The idea of interacting with the FDA is sometimes mysterious and unsettling for a pharmaceutical company. The average person finds it difficult to work with a large organization that they don’t understand. For example, large banks understand this and advertise themselves as the friendly bank that works to help “their neighbors” with buying a house. The FDA’s clients are pharmaceutical companies. Unlike banks, the FDA has significant leverage over the company because it is responsible for reviewing a company’s drug with the hope that FDA will approve it. While many companies are also large, there is no real leverage that the company has over the FDA. Thus, the company is at a distinct unsettling disadvantage. However, both parties have the common desire to market safe and effective drug products. Where the rubber hits the road is that the two parties need to agree on what is needed to demonstrate that the drug is safe and effective.
The key that allows the two parties to work together successfully is usually good communication. Good communication can be described as honest, frank, clear, scientifically sound, succinct, respectful communication with no hidden agendas. Each party should treat the other as they would like to be treated.
The company puts together a project team that will guide a chemical through development. A key player on the team is the regulatory person. This person will be the “face and voice” of the team at the FDA. While individual members are responsible for their scientific areas, each member needs to comply with the needs of the regulatory person who reflects the needs of the FDA. Thus, the regulatory person serves as the conductor for the orchestra.
One of the core responsibilities of the project team is to develop a clinical strategy which should be the heart of the Investigational New Drug (IND) application that describes the company’s thoughts about how the drug will be developed. If the new drug is not the first drug in a particular therapeutic area, it is often useful to examine what clinical studies
were done to support the approval of the earlier drug. Much of the information can be pulled out of the drug’s prescribing information and the Clinical Trial Registry.
Listed below are basic questions that the project team should ask itself:
- What are the basic characteristics of the drug, e.g. mechanism of action, physical structure, aqueous solubility, elimination half-life, oral absorption?
- What are the patient demographics that would likely use the drug, e.g. therapeutic area, age, gender?
- What other drugs will likely be co-administered with it?
- What drugs are currently being used for the target illness and what are their limitations and strengths?
- What are the key clinical therapeutic and safety endpoints?
Answering these questions should give you a good outline of what kind of data needs to be collected in your clinical studies. The IND is the first official document that is sent to the FDA for review of the company’s plan for development. Questions/issues that are raised by the study team should also be identified at this time so that the FDA can respond to these questions. It is important that the questions be clear, concise, and specific. Overviews of the following areas should form the structure of these questions:
- Disease condition that will be addressed
- Pathophysiology of disease condition and currently available treatments and/or prevention strategies
- Incidence and prevalence in populations
- Drug Product
- Mechanism of action and potential therapeutic benefits
- Possible therapeutic uses beyond the disease condition described
- General products that will be initially developed, e.g. intravenous solution, oral tablet, and subsequently developed, e.g. pediatric oral solution, controlled release.
- Patient Populations
- Initial population, e.g. adults and pediatric population over age of 11
- Subsequent population, e.g. children between 4 – 11 years old
A full protocol for the first or two clinical studies will be needed. This is usually the first time-in-man study following single and multiple doses. The FDA prefers outlines of subsequent studies at this time. The outlines should include: title, background, objectives, subject populations, study design, study endpoints, and analysis approach.
Questions raised by the sponsor should also be presented for FDA input. However, the question should not be open-ended. So, rather than say, “What studies should be run to determine the safety of the drug?”, the question should be “We are planning to run the following studies to determine pharmacokinetics and safety: Study 1, 2, 3, 4, 5, and 6. Do you agree that these studies are needed?” An outline of each study should be included in the package.
All correspondence between the company and FDA should go through the regulatory member of the project team. This correspondence will be sent to that person’s counterpart in the regulatory group that was assembled to review the IND. Correspondence can be handled by mailings, emails, and in-person meetings. Of course, the person asking the question also needs to be involved. However, that person cannot independently send information to the FDA. It needs to go through the team’s regulatory contact.
Prior to a face to face or conference call meeting, the regulatory contact is responsible for arrange meeting rehearsals, where people who will be attending the meeting practice their presentations and answer any questions that the FDA may ask. This is a very important task.
