Roche, perhaps, more than any other pharmaceutical company, is banking heavily on the combination of diagnostics and drug development to drive pharmaceutical innovation. In reporting its 2010 results in February 2011, Roche reported that it had 12 new molecular entities in late-stage development, of which six were potential personalized healthcare medicines with planned companion diagnostic tests, which included Zelboraf (vemurafenib) and its companion diagnostic for BRAF mutation-positive metastatic melanoma. FDA approved Zelboraf for treating BRAF V600E mutation-positive, inoperable, or metastatic melanoma and the cobas 4800 BRAF V600 Mutation Test, a diagnostic test developed by Roche, in August 2011.

Earlier this month, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended that Zelboraf be granted full marketing authorization as a monotherapy for treating adult patients with BRAF V600 mutation-positive unresectable or metastatic melanom. The corresponding European Commission decision on the marketing authorization of Zelboraf is expected in February 2012. Marketing authorization submissions for Zelboraf also are under review by health authorities in Australia, New Zealand, Brazil, India, Mexico, Canada, and other countries worldwide.

Roche also is using its diagnostic strategy to support new indications for existing drugs. Last month, Roche reported that the cobas EGFR Mutation Test was CE-marked, an indicator of a product’s conformity with EU requirements, and is now commercially availabile in Europe and other countries that recognize the CE mark. The cobas EGFR Mutation Test is a companion diagnostic to identify patients with non-small-cell lung cancer (NSCLC) who harbor mutations in the EGFR (epidermal growth factor receptor) gene and who may benefit from treatment with anti-EGFR tyrosine kinase inhibitors, such as Roche’ Tarceva (erlotinib). Tarceva, an oral EGFR inhibitor, was first approved in September 2004 to treat locally advanced or metastatic NSCLC after failure of at least one other chemotherapy treatment. It later was approved by the European Commission in September 2011 as a first-line monotherapy in people with locally advanced or metastatic NSCLC with EGFR-activating mutations.

Other companies also are reporting success with certain personalized medicines. In August 2011, FDA approved Pfizer’s Xalkori (crizotinib) for treating locally advanced or metastatic NSCLC that expresses the abnormal anaplastic lymphoma kinase (ALK) as detected by an FDA-approved test. The agency approved the drug along with a diagnostic test for the ALK gene abnormality, Abbott Molecular’s Vysis ALK Break Apart FISH Probe Kit. Up to 7% of those patients with NSCLC, typically patients without a history of smoking, have the gene abnormality.

Although personalized medicines will likely hold only a small part of the overall pharmaceutical market by value and volume in the near term, these successes portend of a changing paradigm in drug development.

Under a user-fee program, industry agrees to pay fees to help fund a portion of the FDA’s drug-review activities while the FDA agrees to overall performance goals, such as reviewing a certain percentage of applications within a particular timeframe. The proposed user-fee programs for generic drugs and biosimilars are modeled on the PDUFA program. PDUFA was created by Congress in 1992 and must be reauthorized every five years. The current program, known as PDUFA IV, will expire on Sept. 30, 2012, unless reauthorized by Congress. FDA’s recommendations for PDUFA V were developed in consultation with drug-industry representatives and with patient and consumer advocates, according to an FDA press release.

The proposed new generic-drug user-fee program would provide the FDA with funding at a time when generic-drug applications are on the rise. FDA receives 800 to 900 new generic-drug-related applications annually, according to the agency. In exchange for fees on facilities and product applications, the proposal includes performance metrics, such as review timeframes and a commitment to achieve parity between surveillance inspections of foreign and domestic establishments by fiscal year 2017. FDA expects that the proposal would effectively eliminate the review backlog and significantly reduce review times.

The Generic Pharmaceutical Association (GPhA) issued its support for a proposed Generic Drug User Fee Act (GDUFA) and FDA’s recommendations for a generic-drug user-fee program. “This is an important landmark that could not have been achieved without the extraordinary efforts of the FDA, my colleagues in the generic industry, and all other stakeholders,” said Ralph G. Neas, President and CEO of GPhA, in a Jan. 13, 2012, GPhA statement. “We now look forward to working with members of Congress in the weeks and months ahead to ensure that the final program is one that expedites access to low-cost, high-quality generic drugs for Americans and further safeguards the quality and accessibility of our nation’s drug supply.”

