Altered States
Safety Assessment
Shawna Jackman, PhD

Altered States

An earlier version of this article appeared in The Scientist.

As academia embraces product development, stem cell science offers lessons on how hard it can be to straddle these very different worlds.

There used to be a straight line dividing academia and industry. So much so that when aspiring scientists sat down to weigh the intellectual prestige of an academic position against a career in industry, it was widely expected that whatever track they ultimately chose would last a lifetime.

Times change. The lines have been blurred. It is evident that academia is embracing entrepreneurial and collaborative endeavors in a big way. Universities now house about a third of the more than 1,200 so-called business or technology incubators in North America, places like Georgia Tech’s VentureLab that has launched more than 150 start-ups or Cellular Dynamics International created by University of Wisconsin-Madison’s stem cell pioneer James Thompson in 2004 to commercially produce induced pluripotent stem (iPS) cell lines and tissue cells. Even if universities don’t have an established tech incubator, almost every university now has a technology transfer office offering guidance on funding and intellectual property to support the entrepreneurial academic. Moreover, large pharmaceutical companies on down to small biotechs have been outsourcing drug research and development, and striking collaborations with universities on early-stage drug discovery at an increasing pace.

The cross-fertilization occurring between academic and industry has its advantages, particularly in the red-hot field of stem cell therapies. However, the melding of these two philosophies still has a ways to go. As we all know, potential cell therapy products are being investigated and developed by academic laboratories at an astonishing rate. Investigational New Drug (IND) and Investigational Device Exemption submissions to the US Food and Drug Administration (FDA) for cell therapies almost doubled over the last five years—from 60 to around 100—and the expectation is that we will see more clinical trials related to these products.

Much the of the initial work behind these therapies—from embryonic stem cells, mesychemal stem cells and most recently iPS cells—blossomed on university campuses. And why not? Academia researchers are driven by hypotheses and new discoveries, elucidating the how’s and why’s no matter how many experiments and tangential projects it takes to find the answers. Academic laboratories have the capabilities and research know-how to develop novel techniques necessary to create new cell therapies and evaluate the cell properties and efficacy of the cells.

What these academic labs may not be so comfortable navigating is the hyper-staccato world of product development—when drug discovery begins to move downstream and into the more regulatory-driven requirements of preclinical testing. Safety programs for new investigational drugs must follow rigid objectives and study designs, and be conducted under Good Laboratory Practice (GLP) regulations to ensure repeatability and reliability of the data.

Regulatory Hurdles

Because cell-based therapies are considered both biologics and drugs, the stew of regulatory requirements set by the US Food and Drug Administration are far-reaching, complex and for the uninitiated, confusing. As biologics, cell-based therapies fall under the Public Health Service(PHS) Act, sections 351 and 361, because they convey infectious disease. But because they are used to mitigate, treat and prevent disease, cellular therapies are also considered drugs, and therefore are regulated by the Federal Food Drug and Cosmetic Act.

The safety requirements for preclinical testing of biologics are similar to that of drugs. The cellular therapies must demonstrate that they are reasonably safe to use in Phase 1 studies. The cell product must also be consistent and well-characterized, and the safety studies used to determine toxicity and tumor-forming potential must be conducted with a biocompatible formulation utilizing the intended route of administration.

More than minimally manipulated cell products require INDs and supporting studies to provide data for proof of concept and safety, and must follow Title 21 CFR Part 58 of the Code of Federal Regulations, for Good Laboratory Practice for Nonclinical Laboratory Studies. The regulatory expectations are clearly described for drug development for biologics under ICH-S6, the comprehensive list of guidelines adopted by the FDA for preclinical safety evaluation of biotechnological products.

In addition to these regulatory requirements, the FDA finalized the Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products  in November that spells out the substance and scope of preclinical information needed to support clinical trials for investigational cellular therapies, gene therapies, therapeutic vaccines, xenotransplantation, and certain biologic-device combination products. This guidance is the beginning of efforts to standardize approaches and requirements for these novel products and delineate the risk versus benefit of these therapies.

Help From Outside

Is it any wonder that academic laboratories, driven by the pursuit of discovery—and with limited funding—have a hard time grasping the strict requirements of regulatory safety and the large price tag that comes with it?

Funding agencies such as the California Institute for Regenerative Medicine—which is currently supporting over 80 research projects—have been proactive in educating academic and industry researchers alike about the challenges of bringing a product to market, including manufacturing scale-up and regulatory expectations. In fact, when considering granting funds to a promising project, the researcher’s testing, development and manufacturing plans are considered as important as the science and efficacy data driving the product itself.

Contract-research organizations (CROs) such as Charles River, which are increasingly being used by biopharmaceutical companies for drug discovery, are another way academic laboratories can supplement their in-house expertise in early-stage drug development.

But while this makes complete sense from a product development point of view—and could help bring many of these new therapies to the clinic—it still represents a sea change for an academic laboratory with little expertise or understanding of the need for regulatory requirements for GLP or Good Manufacturing Practice (GMP), not to mention the time and money it takes to fully assess a product and produce reliable repeatable study data to support the use of the therapy safely in humans.  Moreover, at the end of the day, the products developed, the services launched and the patents secured still may not hold as much prestige as the academic recognition that comes from earning multi-year NIH grants or acceptance of a paper in a leading peer-reviewed journal.