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FAQs

Q. What does it cost to have nanomaterial characterized by the NCL?

A. If a nanotechnology strategy/material is selected for characterization, NCL’s services are provided at no cost to the submitting investigator. As part of its assay cascade, the NCL will characterize the nanomaterial’s physical attributes, their in vitro biological properties, and their in vivo compatibility using animal models. The time required to characterize nanomaterial from receipt through the in vivo phase is expected to be one year.

For more information on the NCL assay cascade, visit http://ncl.cancer.gov/working_assay-cascade.asp

Q. I’m studying nanomaterials but my application is not in the area of cancer. Can I still submit a proposal for characterization by the NCL?

A. The NCL serves as a national resource and knowledge base for researchers to facilitate the regulatory review of nanotechnologies intended for cancer therapies and diagnostics. The NCL generally does not accept proposals for characterization of nanomaterials intended for application in areas other than cancer . Cancer-related nanostrategies proposed to the NCL for characterization are ranked according to their projected impact on clinical cancer applications and/or furthering nanotechnology’s compatibility with biological systems. Specific evaluation criteria include, but are not limited to:

  • Previously demonstrated efficacy in vitro and/or in animal models
  • Advantages offered by the strategy over existing cancer therapies or diagnostics
  • Previous physical characterization of the nanomaterial such as purity and stability
  • The nanostrategy’s manufacturing process and compatibility with scale-up
  • The material’s inherent toxicity and/or environmental concerns
  • Plans or approach to transition the strategy to clinical trials such as filing the follow-on IND, IDE or pre-IDE

For detailed information on submitting a proposal for a cancer-related project, please visit http://ncl.cancer.gov/working_application-process.asp

Q. Does NCL provide funding?

A. No. The NCL is a resource enabling researchers in academia, industry, and government to transition their nanotechnology strategies to clinical applications. The NCL provides critical infrastructure and characterization services but does not fund research grants.

Q. If my proposal is accepted, how much material will I be required to submit?

A. We require ½ to 1 gram of your nanomaterial in order to complete all assays. Depending on the availability of resources during the application process, NCL may be able to assist researchers with scale-up in order to have enough nanomaterial to enter the assay cascade. To share and safeguard research material and proprietary information, NCL’s interaction with researchers is normally conducted under a Material Transfer Agreement (MTA), permitting the collaborative exchange of materials and associated information.

For more information on Material Transfer Agreements and intellectual property protection, please visit http://ncl.cancer.gov/working_intellectual-property.asp

Q: How does the NCL determine if an engineered nanoparticle is likely to be safe?

A: In short, the NCL examines the weight of the evidence from preclinical studies, looking for “consensus behavior”. A recently published study1 demonstrated interference of carbon nanotubes with the MTT assay (see “NCL Protocols” in this issue of NCL News for a discussion of the MTT assay). The study showed that carbon nanotubes have the ability to absorb formazan dye, giving the appearance of a reduction in cell viability. This phenomenon helped to explain the lack of consensus behavior of carbon nanotubes in the in vitro toxicology literature where groups were using different cytotoxicity endpoints and arriving at contrasting conclusions regarding carbon nanotube cytotoxicity.

Even if the previous toxic responses attributed to carbon nanotubes in vitro were the result of MTT assay interference, this does not mean that carbon nanotubes are necessarily safe, as often in vitro results are not predictive of in vivo responses due to the complexities inherent in the whole organisms (i.e. exposure-dose-response relationships, cell-cell interactions, etc.). As such, it is important to look at the total body of evidence.

1 Oops, they did it again! Carbon nanotubes hoax scientists in viability assays. Nano Letters 2006 June; 6(6):1261-8.

Q. Is the NCL relationship with the nanomaterial developer considered to be a collaboration? How much control does the nanomaterial developer have during the characterization process?

A. Yes! We view our interaction as a collaboration. Prior to the initiation of a project, the NCL staff and project developers engage in multiple interactions via teleconference, email and face-to-face meetings. Once the project begins, the collaborator receives an update at least once per quarter on the physical characterization, immunology and toxicology data generated from the NCL assay cascade.

The NCL and collaborators jointly work through any issues that might arise. For example, it is not uncommon for a nanoparticle formulation to have impurities in the first batches submitted to the NCL. In these situations, NCL staff work with collaborators to identify any contaminants; the NCL may then recommend methods to further purify the preparation.