GDUFA calls for the generic-drug industry to pay $299 million annually in user fees for the next five years, beginning Oct. 1, 2012. This funding is supplemental to what Congress appropriates to FDA each year and will enable  FDA’s Office of Generic Drugs to hire the scientific resources needed to provide timely approval of generic medicines, according to GPhA. The new fees also will boost spending for generic-drug manufacturer facility inspections, which are required before new generic drugs can be approved.

The proposed Biosimilar and Interchangeable Products User Fee program is intended for products approved under a new abbreviated approval pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed biological product. The Affordable Care Act of 2010 contains a subtitle called the Biologics Price Competition and Innovation Act of 2009, which established this pathway. The recommended user-fee program for biosimilars includes fees for products in development to generate revenue in the near term and to provide FDA with the resources needed to support development-phase meetings with sponsors of biosimilar biological product candidates.

The Pharmaceutical Research and Manufacturers of America (PhRMA) supports the premise of a biosimilar user-free program.” We endorse a clear, science-based, separately funded regulatory program for biosimilars that is supported by a mix of appropriations dollars and user fees,” said a PhRMA Vice-President Sascha Haverfield-Gross in a Dec. 6, 2011, statement.

The Biotechnology Industry Organization (BIO) did not comment on the proposed generic-drug and biosimilar user-fee programs, but offered its support for the reauthorization of PDUFA. “BIO strongly supports the PDUFA V recommendations as they will enhance the drug-development and review process through increased transparency and scientific dialogue, advance regulatory science, and strengthen postmarket surveillance,” said BIO president and CEO Jim Greenwood, in a Jan. 13, 2012, statement. “Most importantly, PDUFA V will provide patients and doctors with earlier access to innovative new therapies.”

Congress will take up the issue of user fees in a series of Congressional hearings, scheduled for next month. The House Energy and Commerce Health Subcommittee will hold hearings on Feb. 1, 2012, on PDUFA reauthorization and on Feb. 7, 2012, on the proposed generic-drug user fee and biosimilar user-fee programs. Senators Tom Harkin (D-IA) and Mike Enzi (R-WY), the chairman and ranking member of the Senate Committee on Health, Education, Labor and Pensions (HELP), offered their support for the PDUFA reauthorization and the proposed generic-drug and biosimilar user fee programs. “These user fee agreements are crucial to ensuring that medications become available to the American public quickly and safely,” said the senators in joint Jan. 13, 2012, statement. “We applaud the FDA and the industries for the dedication and hard work it took to finalize these agreements.” During the past several months, the HELP Committee has convened a series of hearings to explore issues related to the user-fee legislation.

With strong fiscal constraints, the user-fee programs, both the PDUFA reauthorization and user-fee programs for generic drugs and biosimilars seem likely. The key item in the coming months is to see if Congress will be able to move forward with the initiatives per FDA’s recommendations.

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Beginning this month, we are featuring monthly reader polls to gain your feedback on key advances in the pharmaceutical sciences and manufacturing. As the scientists and technical experts on the front lines, your input is a crucial component in understanding what the industry has achieved and where it will go in the future. We encourage you to provide your feedback in our first poll, which is examining advances in oral drug delivery and oral product forms. We will share the results with you at PharmTech.com, and along with further analysis, our July issue will take a retrospective and prospective look at drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing.

We are interested in your feedback as well. In addition to our reader polls, we invite you to provide your input on what you think have been major achievements in drug substance and finished drug-product manufacturing, formulation development and drug delivery, outsourcing, and analytical testing. Lend your expertise and offer your input in the comment section to this blog or email your input to Patricia Van Arnum, executive editor, pvanarnum@advanstar.com. We look forward to hearing from you.

