January 1, 2008 (Vol. 28, No. 1)

Regulators and Companies Are Laying the Groundwork for a Predicted Bright Future

As the regulatory pathway to approval for biotech products becomes more arduous, lengthy, and expensive, biofirms are fighting to keep pace with a rapidly changing regulatory landscape. They also are trying to find out how the FDA is going to look at nanotechnology product development.

A number of biotech companies along with legal consultants and former and current FDA officers gathered in Alexandria, VA, at last month’s “From Pipeline to Product” conference, sponsored by Pharmaceutical Education Associates. Participants discussed their experiences to help companies expedite their products through the pipeline and expressed their views on the emerging nanotech field.

“The FDA’s Product Quality Initiative, Critical Pathway Initiative, and Drug Safety Reform are responsible for changing the entire horizon of the drug approval process,” said Helen Winkle, director of the agency’s office of pharmaceutical science at the Center for Drug Evaluation and Research (CDER). Each initiative aims to facilitate the development of higher quality drugs with better safety profiles, clearer manufacturing specifications, and international harmonization without excess oversight, according to Winkle.

Regarding nanotech, “We are trying to get a handle on where we are for the nanotechnologies,” said Winkle. “I wouldn’t be the least bit surprised if we set up a new office.”

Case-by-Case Basis

In the meantime, FDA is reviewing nanotech drugs, devices, and combination products on a case-by-case basis, primarily based on their mechanism of action, noted Winkle. It is doing so because nanotech products currently cover a wide range of disparate technologies, added Greg Mandel, J.D., professor of law at Temple University.

“The rise of nanotechnology is raising new challenges and problems for an already overburdened system,” noted Raj Bawa, Ph.D., president of Bawa Biotechnology, an adjunct professor at Rensselaer Polytechnic Institute, and an advisor to RPI’s office of technology commercialization. Dr. Bawa predicted that more site-specific data will be required by the FDA in the future to show safety, as there is now some evidence that carbon nanoparticles can cross the blood-brain barrier.

Overall, nanomedicine products will play a bigger role in the future in addressing failures of traditional drugs, such as poor water solubility and lack of specificity, he said.

In the past few years, there has been a steep increase in nanotech-related patent applications and patents issued, and there is concern that issued patents may be overlapping and too broad, which could ultimately impede commercialization. “A sort of patent land-grab is in full swing by patent prospectors during these critical, early days,” maintained Dr. Bawa. While there are relatively few products currently based on nanoparticles, there are many patents already, and even some patent disputes (e.g., the one between Elan and Abraxis Bioscience).

Cancer Therapeutics and Diagnostics

Esther Chang, Ph.D., professor of oncology at Georgetown University Medical Center and a consultant to SynerGene Therapeutics, described the company’s work in gene-based nanotech cancer therapeutics and diagnostics. SynerGene is developing man-made, virus-like nanoparticles to target primary tumors and metastases. These particles are composed of cationic lipid shells that encapsulate various molecular therapeutics, including tumor suppressor genes, which can be used against cancer, including therapy-resistant tumors.

Attached to these nanoparticles are tumor-targeting molecules, i.e., transferrin, folic acid, or a single-chain antibody fragment, directed against the transferrin receptor, which bind to their respective receptors that are overexpressed on tumor cells. Thus, when systemically delivered, these particles zero in on both primary tumors and metastases.

“We did not originally call the treatment a nanomedicine, although it actually was. We do now,” she said.

The company performed more preclinical animal studies than it needed for the IND. “Only one relevant species is required for animal models, which are not necessarily large animals,” said Dr. Chang. The key is determining and demonstrating which species is the most relevant for your particular agent, she added. To achieve that, SynerGene conducted numerous preclinical analyses in panels of tissues from mouse, rat, dog, and two monkey species, and found that the pattern of binding of its targeting molecule was most similar between human and mouse tissues.

SynerGene is poised to begin recruiting patients for a Phase I trial for delivery of the p53 tumor suppressor gene in patients with advanced solid tumors, at the The Mary Crowley Medical Research Center, located within the Baylor University Medical Center. The company also anticipates starting a second Phase I trial delivering the RB94 gene at the M.D. Anderson Cancer Center.

SynerGene is also developing gadolinium-encapsulated diagnostic nanoparticles as an MRI contrast agent, which can detect lung cancers 5 to 10 times smaller than currently distinguishable with CT, Dr. Chang reported.

“We worked with consultants to help us meet FDA requirements,” noted Dr. Chang. The expertise of consultants, many of whom have worked at the FDA, is especially important and helpful for academic researchers. “We also had pre-pre-IND meetings early on, which I recommend as they can truly help avoid much pain and suffering. On the whole, our dealings with the FDA have gone smoothly,” she said.

Referring to biotech products in general and not just to those based on nanotechnology, G. Alexander Fleming, M.D, president and CEO of Kinexum (www.kinexum.com) and former group leader of CDER’s metabolism and endocrine drug projects, also stressed the importance of clear pre-IND communication, in light of the fact that drug development is getting harder, riskier, and more expensive. He advised companies to maximize their contact with the FDA by asking concrete and not open-ended questions and making specific proposals.

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