FDA’s Regulation of Products Derived Through Nanotechnology: Controversies and Potential Impacts on Nanomedicine

Ricardo Carvajal

Hyman, Phelps & McNamara, P.C.

www.hpm.com

www.fdalawblog.net

3rd Annual Unither Nanomedical &

Telemedical Technology Conference

February 2010

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600

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1000

1997 1998 1999 2000 2001 2002 2003 2004

Investm

en

t ($

M)

Japan

W. Europe

U.S.Others

Source: PCAST/NSF

International Government Investment

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National Nanotechnology Initiative

A government program established in 2001 to coordinate federal nanotech R&D

25 agencies participate, including FDAMore than $1.5 billion has been

allocated to 13 agencies

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National Nanotechnology InitiativeInvestments by AgencyFY 2001-2010 ($ in millions)

FY 2001 2002 2003 2004 2005 2006 2007 2008 2009†† 2010††† Total†

DOD 125 224 220 291 352 423.9 450.2 460.4 464.0 378.5 3389.0NSF 150 204 221 256 335 359.7 388.8 408.6 505.0 423.0 3251.1DOE 88 89 134 202 208 231 236.0 244.7 361.9 351.4 2146.0DHHS / NIH 40 59 78 106 165 191.6 215.4 304.5 311.3 325.6 1796.4DOC / NIST 33 77 64 77 79 77.9 87.6 85.6 94.4 90.5 766.0NASA 22 35 36 47 45 50 19.8 17.4 16.6 16.6 305.4EPA 5 6 5 5 7 4.5 7.6 12.1 16.4 17.7 86.3DHHS / NIOSH 3 3.8 7.3 6.9 7.4 12.4 40.8USDA / NIFA* 2 3 3.9 3.9 5.5 3.3 3.3 24.9USDA / FS 2.3 2.9 4.6 5.4 5.4 20.6DOJ 1 1 1 2 2 0.3 1.7 0.1 0.3 0.4 9.8DHS 2 1 1 1 1.5 2.0 3.2 9.1 11.7 32.5DOT 0.9 0.9 0.9 2.5 2.5 7.7

Total† 464 697 760 989 1200 1351.3 1424.1 1554.5 1797.6 1639.0 11876.5

NNI Funding, 2001 - 2010

•FDA funding?•EHS funding?

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FDA’s Nanotechnology Task Force Report

FDA’s Nanotechnology Task Force established in 2006

Public meeting and comment solicitation in 2006

Report was issued in 2007, but FDA considers the report to be current

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Nanotech Task Force Report: Scientific Capacity

FDA’s scientific capacity needs to be improved.

Adequacy of tools needed to describe and evaluate nanomaterials should be assessed.

Lack of data on nanomaterial safety is a problem.

Early consultation with the agency is highly recommended, especially for combination products.

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Nanotech Task Force Report: adequacy of FDA’s authority

Existing statutory authority is “generally adequate” to address risks

Nanotech-specific regulations are unwarranted.

Authority is “more comprehensive” for products subject to premarket authorization

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Nanotech Task Force Report: recommendations for guidance

FDA should issue guidance that addresses submission of additional data, potential effects on regulatory pathways, additional steps needed to address safety or quality issues.

A chicken and egg problem?

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FDA Science and Mission at Risk

Report of the Subcommittee on Science and Technology

Prepared for FDA Science Board, November 2007

FDA cannot fulfill its mission because:

scientific base has eroded and scientific organizational structure is weak

scientific workforce does not have sufficient capacity and capability

IT infrastructure is inadequate

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How does FDA regulate nanotechnology?

No regulatory definition Risk-based approach that focuses on products, not

processes Insufficient scientific basis to conclude that, as a

class, products derived through nanotechnology pose greater human health risks

A familiar tension – the need to minimize regulatory burdens, consistent with need to protect public health

11Courtesy Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy

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FDA’s flexible regulatory scheme

Identity?Intended use?

Article

Drug

Cosmetic

Device

Biologic

Combo

Food &Supplements

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A word about combination products

Primary mode of action governs assignment: which mode of action makes the greatest contribution to the overall intended therapeutic effects?

Tiebreaker: which center has experience or expertise with safety and effectiveness questions presented?

One center takes the lead, but consults with others. Both formal and informal determinations of

jurisdiction are available.

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Drug Approval Process

CDER Handbook

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“Post-market oversight” doesn’t mean “no authority”

FDA has authority to take unsafe products off the market.

