Regulatory Submissions

BioPharma Global offers a broad scope of regulatory submission writing services in the high unmet medical needs and rare disease space. We have extensive experience in drug, biologic, and device products for the treatment of adult and pediatric indications. Our recent experience includes immune-oncology, neurology, ophthalmology, oncology, hematology, dermatology, metabolic, infectious, genetic, pulmonary, renal, and mitochondrial diseases.

For our Regulatory Strategy Development services, click here.

Electronic Publishing and Submission

 

As of May 5, 2018, all marketing and commercial IND applications, all subsequent submissions to these applications, and most master files, are required by the US FDA to be submitted using the eCTD format. Our regulatory publishing team will support the electronic publishing and submission of your regulatory documents to US FDA through the Electronic Submission Gateway (ESG). Our team is highly experienced in navigating the complex publishing requirements using industry-leading publishing systems and tools.


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*Most applications mentioned below can be submitted electronically, except ODD and RPD.

 

FDA Applications

In certain cases, an investigational drug will take years to show any significant effects on a very slow-acting or long-lasting disease. Accelerated Approval was instituted by the FDA in 1992 to allow drugs that treat serious conditions and filled an unmet medical need to be approved based on a surrogate or an intermediate clinical endpoint.

Biopharma Global can write and review your annual reports for various submissions (i.e. ODD, IND)

A Biologics License Application (BLA) is a request for permission to commercialize a biologic product. BLA must include specific information on the product/manufacturing processes, preclinical and clinical results, chemistry, pharmacology, labeling information, and the medical affects of the biologic product. The BLA must provide enough information to allow the FDA to determine the following:

  • Drug safety, purity, and potency
  • Quality of drug manufacturing
  • Drug labeling
 

Breakthrough Therapy Designation allows for the expedited development and review of a drug that is intended to treat a serious disease and has evidence that shows a substantial improvement over current therapy for clinically significant endpoints.

Upon designation, the FDA ensures that the sponsor receives timely interactive communications to help them design an efficient drug development program by involving experienced regulatory project managers in a cross-disciplinary review. Where appropriate, a cross-disciplinary project lead is assigned to the review team to facilitate an efficient review of the drug development program, as well as act as a scientific liaison between the review team members.

Designation also includes a rolling review to allow the sponsor to submit portions of the marketing application to the FDA counting towards the complete application.

Eligibility Criteria:

  1. The disease must be recognized as a serious condition.
    • The FDA considers a disease as a serious condition when it is associated with morbidity that has substantial impact on day-to-day functioning.
    • In addition, the drug itself must be intended to treat the serious condition. To satisfy this, the drug’s intended effect must apply to a serious condition or a serious aspect of the condition. This can be a serious manifestation or symptom.
  2. The preliminary clinical evidence must show that the investigational drug exhibits a substantial improvement on one or more of the clinically significant endpoints.
    • FDA generally considers available therapy as a therapy that is approved or licensed in the United States for the same indication being considered for the new drug, and is relevant to current U.S. standard of care (SOC) for the indication. This consideration is carried out by the FDA themselves, but FDA may consult with special Government employees or other experts as needed when making an available therapy determination.
    • The FDA expects that this data generally comes from credible Phase 1 or Phase 2 clinical trials. These studies usually also compare the investigational drug to an available therapy or placebo if no current therapy exists. An improvement is considered to be substantial depending on the drug’s magnitude of effect on a clinically significant endpoint, and the importance of the effect in relation to the overall improvement of the serious condition or aspect of the serious condition.
      • A clinically significant endpoint is generally an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. A sponsor should provide a justification for why the endpoint or other findings should be considered clinically significant.
 
 

Fast Track Designation allows for better facilitation of drug development and an expedited review process by the FDA. Fast Track Designation provides a rolling review submission process, enabling the sponsor to submit portions of the marketing application to the FDA  counting towards the complete application.

