Nanomedicines: Addressing the Scientific and Regulatory Gap

Resources

Commercialization and critical patent issues

Bawa, R. Nanopharmaceuticals. Eur J Nanomed. 2010;3:34-9.

Bawa, R. Regulating nanomedicine — can the FDA handle it? Curr Drug Deliv. 2011;8(3):227-34.

O'Neill S, Hermann K, Klein M, et al. Broad claiming in nanotechnology patents: is litigation inevitable? Nanotechnology Law & Business. 2007;4(1):595-606.

Pearce JM. Physics: Make nanotechnology research open-source. Nature. 2012;491:519-21.

Lessons learned from the NCL

National Cancer Institute. Application Process. National Characterization Laboratory

Nel AE, Mädler L, Velegol D, et al. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater. 2009;8:543-57.

FDA approach to regulation of nanotechnology products

Cruz CN, Tyner KM, Velazquez L, et al. CDER risk assessment exercise to evaluate potential risks from the use of nanomaterials in drug products. AAPS J. 2013;15:623-8.

Hamburg MA. Science and regulation. FDA's approach to regulation of products of nanotechnology. Science. 2012;336:299-300.

Sadriehn. Overview of CDER experience with nanotechnology-related drugs. Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. 2012.

U.S. Food and Drug Administration. FDA's approach to regulation of nanotechnology products. Science & Research: Science & Research Special Topics: Nanotechnology. 2012.

EMA guidance

Duncan R, Gaspar R. Nanomedicine(s) under the microscope. Mol Pharm. 2011;8:2101-41.

European Medicines Agency. Committee for medicinal products for human use (CHMP) assessment report on Doxorubicin SUN. 2011.

European Medicines Agency. Joint MHLW/EMA reflection paper on the development of 4 block copolymer micelle medicinal products. 2013.

Gaspar R. Nanoparticles: pushed off target with proteins. Nat Nanotechnol. 2013;8:79-80.

"Nano-similars" and follow-on nano-sized therapeutics

European Medicines Agency. Reflection paper on the data requirements for intravenous iron-based nano-colloidal products developed with reference to an innovator medicinal product. 2013.

Schellekens H, Stegemann S, Weinstein V, et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2014;16:15-21.

Lessons learned from Doxil

U.S. Food and Drug Administration. Draft guidance on doxorubicin hydrochloride. Recommended Feb 2010; Revised Nov 2013.

Garbuzenko O, Barenholz Y, Priev A. Effect of grafted PEG on liposome size and on compressibility and packing of lipid bilayer. Chem Phys Lipids. 2005;135:117-29.

Albumin-bound nanoparticles: what did we learn?

Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 200;12:1317-24.

Ehmann F, Sakai-Kato K, Duncan R, et al. Next-generation nanomedicines and nanosimilars: EU regulators' initiatives relating to the development and evaluation of nanomedicines. Nanomedicine (Lond). 2013;8:849-56.

European Medicines Agency. Reflection paper on surface coatings: general issues for consideration regarding parenteral administration of coated nanomedicine products. 2013.

TNF-PEGylated gold nanoparticles: a platform for a family of nanomedicines

Libutti SK, Paciotti GF, Byrnes AA, et al. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clin Cancer Res. 2010;16:6139-49.

Stern ST, Hall JB, Yu LL, et al. Translational considerations for cancer nanomedicine. J Control Release. 2010;146:164-74.

Combination nanotechnology: drugs or medical devices?

Pottier A, Borghi E, Levy L. New use of metals as nanosized radioenhancers. Anticancer Res. 2014;34:443-53.

At the Academy

Nanotechnologies in Cancer Diagnosis, Therapy, and Prevention

Sponsors

eBriefing Sponsor

Presented by

Keynote Speaker:
Sally Tinkle, Science and Technology Policy Institute, IDA

Introduction

Nanomedicine is the application of nanotechnology to health care for the treatment, diagnosis, and monitoring and control of biological systems. Nanomedicines exploit the nanoscale manipulation of materials to improve medicine delivery, and researchers hope these technologies will enable breakthroughs in many disease areas, especially in cancer therapy. Several approaches have been proposed for delivering medicines using nanoparticles, with some success in the market. But the rapid development of these approaches has left both regulatory frameworks and scientific assessment tools struggling to keep up.