Q. What are the deliverables provided to the collaborator by the NCL?

A. Updates and reports on the progress of the nanomaterial characterization are provided to NCL collaborators at regular intervals – at least once per quarter. Once characterization of the nanomaterial is complete, a formal report of data from the NCL assay cascade is provided to the collaborator. Nanoparticle characterization data presented in the report are peer-reviewed by the NCL Scientific Oversight Committee (SOC) consisting of experts from the supporting organizations (i.e., NCI, NIST, and FDA).

Q. How do you protect the collaborator’s proprietary information?

A. The exchange of confidential information and the materials between the provider and NCL is protected by the terms of the Material Transfer Agreement (MTA)

(http://ncl.cancer.gov/working_application-process_annex2.pdf). All confidential/proprietary information disclosed to the NCL is strictly protected and will not be disclosed.

Q. What happens if the NCL determines nanoparticles are toxic or cannot reproduce a collaborator’s results? Does the NCL publish "unfavorable" results?

A. The NCL works closely with its collaborators to address any safety/efficacy issues or inconsistencies. Development of a collaborator’s nanotech strategy is an iterative process and the NCL will attempt to offer suggestions as to how to further optimize a sponsor’s nanoparticle. The NCL will then characterize the improved “batch” of nanoparticles.

If the scope of improvements to a nanoparticle’s formulation is drastic, such as a change in the targeting modality, the NCL would require the sponsor to reapply for evaluation. The new material would need to demonstrate efficacy and would require the characterization to start from scratch.

Q. How is an NCL collaborator’s intellectual property safeguarded by the NCL?

A. The NCL takes the same security measures for protection of NCL sponsor intellectual property as for NCL data; every effort is made to ensure security and confidentiality. To share and safeguard research material and proprietary information, the NCL’s interaction with sponsors is normally conducted under a Material Transfer Agreement (MTA) which includes a non-disclosure clause. The MTA permits the collaborative exchange of materials and data between the NCL and the sponsor. In certain circumstances, NCL–sponsor inter­action is conducted under a Cooper­ative Research and Development Agreement (CRADA).

Q. How does the FDA use NCL data when an NCL collaborator submits an Investigational New Drug (IND) filing?

A. Data derived from the NCL assay cascade are intended to be included in an investigator-led filing of an Inves­tigational New Drug (IND) with the FDA. Since the NCL sponsor initiates and files the IND, the sponsor decides if and how NCL data are presented to the FDA in the IND filing. NCL data alone, however, will not be sufficient to meet the FDA’s requirements for an IND. If the NCL’s assays predict favor­able in vivo safety and efficacy, NCI and the NCL anticipate the sponsor will pursue the translation of the tech­nology into clinical applications.

Q. What information about the nanomaterials the NCL characterizes does the NCL provide to the FDA?

A. As a formal collaboration between the National Cancer Institute (NCI), the National Institute of Standards and Technology (NIST), and the Food and Drug Administration (FDA), the NCL makes an effort to maintain transpar­ency to its governing institutions. In that spirit, all NCL characterization data are available to the FDA. The NCL and FDA work together on many aspects of nanomaterial characteriza­tion, and the FDA is informed about the properties of NCL nanomaterials as data are being generated. Charac­terization data that appear in NCL reports are peer-reviewed by FDA scientists who serve on the NCL’s Scientific Oversight Committee (SOC). Biannually, NCL scientists formally present characterization information and data related to NCL nanomaterials to the NCL’s SOC, which includes representatives from the FDA.

However, as mentioned previously, if an NCL sponsor initiates and files an IND with the FDA, the sponsor decides what NCL data are included in the IND and how the NCL information is presented.

Q. Does the NCL publish proprietary information provided to them by their collaborators?

A. Absolutely not! The NCL does not publish information provided by its sponsors without their express written permission.

In contrast, data generated by the NCL from characterization of a material may be presented in scientific and public forums if such data are deemed to benefit the cancer research community. This public disclosure, however, pertains only to data generated by the NCL; a sponsor company’s proprietary/confidential information is protected and will not be disclosed under any circumstances. Furthermore, the NCL and its sponsors agree to treat in confidence any written information about the research materials that is indicated as confidential.

Q. How does the NCL safeguard nanomaterial samples during and after characterization?

A. The nanotechnology samples represent significant investments on the part of the laboratories and investigators submitting to the NCL. Many of these samples took years to develop and optimize. The NCL is cognizant of this, and is careful to retain control of the samples. NCL samples are not transferred to anyone not under the direct supervision of the NCL without advance notification to the sponsor. The samples are used only for research purposes, not for commercial purposes such as production or sale. When NCL characterization is complete, the NCL archives a sample of each submitted nanomaterial. Any remaining sample is disposed of or returned to the sponsor.

