FDA Drug Approval. Start to Finish.
Step 1: Preparation
The first step is to plan your strategy. Do you want to make a structure and function claim or a drug claim?
Structure & Function Claims: If your end goal is a new structure & function claim, beware that borrowed research is rarely sufficient to meet the FTC's requirements of substantiation. Your product will need its own clinical trial to substantiate its claim. The good news is that no IND is required and most structure/function claims can be substantiated with only 1-2 phase 2 clinical trials. Because the endpoint is a S/F claim, these studies are typically much faster and more affordable than studies with drug claims as the endpoint.
Drug Claims: To establish your product as an FDA-approved drug, in the absence of existing OTC monographs for your ingredients, you must follow the FDA's botanical drugs guidance. This outlines the process by which botanical products can become drugs. The first step will be to compile an IND to receive FDA authorization to investigate an investigational new drug (IND). You will also need to evaluate whether your goal is to obtain authorization for a new OTC drug or a prescription drug.
Step 2: Investigational New Drug status with the FDA
The Investigational New Drug (IND) application is the document which compiles all of the existing data on a proposed new drug to demonstrate to the FDA that the proposed new drug is 1) safe and 2) likely to be effective at its stated purpose. This is a requirement of the FDA to ensure that clinical trials are only conducted using products that are safe for human participants and likely to achieve beneficial results. For most pharmaceutical companies, this requires conducting extensive laboratory research both in petri dishes and in animal models.
There are 6 key parts to this application:
- Chemistry, Manufacturing, & Control Information
- Pharmacological & Toxicological Information
- Investigator's Brochure
- Clinical Protocol for Proposed Clinical Trial
- Previous Human Experience
Because most botanicals have a lengthy history of use, most INDs for proposed botanical drugs can be completed through the use of existing scientific research. Pharmaceutical companies typically must invest substantially to obtain the scientific information required to proceed to human clinical trials. Botanical product manufacturers, however, are typically able to obtain all of the required scientific information from existing studies in the literature, combined with traditional knowledge of a botanical's primary effects.
Our team is able to compile a complete botanical drug IND in 6-12 weeks. The complete application requires approximately 100 consulting hours from our team. Once the application is complete, the company may determine that a pre-IND meeting is required. This occurs when, after compiling all of the existing scientific evidence on the proposed new drug, there remain questions regarding the thoroughness of the science and/or the suitability of the proposed study. When this is required, an additional 4-6 months are required to request the meeting, obtain a meeting, hold the meeting, and receive all follow-up information.
When the team is comfortable with the application, it is submitted to the FDA. The FDA has 30 days to review and respond to IND applications. There are two possible responses: Authorization or a Clinical Hold. A clinical hold may be substantial, such as finding that human subjects would be exposed to unreasonable and significant risk of injury, or minor, such as requiring adjustments to the clinical protocol. For most requirements, the FDA works with the company to resolve any issues prior to issuing the hold and/or to resolve the hold in a timely manner. Once a hold is lifted, our team proceeds with the research studies.
Note: For trials substantiating structure and function claims, no IND is required.
Step 3: Phase 2 Clinical Trials
For laboratory-developed drugs, this stage does not occur until after extensive laboratory tests and phase 1 clinical trials. Most botanical products, however, are able to enter the drug testing process at stage 2 clinical trials.
The purpose of these studies is to evaluate whether or not the product actually works when compared to a suitable placebo. Because these are human subject clinical trials, all trials evaluating medical outcomes require an active IND before the trial can begin. Studies assessing structure function outcomes do not require an IND.
Phase 2 clinical trials typically require 50-250 human subjects. The exact number of subjects required is determined by a statistical analysis of the existing evidence on the ingredient's actions. Products with robust effects require fewer subjects while products with milder effects require more subjects. While studies are billed per subject, it is important to remember that studies with too few subjects are more likely to fail to capture the beneficial effects of a product.