Most people on a company project team would usually prefer a phone call to an in-person meeting because it takes up less time, i.e. no traveling. However, it is particularly advantageous to have the meeting discussing the IND application in person. This is because it usually helps members on both sides know their counterparts on the other team. Hopefully, this will result in developing trust.
The FDA/company relationship must develop a sense of reliability. While the FDA understands that the proposed timeline is tentative, the company needs to let the FDA know if an action date will be missed. This should also include a revised date for this action.
During the project’s lifetime, there are other landmark meetings that need to be held. Early clinical studies are labeled Phase I and include the initial safety studies in healthy volunteers. Drug concentrations in the blood are used to help understand what levels result in safety issues. The science of this information is called pharmacokinetics. At some point patients are tested to provide data in the population of interest. It is not uncommon for 6 – 8 Phase I studies to be conducted. As these studies are winding down, the project team’s regulatory person will contact his/her counterpart at the FDA to setup an “end of Phase I meeting.” The results of these studies should be sent to the FDA for review several weeks before the meeting. It is important for the regulatory group to have enough time to review the data among themselves and indentify questions that they need to ask.
Another important part of the meeting is to discuss the Phase II studies that the company is planning. Phase II studies are efficacy/safety studies in the patient population chosen. The full protocols are provided for FDA review. Often, pharmacokinetic data are gathered in patients to help understand what doses are needed to provide required drug concentrations in the blood that will provide the necessary therapeutic response. As the Phase II studies wind down, the regulatory contact sends over results of the studies along with a request for an “End of Phase II Meeting.” This is usually accompanied by company recommendations for dosing. Often, the company will fine-tune the target population and dose based upon study results.
Another valuable component of the End of Phase II Meeting is a discussion of the two Phase III studies that are proposed by the company. The full protocols will be provided for review. The Phase III studies will likely involve several thousand patients rather than several hundred in Phase II studies. The results of the Phase II studies often identify narrower population of patients which will result in a narrower indication. However, the Phase II studies can also identify factors in a particular population that require a larger population size for statistical purposes.
If FDA issues are properly addressed, the company prepares a New Drug Application (NDA). This document is the formal submission document that FDA reviews to determine if the drug will be approved. It summarizes the preclinical, formulation, Phase I and Phase II results provided in previous documents and describes in detail the Phase III results. Recommendations for a well-defined indication for the product are provided and serve as the starting point for the final indication.
There are basically four decisions that the FDA can make: approve, approve with minor changes, approve with Phase IV commitment, or not approve. In some instances the FDA may require a Phase IV study to address a question that needs to be answered. However, answering this question may not be important enough to prevent the drug from being approved. Assuming that the company agrees to conduct the Phase IV study within a certain time period after approval, the drug will be approved and marketed.
Note: The views expressed in this article are those of the author and do not necessarily represent those of his or her employer, GxP Lifeline, its editor or MasterControl Inc.
Bob Kunka is a scientist who has a long history of getting drug approvals quickly. The secret of his success is the fusing of his broad and deep experience in drug development over a number of therapeutic areas and an intuitive approach to problem solving. His understanding of regulatory needs resulted in the timely FDA approval of 28 products in eight therapeutic areas including Advair, Flovent, Retrovir, Valtrex, Imitrex, Combovir, Maxaquin, Zofran, and Calan. Prior to this, he was Assistant Professor in the Pharmaceutics Department at the University of Pittsburgh School of Pharmacy where he taught graduate and undergraduate courses in pharmacokinetics. Bob earned his Ph.D. in Pharmacokinetics at the University of North Carolina (UNC) at Chapel Hill and Bachelor of Science in pharmacy at the University of Illinois at the Medical Center in Chicago. He has authored over 75 publications and presentations at international scientific meetings and served as a reviewer for the Journal of Clinical Pharmacology. In July 2014 Bob will be presenting a talk at the 17th World Congress of Basic and Clinical Pharmacology in Cape Town, South Africa entitled “Pediatric Drug Development from Sponsor’s Perspective and Bridging to Relevant Data”.