The FDA has published new draft guidance, Postmarketing Studies and Clinical Trials — Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act

Introduction

This guidance provides information on the implementation of new section 505(o) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(o)), added by section 901 of the Food, and Drug Administration Amendments Act of 2007 (FDAAA). Section 505(o) authorizes FDA to require certain post marketing studies and clinical trials2 for prescription drug and biological products approved under section 505 of the Act or section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262). This guidance provides information about the requirements for postmarketing studies and clinical trials under section 505(o) of the Act. The guidance also describes the types of postmarketing studies and clinical trials that:

• will generally be required under the new legislation (postmarketing requirements (PMRs)) and
• will generally be agreed-upon commitments (postmarketing commitments (PMCs)) because they do not meet the new statutory criteria for required postmarketing studies and clinical trials

Background

On September 27, 2007, the President signed FDAAA (Public Law 110-85). Section 901 of  Title IX of FDAAA amended the Act by adding new section 505(o). Section 505(o) authorizes  FDA to require certain postmarketing studies and clinical trials for prescription drug and biological products approved under section 505 of the Act or section 351 of the PHS Act.

Past Practice

In the past, FDA has used the term postmarketing commitment (PMC) to refer to studies (including clinical trials), conducted by an applicant after FDA has approved a drug for  marketing or licensing, that were intended to further refine the safety, efficacy, or optimal use of a product or to ensure consistency and reliability of product quality. These PMCs were either agreed upon by FDA and the applicant or, under certain circumstances, required by FDA. Prior to the passage of FDAAA, FDA required PMCs in the following situations:

• Subpart H and subpart E accelerated approvals for products approved under 505(b) of the Act or section 351 of the PHS Act, respectively, which require postmarketing studies to demonstrate clinical benefit (21 CFR 314.510 and 601.41);
• Deferred pediatric studies, where studies are required under the Pediatric Research Equity Act (PREA) (21 CFR 314.55(b) and 601.27(b)); and
• Animal Efficacy Rule approvals, where studies to demonstrate safety and efficacy in humans are required at the time of use (21 CFR 314.610(b)(1) and 601.91(b)(1)).

New FDAAA Authority and Requirements

Section 505(o) of the Act authorizes FDA to require postmarketing studies or clinical trials at the time of approval or after approval if FDA becomes aware of new safety information. Section 89 505(o)(3)(A) states that postmarketing studies and clinical trials may be required for any or all of  three purposes listed in section 505(o)(3)(B):

• To assess a known serious risk related to the use of the drug
• To assess signals of serious risk related to the use of the drug
• To identify an unexpected serious risk when available data indicate the potential for a serious risk

Applicants Are Required to Report on the Status of Studies and Clinical Trials.

The applicant is required to provide certain information to FDA with regard to required postmarketing studies and clinical trials (section 505(o)(3)(E)(ii)). Under section 505(o)(3)(E)(ii), this information must include:

• For all required postmarketing studies and clinical trials, a timetable for completion
• For each study required under section 505(o), periodic reports on the status of the study, including whether any difficulties in completing the study have been encountered
• For each clinical trial required under section 505(o), periodic reports on the status of the 128 clinical trial, including:
  • whether enrollment has begun,
  • the number of participants enrolled,
  • the expected completion date,
  • whether any difficulties completing the clinical trial have been encountered, and
  • registration information with respect to the clinical trial under section 402(j) of the PHS Act (42 U.S.C. 282(j))

Implementation of postmarkeing study and clinical trial requirements under FDAAA

Under section 505(o)(3) of the Act, FDA will require applicants to conduct a postmarketing study or studies or clinical trial(s) when the following conditions are met:

1. When the decision to require a postmarketing study or clinical trial is based on scientific data deemed appropriate by FDA, including information regarding chemically-related or pharmacologically-related drugs; and
2. When FDA has found —
   1. before requiring a postmarketing study, that adverse event reporting under section 505(k)(1) of the Act and the new pharmacovigilance system that will be established under section 505(k)(3) will not be sufficient to meet the purposes described in condition 3 below; and
   2. before requiring a postmarketing clinical trial, that a postmarketing study will not be sufficient to meet the purposes in condition 3 below; and
3. When the purposes of the study or clinical trial, as described in section 505(o)(3)(B), are one or more of the following
   1. To assess a known serious risk related to the use of the drug
   2. To assess signals of serious risk related to the use of the drug
   3. To identify an unexpected serious risk when available data indicates the potential for a serious risk

When these conditions are met, the Agency intends to require the study or clinical trial as a postmarketing requirement (PMR).

the draft regulations continue in more detail, Postmarketing Requiremtns (PMRs), Postmarketing Commitments (PMCs), Procedures, Reporting, Dispute Resultion, and Enformcement of Requiremtns for Postmarketing Studies and Clinical Trails.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

Turn your Business Into an Investor Magnet

How to Write a Business Plan – Free E-Course

Get the secrets that turns your project into an investment magnet, 100% of our clients raise the finance they need to take their projects to the next stage, we will share these secrets with you. – Sign up for Free

Grow your Expertise for Free

As you know this website is a great resource for keeping up to date with developments and regulations, why not get our FREE monthly regulatory and market round up. You can un-subscribe at any time and we do not share your details with anybody.

