Tuesday, November 14, 2006

Berube ON FDA (A draft)


The first nanotechnologies that will have an impact on public perception with be those associated with medical care. Quite simply, necrophobia is a powerful fear, and drugs and devices which can delay death will be treated favorably. The primary source materials for the following came from Nakissa Sadrieh of the FDA’s Office of Pharmaceutical Science.

The first problem will be the “…difficult[y] for the FDA to maintain adequate scientific expertise in the field.” This has always been the case with the FDA given the wages available for its personnel should they decide to relocate into the business of pharmaceutical and medical innovation.

Strangely enough, two areas posing the greatest difficulties for the FDA are food supplements and cosmetics, two sets of products which have the weakest legislative history of the entire set of products which might be intuited as under the FDA’s purvey.

Recently, there have been some indications nanoscience will make intrusions into the supplement market according to Ann Dowling, of the Royal Society. There seems to be concern that supplements using nanoparticles are on the Woodrow Wilson inventory though I have not verified this claim at this time.

As we learned from the Magic Nano fiasco not all products claiming to include nanotechnology actually do.

The best example of a nano0supplement to date might be Neosino AG’s Nanosilimagna™ allegedly containing calcium, silicon, and magnesium in the form of nanoparticles. It is marketed as a nutrition supplement for athletes under the name Neosino Sport Nano-Liquid™. Both the German Sports Federation, footballer Roy Makaay, and biking champion Michael Themann endorse it. In addition, it is also used in cosmetics as Neosino Spray-Forte™. Having reviewed one of the studies on its efficacy, there seems little doubt that product claims have been hyperbolized. Of course, the supplements industry does not have to go through clinical trials as required for pharmaceuticals and it is unclear whether any toxicity testing was undertaken. The supplements market is enormous and we can expect more examples to surface.

We know that nanoparticles have been used for over a decade in cosmetics especially sunscreens. This observation was made by ICTG and seven other groups when they filed a petition with the FDA in 2006. They claimed there were at least 116 sunscreens, cosmetics and personal care products currently on the market and warned about the production of free radicals and dermal penetration especially through broken skin. Additional fears about the use of nanoparticles in cosmetics can be found on the Friends of the Earth website.

The ICTA petition calls for a formal opinion on nanotechnology especially in regards to the concept of equivalence and the fast lane approval process. In addition, concerns over health and safety serve as the basis for demands for definitions and characterization, nanomaterials toxicity testing paradigms, and labeling. In addition, the petition calls for nano-specific product regulation much like those advocated by Davies and calls upon the FDA to comply with the National Environmental Policy Act (NEPA). The NEPA can demand a programmatic environmental impact statement as part of its regulatory powers and could serve as the basis of future legal action.

The FDA can only regulate when they have been empowered to regulate and some areas such as food supplements and over-the-counter sunscreens may need legislative activity. Actually, the ICTA complaint demands the FDA amend the OTC sunscreen Drug Monograph to reconsider sunscreens with nanoparticles as “new drugs” which would require the manufacturers submit a “new drug application” (NDA).

New medical nanoproducts will probably be subject to the same rigorous review given current pharmaceutical drugs though the FDA may need additional training in understanding the differences between a medical device, a drug, a biological or chemical entity, especially when a product looks like food but acts like medicine.

It has been difficult determining exactly what the FDA has been doing. Consider the following anecdote from Rick Weiss of the Washington Post (I am not defending its validity at this time). Norris Alderson, director of the FDA, reported in 2004 “the agency had so far approved six nano-based products: two drugs, two medical devices, and two sunscreen lotions. But [when questioned] he did not know whether special safety tests had been required. When pressed for details, an agency representative called back to report that, in fact, no nano-based products have been approved. No explanation for the confusion was offered.” This was a little embarassing. Clearly things have improved. Nonetheless, it is unsurprising that there have been many concerns expressed about the FDA’s regulatory authority and efforts.

These concerns led the 2004 Swiss Re report to conclude that both the FDA in the USA and the EC’s Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers have not established viable hazard guidelines. This complaint was amplified in the previously mentioned petition.

Even without explicit guidelines per se, the FDA seems to have the machinery and a track record that might make them especially viable as a government regulator for many nano-products though the breadth of their current mandate, especially considering advances at the nanoscale, might make their mission unmanageable.

In general, the FDA has a set of centers that deal with particular types of products. For example while the Center for Drug Evaluation and Research (CDER) is responsible for drugs, the Center for Devices and Radiological Health (CDRH) deals with devices. This brings us to the first issue. There are times when it becomes problematic determining when a nanoproduct is a drug, a device, or even a biologic because it has characteristics of all three classes.