Eligibility Criteria:

  1. The drug treats a serious condition.
    • The FDA considers a disease as a serious condition when it is associated with morbidity that has substantial impact on day-to-day functioning.
    • In addition, the drug itself must be intended to treat the serious condition. To satisfy this, the drug’s intended effect must apply to a serious condition or a serious aspect of the condition. This can be a serious manifestation or symptom.
  2. The drug fills an unmet medical need.
    • The information required to prove a drug can address an unmet medical need depends on the stage of drug development at which fast track designation is requested.
      • Early in development: evidence of activity in a nonclinical model, a mechanistic rationale, or pharmacologic data.
      • Later in development: available clinical data should demonstrate the potential to address an unmet medical need.
 
 

The Orphan Drug Act of 1983 defines a rare disease as a disorder or condition that affects less than 200,000 people in the US. This act provides incentives that allows companies to develop drugs for a disease that affects a small portion of the US population without the daunting financial obstacles associated with reduced market size.

Benefits of an Orphan Drug Designation include:

  • Prescription Drug User Fee Act (PDUFA) fee waiver (a value of over $2 million)
  • Guaranteed 7 years of market exclusivity
  • 25% tax credits for all clinical studies conducted within the US

Eligibility criteria:

  1. Reputable data supporting that the indication affects a population of fewer than 200,000 people in the US
  2. Positive drug efficacy data (can be preclinical data) showing that the active ingredient in the proposed drug has been shown to be effective in treating the clinically relevant endpoints associated with the indication.
 
 

Formal meetings with the FDA facilitate communication between the sponsors of a drug and the FDA review staff on regulatory requirements and development. These meetings are scheduled for critical junctures in the drug development process, including:

  • Pre-Investigational New Drug (Pre-IND) Meeting
    • Held prior to IND filing, this meeting allows for very valuable planning and guidance for a drug sponsor on clinical trial design, reducing the chances of clinical holds and fosters early interactions with the FDA. 
  • INTERACT Meeting (Initial Targeted Engagement for Regulatory Advice on CBER ProducTs)
    • One consultation with CBER on issues that to be need to be addressed prior to a pre-IND meeting request
    • Sponsors can obtain initial non-binding advice regarding CMC, pharmacology/toxicology, and/or clinical aspects of the development program for novel and innovative investigational products
  • End-of-Phase Meetings
    • Held for drugs targeting severely debilitating and life-threatening illnesses to review and reach agreement on the next clinical trial design.
    • Determines the safety of proceeding to the next phase, the ability of current studies to assess safety and effectiveness, and organizes the information necessary for a marketing application.
  • Pre-New Drug Application (Pre-NDA) and Pre-Biologics License Application (Pre-BLA)
    • Allows for the clarification of requirements and the organization of information for the NDA/BLA. Early communication with the FDA will also allow for the reviewers to be familiar with the research and drug prior to submission

Types of FDA Meetings:

  • Type A
    • Intended for the continuation of the development of a stalled drug program.
    • Dispute Resolution | Clinical Holds | Protocol Assessment and Evaluation | Post-Action Meetings
  • Type B
    • Pre-Investigational New Drug (pre-IND) | End-of-Phase | Pre-New Drug Application (pre-NDA)/Pre-Biologics License Application (pre-BLA)
    • Risk Evaluation and Mitigation Strategies (REMS) or post-marketing requirements that occur outside the context of the review of a marketing application
    • Post-action meetings requested by the sponsor 3 months or more after an FDA regulatory action other than an approval
    • Meetings held to discuss the overall development program
  • Type C
    • Intended to discuss development and review of a product that is outside the scope of type-A or type-B meeting
    • Longer request and response time
 
 

Federal Law requires that a drug is approved for market before it can be transported or distributed across state lines. However, since a drug sponsor will need to transport the drug across state lines to reach out-of-state clinical investigators, the FDA created the IND application to grant an exemption from that legal requirement.

Types of IND applications:

  1. Investigator Initiated IND – submitted by the physician who both initiates and conducts the investigation, and is responsible for the administration and distribution of the drug.
  2. Emergency Use IND – allows for authorization of an experimental drug by the FDA in an emergency situation where there is not enough time for the entire application submission and approval process.
  3. Treatment IND – reserved for experimental drugs already  that show promise in clinical testing for serious or immediately life-threatening conditions and is considered appropriate by the FDA to use on patients outside of the clinical trials.

