As the United States Food and Drug Administration (FDA) reviews investigational new drug applications (INDs) to permit research studies with potential drugs and New Drug Applications (NDAs) and Biologic License Applications (BLAs) to permit marketing of small molecule drugs and biologics, respectively, they typically ask a number of questions of the firms submitting the applications. As I consider the questions that I have encountered throughout my career, some of which I asked as an FDA reviewer, and some of which I answered as an industry professional, I realize that all of the information requests a pharma company receives from FDA can be grouped into two basic questions. One question covers INDs and the other targets marketing applications (NDAs and BLAs).
1. The question for an IND application is: How safe is it to give this drug to human beings?
This is the case whether we are talking about an initial IND for first in human studies of a drug, or a complex Phase 3 IND involving many hundreds or thousands of patients to definitively determine if a drug works or anything in between. Naturally, there are a number of sub-parts to the IND question. For first in human studies, regulators will want to see the results of animal studies to evaluate the likely impact on humans. Similarly, they expect firms to provide data showing that they know the drug’s composition: structure, purity, and stability determinations with valid analytical methods. In other words, do you know what your drug is? Do you have evidence from animal studies that the size of dose that you plan to start with is likely to be safe? For Phase 2 and Phase 3 trials, have you properly analyzed the results of previous human studies to provide a reasonably safe basis for dosing large numbers of patients with your drug?
For NDAs and BLAs, because they are marketing applications, the fundamental question is different. Approval to market the drug will be based on evidence obtained from the IND studies. Now the stakes are different. Instead of hundreds or thousands of patients exposed to the drug in clinical trials, a marketed drug can be used by millions of patients.
2. As a result, the question for NDAs and BLAs is: What is the risk/benefit ratio?
The expectations for a drug will depend critically on the indication. Risks that might be tolerable for a drug intended to treat an otherwise untreatable cancer, would be completely unacceptable for a drug indicated for reversing male pattern baldness, for example. This means that the anticipated side effects must be evaluated during the clinical trials, and their likelihood and impact determined. Have you studied the drug in enough patients to have statistical assurance in your conclusions? What about different patient populations, the impact of age, kidney function, pregnancy, or ethnicity on the effectiveness of the drug and the risks of side effects? FDA conclusions are based on the results seen in clinical trials, in particular, those obtained in Phase 3. Now, can you make the drug the same every time? Do you have the necessary manufacturing controls in place to ensure that this is true? If you change the manufacturing process, is the resulting drug comparable to the one used in clinical trials?
Only two questions: for INDs, how safe is it to give this drug to human beings? For NDAs and BLAs, what is the risk/benefit ratio? Now that you know the questions, do you know what evidence, what data the FDA expects to see in satisfactory answers to those questions and the questions that follow from them? Pearl Pathways is here to help you give solid, data-driven responses to those questions which will speed your drug to patients. Whether you are a pre-commercialization startup pharma company or already have one or several products on the market, you can contact us today for a free consultation with our team.