The FDA has published guidance on “Updating Labeling for Susceptibility Test Information in Systemic Antibacterial Drug Products and Antimicrobial Susceptibility Testing Devices.  The purpose of this guidance is to inform industry of how the FDA intends to comply with section 1111 of the Food and Drug Administration Amendments Act (FDAAA), which requires FDA to identify and periodically update susceptibility test interpretive criteria for antibacterial drug products and to make those findings publicly available. Because susceptibility test interpretive criteria, susceptibility test methods, and quality control parameters are interrelated, this guidance addresses procedures for updating all three of these elements of labeling of antibacterial drug products for human use. The guidance is also intended to remind drug application holders of their responsibility to update this information in the labeling of their antibacterial drug products. In addition, this guidance provides directions to manufacturers of antimicrobial susceptibility testing (AST) devices for updating labeling regarding susceptibility testing information.

The Importance of Susceptibility Test Interpretive Criteria

Antibacterial susceptibility testing is used to determine if bacteria that are isolated from a patient with an infection are likely to be killed or inhibited by a particular antibacterial drug product at the concentrations of the drug that are attainable at the site of infection using the dosing regimen(s) indicated in the drug product’s labeling. The results from antibacterial susceptibility testing generally categorize bacteria as “susceptible,” “intermediate,” or “resistant” to each antibacterial drug tested. When available, culture and susceptibility testing results are one of the factors that physicians consider when selecting an antimicrobial drug product for treating a patient.

Antibacterial Drug Product Labeling

FDA regulations require that information on susceptibility testing be included in the labeling for antibacterial drug products (see 21 CFR 201.57(c)(2)(i)(C)). The INDICATIONS AND USAGE section of labeling for antibacterial drugs includes the condition(s) for which the product has been found to be safe and effective if used as described in the product labeling. The INDICATIONS AND USAGE section also includes a list of specific microbial organisms for the particular indicated condition(s). The results from culture and susceptibility testing can be used to guide selection of an appropriate antibacterial drug product. Over time, additional information may become available and/or changes may occur regarding the susceptibility of certain bacteria to antibacterial drugs.

Consequently, it is important that the in vitro susceptibility test methods, the susceptibility test interpretive criteria, and the quality control parameters listed in the labeling for a product be reviewed on a regular basis and updated to reflect the most current information.

The FDA approach

Where appropriate, FDA intends to recognize susceptibility test interpretive criteria, and associated test methods and quality control parameters, by publishing annually in a Federal Register notice certain standards developed by one or more nationally or internationally recognized standard development organizations. Under this approach, FDA retains the authority to accept or reject for recognition (based on our scientific judgment) any susceptibility test interpretive criteria, or associated susceptibility test method or quality control parameters, developed by a standard development organization for a specific bacterium treated by a specific approved antibacterial drug product.

Updating Susceptibility Test Information

Holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) that are designated as a reference listed drug (RLD) for systemic antibacterial drug products should review their product labeling at least annually to evaluate whether the Microbiology subsection is up to date.

This guidance describes two approaches for application holders to update labeling as follows:

• Updating information in the Microbiology subsection of product labeling by submitting revised product labeling that is in conformance with a standard that has been recognized by the Agency.
• Submitting data that support a change in the information in the Microbiology subsection of product labeling that differs from the Agency’s recognized standard

Applicants Believes No Change to the Labeling is Needed.

If the information in the applicant’s product labeling differs from the standards recognized by the Agency and the applicant believes that changes to the labeling are not needed, the applicant should provide written justification to the FDA within 90 days following the publication of the Federal Register notice.

In-Vitro Diagnostic AST Devices

Where appropriate, FDA intends to recognize susceptibility test interpretive criteria, and associated test methods and quality control parameters, by publishing annually in a Federal Register notice references to standards developed by one or more nationally or internationally recognized standard development organizations. Once FDA has recognized a standard, NDA holders should update their drug labeling as described in section IV and FDA will make the approved, updated drug labeling publicly available. If the susceptibility test interpretive criteria in the labeling for an AST device do not conform with the updated drug labeling, AST device manufacturers should update their labeling to conform with the new, publicly available drug labeling within 90 days.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

Grow your Expertise for Free

As you know this website is a great resource for keeping up to date with developments and regulations, why not get our FREE monthly regulatory and market round up. You can un-subscribe at any time and we do not share your details with anybody.