Requirements for successful IND filing:

  • Positive preclinical animal efficacy and toxicology data.
  • Manufacturing information outlining the composition, manufacturer, stability, and quality controls used for manufacturing the drug.
  • Protocols for the proposed clinical studies to assess risks and safety for the subjects.
 

The New Drug Application (NDA) is the formal final step taken by a drug sponsor to get approval from the FDA for commercialization of a drug. The NDA must showcase the drug’s whole story, including preclinical and clinical studies, drug ingredients, pharmacodynamics, manufacturing, and packaging processes. The NDA must provide enough information to allow the FDA to determine the following at least:

  • Drug Safety and Efficacy
  • Drug Labeling and Package Insert
  • Quality of Drug Manufacturing
 

The FDA normally takes a maximum of 10 months to act on a marketing application for a drug. When granted priority review, this timeframe shrinks to a maximum of 6 months. This designation will direct the FDA’s resources to the evaluation of applications for drugs that would be significant improvements in the safety or effectiveness of the diagnosis, treatment, or prevention of serious conditions when compared to normal applications.

Eligibility Criteria:

  1. The disease must be recognized as a serious condition.
    • The FDA considers a disease as a serious condition when it is associated with morbidity that has substantial impact on day-to-day functioning.
    • In addition, the drug itself must be intended to treat the serious condition. To satisfy this, the drug’s intended effect must apply to a serious condition or a serious aspect of the condition. This can be a serious manifestation or symptom.
  2. The drug must demonstrate the potential to be a significant improvement in safety or effectiveness.
    • The FDA will determine if the proposed drug would be a significant improvement in the safety and efficacy of treatment, prevention, or diagnosis of a serious condition. A significant improvement can be demonstrated by increased effectiveness of treatment/diagnosis/prevention, elimination or reduction of adverse reaction to treatment, enhancement of patient compliance leading to improved outcomes, or evidence of safety and effectiveness in a new subpopulation.

Priority Review Voucher (PRV)

The Priority Review Voucher (PRV) is granted by the FDA as an incentive for the development of drugs, which would otherwise not be worth development due to their specialized markets. The voucher can be used to request priority review for any drugs being developed by the submitting sponsor. The voucher is transferable and can be sold to other sponsors or companies.

The PRV can be granted to drugs being developed for rare pediatric indications, a list of tropical diseases, and medical countermeasure diseases.

 
 

QIDP (Qualified Infectious Disease Product) designation is offered by the US FDA to help incentivize the development of treatments for infectious diseases. Title VIII of FDASIA, Generating Antibiotic Incentives Now (GAIN), added section 505E of the Food, Drug & Cosmetic Act, providing incentives for the development of antibacterial and antifungal drugs for human use intended to treat serious and life-threatening infections. Incentives available to sponsors of QIDP include fast track designation, priority review designation, and 5 years of additional market exclusivity.

The term “qualifying pathogen” in section 505E(f) of the Federal Food, Drug, and Cosmetic Act is defined to mean any of the following:

  • (a) Acinetobacter species
  • (b) Aspergillus species
  • (c) Burkholderia cepacia complex
  • (d) Campylobacter species
  • (e) Candida species
  • (f) Clostridium difficile
  • (g) Coccidioides species
  • (h) Cryptococcus species
  • (i) Enterobacteriaceae
  • (j) Enterococcus species
  • (k) Helicobacter pylori
  • (l) Mycobacterium tuberculosis complex
  • (m) Neisseria gonorrhoeae
  • (n) Neisseria meningitidis
  • (o) Non-tuberculous mycobacteria species
  • (p) Pseudomonas species
  • (q) Staphylococcus aureus
  • (r) Streptococcus agalactiae
  • (s) Streptococcus pneumoniae
  • (t) Streptococcus pyogenes
  • (u) Vibrio cholerae
 

A rare pediatric disease designation may be granted by the FDA to drugs and biologics intended to treat orphan diseases affecting fewer than 200,000 patients in the U.S., primarily aged 18 years or younger. The designation provides incentives to advance the development of rare disease treatments, including access to FDA’s expedited review and approval programs. A sponsor that receives approval for biologics treating a rare pediatric indication may be eligible to receive a voucher for a priority review of a subsequent marketing application for a different product. The program has recently sunset. 

