The use of viruses as therapies have come a long way since the early virotherapy research of Virchow, Lister, Koch, Pasteur in the late 19th century. Considerable advances in genetic engineering and biotechnologies have enabled growing numbers of virotherapies to enter the development pipeline. With emerging, translational therapies, however, the path from design to clinical trial and beyond can be convoluted and confusing, particularly for those who have not taken this journey before.
In this article, we outline:
- The regulatory bodies that authorize the use of investigational new drugs in clinical trials
- What an investigational new drug (IND) application is, and why it is needed
- The structure of an IND application
- Key manufacturing considerations that must be made prior to the application being submitted
- The need to open communication with regulators and manufacturing partners throughout the application process
Which regulatory body oversees progress to clinical trial?
Clinical studies are a key part of a new therapeutic agent’s journey to market and are needed to collect safety and effectiveness information to support marketing applications for biologic products.
In the US and the EU, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) are the governing bodies that regulate the use of investigational new drugs, respectively. For investigational drugs to be studied in human subjects (in clinical trials), documentation must be submitted and reviewed by these regulatory bodies. Only once authorization to start human trials is granted by regulators can an investigational new drug be administered to human patients (unless specific exemption criteria are met).
In the US, the initial submission for the use of an investigational drug in a clinical setting is called an investigational new drug (IND) application; in the EU, this documentation is submitted within a clinical trial application (CTA). The successful completion of the subsequent clinical test results in a new drug application (NDA) and the drug being listed in the Pharmacopoeia, allow the project to continue to progress to a commercial level.
What is an IND application?
An IND application will contain the key information required by the FDA to make a sufficient judgment on the safety, pharmacokinetics (PK), toxicology, and efficacy of an investigational new drug before first-in-human (FIH) trials are initiated. It is an official regulatory document and as such, it is governed by federal regulations (in the Code of Federal Regulations [CFR]). For the IND itself, regulatory considerations can be found in 21 CFR Part 312.
Despite popular belief, the FDA does not technically “approve” an IND but must be given the opportunity to raise objections to it. Once submitted, the sponsor must wait 30 calendar days while the FDA makes this assessment, and, if no objections are made, the proposed clinical trials can proceed.
When is an IND needed?
The IND process is often time-consuming and costly, so it is important to understand when an application is needed. Although most IND applications have the intention of advancing a new investigational drug originating from either research or commercial sources to FIH clinical trials, there are a wide array of instances where an IND will be required:
- A new investigational medicinal product needs to be administered to humans for the first time in FIH clinical trials
- A new therapeutic indication is sought for an investigational product already in clinical trials
- For compounds already marketed where a new therapeutic indication not currently approved is being sought
- For the continued longer-term use of a non-marketed investigational drug
- For exploratory IND clinical studies that involve limited human exposure and where the drug has no therapeutic or diagnostic intent
Typically, preparations for an IND will take between six months to two years to complete, depending on the project-specific issues that might arise. Even the most minimal preclinical application will often approach or exceed $1 million. As a result, the IND process will only be initiated if there is a high level of confidence that the candidate drug has the required safety profile, efficacy, and pharmacokinetic/pharmacodynamic properties to successfully complete clinical trials.
What does an IND application look like?
Although every IND application will be unique, all will have the same basic structure, encompassing ten sections or “parts”. The exact content of each part will vary depending on the information available at the time of the application.
Part 1 – Cover sheet
For triaging and routing of the IND application within the FDA. This should include a brief explanation of the intended investigation, the disease or condition under investigation, and the investigational new drug product’s name and proposed formulation.
Forms 1571, 1572, and 3674
These forms include administrative information, a statement of the investigator conducting clinical research under the IND application, and a certification of compliance with the requirements of ClinicalTrials.gov Data Bank, respectively.
Part 2 – Table of contents
A detailed contents page that will allow FDA reviews to locate items in the application quickly.
Part 3 – Introductory statement and general investigational plan
A section to help place the clinical development plan for the IND into perspective to help the FDA anticipate future program needs.
Part 4 – Chemistry, Manufacturing, and Control Information
The Chemistry, Manufacturing, and Control (CMC) information is required to show that a drug is and will be what it is supposed to be, without any contaminants. The details provided should assure regulators that the drug will maintain its purity and potency for at least the duration of the clinical studies. As the Sponsor optimizes processes and formulations over time, these data can be expected to evolve.