In principle, it would be most efficient to set up a single drug approval process that would apply in all countries. However, the very different legal frameworks in operation make such regulatory harmonization seem like a distant goal. In the United States, the Food and Drug Administration (FDA) is responsible for consumer products such as food and cosmetics and for drugs and medical devices. It also develops product-specific policies within an overarching framework. In contrast, many attendees regarded drug regulation to be aiming at distinct goals that require a completely different framework from that governing other products. But European medical regulators also operate under a much less prescriptive legal mandate than the FDA. For now, perhaps the current diverse assortment of approaches will help us to determine the best regulatory practices.

Follow-on products illustrate the challenges inherent in evaluating nanomedicines, but recent efforts may also clarify the regulatory processes that are needed for nanodrugs. Approval of generic substitutes for small-molecule drugs relies on precise characterization techniques that reliably establish biological equivalence. For complex structures used for nanomedicines, a larger suite of characterization tools is needed, and even the best set of tools is often insufficient to assure safety and efficacy without further clinical trials to assess a follow-on candidate.

The conference featured four case studies highlighting nanomedicines in different stages of development. For the two approved drugs, some proposed substitutes have clearly failed to achieve therapeutic equivalence. Recurring requirements for successful nanodrug development included robust manufacturing process and sophisticated characterization of nanomaterials.

Keynote address

In her keynote presentation, Sally Tinkle of the Science and Technology Policy Institute at the Institute for Defense Analyses drew on her U.S. government experience to review the evolution of nanotechnology from a vision to a commercial reality in little more than a decade. The rapid growth and commercialization of nanotechnology has required the development of new standards while the science is still evolving. The timeline posed challenges in establishing basic characterization techniques and nomenclature for the new compounds. In addition, the movement of products into the market has demanded new legal and regulatory frameworks. "We started facing all of these competing priorities and challenges simultaneously," Tinkle said. Compared to research, "policy and regulation move at entirely different timelines," although both depend on the scientific evidence that research generates. "This mismatch became part of the ecosystem in which we were trying to work."

"Nanomaterials and devices may not fit the traditional chemical assessment and regulatory paradigms."

"Nanomaterials and devices may not fit the traditional chemical assessment and regulatory paradigms," Tinkle said. Most legislation is decades old—written before nanomaterials were invented—and often does not reflect the greater emphasis now put on anticipating environmental and ethical issues brought up by new technologies. She encouraged participants to "think in terms of new partnerships for policy and regulation" that might be needed for nanomaterials.

Critical stages in nanomaterial production include research and development, product development, policy evaluation, and regulation. Competing priorities emerge for regulating new nanotechnologies. (Images courtesy of Sally Tinkle)

Speakers:
Raj Bawa, Bawa Biotech LLC; Rensselaer Polytechnic Institute
Scott E. McNeil, Nanotechnology Characterization Laboratory – Frederick National Laboratory for Cancer Research

Highlights

• The U.S. Nanotechnology Characterization Laboratory assists developers of nanotechnology-based cancer therapies.
• Properties such as immunogenicity should be evaluated early in the development of products and manufacturing processes.
• Rapid progress and confusing definitions have led to overly broad and overlapping patents in nanotechnology.

The patent thicket

Ambiguous or contradictory nomenclature is particularly problematic for patenting nanotechnology, explained Raj Bawa of Bawa Biotech LLC and Rensselaer Polytechnic Institute, because nomenclature standards are critical for determining whether patents conflict. In addition to discrepancies between scientific disciplines in nanomaterial nomenclature, there are also incompatible definitions of the "nano" regime—that is, the classification of substances as nanomaterials. Although the National Nanotechnology Initiative proposed a size range from 1–100 nanometers (nm), Bawa advocates including particles as large as 1000 nm (1 micron) if the particles gain "at least one novel property or characteristic" from their small size. The U.S. patent office has adopted this function-based definition, which aligns with functionality requirements for patents in general and is similar to the working definition of nanomaterials used by the FDA.

There has been a "patent land grab" in nanotechnology.

