NDA BLA

Key IND Enabling Studies: Navigating Preclinical Development Regulations

January 7, 2024 by Jose Rossello Leave a Comment

Investigational New Drug (IND) applications represent a critical stage in the development of new pharmaceuticals and biologics. Before a new drug can be administered to humans in clinical trials, the U.S. Food and Drug Administration (FDA) requires substantial evidence that it is safe and potentially effective. This is where IND-enabling studies play a pivotal role, providing the requisite data on pharmacology, pharmacokinetics, and toxicology to understand the drug’s behavior in the body and its potential effects on various biological systems.

IND-enabling studies are a series of preclinical assessments that form the foundation for an IND application. They typically include evaluations of a drug’s effects on the cardiovascular, central nervous, and respiratory systems through safety pharmacology studies in animal models. The objective is to identify any potential toxic effects and to establish a safe initial dose for the first-in-human trials. The data from these studies must be comprehensive and convincing to satisfy the regulatory requirements.

The IND program is heavily regulated to ensure the protection of human subjects and the integrity of scientific data. Regulatory guidance for IND-enabling studies calls for methodical planning and implementation. Companies aiming to navigate through this phase successfully must exhibit rigorous scientific methodology and a clear understanding of regulatory criteria. These early-stage studies are not only essential but can significantly influence the trajectory of the drug development process, dictating the speed and potential success with which a drug enters clinical trials.

Overview of IND-Enabling Studies

IND-enabling studies serve as a critical step in the transition from preclinical research to human clinical trials. These studies are designed to assess the safety and efficacy of a drug candidate, thereby supporting investigational new drug (IND) applications to regulatory agencies.

Definition and Purpose

IND-enabling studies are a series of preclinical assessments intended to evaluate the safety and biological activity of a drug candidate before it is administered to humans. The primary purpose of these studies is to ensure that the drug is reasonably safe for initial use in humans and to support the clinical trial authorization process.

Key Components

The key components of IND-enabling studies include broad but detailed datasets from the following domains:

Pharmacology:
- Safety Pharmacology Studies: These investigate the effects of the drug on physiological systems, focusing on cardiovascular, central nervous, and respiratory systems.
Toxicology Studies:
- Acute and Subchronic Toxicology: They determine the adverse effects of the drug, establishing a safe starting dose for humans.
- Genotoxicity: This evaluates the drug’s potential to cause genetic damage.
Chemistry, Manufacturing, and Controls (CMC):
- Drug Substance Characterization: Detailed information on the drug’s composition, synthesis, and stability.
- Drug Product Formulation: Information on the composition of the final product to be used in clinical trials, including excipients and manufacturing processes.

IND-enabling studies are meticulously designed to comply with regulatory guidelines, ensuring that a clear understanding of the drug’s safety profile is established before entering clinical phases. These components collectively enable an informed assessment of the drug’s potential risks and benefits.

Regulatory Framework

The regulatory framework for IND-enabling studies is critical and consists of various guidelines and regulations. Adherence to these protocols is mandatory to ensure safety and move forward with clinical trials.

FDA Guidelines

The Food and Drug Administration (FDA) plays a pivotal role in regulating investigational new drugs (INDs). They provide a comprehensive set of guidelines to protect public health by ensuring drug safety and efficacy. Specific guidance documents are issued by the FDA to aid sponsors in complying with regulatory requirements.

Code of Federal Regulations (CFR)

The Code of Federal Regulations (CFR) is a codification of the general and permanent rules published in the Federal Register by the departments and agencies of the federal government. Title 21 of the CFR specifically outlines the regulations related to food and drugs. This section informs the sponsors about the necessary studies to support an IND, including pharmacology, toxicology, and pharmacokinetics.

Other Global Regulations

While the FDA and CFR predominantly govern regulatory standards in the United States, other global regulatory bodies have their own sets of rules. Each country may have specific regulations that align with international standards but also cater to local legislative requirements. Compliance with these international guidelines is crucial for global drug development and approval processes.

Preclinical Studies

Preclinical studies are critical in affirming the safety and efficacy of a drug before clinical trials in humans begin. They involve a series of structured experiments designed to understand the drug’s mechanism of action and potential toxicity.