Q. Can I publish data generated by NCL?

A. Certainly. NCL scientists greatly appreciate the opportunity to collaborate on publications. NCL data are intended to be used in regulatory filings, in publications, and to garner interest from venture capital.

Q. Does every nanoparticle submitted to the NCL undergo every experiment in the full NCL Assay Cascade? Who/what determines which assays will be used to test my nanoparticle?

A. Not every submitted nanoparticle goes through the entire assay cascade. Every particle does go through “the prescreen”–physicochemical tests in solution to confirm formulation identity, and tests to verify the formulation is free of bacteria, yeast, mold, or endotoxin contamination. Beyond the prescreen, the collaborator and NCL scientists jointly determine and prioritize characterization experiments. Factors influencing this plan include the type of nanomaterial (e.g. many of the physicochemical assays are material-specific), the collaborator’s previous characterization of the material, the collaborator’s desired knowledge of the material, and the intended final application of the material.

Q. How many nanoparticles may I submit for characterization?

A. Generally speaking, the NCL would prefer to characterize only one lead nanomaterial -- your most promising candidate formulation for promotion to clinical applications. In addition, the NCL usually requires control nanomaterials and synthetic precursors for experimental comparison.

If you’ve not yet decided on a lead formulation, NCL may be able to help with lead selection, but these experiments have a lower priority at NCL than IND–directed characterization experiments. NCL has over 50 collaborations, and we prioritize experiments on a weekly basis based on our characterization demands and results (efficacy, pharmaceutical viability, etc.). We assign a higher priority to formulations that have already gone through the lead selection process.

That said, if something unexpected happens and you decide you’re not taking that formulation to clinic, you are welcome to apply for characterization of other formulations, and NCL is happy to apply whatever it learned about the first particle to subsequent formulations. Previous acceptance of one formulation, however, does not automatically guarantee acceptance of a subsequent formulation for NCL characterization.

Q. How long does NCL nanoparticle characterization take?

A. The entire assay cascade can be completed in one to one-and-a-half years. However, many factors may shorten or lengthen this timeframe. Issues with nanomaterial sterility, endotoxin levels, and production of adequate amounts of material can delay the process.

Here is a general timeline for NCL characterization:

1-1.5 months

In general, we perform the “NCL prescreen” within 45 days of receiving your nanomaterial. The prescreen consists of tests for contamination (bacterial, yeast, mold and endotoxin), as well as preliminary physicochemical tests for size distribution, such as dynamic light scattering (DLS).

1-3 months

Once the prescreen is complete, if everything looks good, we continue with physicochemical and in vitro characterization. This includes measurement of physicochemical characteristics like drug loading, charge, purity, stability and surface characteristics and evaluation of in vitro blood contact properties (plasma protein binding, hemolysis, platelet aggregation, complement activation, etc.). This phase of characterization also includes evaluation of effects on cell viability using a variety of methods. This “second phase” of NCL characterization generally takes about 45-60 days. This phase can be slowed considerably if one of our experiments appears to give spurious results (results not in-line with the results of the other experiments) or if we discover a property of the nanomaterial that was unanticipated (e.g. unexpected toxicity or interference with the assay).

3-12 months

Physicochemical and in vitro characterization continues during this period, and, finally, if everything continues to look promising, we begin in vivo experiments. We usually start with a dose-range finding toxicity study to determine the toxic dose and target-organs for any toxic response to the nanomaterials. This takes 1-2 months. This is usually followed by a biodistribution study, using available methods to track the distribution and clearance of the nanomaterial, and/or an efficacy study, evaluating the nanomaterial in either a xenograft or transgenic cancer model in rodents. Each of these studies typically takes 2-3 months to plan, conduct, and analyze the results. Finally, we usually conduct the full subacute toxicity study as the final phase of NCL characterization. This study is very involved and may take 4-6 months to complete. It is also the most expensive, and likely the most important for an IND.

Keep in mind that the above timeline assumes everything goes well and that there are no unexpected results – this is uncommon, since there are almost always unexpected results!

Q. How will I access NCL data?

A. NCL data is provided to our collaborators via webconference throughout the study period, several times a year, with ample opportunity for discussion of results and development of upcoming experimental plans. When characterization is complete, a fully inclusive report is presented to the collaborator detailing results of all NCL experiments.

 

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National Cancer InstituteDepartment of Health and Human ServicesNational Institutes of HealthFirstGov.govNCI - Alliance for Nanotechnology in Cancer
National Cancer Institute U.S. National Institutes of Health www.cancer.gov Nanotechnology Characterization Lab