Don’t Fear the IND Labyrinth: 5 Lessons Learned at an Academic Site

The challenge was delivered with stark clarity. “We need to establish a new approach to make it easy and affordable for our faculty to quickly transition their imaging probe research from cells and what they see in animal models into human subjects. We must develop an uncomplicated way at a fraction of the cost and then provide the approach to others to help mobilize the field of PET probe discovery and development.” The issuer was Michael Phelps, PhD, chair of the department of molecular and medical pharmacology at the David Geffen School of Medicine, University of California Los Angeles. The receiver was Sherly Mosessian, PhD, the department’s chief administrative officer.

Seven months later, despite Mosessian having zero prior experience with FDA’s Investigational New Drug (IND) processes, the department had obtained approvals to translate three new fluoro-arabinofuranosylcytosine (FAC) analog PET probes to phase I clinical trials. These approvals documented the validity of the approach taken by UCLA, and the department spent less than $50,000 per test probe to get the job done. That figure represents a substantial savings over the estimate of $150,000 they received from a contract research organization for just completing the preclinical safety, dosimetry and toxicology testing portion of the process—not including manufacturing and regulatory support for preparation and submission of the IND, with one test probe and a vehicle control.

Mosessian, coordinator of the effort and lead author of a recent Molecular Imaging and Biology report describing it, attributes her team’s success in winning approval of INDs and saving money to two key pre-project decisions. One, they would conduct assessments of drug toxicology and safety pharmacology for all three probes, allowing one vehicle control to be used for all three tests. And two, they would rely entirely on in-house facilities, outsourcing no work at all to a contract research organization (CRO).

Mosessian says she hopes other academic sites can learn from UCLA’s first foray into IND territory. She and Phelps, her boss, shared with Molecular Imaging Insight five pointers the group picked up along the way.

1. Spend time becoming familiar with the relevant FDA guidance documents and rules. “It’s a little daunting at first, but as you go through all the FDA materials, you start to un derstand the process and see the light at the end of the tunnel. Eventually everything comes together,” says Mosessian, adding that FDA has developed “a very strong presence” in the PET community to facilitate personal interactions and discussions.
2. Organize a multidisciplinary team around interest in the science, communicativeness within the institution and enthusiasm over the probe’s clinical potential. UCLA’s molecular and medical pharmacology department only needed to tap the proverbial shoulders of, for example, the chief of nuclear medicine at UCLA Geffen for clinical leadership and the director of UCLA’s biomedical cyclotron facility for expertise with Current Good Manufacturing Processes. The one missing piece, and so the most challenging, was the know-how to do safety pharmacology and toxicology work compliant with Good Laboratory Practices. The team found what they were looking for in UCLA’s division of laboratory animal medicine, which had the experience and agreed to do what a CRO would have done—all on a nonprofit, fee-for-service basis.
3. Get your team to take joint ownership of project management. When it came to moving things forward on schedule and on budget, the group rallied, says Mosessian. “Where there’s an academic team, there’s a mutual desire to succeed and advance the research. You break even and make sure all your costs are covered. It’s not about making a profit but about advancing the research.” She points out that, with grant funding for research significantly reduced, “it’s really critical to set up a good template,” and that won’t happen without broad institutional buy-in. “A lot of probe discovery happens in academic settings,” she adds, “so if that path is blocked or the flow to the clinic is stopped or reduced because of the cost—or lack of knowledge on the regulatory aspects—It does harm to the PET community.”
4. Consider your initial IND experience equal parts excitement and experiment. “For us, FAC was a test subject. It’s a very exciting probe discovery story” in its own right, says Mosessian. “At the same time, we now feel we can efficiently and cost-effectively move forward any other promising PET probes that our faculty has developed.” In other words, they can quickly get to the final question: Is this probe valuable or not? Mosessian notes that many academic sites spend years with a mouse model before—and sometimes without—ever defining issues of biodistribution and toxicity in humans subjects.
5. 5. Engage FDA early and often. “Even though it’s optional, I highly recommend a pre-IND meeting with FDA before planning studies,” says Mosessian. She also emphasizes compliance with Current Good Manufacturing Practices by doing routine internal and external mock inspections while going through the FDA guidance documents. This helped their cyclotron facility successfully pass FDA’s pre-approval inspection, which led to approvals of two Abbreviated New Drug Applications for FDG and ammonia, notes Phelps.

“Plus it’s important to be open and honest about your shortcomings as well as your strengths,” says Mosessian. Speaking of FDA, Mosessian believes that PET probes ought to be regulated more leniently than drugs. Mosessian notes several individual FDA officials as responsive collaborators rather than the bureaucratic naysayers.

“There’s actually a quote from me on a board in Dr. Phelps’s office. It reads, ‘FDA has been wonderful to work with.’” So it is that some experiments produce unexpected results.