• Non-clinical data on anti-fungal activity that should be generated prior to and during the clinical development programme.
• Clinical study design recommendations for studies that evaluation anti-fungal agents for the treatment of invasive fungal disease
• Drug development guidance for; drug combinations, salvage therapy, studies in neutropenic patients and the assessment of prophylaxis
• Bio-marker guidance for patient selection
• paediatric development plans (a regulatory requirment discussed extensively on this site)
• Clinical Safety Assessment
• SPC sections 4.1 and 5.1 layout and content

Background

Clinical and drug development of anti-fungal agents for the treatment and prophylaxis of invasive fungal disease (IFD) requires special attention because IFD occurs in a heterogeneous group of patients most of whom have evidence of debilitation and/or immunosuppression. IFD may occur with or without detection of fungi in the blood cultures, and in some cases it is detected in the blood but source of infection can’t be found.

Factors such as infection site and fungal pathogen, complexity of the underlying illness, variable degree and duration of immunosuppression and its mode of management and incidence of concomitant infections with bacteria and viruses may affect the mycological response to therapy and the overall clinical outcome.

Changes in the clinical practice has prompted these updated guidelines:

• Increased availability of anti-fungal agents
• Prophylaxis use has increased
• Emergence of rapid diagnostic tests
• Revised definitions of IFD published by the Invasive Fugal Infections Co-operative Group (IFIG) of the European Organization for Research and Treatment of Cancer, and the Mycosis Study Group of the National Institute of Allergy and Infections Disease (NIAID)
• Anti-fungal susceptibility testing standardisation published by The European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Drug Development Guidance Scope

The guideline is primarily concerned with the content of clinical development programmes to assess the safety and efficacy of anti-fungal agents administered by oral or parenteral routes for the treatment and prophylaxis of IFD. The guidance includes:

• Consideration of the non-clinical data on anti-fungal activity that should be generated prior to and during the clinical development programme
• Criteria for enrolment and criteria for assessing the certainty of diagnosis
• The assessment of clinical efficacy including the design of studies that evaluate antifungal agents for treatment or prophylaxis of IFD.
• The assessment of clinical safety.
• Reflection of the mycological and clinical data in the SPC.

Clinical Evaluation

Assessment of antifungal activity is required:

• Spectrum of in-vitro antifungal activity.
• Mode of action
• Mechanism(s) of resistance
• Cross-resistance within and between anti-fungal drug classes.
• Synergy or antagonism with antifungal agents of different classes
• Efficacy in animal models
• Pharmacokinetic/pharmacodynamic (PK/PD) relationship.

Assessment of Efficacy:

• All fungi that are isolated and considered to be causative of IFD should be forwarded to one or more designated reference laboratories for confirmation of identity and susceptibility testing
• Clinical and mycological outcomes should be analysed in the light of in-vitro susceptibility and patient pharmacokinetic data to further assess the PK/PD relationship
• It is recommended that at least some of the in-vitro data should be generated using susceptibility testing methodologies published by EUCAST since this will facilitate the setting of EUCAST-recommended breakpoints.
• Any available EUCAST-recommended susceptibility testing breakpoints for common Candida species and Cryptococcus species should be included in the SPC
• Susceptibility and resistance should be further assessed in the post-approval period

Patient Selection Criteria

• Sponsors may choose to enrol patients who already have proven or probable IFD
• studies may enrol patients who are considered likely to have the type of IFD under investigation.
• Patient Selection Criteria:
  • Clinical history, signs and symptoms
  • Imaging studies
  • Microscopic findings in suitable specimens
  • Rapid antigen or nucleic acid detection tests.
  • Culture results from suitable specimens
  • Histological findings
  • The presence (degree and prior duration) or absence of neutropenia at baseline.
  • Prior IFD within a defined timeframe and/or during a previous period of neutropenia
  • Specific pre-disposing factors for IFD (e.g. HIV infection, type of immunosuppressive therapy).

Treatment Regimens

Monotherapy – The selection of proposed regimen(s) to be studied in confirmatory studies of clinical efficacy should be based on all the available non-clinical data, human pharmacokinetic data and exploration of the PK/PD relationship. Whenever possible the active comparative therapy should be restricted to a single regimen. The protocol should pre-define a minimum duration of therapy for patient evaluability and a maximum duration beyond which patients who have not met the response criteria should be considered to have failed therapy.

Combination Therapy

The choice of antifungal agents to be co-administered should take into account the in-vitro activity of the combination against target genera/species. if possible, the selection of combination regimens to treat specific types of IFD should also be supported by a demonstration of benefit for co-administration over each agent given alone in an animal model. Consideration should also be given to the potential for significant drug-drug pharmacokinetic or pharmacodynamic interactions to occur, which may preclude co-administration or may indicate a need for dose adjustment of one or both agents.

The guidance goes on to give plenty of details of the study designs. Outcomes testing and specific patient groups, its a detailed guidance that needs careful consideration for anybody working in the area.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.

Grow your Expertise for Free

As you know this website is a great resource for keeping up to date with developments and regulations, why not get our FREE monthly regulatory and market round up. You can un-subscribe at any time and we do not share your details with anybody.