For new structure and function claims, sufficient evidence can typically be obtained in 1-2 clinical trials. Each trial can be completed in 4-16 months, depending on the product's effects and total sample size required. Studies can run concurrently, though we typically advise against that approach. For studies intended to lead to FDA drug approval, the total number required to advance to phase 3 clinical trials depends on the product. The FDA requires sufficient evidence that the product works before allowing phase 3 studies. For many botanical drugs, this can be obtained in 2-3 studies thanks to the large effect size, general lack of adverse effects, and lengthy traditional use. It is not u
To protect out clients' research investments, we take multiple steps to enhance the benefits of phase 2 clinical trials. 1. Prior to accepting contracts to conduct clinical trials on botanically based products, our team of integrative health professionals assesses the product against the existing body of evidence. We only accept contracts for products our team considers to have a high likelihood of success. This is to protect not only our clients' investment but also the wellbeing of our human research participants and our research team's reputation. 2. All of our initial clinical trials are conducted with multiple end points, including structure and function claims. This provides a robust body of evidence on the complete actions of the product. The use of multiple methods of measurement and multiple endpoints allows our team to provide a complete evaluation of the product's benefits.
Step 4: Phase 3 Clinical Trials
Phase 3 studies can take place once the FDA determines that the quality and quantity of evidence received in phase 2 studies is sufficient. There is no set number of studies required to proceed to phase 3; the total amount of evidence required depends on the effect size of the botanical product and how much information was available in the literature at the start of the process.
During this step of the process, the goal is to study large numbers of human subjects for two purposes: 1) to ensure that the product works in diverse groups of people (i.e. different ages, sexes, races, regions, etc) and 2) to identify all of the rare side effects or adverse effects that take place. The first goal is to ensure that the product really does work for everyone, not merely a specific type of person. The second goal is to identify all the possible ways someone may not benefit from the product so that the drug label can clearly communicate to patients what risks and benefits are being offered.
These studies typically require 500-5,000 participants, depending on the evidence collected prior to this stage. The end goal of this step is to have a completed New Drug Application (NDA) for the FDA to review. Some companies have successfully received approval with 1-2 stud(ies) at this step, while others require far more. Until preliminary findings from phase 2 studies are available for review, it is difficult to predict how many studies and patients will be required to fulfill the requirements in this final step.
Because these studies are larger and require more diversity in human subjects, they are the most expensive studies to conduct. For a botanical product, these may range from $300k to $1 million+. Cost is determined by the total number of human participants required, study duration, the severity of the condition being treated, and similar factors. (See tips for keeping costs low here.)
Step 5: New Drug Application & Approval
The New Drug Application (NDA) is the formal request for FDA approval to market a product as a drug in the US. The NDA must include all existing data (and analyses of the data) compiled in the previous steps. When the NDA is complete, it is submitted to the FDA to enter the review process. The focus of the FDA is to evaluate the benefits and risks of the product. A drug is approved when the benefits clearly outweigh the risks, based on an assessment of high quality evidence.
During this process, a multidisciplinary team of experts from the FDA reviews the clinical evidence compiled in the studies conducted under the IND, the statistical analysis of these studies, toxicology, pharmacology, and chemistry of the product, and the proposed drug label.
Within the first 60 days, you will know if the FDA has accepted the application for filing. Assuming it is accepted, you will receive a "74-day letter" confirming the type of review for your product (standard v priority), any action items requiring immediate update in the application, and the action date.
Over the next several months, the FDA will send information requests. These vary from questions on where information can be found in the NDA to requesting additional analyses of data. During the final weeks, the wording on the label is negotiated. This is typically the time of greatest activity and rapid turnarounds are expected. The entire process from application to label negotiation takes approximately 8-12 months.
Meet Dr Hawkins
Dr. Hawkins brings 20 years of expertise in the integrative health field to her role as Executive Director of the Franklin School of Integrative Health Sciences and the leader of our clinical research team.
She holds a Bachelor’s Degree in Environmental Health from Union Institute and University, a Master’s Degree in Health Education & Promotion from the University of Alabama, a post-graduate certificate in epidemiology from the London School of Hygiene and Tropical Medicine, a PhD in Health Research from Middle Tennessee State University, and is completing the post-doctoral Global Scholars Research Training Program at Harvard Medical School. She also holds certifications in numerous natural health fields including aromatherapy, aromatic medicine, herbalism, childbirth education, and labor support.