Following on the heals of the FDA Modernization Act on 1997, two initiatives, the Tissue Reference Group in 1998 and the Device Action Plan in 1999, helped streamline jurisdictional issues. Today, when there is a question about jurisdiction, the Office for Combination Products resolves it. To help, the FDA has a Nanotechnology Interest Group (NTIG) with representatives from each center. Generally, the decision is based on the primary mode of action of the combination product. A ruling on the primary role of action of a combination product has been defined as “the most important therapeutic action” and this definition has been published in the Federal Register. In addition, the NTIG will facilitate inter-center communications. Kudos to the FDA.

Both devices and materials used in vivo undergo rigorous trials. For drugs, it begins with an Investigational New Drug (IND) application which generally involves small-scale clinical studies and animal testing. The next step requires clinical studies which follow a NDA. There are three phases. In Phase I, safety data is obtained from human subjects. Phase II generates data on effectiveness. Phase III expands on phase I and II by increasing the sample of subjects. A NDA review follows.

Here’s a review of some action to date.

Using technology developed by Elan Drug Delivery, Wyatt, Merck, Abbott, and American Pharmaceutials all developed nanoparticulate drugs and received FDA approval. Elan developed a milling technique which increases the bioavailability of some of these companies' products.

The IND-NDA three phase process described above was the route taken by Merck, Wyeth and American Pharmaceuticals. The FDA approved Abraxane™ in January 2005 for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Abraxane™ is touted in the literature as the first approved nano-drug per se.

Merck proceeded with Emend®, the nanoparticulate drug aprepitant. Wyeth brought their drug sirolimus to Elan for development of a nanoparticulate formulation of sirolimus called Rapamune® which successfully obtained approval as well.

Instead of pursuing the clinical trail route, a company may elect to claim bio-equivalence as was done by Abbott in the case of TriCor® which was claimed as equivalent to fenofibrate. This seems the best place to begin the discussion on new versus existing.

In terms of devices, NanoOss® is a nanocrystaline version of hydroxyatite that is less likely to crack, hence is “has the strength of steel.” NanoOss® was considered as a Class II device and Angstrom Medica got FDA approval.

Devices are classified into three categories by the CDRH. Class I devices are subject to general controls and include band-aids and crutches. Class II devices need to show substantial equivalence, much like bio-equivalence above and include items like wheelchairs and tampons. Class III devices involve the “introduction of a new material, procedure, or device without a substantial equivalent in the marketplace.” “In the eyes of the FDA, NanoOss® was just calcium phosphate.” Hence, we see another instance when a nanoproduct is viewed as equivalent to its more bulk chemical equivalent for purposes of regulation.

Another device, CardioMEMS’ EndoSure Wireless AAA Pressure Measurement System, was designed to treat an aneurism of the lower abdominal aorta and it received FDA approval in February 2004. According to CardioMEMS’ CEO Davis Stern had to prove the materials it used were bio-compatible and stable. As a Class III device, clinical tests began in March 2004 in Brazil and eventually included populations in Argentina, Canada, and the USA.” If there is an area that the ETC Group should begin to question, it might be the use of developing countries' citizens [thought I would not classify Argentina and Brazil as developing countries per se] as test subjects in the approval process.

Immunicon received FDA approval for its CellSearch Circulating Tumor Cell Kit, Immunicon CellTracks AutoPrep System, and Immunicon CellSpotter Analyzer Cell Analyzer using magneto-nanoparticles called ferrofluids in August 2004.

In another case reported by Small Times’ David Forman, AcryMed’s product known as SilvaGard® got approval. SilvaGard® is an antibacterial nanoparticle coating for medical devices. As such, AcryMed’s customers file for FDA approval rather than AcryMed. In December 2005, I-Flow Corp.’s ON-Q SilverSoaker® antimicrobial catheter using SilvaGard® was approved.

The FDA cites that it has traditionally regulated many products with particulate materials in the nano-size range and that the current pharmacotoxicity tests are sufficiently adequate for most nanotechnology products that it will regulate.” In case, where current tests are inadequate, the FDA can require the petitioner to meet higher burdens of proof.

The FDA also has authority for post-market surveillance. While some consumer confidence has eroded after the heart damage problems associated with Vioxx and other Cox 2 inhibitors, Congress is anticipating internal reforms and there is some support for new legislation as well.


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