 

RMAT Designation is reserved for drugs that are considered regenerative medicine therapies, such as cell and gene therapy, therapeutic tissue engineering products, human cell and tissue products, or any combination product using the listed therapies. Similar to BTD, RMAT Designation grants earlier interactions with the FDA, as well as potential eligibility for priority review and accelerated approval.

Eligibility Criteria:

  1. The drug is a considered a regenerative medicine therapy.
  2. The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
  3. Preliminary clinical data shows that the drug can address an unmet medical need.
 

EMA Applications

 

Biopharma Global can write or review your annual reports (i.e. EMA ODD, CTA).

 

Under the clinical trial application (CTA) procedure, sponsors will be required to apply via a EU portal for authorization to conduct an interventional clinical trial with medicines in Europe. CTA provides comprehensive information about the investigational medicinal product(s) and planned trial, enabling regulatory authorities to assess the acceptability of conducting the study. It is a procedure that not only combines the content of what is can be currently referred to as the “regulatory” and “ethics” applications, but also combines the scientific, technical and ethical review necessary to receive approval to conduct a CT in the EU. The application is submitted via the portal to all Concerned Member States (CMS) where the Sponsor intends to conduct the CT.

The EMA will approve a drug for market after a full scientific evaluation following submission by the drug sponsor. Once a drug is approved, the marketing authorization applies to all European Union Member States, as well as Iceland, Norway, and Lichtenstein. 

Types of MAA:



Centralized Procedure

Mandatory for products derived from biotechnology, orphan drugs, and medicinal products for human use which contain an active substance authorized in the community after 20th May, 2004, and are intended for the treatment of AIDS, cancer, neurodegenerative disorders, or diabetes. Mandatory for products that are used as performance enhancers or to increase yield from animals.

Mutual Recognition Procedure
Mandatory for all medicinal products to be marketed in a member-state other than they were first authorized in, since 1st January, 1998.

National Procedure
For an individual member-state and follows guidelines similar to other MAA procedures.

Decentralized Procedure
Mandatory to acquire marketing authorizations in several member states, even though no marketing authorization has been granted in the European region.

Similar to the FDA Orphan Drug Designation, the EMA provides incentives for developing drugs that treat rare diseases affecting less than 5 in 10,000 people in the EU. The EMA defines an Orphan Medicine as a drug intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating rare disease. 

Benefits:

  • Fee reduction/exemption for scientific advice and protocol assistance
  • Guaranteed 10 years of drug exclusivity
  • Centralized Marketing Authorization Procedure
 

The PRIME program was established to aid the development of drugs that target an unmet medical need. Like Fast Track, PRIME provides support for the clinical research and development of a medicine via accelerated assessment and initiating earlier dialogue with the EMA. Priority Medicines are considered as drugs that could offer a significant advantage over current therapies, or benefit patients who do not currently have any other treatment options. To be accepted, a medicine must show potential benefit to patients with unmet medical needs based on early clinical data.

Benefits:

  • The appointment of a rapporteur to the drug development project
    • The rapporteur can be from the Committee for Medicinal Products for Human Use (CHMP), or from the Committee on Advanced Therapies (CAT) in the case the drug is considered an advanced therapy
    • The project will be provided with continuous support and information before the submittal of the Marketing Authorization Application
  • A scheduled kick-off meeting with the rapporteur and a multidisciplinary group of experts to provide guidance on development and regulatory strategy
  • Provide scientific advice at certain milestones in development, while also involving other stakeholders
  • Confirm the potential for accelerated assessment before marketing authorization