In Vitro Studies

In vitro studies serve as the initial step in drug testing, providing valuable data on a drug’s interaction with biological molecules. These studies typically involve the use of cells and tissues to investigate the absorption, metabolism, and excretion of the drug, as well as any potential safety concerns.

In Vivo Studies

Subsequent to in vitro assessments, in vivo studies involve testing the drug in a living organism, commonly laboratory animals. These experiments help in evaluating the overall pharmacokinetics and pharmacodynamics, and they support the findings from in vitro studies concerning the drug’s safety profile.

Pharmacokinetics (Absorption, Metabolism, Excretion)

Pharmacokinetic studies focus on the drug’s journey through the body. Key parameters include:

Absorption: How the drug is taken up into the bloodstream.
Metabolism: How the drug is broken down or transformed in the body.
Excretion: How the drug is eliminated from the body.

These findings provide crucial information for dosing and potential drug interactions.

Pharmacodynamics

This subsection explores the drug’s biological effects and its mechanism of action. Pharmacodynamics assessments look at the relationship between drug concentration at the site of action and the resulting effect, including the duration and intensity of therapeutic and adverse effects.

Toxicity Profiling

Toxicity profiling is a pivotal component of safety evaluations. It involves extensive testing to identify any potential adverse effects a drug may have on different biological systems. Toxicology studies generally require Good Laboratory Practice (GLP) to ensure the validity and reproducibility of the results, advancing a drug candidate’s journey towards Investigational New Drug (IND) application.

Chemistry, Manufacturing, and Control (CMC)

The Chemistry, Manufacturing, and Control (CMC) is an essential component of Investigational New Drug (IND) applications that details the production process, quality assurance mechanisms, and stability of a drug substance and product.

Manufacturing Information

The manufacturing section outlines the production methods and processes, detailing the equipment used, scales of production, and in-process controls. Specifics such as batch size, raw material sourcing, and processing steps are included to ensure consistency in drug manufacturing.

Equipment and Facilities: Specifications for the design and maintenance of production environments.
Production Scale: Documentation of batch sizes and adaptability for scaling.
In-Process Controls: Methods to monitor and control manufacturing parameters.

Quality Assurance

Quality assurance encompasses the methods and protocols built to ensure the drug meets predefined quality criteria. It mandates detailed descriptions of the analytical testing conducted to ascertain the identity, quality, purity, and potency of the drug substance and product.

Analytical Testing: List of tests performed to confirm specifications.
Validation Protocols: Procedures for method validation ensuring reliability and consistency.
Documentation: Records and reports that certify compliance with regulatory standards.

Substance and Product Stability

The section on stability offers important insights into the shelf life and storage conditions of the drug substance and product, presenting data on how they maintain their identity, strength, quality, and purity over time.

Stability Testing: Summary of tests conducted under various conditions.
Storage Conditions: Parameters for temperature, lighting, and humidity control.
Expiration Dating: Determination of time frames for product usage.

Clinical Trial Design and Procedures

Prior to commencing clinical trials, a meticulously planned design and established procedures are indispensable. They not only aid in anticipating the trajectory of the trial but also ensure the reliability and safety of the study.

Study Design Principles

Clinical trials must be structured around core principles which include establishing clear objectives, determining the patient population, and setting endpoints. Design must align with the IND (Investigational New Drug) requirements to comprehensively assess the safety and efficacy of a new therapy. Study designs often leverage randomized, controlled models to minimize bias and yield statistically significant results.

Selection of Dose and Schedule

The dose and schedule for administration are determined based on preclinical data. Starting doses are cautiously estimated to avoid adverse effects, and escalation protocols are defined to find the maximum tolerated dose (MTD). The chosen regimen should demonstrate a potential therapeutic effect balanced against the risk of side effects.

Initial Dose: Derived from preclinical toxicology studies.
Escalation Scheme: Incremental increases, often in a study cohort.
Evaluation Points: Regular intervals to assess safety and dose-limiting toxicities.

Assessment of Efficacy and Safety

The crux of clinical studies lies in the dual objectives of confirming efficacy and monitoring safety. Efficacy is evaluated against the defined clinical endpoints, using statistical analysis. Safety is continuously assessed through adverse event monitoring, laboratory tests, and patient reports. All these procedures must adhere to the regulatory framework established for clinical trials.