Bawa argued that ambiguity in classifying structures has combined with the rapid growth of nanotechnology to create a "patent land grab," resulting in the issue of "overly broad patents [and] patents for the same invention." If products go to market before these patents expire, he predicted, there will be "a lot of battles." Further patenting complexities have arisen because many nanomedicines are combination products that resist easy classification.

This "patent thicket" could lead to uncertainty and threaten innovation, especially because some patents are foundational to other inventions. Bawa recommended that researchers carefully identify openings in patent coverage early in the drug development process. "Intellectual-property strategy is critical, sometimes even before doing R&D," he said. The situation even led one expert, Joshua Pearce, to propose, in a 2012 Nature article, a moratorium on patents in nanotechnology. But Bawa disagrees with this analysis, and referenced an 1816 quote from Thomas Jefferson, who enshrined patents in the U.S. Constitution, to show that these conflicts are nothing new. "A lot of times, policy and regulatory issues lag behind the technology," Bawa concluded. "There's always a catch up."

Characterizing nanomedicines

To aid in nanotechnology characterization, the U.S. established the Nanotechnology Characterization Laboratory (NCL) at the Frederick National Laboratory in 2004. Jointly sponsored by the National Cancer Institute (NCI), the National Institute of Standards and Technology (NIST), and the FDA, the lab provides free evaluation of potential nanotech-based cancer treatments, explained its director Scott E. McNeil. The NCL accepts proposals from academia and industry in the U.S. and other countries, provided that the technology has "previously demonstrated efficacy in a biological system," he said. "We're in this together. If one of us makes a mistake, we all go down." The lab stands behind its results, which it defends in front of the FDA and explains to venture capitalists.

The NCL's three-phase assay cascade starts with an array of physicochemical characterization, assessing size, composition, and surface chemistry, among other properties. Based on their experience with a broad selection of nanoparticle types, the researchers developed a framework describing which combinations of parameters, such as particle size and surface properties, are likely to be biocompatible.

Effective nanomedicines for cancer have the right combination of size and surface properties (lower-right corner). (Image courtesy of Scott E. McNeil)

The second phase of testing concerns in vitro properties, of which immunogenicity is especially important. The body will treat nanoparticles as foreign material, McNeil noted, in the absence of measures such as PEGylation (coating with polyethylene glycol) to avoid recognition by the immune system. "Do not overlook this as you're developing your concepts," he stressed, because the details of nanoparticle preparation can significantly affect, for example, the degree of complement activation.

The NCL also conducts in vivo tests as needed to characterize "initial, dose-ranging toxicity," assessing 42 tissue types in the test animals. Although these tests do not provide sufficient evidence of safety in vivo for drug approval, they can help researchers to understand which characteristics to focus on in later toxicity tests.

With nanomaterials, what's on the label is not necessarily what's in the bottle.

One issue that frequently arises is that "things that are on the label, especially if you have a commercial vendor, are not necessarily what's in the bottle," McNeil said. Such discrepancies show the need for sophisticated characterization tools. But although necessary, these tools cannot always reveal critical differences between nanomedicine formulations.

Speakers:
Ritu Nalubola, U.S. Food and Drug Administration
Rogério Gaspar, University of Lisbon, Portugal
Stefan Mühlebach, Vifor Pharma Ltd.; University of Basel, Switzerland
 
Panelists:
Gerrit Borchard, University of Geneva and University of Lausanne, Switzerland
Ricardo Carvajal, Hyman, Phelps & McNamara PC
Patrick Hunziker, University Hospital Basel, Switzerland

Highlights

• The FDA does not categorically judge products involving nanotechnology to be either inherently benign or harmful. It regulates nanotechnology products under its existing statutory authorities.
• Regulation of drugs and medical devices has different goals and constraints from regulation of consumer products such as foods and cosmetics.
• Characterization of nanomedicines by physical and chemical properties is often insufficient to ensure medical equivalence.
• Evaluation of follow-on nanomedicines does not fit well with current paradigms for either small molecules or biosimilars.
• The limits to establishing pharmacological equivalence in nanomedicines make post-marketing vigilance to assess drug side effects ever more critical.

