guidance:
Process for Handling Referrals to FDA Under 21 CFR 50.54 - Additional Safeguards for Children in Clinical Investigations

Status of Guidance:
Final Guidance released December 2006
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127605.pdf

Target Audience:
Clinical investigators, Institutional Review Boards (IRBs), and sponsors

Laws and Regulations Referenced:
21 CFR 50.54
45 CFR Part 46, Subpart D
45 CFR 46.407
21 CFR Part 50, Subpart D (Subpart D); (See 66 FR 20598)
21 CFR 50.51, 50.52 or 50.53
21 CFR 50.1 and 56.101
CFR 50.55

Summary:
This guidance was created to help clinical investigators, IRBs, sponsors, and other interested parties understand the Food and Drug Administration's (FDA's) process, procedures, and final decisions in regards to clinical investigations that include children as subjects and that have been referred to FDA for review under 21 CFR 50.54.

Rationale:
If an IRB believes that a clinical investigation involving children as subjects does not meet the requirements of 21 CFR 50.51, 50.52 or 50.53, the clinical investigation may still proceed if:

• The IRB provides proof that the clinical investigation presents an opportunity to prevent or alleviate a serious problem affecting the children; and
• The Commissioner of Food and Drugs determines either: a) The clinical investigation does satisfy 21 CFR 50.51, 50.52 or 50.53, or b) The following 3 conditions described in 21 CFR 50.54 are met:

1. The clinical investigation may provide further understanding, prevention, or alleviation of a serious problem affecting the children.
2. The clinical investigation is conducted ethically; and
3. Appropriate soliciting of assent from both children and parents or guardians are made as set forth in 50.55.

Resulting Recommendations:

Public participation is encouraged as such the FDA would like public comment regarding the accepted referral's proposed investigation. The public would have access to review the following materials: the referral documents sent by the IRB, related agency correspondence, public comments on the referral, the transcripts of both the Subcommittee meeting and the PAC meeting, and the final determination of the Commissioner regarding the referral under 21 CFR 50.54. These materials will be available through FDA's Division of Dockets Management or through FDA's Division of Freedom of Information. In addition, the Subcommittee and PAC meetings will be open to the public.

For Clinical Investigators, IRBs and Sponsors - Documents to Include in the Referral:

• IRB's explanation as to why the clinical investigation does not meet the requirements of 21 CFR 50.51, 50.52, or 50.53.
• The research protocol and if applicable, the Investigational New Drug application (IND) or Investigational Device Exemption (IDE).
• All informed consent documents; and
• Any other informative documents (IRB minutes, correspondence between the IRB and the investigator, product labeling, and the investigator's brochure).

When the FDA receives the referral it determines whether the protocol is FDA-regulated and notifies the IRB its determination in approximately 2 weeks.

The Office of Pediatric Therapeutics (OPT) projects the referral process will take approximately six months to complete.

Impact:

"In FDA-regulated clinical investigations involving children, the agency makes every effort to protect the rights, safety, and welfare of those children. In addition, the agency strives to achieve the basic goals of adherence to sound ethical principles, transparency through public and expert input, efficiency, timeliness, clarity, and consistency. FDA believes that these goals are best served by having a clear, efficient, and comprehensive process for referrals by IRBs under 21 CFR 50.54."

Regulatory Blog Post #1 - Exploratory IND Studies

Laura Salomon
September 9, 2010

Name of Guidance:
Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies

Status of Guidance/Release Date:
The final version of this guidance was released by the Center for Drug Evaluation and Research (CDER) in January, 2006.

Link to the Guidance:
The guidance on Exploratory IND Studies can be found at the following location: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm078933.pdf

Target Audience:
Exploratory IND Studies is targeted to sponsors performing preliminary studies in support of Initial New Drug (IND) Applications. The Agency believes that this guidance’s suggestion of exploratory approaches will allow sponsors to more efficiently develop potential drug candidates. Particularly, these approaches are meant for pharmacology/toxicology scientists and researchers who would be involved in the clinical drug development program prior to traditional dose escalation, safety, and tolerance studies.

Laws and Regulations Referenced:
Code of Federal Regulations
21 CFR 312.23(a)(8) IND Content and Format (pharmacology/toxicology data)
21 CFR 312.23(a)(7)(i) IND Content and Format (chemistry, manufacturing, and controls information)
21 CFR 330.1 describes GRAS concept (excipients that are generally recognized as safe)
21 CFR 58 describes processes for ensuring consistency with Good Laboratory Practices
21 CFR 314, Subpart H Accelerated Approval of New Drugs for Serious of Life Threatening Illnesses

Food and Drug Administration Guidances for Industry
Fast Track Drug Development Programs – Designation, Development, and Application Review
Nonclinical Studies for Development of Pharmaceutical Excipients
INDs for Phase 2 and Phase 3 Studies, Chemistry, Manufacturing, and Controls (CMC) Information

International Conference on Harmonisation Guidances for Industry
M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
S7A Safety Pharmacology Studies for Human Pharmaceuticals
S2A Guidance of Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals
S2B Genotoxicity: A Standard Battery for Genotoxicity Testing for Pharmaceuticals

Summary:
The FDA asserts that existing regulations allow for a great deal of flexibility in the amount of data sponsors are required to submit with an IND application, depending on the proposed investigational plan and the specific human testing proposed and expected risks involved. Sponsors have not generally taken advantage of this flexibility and often submit more than what is required; this approach is inefficient and often lengthens the amount of time and resources expended on candidate products that are not likely to succeed. The early phase I approaches described in this guidance are consistent with regulatory requirements and maintain human subject protection, but involve fewer resources, thus enabling sponsors to more quickly distinguish drug candidates that are promising from those that are not.