Efficacy Metrics: Objective response rates, survival rates, etc.
Safety Parameters: Adverse events, serious adverse events, etc.
Data Collection: Standardized forms and electronic data capture systems.

The establishment and adherence to these subsections in clinical trial design are critical in ensuring robust testing and the generation of reliable data for IND applications.

Institutional and Ethical Considerations

In the realm of IND-enabling studies, ethical integrity and institutional oversight are critical. They ensure the protection of human subjects in clinical trials and uphold the scientific community’s standards.

Informed Consent Process

The informed consent process is a vital component that protects participants’ autonomy by ensuring they are fully aware of the study and its potential risks before agreeing to partake. It involves a clear and concise explanation of the study’s purpose, duration, required procedures, and potential risks and benefits.

Explanation: The participant must be informed about the nature and purpose of the trial.
Voluntary Participation: It must be emphasized that participation is voluntary and that the subject can withdraw at any time without penalty.
Understanding: Steps must be taken to ensure that the participant understands the information provided, often requiring a confirmation of comprehension.

Institutional Review Board (IRB)

An Institutional Review Board (IRB) is a committee established to review and approve research involving human subjects. Its role is to ensure that:

The rights and welfare of the participants are protected.
Risks are minimized: Each study is evaluated to ensure that physical and psychological risks to participants are reduced to the greatest extent possible.
Benefit-Risk Ratio: The potential benefits justify the risks involved.
All research complies with applicable ethical guidelines and regulations.

Ethical Guidelines

Ethical guidelines in IND-enabling studies incorporate a framework of principles that safeguard respect for persons, beneficence, and justice. These guidelines influence all facets of a clinical trial, from planning to execution:

Respect for Persons: Recognizing the dignity and autonomy of individuals, particularly concerning vulnerable populations.
Beneficence: The obligation to prevent harm and ensure the participant’s well-being.
Justice: Fair distribution of the benefits and burdens of research, ensuring that no group is unfairly burdened or excluded from potential benefits.

Ethical considerations are deeply integrated into the design and conduct of IND-enabling studies. They reinforce the scientific validity, promote public trust, and protect human subjects throughout the research process.

Advanced Therapy Medical Products (ATMPs)

Advanced Therapy Medical Products (ATMPs) represent a significant development in the treatment of complex diseases, often focusing on therapies that are fundamentally different from traditional pharmaceuticals. They involve the use of biologics, gene therapies, and cell-based therapies to treat various medical conditions. The development and regulatory pathways for these products are tailored to address their unique properties and potential risks.

Cell and Gene Therapies (CGTs)

Cell and gene therapies are at the forefront of ATMP innovation. These therapies work by modifying human cells (either in vivo or ex vivo) and are then administered to treat, prevent, or potentially cure diseases. Gene therapy encompasses products like gene therapy medicinal products (GTMPs), which introduce genetic material into individuals for therapeutic purposes. Cell therapy, including somatic cell therapy medicinal products (SCTMPs), uses cells to restore, maintain, or improve function.

Gene Therapy:
- Introduce, remove, or alter genetic material
- Address inherited or acquired diseases
Cell Therapy:
- Somatic cell therapies (often autologous)
- Can be part of tissue-engineered products

Biologics and Biosimilars

ATMPs include a broad category of products classified as biologics. These are large, complex molecules derived from living organisms, used in the treatment, diagnosis, or prevention of diseases. Biologics can be composed of sugars, proteins, or nucleic acids and can also encompass cells and tissues. Biosimilars are highly similar to an already FDA-approved biologic product and are expected to possess similar safety and efficacy profiles.

Biologics:
- Complex structures from living organisms
- Include a wide range of product types
Biosimilars:
- Highly similar to reference biologics
- No clinically meaningful differences

Regulatory Pathways for ATMPs

The regulatory pathways for ATMPs are specialized given their complexity and potential for significant clinical benefits and risks. Regulatory agencies have established distinct pathways to evaluate the safety pharmacology, efficacy, and quality of these products. The Investigational New Drug (IND) application is a critical step in the regulatory process, where safety and study design data are evaluated to determine if clinical trials can commence.

Key Regulatory Considerations:
- Safety pharmacology evaluations
- Manufacturing and control strategies
- Efficacy demonstration through clinical studies
IND Application Process:
- Preclinical study data
- Proposed clinical trial protocols
- Patient risk-benefit analysis

Each ATMP category—gene therapies, somatic cell therapies, and tissue-engineered products—must adhere to rigorous regulatory scrutiny to ensure they are safe and effective for their intended use.