Flow of information – premarket v. post-market

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Examples: products on the market

Drug: Abraxane, paclitaxel in an albumin nanosphere, cancer

Device: NanoOss, nanocrystalline hydroxyapatite, bone void filler

Cosmetic: Hydra Zen, nanoencapsulated triceramides, moisturizing cream

Dietary supplement: NanO Bio-Sim, nanosized diatomaceous earth, immune system support

Food packaging w/silver nanoparticles, antimicrobial

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In some sectors, a rush to market?

Hundreds of “nanotech” cosmetic and dietary supplement products” have sped to market.

Project on Emerging Nanotechnologies (PEN) inventory

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Been there, done that...

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Sunscreen: safety concerns?

FDA started rulemaking on the sunscreen OTC monograph in 1978.

1993 – proposed tentative final monograph. 1999 – issued final monograph, effective in

two years. 2001 – final monograph was stayed. 2007 – proposed amendment of final

monograph.

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In the interim, enforcement discretion

FDA policy: no action against OTC products until review is complete unless product poses a potential health hazard to the consumer.

FDA, 1999: “micronized titanium dioxide” is not a new ingredient, but is instead a specific grade of titanium dioxide for which there is no evidence of a safety concern.

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ICTA citizen petition

International Center for Technology Assessment petitioned FDA to amend the sunscreen monograph to address engineered nanoparticles

Manufacturers of sunscreens that contain nanoengineered titanium dioxide or zinc oxide should be required to file new drug applications.

Marketing should be prohibited, and all products recalled.

Strange question: is nanotechnology safe to slather on our children?

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To label or not to label?

Product labeling cannot be misleadingHas a material fact been omitted with

respect to consequences that could result from use of the product?

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How much milk can a dairy cow yield?

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rbST, a bioengineered animal drug

Approved in 1994, rbST is a bioengineered hormone given to cattle to increase milk production.

FDA’s approval was challenged administratively and judicially – FDA won.

FDA also won in rejecting mandatory labeling. rbST foes want voluntary labeling; rbST advocates

contend that labeling is false or misleading. Human safety? Animal safety? Effect on small

farms?

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... our yoghurt is made with fresh cow’s milk that is free of any artificial growth hormones. Look for the “No artificial growth hormones” announcement on our lid. It means the yoghurt inside is rbST-free ...

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The rbST labeling battle continues, state by state

FDA is unlikely to expend resources on issues where there is no clear impact on public health.

Advocates on both sides have turned to the states.

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The danger of a vacuum at the top

Local restrictions on nano are already coming into play, e.g., Berkeley.

California has issued call for data on carbon nanotubes.

Zeal for regulation tempered by desire to attract/retain high-tech incubators?

28McKinsey & Co., February 2009

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The essentials

SafetyBenefitsChoiceEffective, transparent, predictable

regulation

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Reported nanosafety practices in research laboratories worldwide

Francisco Balas, Manuel Arruebo, Jone Urrutia & Jesus Santamaria, Nature Nanotechnology 5, 93 - 96 (2010)

“[M]ost researchers do not use suitable personal and laboratory protection equipment when handling nanomaterials that could become airborne.”

“One of the most surprising results is that nearly three quarters of respondents reported not having internal rules to follow regarding the handling of nanomaterials.”

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Thank you!

Ricardo Carvajal

Hyman, Phelps & McNamara, P.C.

www.hpm.com

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NIH Nanomedicine Roadmap Initiative

Phase I - gather information about chemical and physical properties of nanoscale biological structures (2005-2010)

Phase II – apply knowledge and tools to treating

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NIH Nanomedicine Development Centers

Nanomedicine for Nucleoprotein Machines Phi26 DNA-Packaging Motor for Nanomedicine Center for Cell Control NDC for the Optical Control of Biological Function Center for Protein Folding Machinery National Center for Design of Biomimetric Nanoconductors Engineering Cellular Control: Synthetic Signaling and Motility

Systems Nanomedicine Center for Mechanobiology Directing the

Immune Response

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European Technology Platform (ETP) on Nanomedicine

Initiative led by industry, set up with the European Commission – industrial and academic experts

“it has become increasingly clear to the industrial sector that an academic driven or laissez faire approach to nanomedicine will be an inefficient process”

Research agenda Nanotechnology-based diagnostics including imaging targeted drug delivery and release regenerative medicine