A U.S. view

"The descriptions and definitions of nanotechnology and the scope of nanomaterials for regulatory context are still evolving," both in the U.S. and in other countries, said Ritu Nalubola of the FDA. "One of the goals for FDA has been to provide regulatory certainty to both the industry and consumers to help with product innovation and support the responsible development of nanotechnology products."

Nalubola described a science-based, coordinated approach taken by the U.S. government to consistently assess nanotechnology applications, beginning with policy documents issued by the White House in 2011. The principles include scientific integrity in risk assessment, public participation, and evaluation of risks and benefits.

Building on this framework, the FDA documented its own agency-specific principles in 2012. One challenge is that the agency deals with a range of products with different applications, properties, and regulatory frameworks. "Our statutory frameworks across the board are somewhat different," Nalubola acknowledged. In particular, for cosmetics and certain food substances the agency generally does not review or approve products before they reach the market. In contrast, their involvement begins much earlier in the development of drugs and medical devices and explicitly includes premarket review of benefits and risks.

"Current regulatory frameworks for evaluating safety are sufficiently robust and flexible."

In spite of rapid developments in nanotechnology, the FDA position is that "the current regulatory frameworks for evaluating safety are sufficiently robust and flexible to consider a variety of materials, including nanomaterials," Nalubola reported. This conclusion applies not only to food and cosmetics but also to the Center for Drug Evaluation and Research (CDER), which evaluates nanomedicines. But because the field is evolving rapidly, the FDA "encourage[s] industry to consult with [the FDA] early in the product development process, so that any questions related to safety, effectiveness, and/or regulatory status can be adequately identified and then addressed."

To get a better understanding of trends in product development and potential benefits and concerns, the CDER has established a process for continually tracking applications based on nanotechnology. The FDA identifies these products based on not just size but also "potential novel and unique properties." Nalubola cautioned that this is "not a regulatory definition." In a preliminary analysis of this ongoing activity, the platforms include liposomes and a variety of nanoparticles. Most of the indications are related to cancer. An analysis of a risk-assessment and management exercise for drugs suggested the need for "increased regulatory science," as well as staff training in standardized review procedures.

Early nanotechnology applications surveyed by the Center for Drug Evaluation and Research cover a variety of platforms. (Image courtesy of Ritu Nalubola)

In the afternoon panel session, Ricardo Carvajal of the law firm Hyman, Phelps & McNamara said that "for a field that's developing as quickly as this one" fixed regulations will have trouble keeping up. For this reason, he regards the FDA's current approach of instead issuing guidance documents as completely appropriate.

Nalubola outlined numerous ways the FDA is coordinating its activities with regulatory agencies in other countries, including its policies for sharing data and general scientific frameworks, as appropriate. But in the panel session, she expressed caution about formal alignment of the legal frameworks. "There are limitations to achieving full harmonization, particularly in the regulatory arena, given our statutory mandates," she noted.

"The European agency is not a federal agency but a coordinating body," agreed Gerrit Borchard of University of Geneva and the University of Lausanne during the midday panel discussion. Compared to the FDA, "it's much more free to give scientific advice without being linked to a procedure," he said.

A European view

"In Europe we don't have the ambition to regulate nanomaterials as an entity," reiterated Rogério Gaspar of the University of Lisbon. Although Nalubola had referred to a "European Commission Recommendation" about how to define nanoparticles, for example, he stressed that the cited guidelines were only "a recommendation of independent panel of experts; it doesn't [convey an] official opinion." Despite their differences, Gaspar said, "it's very important to see different regulatory agencies working together ... to define common regulation," although he noted that regulatory inconsistency is only one of several hurdles in drug development.

We should not regulate medicinal products and consumer products in the same way.

During the midday panel discussion on regulatory gaps, Gaspar strongly warned that medicines and medical devices cannot be governed by the same regulations as other commercial products. "We shouldn't make the mistake of trying to put [them] in the same basket," he said. "When you look at nanopharmaceuticals and nanomedicines, the basic principle is the same: it's the assessment of the risk/benefit balance." In contrast, for nanomaterials, "we'll be looking at environmental impacts, accidental exposure, hazardous exposure. It's a completely different world in terms of regulation."