Exploratory IND studies involve limited human exposure and have no therapeutic or diagnostic intent. This guidance proposes that such studies can help sponsors make early distinctions among potential drug candidates in several ways:

• Gathering information on the mechanism of action defined in experimental systems (e.g. binding property or enzyme inhibition) that may or may not be observed in humans
• Selecting a promising lead product for a particular therapeutic human target based on pharmacokinetic (PK) or pharmacodynamic (PD) properties
• Exploring a product’s biodistribution characteristics using imaging technologies

The guidance continues to provide sponsors with instruction on how to utilize exploratory IND studies in an overall Initial New Drug Application, including information on constructing an appropriate clinical development plan, CMC information, pharmacology and toxicology sections, and previous human experience (if any). Depending on the study, the preclinical testing programs that utilize exploratory IND studies can be less extensive than those for traditional IND studies because they involve sub-pharmacologic doses of candidate programs and therefore present fewer potential risks to humans.

Rationale:
This guidance references the FDA’s March, 2004 report, Innovation or Stagnation, Challenge and Opportunity on the Critical Path to New Medical Products, as its rationale. As part of its effort to reduce the time spent in early drug development on products that are unlikely to succeed, the Agency recommends sponsors take advantage of exploratory approaches, which are consistent with regulatory requirements but allow for a more efficient separation of potential drug candidates from hundreds or thousands of new molecular entities that a sponsor may develop.

Resulting Recommendations:
The Agency recommends that sponsors take advantage of the flexibility in IND data required, which varies according to the goals of a proposed investigation, specific human testing proposed, and expected risks. This flexibility allows for exploratory IND research techniques that may reduce the time and resources needed for sponsors to indentify promising potential drug candidates.

Impact:
As part of the FDA’s continuous effort to reduce unnecessary time and resources in drug development programs, the impact of this guidance is widespread in industry. Sponsors focused on exploratory studies may be able to more efficiently identify a potential drug candidate and therefore make better use of time and resources. Reducing costs and time involved in drug development results in huge gains for the sponsor: they spend less on drug development and have the potential to bring therapeutic products to market more quickly. The Agency benefits as well – receiving more focused IND applications based on exploratory studies without extraneous data allows for a more efficient review process and may enable sponsors to move forward with later phase clinical trials more quickly.

Blog #1: Industry-supported Scietific and Educational Activities

Theresa Seiverd
BW706-Blog 1
1. Name: Industry-supported Scientific and Educational Activities
2. Status: Final Guidance
3. Release Date: December 3, 1997
4. Link to Guidance: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM125602.pdf
5. Target Audience: Health care professionals, companies (ie, sponsor of the marketed product), providers, provider (ie, individual or consultant that facilitates the educational activities)
6. Laws and regulations referenced: There are no regulations referenced in this guidance. The FDA (ie, the agency) has not had oversight into company activities that support scientific seminars and educational forums and does not intend to regulate these activities which are considered independent of the supporting sponsor.
7. Summary:
The goal of the guidance is to ensure that industry-supported scientific and educational activities are designed to be nonpromotional and independent of any outside influence from individuals by evaluating programs and presenters by the following factors:
o Control of content and selection of presenters and moderators: The agency will take into consideration whether the sponsor maintained control over the content of the program and selection of speakers.
o Disclosures: The agency will take into consideration the company’s funding and the relationship between the presenters and the sponsor. The agency will also consider if any unapproved uses of the product are planned to be discussed.
o Focus of the program: the agency will take into consideration the content of the program is independent of any commercial influence and ensure the content is provided in the context of relevant and reasonable options or alternative therapies.
o Relationship between the provider and supporting company: The agency will take into consideration the relationship between the company and the provider to ensure the company has no influence over the content being presented.
o Provider involvement in sales or marketing: The agency will consider if the provider that is involved in conducting the scientific or educational activities is not involved in any sales or marketing of the company’s product.
o Provider’s demonstrated failure to meet standards: The agency will take into consideration the provider’s history in conducting educational programs and whether they met the expectation of conducting an independent educational program free of any promotional bias or external influence.
o Multiple presentations: The agency will consider if multiple presentations are being held with the understanding that sometimes multiple presentations are necessary and in the public’s best interest.
o Audience selection: The agency will take into consideration if the sales and marketing departments of the sponsor company were involved in generating the mailing list and invitations for the educational or scientific-supported event.
o Opportunities for discussion: The agency will take into consideration the discussion or questioning period of the program.
o Dissemination: The agency will take into consideration if the information is further communicated after the initial program through an independent provider.
o Ancillary promotional activities: The agency will take into consideration any promotional activities (ie, sales presentations or exhibits) taking place in addition to the education program.
o Complaints: The agency will take into consideration any complaints from the program’s participants, the provider, or presenters with regard to the sponsor influencing the content presented.
8. Rationale:
This guidance seeks to protect the sponsors, providers, health care professionals, and ultimately the patients to ensure educational and promotional activities of a product’s benefits are not potentially jeopardized from false or misleading information be communicated. Information must be presented independently of any bias being introduced by the sponsor such as unapproved uses for the product that are not indicated on the label, and discussions of the product’s use that are misleading or not scientifically proven. This same expectation is applied to a company’s competing products too. Information being communicated must be scientifically supported and indicated in the product label.
9. Resulting recommendation: The agency does not mandate, but recommends there is a written agreement between the company sponsor and provider. The agreement should be reflective of the responsibility of the provider to design and conduct an educational activity that is free from any company or commercial influence.
10. Impact: This guidance offers companies and educational providers a basis for how to conduct educational activities in a manner that is responsible, accurate, and professional for both sides. The considerations put forth by the agency are appropriate and adequate to ensure industry supported scientific and educational programs are communicating information to health care professionals that have the patient’s best interest up front.