Operational and Strategic Planning

The pharmaceutical landscape necessitates meticulous operational and strategic planning to ensure the success of Investigational New Drug (IND) applications. This involves an intricate balance of project management, selecting suitable contract research organizations (CROs), and navigating the regulatory framework.

Project Management in Drug Development

Effective project management is pivotal in steering the drug development process from discovery to submission of an IND application. It requires establishing clear objectives, a timeline, and resource allocation to manage activities such as pharmacology, pharmacokinetics, and toxicology studies. Strategic project planning assists in mitigating risks and addressing any unforeseen challenges that could impede the progress of the IND-enabling studies.

Timeline: An optimized Gantt chart encapsulating key milestones
Resource allocation: A breakdown of financial, human, and material resources

Engaging Contract Research Organizations

Selecting an adept CRO is crucial for conducting specialized IND-enabling studies. A well-chosen CRO brings experience and a practical operational framework to the table, enhancing the study design and ensuring adherence to Good Laboratory Practices (GLP). Organizations should assess potential CROs on parameters such as:

Expertise: Assess their track record in similar IND-enabling studies.
Capabilities: Ensure they have the necessary equipment and personnel.

Regulatory Affairs and Strategy

The role of regulatory affairs in operational and strategic planning cannot be overstated. They provide guidance on the regulatory requirements across jurisdictions, such as those mandated by the FDA or EMA. Their expertise ensures that IND-enabling studies are designed to meet stringent regulatory standards and strategic planning aligns with the intended regulatory submission. Key tasks include:

Documentation: Preparation of key sections of an IND application.
Liaison: Communicate with regulatory agencies to ensure compliance.

Through meticulous project management, judicious engagement with CROs, and strategic regulatory planning, organizations can navigate the complexities of drug development and increase the likelihood of successful IND approval.

Jose Rossello

Review of Safety in FDA Medical Reviews

March 24, 2019 by Jose Rossello 3 Comments

Analysis of the latest review of safety sections for new drug applications (NDAs and BLAs)

I found interesting to analyze the latest Reviews of Safety for the FDA submission classification Type 1 – New Molecular Entity. To obtain the medical reviews I accessed the FDA Approved Drug Products web page, and selected “Drug Approval Reports by Month”, and then “Original New Drug Approvals (NDAs and BLAs) by Month. I chose twenty clinical reviews, from October 2018 to March 2019.

Some of the clinical reviews were found as individual documents on the approval package, under the name of “Medical Reviews“, while other clinical reviews were embedded into a big file named “Multi-discipline Review“, containing the summary review, office director, cross discipline team leader review, clinical review, non-clinical review, statistical review, and clinical pharmacology review.

Another interesting aspect of this analysis is that older reviews have a specific headline for “Reviewer comments”, being each section followed by the comments of the reviewer at the end of it. However, more current clinical reviews do not differentiate the reviewer comments; actually, it looks like all text comes from the reviewer, instead of separating what the applicant submitted from what the reviewer commented. I think the newer approach is better, as the reviewers elaborate their thinking in a more extensive fashion.

If you are in a hurry, just go to the Conclusions at the end of this post.

CDER Clinical Review Template

According to the CDER Clinical Review Template 2015 for New NDA or BLA, the Review of Safety outline is as follows:

1. Review of safety
1.1 Safety review approach
1.2 Review of the safety database
1.3 Adequacy of applicant’s clinical safety assessments
1.4 Safety results
1.5 Analysis of submission-specific safety issues
1.6 Specific safety studies / clinical trials
1.8 Additional safety explorations
1.9 Safety in the postmarket setting
1.10 Additional safety issues from other disciplines
1.11 Integrated assessment of safety

However, although the basic outline for the review of safety section is the same, there are some variations, depending on the drug evaluated, wheter or not a subsection is pertinent and, possibly, the reviewer preferences or style.

Let’s go through each section and analyze what the reviewers have to say.

Safety review approach

Reviewers explain what the evaluation of safety for the product in questions is based on, which is, most of the time clinical trials. Among the clinical trials, which ones contribute the most, whether or not they perform pooling of data from different trials, and which treatment arms are to be considered.