Topical formulations can be used to treat local and systematic indications, offer ease of delivery, facilitate patient compliance, and avoid the problem of first-pass metabolism. Successfully developing a topical formulation requires an understanding of the physiochemical properties, such as release characteristics, composition of the drug-delivery system, and the nature of the drug-delivery vehicle. Manufacturing a semisolid dosage requires implementing a CMC (chemistry, manufacturing, and controls) strategy to ensure stability, photosafety, avoidance of product degradation, and minimization of process impurities. The Pharmaceutical Technology webcast, “Optimizing Topical Drug Formulation and Manufacturing,” provides insight on recent advances in topical drug formulations, the latest regulatory/pharmacopoeial requirements in product quality and product performance, and strategies to optimize manufacturing for topical drug products.

Speakers include: Vinod Shah, PhD, chair of the Special Interest Group, Regulatory Science of the International Pharmaceutical Federation and distinguished pharmaceutical scientist and consultant to the US Pharmacopeia; Majella Lane, PhD, senior lecturer in pharmaceutics at the School of Pharmacy at the University of London; and Michael Lowenborg, R&D manager of formulation and process development at  DPT Laboratories.

Additional information and registration for the webcast may be found here.

The joint venture with Kyowa Hakko Kiron is expected to begin in the spring of 2012. In April of this year, Fujifilm completed its acquisition of the former Merck Biomanufacturing Network, which provides contract biologics manufacturing. The acquisition included facilities in Research Triangle Park, North Carolina, and Billingham, United Kingdom. Merck & Co. had acquired the Billingham facilities through its 2009 acquisition of the contract manufacturer Avecia and the Research Triangle Park facilities as part of its acquisition of Schering-Plough in 2009. Diosynth was the former contract manufacturing activities of Organon, the pharmaceutical business of the Dutch chemical company Akzo Nobel. Schering-Plough acquired Organon in 2007, and Merck & Co. acquired Schering-Plough in 2009. Merck combined the UK and US contract biologic activities into the Merck Biomanufacturing Network, which was acquired by Fujifilm in 2011, and later named Fujifilm Diosynth Biotechnologies.  Also in 2011, Fujifilm formed a partnership with Mutsubishi for contract biologics manufacturing under which Mitsubishi took a 20% equity interest in FujiFilm Diosynth Biotechnologies.

In addition to Fujifilm, other nonpharma players have joined the biosimilars fray. In February of this year, Samsung Electronics entered into a strategic partnership with the CRO Quintiles as part of Samsung’s entry into the biopharmaceuticals market. The companies formed a new joint-venture company to provide biopharmaceutical contract manufacturing services in South Korea, with Samsung owning 90% and Quintiles 10%. At the time of the announcement in February, Samsung said it plans to commercialize biosimilars by 2016 and to expand into innovative biologics in the future. The joint-venture company plans to construct a biopharmaceutical manufacturing plant in South Korea with the goal of beginning full-scale operations in April 2013.

In another deal, in June 2011, Merck & Co. partnered with the Korean chemical company, Hanwha Chemical, to develop and commercialize HD203, a biosimilar candidate of Enbrel (etanercept). Under the agreement, Merck will conduct clinical development and be responsible for manufacturing. In addition, upon marketing approval, Merck will commercialize HD203 globally, except for in Korea and Turkey, where Hanwha retains marketing rights. In return, Hanwha received an upfront payment from Merck and will be eligible for additional payments associated with milestones for technology transfer and regulatory progress as well as tiered royalties on sales.

It is said that “politics makes for strange bedfellows,” but in these instances, the biosimilars market is engendering the entry of some nontraditional players and unexpected alliances as well.

Topical formulations can be used to treat local and systematic indications, offer ease of delivery, facilitate patient compliance, and avoid the problem of first-pass metabolism. Successfully developing a topical formulation requires an understanding of the physiochemical properties, such as release characteristics, composition of the drug-delivery system, and the nature of the drug-delivery vehicle. Manufacturing a semisolid dosage requires implementing a CMC (chemistry, manufacturing, and controls) strategy to ensure stability, photosafety, avoidance of product degradation, and minimization of process impurities. The Pharmaceutical Technology webcast, “Optimizing Topical Drug Formulation and Manufacturing,” provides insight on recent advances in topical drug formulations, the latest regulatory/pharmacopoeial requirements in product quality and product performance, and strategies to optimize manufacturing for topical drug products.