Gaspar noted that regulators worldwide are becoming involved much earlier in the drug development process, even if some guidelines do not have the force of law. He approvingly mentioned a recent guidance document on block copolymer micelles issued by European and Japanese authorities. This is "the first time that a regulatory agency has approved a guidance document about a technology which doesn't have a product on the market yet," he said.

There are a "huge number of products coming up in the pipeline," Gaspar said, including lipidic systems, organic and inorganic nanoparticles, and macromolecular conjugates. Other products involve newer engineered materials, including dendrimers, carbon nanotubes, and quantum dots, which could raise unanticipated problems in applications.

Upcoming nanomedical platforms in Europe. (Image courtesy of Rogério Gaspar)

The European community has been wrestling with approval of complex drugs for nearly 20 years, Gaspar reported, since the end of the cold war brought in many new member states. The initial approval challenges in nano-based drugs, in 2007 and 2008, involved biosimilar nano products ("nanosimilars"), which are much harder to characterize than conventional small-molecule generics. "We had already 10 years of extensive scientific discussion on the biosimilars," including clinical, manufacturing, and analytical experience, he noted. "You have to bear in mind the complexity of those aspects to deliver a product that behaves in terms of safety and efficacy in a comparable manner to a pre-existing product."

Gaspar mentioned two cases in which follow-on nanomedicines behaved differently from the original. The first concerned the iron colloids long used for anemia, later described by Stefan Mühlebach, which Gaspar said showed that "we cannot have generalizations from the physicochemical characterization data to these kind of complex systems." The second concerned liposome-based delivery, used in medicines such as Doxil, described by Yechezkel Barenholz. The profound differences found between the original system and a proposed substitute formulation led the European agency to issue detailed guidance describing the particle characterization and manufacturing processes needed to demonstrate similarity.

Despite these complexities, requiring a complete set of clinical trials before each new product can be approved would be not only expensive and impractical, but unethical, Gaspar said. Based on the Declaration of Helsinki, "we have an ethical responsibility as scientists and as regulators, when we can deliver a conclusion of the process without a clinical trial, not to press for a clinical trial."

"Justice also includes a distribution of scarce health care resources" to developing countries, cautioned Patrick Hunziker of University Hospital Basel during the midday panel. "Regulation runs the risk of limiting access by increasing the price of development, depending on how you formulate such regulations."

The limits of similarity

"Normally, generics are interchangeable, substitutable, and therapeutically equivalent, and no clinical and safety studies are required," said Stefan Mühlebach of Vifor Pharma Ltd. and the University of Basel. Small molecules, with a molecular weight below about 500, can be completely characterized in vitro and shown to be the same as an approved drug, and pharmacokinetics and biodistribution can be established in healthy volunteers.

"Things are a little bit more complicated with biologics, but there, from the very beginning, it was clear that we have a new kind of product. They cannot be fully characterized, so their approval is based on bio-equivalence," using characteristics such as pharmacokinetics.

Mühlebach argued that neither paradigm is appropriate for nanodrugs, which he described as "non-biological complex drugs," or NBCDs. These entities are "as large as biologics, [and] as complex or even more complex as the biologics," he said. "Their properties cannot be fully characterized by physicochemical means. That is not a question about techniques to be used—it's [that] we do not know always what to look for. Therefore, the product and its characteristics are mainly given by the manufacturing process." The surface properties and coatings of the final product are often crucial to safety and efficacy. Mühlebach advocated the terminology "similars" (or "nanosimilars") to describe the new regulatory paradigm these NBCDs demand.

The approval process for follow-ons of non-biological complex drugs (NBCDs) may need to be different from that used for either small molecule generics or biosimilars. (Image courtesy of Stefan Mühlebach)

Several years ago, in the so-called Leiden workshop, Mühlebach and others proposed a third assessment process for these "similars." The process requires explicit demonstration of therapeutic equivalence in both physicochemical properties and animal toxicity. Clinical data may also be required, determined on a case-by-case basis. "Only if you have all coming together and comparable in a given range, then there is a possibility to exchange such products," Mühlebach said. But he noted that this new process is "not yet written in official procedures in the regulatory authority pathways."