Also, reviewers determine whether or not the methods to assess safety in the individual clinical trials and in the integrated summary of safety are considered appropriate.

FDA performs their own analysis using a variety of applications for drug safety analytics, like MedDRA Adverse Event Diagnosis Service (MAED), JMP amd JMP Clinical, while using analysis data model (ADAM) and study data tabulation model (SDTM) data sets, looking for differences in findings by the FDA reviewer compared to the applicant, among other aspects of the analysis.

If there are adverse events of special interest (AESI), they are stated here.

Review of the safety database

The review of the safety database includes the overall exposure, relevant characteristics of the safety population, and the adequacy of the safety database.

Overall exposure is summarized in a table. Depending on the product, the table may content number of individuals by arm, and if for example race is an important variable to understand pharmacokinetics (PK) data, that information should be included too, at least in the text.
Duration of exposure is an important aspect of exposure described here. They make a lot of emphasis in comparing median exposure times among groups. Reviewers will be concerned if those times are significantly different.

In this section, relevant characteristics of the safety population are also described. Demographics and baseline characteristics are included. Populations that are underrepresented are also highlighted. Whether or not important subgroup populations are well represented is something reviewers take into account. It is important to highlight whether or not the final safety database is well balanced in terms of baseline demographics and disease characteristics.

With respect to the adequacy of the safety database, the reviewers determine if the data are sufficient as to characterize the safety profile of the product. They evaluate if the total number of individuals in the safety database is enough or lower than recommended in FDA guidance, depending on the product under study. On occasions, the reviewer may recommend adding additional information to confirm safety of long-term use of the investigational product, in general or in specific subpopulations (like older people).
Another aspect of relevance is if there are evidence of safety signals in the clinical and pre-clinical development program.

Adequacy of applicant’s clinical safety assessments

Reviewers evaluate:
– Issues regarding data integrity and submission quality, that have an effect on the safety review.
– Categorization of adverse events. Adverse event and serious adverse event definitions are evaluated, as well as the safety reporting period for SAEs. Identification of issues with respect to recording. coding, and categorizing AEs, and if the applicant has used SOC and PTs applying MedDRA coding. Categorization of AE severity according to the CTCAE criteria is used in the majority of occasions. Interestingly, they tend to perform analysis of AEs/SAEs Grade 3 and up. Basis for the causality assessment. MedDRA version is also stated, as well as the selection of PTs by the use of Standardized MedDRA Queries (SMQ).
– Routine clinical tests, pregnancy tests, and acceptability of the schedule of events.

Safety results

Here reviewers pay attention, specifically to:
– Deaths. Reviewers evaluate whether or not they agree with applicant assessment of relatedness with the use of the investigational product.
– Serious Adverse Events (SAEs). Same as for deaths, reviewers make an opinion of agreement / disagreement with Company causality for each one of the SAE cases, as well as for the death cases.
– Dropouts and/ or discontinuations due to adverse effects. Here there is an evaluation of AEs leading to discontinuation. These significant adverse events are evaluated in terms of severity (defined by the applicant), and of the presence of patterns or concerns for these events. Distinction is made here to not include patients who discontinued due to events related to the disease rather than to the product.
– Treatment emergent adverse events (TEAEs) and adverse reactions. In general, this is the section where AEs are presented in tables, depending on the percentage of occurrence by study arm. Sometimes reviewers recommend including laboratory-related adverse reactions in a separate table in the package insert.

INTERESTING: Adverse Reactions. In one study, the applicant defined Adverse drug reaction as: “one that was reported in at least 2% of subjects who received the investigational product, occurred at a higher incidence than in placebo in the pooled pivotal trials, and was attributed to the study drug by the investigator. And the reviewer stated:

Using that definition, no ADRs would be listed in Section 6 Adverse Reactions section of the package insert. In the opinion of this reviewer, stating that there were no ADRs associated with the investigational drug might mislead health care providers and patients about the risks and benefits associated with taking the investigational drug. Therefore, the adverse events reported in at least 1% of subjects in the pivotal trials will be included in the package insert.

Comments regarding laboratory values, vital signs, ECG, QT, and immunogenicity were related to the presence of trends or abnormal values taking into account the expected changes explainable by the underlying disease. They analyze dose-dependency in relation to change in all those values.