Speakers include: Vinod Shah, PhD, chair of the Special Interest Group, Regulatory Science of the International Pharmaceutical Federation and distinguished pharmaceutical scientist and consultant to the US Pharmacopeia; Majella Lane, PhD, senior lecturer in pharmaceutics at the School of Pharmacy at the University of London; and Michael Lowenborg, R&D manager of formulation and process development at  DPT Laboratories.

Additional information and registration for the webcast may be found here.

The rationale for such an approach is clear. One needs to only look  down the rows of the more than 1800 exhibitors at CPhI to see the requisite  for contract-service providers and suppliers to achieve competitive advantage through product and service differentiation. For pharmaceutical companies, among the more than 25,000 attendees at CPhI, the decision of with whom to partner is crucial for successfully implementing their drug-development and manufacturing strategies.

The strategic partnership model was discussed at a conference session at CPhI. Moderated by Jim Miller, president of PharmSource Information Services and contributing editor to Pharmaceutical Technology, the panel featured presentations from Sanjit Singh Lamba, managing director of the  Knowledge Center for Eisai, Massimiliano Brescia, global pharmaceutical operations at Abbott, and  Philip Pratten, vice-president of business development, contract pharma services with Alkermes.  The panelists discussed the drivers behind the adoption of strategic partnerships and best practices in optimizing such relationships.

For pharmaceutical companies, they face ongoing pressure to reduce costs while maintaining quality and security of supply, are seeking to   reduce their supplier base to more efficiently manage their drug-development activities and manufacturing network on a global basis, and want to gain continuous improvement and innovation in technology, processes, and  project management. For contract service providers, such strategic partnerships are a way to meet the expanding and diverse needs of pharmaceutical customers  by building long-term and stable relationships. The panelists shared perspectives on performance metrics, communication approaches, and best practices in technology transfer in meeting the evolving needs of pharmaceutical companies.

So what is the take-away? Effective relationship builing, project-management competency, continuous-improvement strategies, and supplier innovation are evermore important elements of the toolboxes of contract-service providers.

The researchers recently reported their research in the Journal of Clinical Investigation (1). CD8⁺ T cells are an important element of the immune response to viral infection, and an inadequate CD8⁺ T cell response is thought to be partly responsible for the infection that arises following infection with HIV (1). Scientists would like their vaccines to provoke T cells to recognize and kill HIV-infected cells, but it is not easy to monitor whether T cells are provoking an adequate or inadequate response, according to a MIT press release describing the research.

The researchers pointed to two key challenges. Although IFN-γ production is used as a measure of T cell function, the relationship between cytokine production and the ability of a cell to lyse virus-infected cells is not clear. Additionally, the ability to assess multiple CD8⁺ T cell functions with single-cell resolution using freshly isolated blood samples and recovering these cells for further functional analyses also has been a challenge (1).

To address these issues, the researchers developed a high-throughput, automated assay in 125-pl microwells to simultaneously evaluate the ability of thousands of individual CD8⁺ T cells from HIV-infected patients to mediate lysis and to produce cytokines (1). Using this approach, the researchers could detect whether the T cells killed the infected cells with probes that glow when the dying cells’ nuclei become compromised. The next step was to measure  interferon gamma production with a microengraving technique that the researchers had earlier developed. Secretions from each cell are imprinted on a glass slide, which can then be tested for the presence of specific proteins. Because each cell has its own “address” on the slide, the secretions can be traced back to individual cells, and their interferon gamma production can be correlated directly to their cell-killing ability, according to the MIT release. The same technology could potentially be adapted to measure cells’ output of any other immune system protein. In this study, the researchers found that while the percentage of T cells that secrete interferon gamma is similar to the percentage of those that kill infected cells, the populations are not identical. In future studies, the researchers hope to find markers that correlate with cell-killing ability, thereby making it easier to evaluate a potential vaccine’s effectiveness, according to the MIT release.

Although more research will be needed to develop the technology to the point where it can be used routinely in vaccine trials for large-scale studies of patient samples, it is a positive accomplishment in gaining understanding for developing an HIV vaccine.

Source

1. N. Varadarajan et al., “A High-Throughput Single-Cell Analysis of Human CD8+ T Cell Functions Reveals Discordance for Cytokine Secretion and Cytolysis,” J. Clin. Invest. online, DOI:10.1172/JCI58653, Oct. 3, 2011.

