Clinical Review Process for New Drug Development and Application Shen Xiao, MD, Ph.D. Senior Medical Officer Division of Cardiovascular and Renal Products Center for Drug Evaluation and Research (CDER) US FDA Good afternoon. I hope you enjoy your lunch and also hope this discussion make your lunch more enjoyable. Many thanks to Ravi and the committee for providing this good opportunity that we can share our thoughts with our CRRT community from regulatory perspective for these very important solutions and the life-saving therapy.

Disclaimer The views presented in this presentation are the opinions of the presenter and not official policy statements of the FDA. As usual, this talk does not represent the FDA official policy

Clinical Reviewer Job Category Medical Officer Series 0602 Physician with active US medical license USMLE board certified (before 2009) Clinical Analyst Experienced Reviewers in FDA including pharmacologist, epidemiologists, other health professionals, etc. As you may know, based on the federal law, the Code of Federal regulations, CFR, that peritoneal dialysis solutions, replacement solutions for HF, HDF and CRRT which are injected into the body directly are considered as drugs and are regulated by CDER (center for drug evaluation and research). I will explain what the 505 (b) (2) means For hemodialysis solutions, as the solutions are not injected into the body directly but circulated in a system, based on the law, it should be considered as a device and is regulated by CDRH (Center for Devices and Radiological Health) and I will very brief explain the 510 (K) later.

Responsibility and duty of Clinical Reviewers New Drug Development (IND) New Drug/Biological Products Application (NDA, BLA) Post Marketing Consultations Interactions with Academia and Industry: Scientific and Regulatory activities Medical Devices in CDRH; Biological Products in CBER So, in summary of my brief talk,

New Drug/Biological Product Development (IND) From non-clinical to first in human study including PK/PD studies Proof of concept study-efficacy Population selection: inclusion/exclusion criteria Safety and efficacy determination: endpoint, drug dose-selection, safety monitoring, biomarkers, etc. Pivotal study: special protocol assessment So what is 505 b(2). 505 (2) in a simple way means you may get some important information from other similar products that have been approved and are on the market. It is not your own data from this product. This is different from 505 b(1), which is a brand new product. For 505b(1) you have to conduct Ran, DB, Placebo-controlled trial. As you know CRRT started early 1990s, there was no approved replacement solutions until 2007. This is because FDA took the solution as the 505 b(1), a brand new drug and asked for Ran, DB, Placebo-controlled trial which is not feasible. So in 2006, we take this type of solution as 505b(2) compared to approved solutions, such as peritoneal dialysis solutions, iv injected solutions such as sodium hydrochloride solution, sodium bicarbonate solution, and Ringer’s solution, etc. Based on these data, we have approved two bicarbonate-based CRRT replacement solutions. So, based on the law, the replacement solution is considered as a drug, and our current thinking is that it is belong the 505 b(2).

New Drug/Biological Product Application (NDA, BLA) Document submission Safety review Efficacy review Inspection labeling For 510(K), it means the device has to be substantial equivalence to the original approved device. Although there are many hot debates about how the “substantial equivalence” are defined. We don’t have time to discuss this concept.

Post Marketing Agency surveillances Applicant annual report Additional applicant supplements Post marketing information from other sources: published literature, patient petition, professional communities, As I just mentioned before, we considered the replacement solution as a 505 b(2)drug, at the same time we also took the different concentrations of electrolytes in the solution as a one drug with a different dosage. So, in this situation, you only need a one drug application. Now, we got a problem recently, if a new electrolyte is added to the solution, for example, you add the new calcium or potassium, or phosphate to the solution, it is considered that the new active component is added and it should be considered as a new drug based on the law, and you have to pay the new drug application fee. We are currently working hard to try to solve this problem. However, there is no good answer so far.

Consultations Centers in FDA: Other Divisions in CDER, CBER, CDRH Other Agencies in HHS: NIH, CMS, CDC, AHRQ Other Government Agencies: DOJ, DOD, etc US Public: Patient petitions, Issues in hospitals International Regulatory Agencies: EMA, Health Canada, PMA, and TGA For hemodialysis solution, there is no such issue. It is called notification not application. Different concentration or new component addition may still be considered as the same device.

Questions?