A variety of statistical and epidemiological analyses may be applied here. It is not infrequent to find survival analysis curves applied to time-to-adverse event analysis.

Analysis of submission-specific safety issues

Here reviewers analyze a set of safety concerns that are related to the specific submission. For example, if hepatic toxicity is a concern, they evaluate liver effects. In some cases, those events are considered adverse events of special interest.
Description of clinical cases is something that occurs when a specific safety concern is analyzed.

Safety analysis by demographic subgroups

The purpose of this sub-section is to provide analyses of safety information for demographic interactions. Several methods and analytics may be applied here to explore the effects of possible interactions on safety signals / events. For many applications, individual clinical trials may not be powered enough to reach conclusions regarding safety among the demographic subgroups (age, gender, and race). Pooled analysis, when appropriate, will have greater power, interpretations about subgroup data should be made with caution. Nonetheless, these analyses should be performed when feasible, and tables and graphics should be created. Analysis of adverse events (real world data) by geographic region is also appropriate.

This type of analysis could be placed on Safety analysis section. Sometimes it appears here.
In this section, specific safety analysis and tables by age, gender, and race are presented and discussed. What is important here is if there are safety differences by age groups, sex, or race that could indicate a different safety profile or behavior.

Clinical outcome assessment (COA) analyses informing safety/tolerability

Sometimes, when pertinent, this section is included. For example in case of the application of patient reported outcomes (PRO) instruments. According to one reviewer, “PRO results are not likely to offer unbiased and conclusive evidence of patient’s quality of life.” This statement was probably made because the applicant wanted to include some benefit language in the product label.

Specific safety studies / clinical trials

Reviewers evaluate here if there was a study for the assessment of a specific safety issue, to identify or quantify a particular safety concern.

Additional safety explorations

Typically here human carcinogenicity or tumor development, human reproduction and pregnancy, and pediatrics and assessment of effects on growth are explored here. Moreover, overdose, drug abuse potential, withdrawal and rebound issues are discussed here too.

Safety in the postmarket setting

Sometimes the drug under investigation has some postmarket experience, in some specific countries, for example. That postmarket experience needs to be analyzed y evaluated from the safety point of view. The safety review of postmarket experience centers basically on serious adverse events. The expectations from safety in the post-marketing setting are also stated. In general, routine pharmacovigilance activities are in order.

Additional safety issues from other disciplines

In general, safety issues from other disciplines are discussed in their respective sections of the approval review.

Integrated assessment of safety

I have found a variety of approaches reviewers take to write this section. It goes from a minimalist (and I believe a little off) “The above safety assessment incorporates data from X trials and is therefore integrated”, to a short summary of all the previous sections, to an extended safety assessment of 2-3 pages. It normally determines if there are or not concerning safety findings. It is also stated whether or not the safety issues are correctly communicated in the product label, or determine if the applicant should include any AEs in “Warnings and precautions” section of the product label.

Postmarket commitments like PMR studies or REMS, boxed warnings, and enhanced pharmacovigilance are recommendations made by the reviewers in the integrated assessment of safety.

Conclusions

Analysis of the clinical reviews found in the approval packages from recently approved drugs is of great help understanding how review of safety is performed.
Read the FDA Clinical Review Template. That will give you an incredible insight on what reviewers are looking for.
After reviewing the first 10 reviews of safety, little to no information was added to my analysis by reading the next 10 ones.
Reviewers follow the main clinical review outline, but there is a wide variety of approaches to the evaluation of the different aspects and data of the Review of Safety.
Many of the subtle differences among the reviews of safety evaluated are product-related. So it would be advisable to review, for example, the 10 latest clinical reviews from approved oncology products if you are submitting an oncology product.
There is no mention of statistical analysis in the Review of Safety. Reviewers do a great job with extensive descriptive analysis. This is also helpful to avoid arguments related to applying statistical testing to pooled data.
Honest description of our safety data, making use of our current knowledge is generally more than enough to elaborate an appropriate safety profile of our product in our population(s). No rocket science needed.
This exercise helped me to obtain responses on what reviewers are looking for and, consequently, better prepare for NDA/BLA submission and success from the safety review perspective.
Although this post refers to the review of safety section of the clinical review, this approach can be applied to the rest of documents constituting the submission package for NDA / BLA approval.

Jose Rossello