Looking at the pharmaceutical industry as a microcosm for economic activity, there are certain fundamentals that cannot be ignored: demand in established markets is weak and demand in emerging markets is strong. In 2010, on a constant dollar basis, the North American pharmaceutical market increased only 1.9% compared with 2009, and Europe’s pharmaceutical market increased only 2.4%, according to data from IMS Health. In contrast, the pharmaceutical markets for Asia/Africa/Australia (excluding Japan) increased 14% and 14.2% in Latin America in 2010, both on a constant dollar basis. Admittedly, the sizes of emerging markets are less than established markets. In 2010, North America’s pharmaceutical market was valued at $335 million, Europe’s at $253 million, Asia/Africa/Australia (excluding Japan) at $130 million, and Latin America at $54 million on a constant dollar basis.

What these numbers show, however, is a basic truth that policymakers cannot ignore: when companies are investing, they are investing where there is market demand, namely, in emerging markets. Although some proposals in the President’s plan, such as payroll tax relief or accelerated deductions for businesses, would be helpful to businesses in the short term, they cannot alter the demand–supply fundamentals that are behind the shifts in capital investment.

Within specific sectors, it is more helpful to examine where federal policy can make a difference. One area in the pharmaceutical industry where there seems to be a disconnect in federal policy is in the manufacture of pharmaceutical ingredients and related supply to the US market. A recent report by the US Government Accounting Office (GAO) points to the ongoing challenges that FDA faces in overseeing the foreign drug-manufacturing supply chain. In 2010, GAO estimated that FDA inspected 11% of foreign drug-manufacturing establishments subject to inspection, and that it would take approximately nine years for the agency to inspect such establishments at that rate. In contrast, in fiscal year 2009, FDA conducted 1015 domestic inspections, representing approximately 40% of facilities, which would allow the agency to inspect domestic facilities at the rate of once every 2.5 years. To address this challenge, in its recent report, Pathway to Global Product Safety and Quality, FDA outlined its efforts to increase foreign inspections, increase staffing overseas for such inspections, and other cooperative measures among national regulatory agencies.

Although such efforts are important and necessary from a product-safety perspective, a more fundamental question arises for federal policymakers: is it really prudent for the US to allocate federal resources to increase inspection staff to support offshore manufacturing for pharmaceutical ingredients and products for the US market?  Would it be better policy to align product supply with what can be reasonably overseen by national regulatory agencies through domestic production and in the process not only support but expand domestic pharmaceutical production? Given the regulatory oversight required to ensure quality and safety, a pharmaceutical product is different than other industrial or consumer products, and therefore, the rules of market engagement would seem to differ. There is always much discussion on the value of keeping technology-based and science-based jobs in the US, but in the context of pharmaceutical development and manufacturing, are we really pursuing a cohesive federal policy? That perhaps is the question we should be debating.

See related stories,”Big Pharma’s Manufacturing Blueprint for the Future.”

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In hot-melt extrusion, an amorphous solid solution of the crystalline drug substance is formed under shear and heat. Solubility parameters, combined with other physiochemical characteristics of the drug and excipients, can by used as predictive indicators in selecting initial formulation components. Successfully implementing pharmaceutical hot-melt extrusion dosage product development, however, requires not only careful selection of the active and inactive ingredients, but also of the appropriate processing conditions. Inadequate processing conditions can lead to thermal degradation of polymers, drug, or other formulation components. Melt-extrusion processing temperature, screw speeds, feed rates, and screw design play a crucial role in implementing the technology.

Producing a desired dosage form requires the optimization of both the formulation-development and manufacturing processes. The upcoming webcast, “Pharmaceutical Melt Extrusion Process Development,” examines how initial process parameters can be selected and optimized for a product produced using hot-melt extrusion. The webcast includes speakers from Roche, American Leistritiz, and Evonik, and will be broadcast on Oct. 4. Details may be found here at the PharmTech website.

Reference

1. P. Van Arnum, “Solubilizing the Insoluble,” Pharm. Technol. 34 (11), 50–56 (2011).