A Sea Change
Safety Assessment
Nikolay Turovets

A Sea Change

Academic researchers face a rising tide of rules and regulations when their stem cell discoveries move toward clinical trials

Most academic labs specializing in stem cell biology and focusing on cellular therapies are really good at activities associated with basic research. Most great inventions that are now in clinical trials (or are almost there) came from academic labs. Such inventions form remarkably strong foundations for the clinical applications of stem cells and provide real hope to people who are suffering from cruel diseases or injuries. The majority of activities associated with basic research usually relate to isolation (or creation) of potentially therapeutic cells, developing methods for cell expansion and preservation and to the initial evaluation of cell efficacy in veracity of animal models.

By the time they reach the stage of translational research, academic scientists often face obstacles associated with this more rules-driven environment, and from time to time need to operate outside of their comfort zone. Scientists should be standardizing stem cell growth conditions and developing a research cell bank. They should be finding reproducible methods to produce a cell product of sufficient purity and developing assays to characterize the cell product. They also ought to be developing methods to deliver cells to target tissue, and demonstrating reproducible evidence of disease-modifying activity in vitro and in vivo in several relevant models (proof-of-concept studies). As if that isn’t enough, they also need to be initiating mechanism of action (MOA) studies, and assessing the dose, formulation, stability and safety (including immunogenicity) of the compound.

The world of preclinical development—the final stage before filing Investigational New Drug (IND) application with the US Food and Drug Administration (FDA) required for human clinical trials—can be even harder for academic scientists to navigate. At this point, cell therapy teams must develop formulation and scaled production methods under current Good Manufacturing Practice (cGMP, and produce cGMP lots of master and working cell banks. They must also perform stability studies, perform IND-supporting safety/toxicology studies and develop clinical protocol and prepare IND package in order to receive FDA clearance for human clinical trials. The highly-specialized work involved in the preclinical development of cellular therapeutics requires multidisciplinary teams of experts from regulatory, manufacturing, toxicology and clinical medicine.

Since academic institutions typically stick to basic research—and to a lesser extent translational research—they do not aim to provide the kind of  environment that supports preclinical developmental activities, such as GMP manufacturing and formal IND-enabled toxicology, tumorigenicity and biodistribution studies that need to be conducted  under strict GLP conditions with GMP-manufactured cells.

The GLP Way

Unlike basic research where flexibility is acceptable, virtually every aspect of a GLP study is documented in a very specific rule-driving format, from the study design and recording of raw data, to the reagents and equipment. The GLP principle is thus: If the procedure was not recorded it never happened. Methods and practices must be documented and performed in accordance with pre-specified Standard Operation Procedures (SOPs). Each piece of equipment must be validated in accordance with specially designed procedures. The work and document flow for each reagent must be precise and include special procedures for receiving, processing and discarding each reagent.

A good example is the study protocol. While basic research experiments and GLP studies both adhere to detailed study protocols, there are also some subtle differences. In GLP studies, the protocol must be signed by the Study Director and Principal Investigator before the study starts, and every change thereafter documented using one of two formats that track protocol changes. Any missteps in this process can jeopardize the entire study.

CROs Can Help

Needless to say, academic scientists working on cell therapies have a tough time making sense of all this, as evidenced by a joke I heard recently. An academic researcher and a regulatory consultant were reviewing a GLP study protocol when the academic turned and asked: “So are we talking now about science or regulatory?”

Actually, I would say that the scientist who asked this question has it wrong. The purpose of GLP studies and basic research are different. Basic research aims for discoveries and GLP studies provide the FDA and other regulatory agencies data that help move those discoveries forward. Similar to basic research GLP work is high-level science, just executed in accordance with very specific regulatory requirements.

Outside regulatory consultants and contract research organizations (CROs) can help bring value to projects as early as the translational research phase by making sure that study designs match regulatory requirements (see accompanying blog). CROs with a lot of experience in conducting certain kinds of studies or in particular disease areas can help close the gap between academic research experiments and IND-enabled GLP studies. But choosing the right CRO is as important as the science. How successfully and how fast you execute GLP studies will really depend on the experience and background of the CRO.

While “playing by ear” may be well-suited for basic research experiments and deliver remarkable discoveries, it is unacceptable and absolutely damaging to the more staccato world of GLP studies. Face it. It’s a long way from the research to the clinic. Learning to bridge this gap early on is essential for academics if they expect their discoveries to ever make a difference to people.