Part 5 – Pharmacology/ Toxicology Information
A description of the preclinical pharmacology, safety, absorption, distribution, metabolism, excretion, and toxicology of the NCE derived from animal studies.
Part 6 – Investigator’s brochure
This part is expected to contain a brief description of the drug substance and the formulation, a summary of the pharmacological and toxicological effects of the drug in animals, information relating to the safety and effectiveness in humans, and a description of possible risks and side effects.
Part 7 – Clinical Protocol
To be submitted for each planned clinical study or trial. Depending on whether these trials are Phase I, Phase II, or Phase III, different considerations will be needed.
Part 8 – Summary of previous human experience with the investigational drug
There is no specific format for describing any previous human experience with the investigational drug, however, if no previous experience exists, this should be stated in this section of the IND application.
Part 9 – Additional information
A section to include any additional information, possibly including drug dependence and abuse potential, radiation absorption calculations for radioactive drugs, or plans for pediatric studies.
Part 10 – Other relevant information
Any other relevant information pertinent to the review of the IND application that the FDA has requested to be submitted should be added here.
Understanding the CMC information requirements
The CMC part of the IND applications is one of the more detailed and requires extensive information about the composition, manufacturer, stability, and controls that will be used in the production of the drug. In the early stages of the drug lifecycle, it can be a challenge for developers to proactively consider all necessary factors that could come into later stage manufacturing.
In this part of the IND application, the sponsor will need to provide information to assure regulators that the drug will be made under controlled conditions.
The CMC part of the application is broken into 5 parts:
- Drug substance (DS)
As well as the name and address of the manufacturer, this section will include a description of the general preparation method of the DS, including a list of any reagents, solvents, and catalysts used. The acceptable limits and analytical methods used to ensure the identity, strength, quality, and purity of the drug substance, with a brief description of the test methods should also be included.
- Drug product (DP)
This section should include a list of all components and compositions used in the manufacturing process and a summary of the quantitative composition of the investigational new drug product. Additionally, a general description of the manufacturing process, packaging procedure, and other relevant tests, as appropriate for the product, should be incorporated here.
- Placebo formulation (if applicable)
A brief description of the composition, manufacture, and control of any placebo formulation to be used in the proposed clinical study.
- Labeling information
Copies of labeling for the investigational product should be provided in this section, when applicable.
- Environmental analysis assessing the effects of the product on the environment
Although this section may require an assessment of the effects of the investigational product on the environment, most products qualify for a categorical exclusion.
As can be seen, a great deal of information is required for the FDA to adequately assess whether a new investigational drug should be administered to humans. This means that developers need to have an intimate understanding of the quality, purity, and strength of the DS prior to initiating the application, with data to back this knowledge up. Similarly, for the DP section, developers need to produce data supporting the assays suggested and acceptable results for assessing its identity, strength, quality, and purity. The CMC section also requires stability data, with evidence on how quality varies under the influence of environmental factors over time to inform the drug product shelf life.
For developers who are new to the IND process, understanding what data is needed (particularly at the manufacturing stage where there could be a great deal of unfamiliarity) can be a significant challenge. Those in this position should consider reaching out not only to the governing regulatory body but also to manufacturing partners that could simplify the application process.
Communication is key
Before initiating the IND application, it is advised that developers plan to arrange a pre-IND meeting with the FDA. This could be particularly helpful for those with little or no prior experience with IND submissions or the formal regulatory preclinical process, as is common for developers with emerging drug products translating out of an academic environment. The pre-IND meeting is an opportunity for the FDA and sponsor to reach an agreement on the proposed animal safety and toxicology testing that needs to be performed to support the Phase I clinical trials design.
As an organization facilitating the approval of new drugs that could change the lives of patients, developers should remember that the regulatory body is aiming for a successful application and will often be keen to provide advice, emphasizing the importance of open communication.
As well as the FDA, developers of investigational new drugs should also consider reaching out to manufacturers with an abundance of experience and expertise working with emerging technologies. With an understanding of the IND application process and a strong understanding of the challenges that can arise with translational products, support from contract development and manufacturing organizations could be the key to a successful IND.
Specializing in live viruses and viral vectors, Vibalogics possesses vital expertise in virotherapies that could help to ease the complications of IND application, particularly the convoluted CMC section.
For more information on how Vibalogics could help progress your preclinical project to the clinic and beyond, contact us today.