The need for new protocols is illustrated by the iron complexes. Although these substances have been used for years, their colloidal nature can give rise to complex and surprising responses. Indeed, some substitute products have led to serious adverse effects. Both the FDA and the European Medicines Agency (EMA) have issued thorough guidance documents on how to assess these and similar substances, which Mühlebach discussed in detail.

Finally, post-marketing surveillance and risk evaluation and mitigation are increasingly important. "A lot of the characteristics are only seen if you have the real exposure to people and patients," Mühlebach concluded.

Speakers:
Yechezkel Barenholz, The Hebrew University Hadassah Medical School, Israel
Neil Desai, Abraxis Bioscience (Celgene Corporation)
Lawrence Tamarkin, CytImmune Sciences
Laurent Levy, Nanobiotix

Highlights

• The liposome-based drug Doxil successfully delivered doxorubicin to tumors at higher concentrations, with reduced exposure in other tissues, but its manufacture has recently been halted for unrelated reasons.
• Abraxane, which consists of albumin-coated paclitaxel particles, delivers the drug to tumors more successfully and with less toxicity than the traditional formulation.
• Small particles can preferentially enter the leaky vascular of some tumors, but both Doxil and Abraxane show additional uptake due to unanticipated active molecular targeting.
• PEGylated gold nanoparticles are entering phase II trials for delivering tumor necrosis factor, whose extreme toxicity has until now prevented its widespread use.
• Nanoparticles could enhance X-ray absorption for radiotherapy, and initial studies show that the particles remain where they are placed in a tumor.

Drug delivery by liposomes

The challenges in nanomedicine can be illuminated by the record of existing and upcoming products, and four examples were highlighted at the conference. The first is the important example of liposomal doxorubicin (Doxil)—the first nanodrug approved by the FDA, in 1995—which was described by Yechezkel (Chezy) Barenholz of the Hebrew University.

Although doxorubicin is a potent anticancer therapy, "every part of the body is affected in an adverse way," Barenholz said. The motivation for the Doxil delivery platform is by now a familiar one: to get more of the drug to the tumor while reducing the toxic exposure of healthy tissues. Increasing the therapeutic index means treatment is more effective, since the dose of chemotherapeutics is generally limited by side effects.

Barenholz and his collaborators focused on liposomal delivery because this was, and still is, "the system you know most about," he said. Liposomes are biocompatible and biodegradable and have low immunogenicity, and their pharmacokinetics, biodistribution, and metabolism are well understood.

Doxil confines doxorubicin in crystalline form within a liposomal envelope, which is in turn decorated with polyethylene glycol (PEG). (Image courtesy of Yechezkel Barenholz)

The researchers decided to make small liposomes, just under 100 nm, which can take advantage of the enhanced permeability and retention (EPR) associated with the leaky blood vessels in tumors. Still, "we know today it's not as simple as that," Barenholz said. "Not all tumors have the EPR effect." He added that Doxil liposomes are selectively taken up because of a substance that is present in the microenvironment of the tumor, but did not elaborate. Nonetheless, he said, if there were a test to show whether a particular patient's tumor exhibits the EPR effect, it would be very helpful in personalizing therapy.

The small size chosen for the liposomes meant that the researchers "needed to develop a more sophisticated method of loading to reach a molar concentration of drug inside the liposome," Barenholz said. The team developed an ammonium-sulfate gradient method for loading the liposome. This process leaves almost all the drug crystallized inside the liposome, where it is very stable.

The developers also optimized a polyethylene glycol coating (PEGylation) for the particles to ensure that they circulate long enough to be taken up in the tumor. Developing this drug required the expertise of many different specialists. "To be successful, you have to work as a team."

"Every detail here matters," Barenholz said. "If you change one thing, this system will fall apart." Scaling up to reproducible manufacturing of such particles is particularly challenging. "These complex systems are much more difficult than the biologics," he explained, "because they're dependent on so many small factors that you have to integrate together in the right way."

This sensitivity has become more obvious recently. Unrelated problems caused the closure of the only manufacturing facility for Doxil in August 2013, in spite of ongoing clinical trials and hundreds of millions of dollars in sales. The FDA expedited the import of another liposome-based doxorubicin product called Lipidox. But as discussed by other speakers, assessing the equivalence of these nanoparticle-based systems is very difficult. Small changes can make a big difference in toxicity and efficacy. "You have to be very, very, careful," Barenholz said. For liposomal doxorubicin delivery, "except for Lipidox, there is no other drug on the market. The reason is that it is very, very difficult to make it."

Drug delivery by protein-bound nanoparticles

"Manufacturing for nanotechnology products may have several more hurdles than conventional products," agreed Neil Desai of Abraxis Bioscience (Celgene Corporation). "But ultimately we can get through them." He described another nanomedicine for cancer, paclitaxel protein-bound particles for injectable suspension, albumin-bound, called Abraxane, which was first approved in 2005.

Paclitaxel is well established for cancer treatment (in a formulation called Taxol), but it is highly insoluble. For this reason, Desai said, "conventional paclitaxel contains cremophor [a modified castor oil], which is toxic," and induces hypersensitivity among other adverse effects. Thus, finding a safer method of delivery was a major motivation for developing Abraxane in the early 1990s. The researchers also wanted to exploit the EPR effect for selective uptake by tumors.

In addition, however, "we did have some idea that albumin had some important biological characteristics," Desai noted. He and his colleagues have since demonstrated that the nanoparticles are also targeted to tumors through an active process of albumin uptake in endothelial cells and retention by albumin-binding proteins. "Something dramatically different is happening with the same drug," he said. "We've changed the way it gets into the tumor."

Following successful trials against Taxol, Abraxane was approved for metastatic breast cancer, non-small cell lung cancer, and pancreatic cancer; a trial against metastatic melanoma was still underway at the time of the conference. Taxol is also still in use, and the cremophor-based formulation actually forms micelles, Desai noted, "so maybe it was a nanodrug after all." But two other paclitaxel formulations, a nanoemulsion called Tocosol and a polymeric conjugate called Xyotax, failed in phase III trials. Desai expressed surprise that they could progress so far without clear warning signs.

Other countries have seen the introduction of drugs that are represented as "similar" to Abraxane. But for one product, a stress test induced the formation of large precipitates that do not appear in the original formulation, raising questions about the safety of the substitute for patients. Tests on another "alleged similar" showed different surface properties, which are important for "biodistribution, PK, tumor uptake, toxicity, immunogenicity, etc." Desai supported the warnings of the EMA, contending that "conventional bio-equivalence is not enough. Maybe actual clinical data is required in order to approve these nanosimilars."

Drug innovators can pursue different strategies for developing nanomedicines, which present a different balance of risk and benefit than traditional formulations. The original goal for Abraxane was "taking an approved drug and converting it into the nano form, in the same indications," Desai said, although success also requires clear benefits over existing drugs. Taxol is not effective for pancreatic cancer, but Abraxane data showed that "we can take a nanomedicine version of a drug that previously didn't work in a certain tumor type and convert it into something that's active and that produces benefit for patients." Even more profound differentiation and patient benefit, he said, would come from "a completely novel nanomedicine with a new drug and a new delivery system altogether, but that hasn't happened yet."

Drug delivery by gold nanoparticles

One of the people hoping to establish a nanoparticle platform for a new drug is Lawrence Tamarkin of CytImmune Sciences. But he acknowledged in the panel session that this approach has made it harder to attract funding. "The fact that we chose to use a very potent, not-approved drug whose therapeutic value has been zero really put us on the edge of not being accepted." Nevertheless, he said, "I felt that our obligation was not simply to reformulate already-approved drugs, but to take drugs whose therapy was unrealized and create them as safe and effective therapies using nanotechnology."

"I felt that our obligation was not simply to reformulate already-approved drugs."

Tamarkin described a platform based on colloidal gold nanoparticles, mostly between 15 nm and 35 nm in diameter. Such colloids have been used since the 1930s to treat rheumatoid arthritis, Tamarkin said, so "this had a long history of safety."

In contrast, the drug payload, tumor necrosis factor (TNF), has not been approved in the U.S., although it is used in Europe for tumors of the arm and leg. In a procedure called isolated limb perfusion, the tumor-bearing limb's blood supply is isolated from the rest of the body with a tourniquet and connected to a heart-lung machine. TNF is then infused, followed by standard chemotherapeutic agents.

Studies by Eggermont and colleagues in the Netherlands have shown an "85%–95% response rate with just one treatment of TNF followed by chemotherapy for the treatment of melanoma and sarcomas," Tamarkin said. TNF is thought to cause the leaky blood vessels in tumors to become even leakier, circumventing the higher pressure in the tumor to allow the other drug to penetrate more deeply into the tumor.

Despite this success, systemic administration of naked TNF would be unacceptable because of the vascular damage it causes. Patients "undergo renal failure, liver failure, and complete failure, the whole constellation of biology that represents septic shock. So you can understand that taking this drug is considered risky."

The unconventional drug tumor necrosis factor (TNF) is bound by a thiol linkage to a gold nanoparticle along with PEG. (Image courtesy of Lawrence Tamarkin)

The gold nanoparticles could change the situation by allowing selective delivery to tumors, and reproducible manufacturing of this type of particle is not difficult. "Gold nanoparticles bind thiols with such avidity that we could make [this drug] at large scale in a very simple process. The process is quite robust," Tamarkin said. As with other particles, PEGylation is needed to avoid scavenging of the particles by the immune system.

Phase I trials confirmed that gold particles delivered TNF to tumors at high concentrations with no indication of the hypotension that would be expected as a side effect of native TNF. Because the particles preferentially accumulate in the tumor, Tamarkin suggested that "treating patients so quickly with surgery may not be the best idea for nanotechnology-based medicines."

A phase II trial for the TNF formulation is underway. Tamarkin and colleagues have also been approached by AstraZeneca to rescue a drug that failed in preclinical studies. The researchers are exploring particles that take advantage of the affinity of TNF for tumors to deliver several drugs in a targeted fashion.

Drug or device?

Citing nanomedicines' novel properties, many speakers described the uncertainty in the field about how nanomedical innovations will be treated by regulators. Laurent Levy and his colleagues at Nanobiotix experienced this confusion first hand: their nanoparticle, NanoXray, is being treated as a drug by U.S. authorities but as a medical device in Europe. Nonetheless, he says the drug/device classification "does not make any difference" to the sorts of data needed to demonstrate patient benefit. "When you want to target an indication in a patient population, the benefit/risk ratio is very important," he said. The assessment depends on "the nature of the product" and not "the regulation."

"Drug/device classification does not make any difference."

The nanoparticles in question are designed to increase the amount of X-rays absorbed by cells, and thus presumably to kill those cells more rapidly. Roughly 60% of cancer patients receive radiotherapy during their treatment, but "you always have damage also in the surrounding tissue," Levy said. Injecting X-ray–absorbing nanoparticles directly into the tumor could improve the benefit of radiotherapy without increasing the dose.

Simulations showed that cells with hafnium oxide nanoparticles received nine times the radiation dose of those without. "The key question here is not about the physics, not about how the product is working, because that's ... the same mode of action as radiotherapy," Levy said.

Instead, the biggest questions at this early stage are "how to deliver the product within the tumor and not in the surrounding healthy tissue," and whether the particles will stay in place over many radiotherapy sessions. Levy and his colleagues developed three formulations for delivery and are conducting a phase I/II trial to explore the spread of the particles in the body. They found no indication of safety issues from the particles themselves and no evidence of spread from the original injection site.

With respect to the effect on tumors, "the statistical benefit cannot be demonstrated, because of the number of patients" in this initial trial. Nonetheless, "the results are encouraging," Levy said. "We have established some kind of proof of concept with this technology."

How much harmonization of drug regulation can reasonably expected between the U.S., Europe, Japan, Canada, and the rest of the world?

Can the safety and efficacy of complex follow-on nanomedicines ever be assured without a full slate of clinical trials?

Will the complexity and expense of approving nanosimilar products tilt the balance in favor of the original inventors even after patents expire?

Is it reasonable to seek a coherent set of principles for regulating products as diverse as cosmetics and cancer medicines?

Will there be a flurry of litigation resulting from the broad and overlapping patents issued in the early years of nanotechnology?

Are there tests that can assess whether a particular patient's tumor will respond to passively targeted nanoparticles?