In terms of background, the BPCI Act was passed in March 2010 as part of Affordable Care Act, and it creates an abbreviated licensure pathway for biological products shown to be biosimilar or interchangeable with an FDA-licensed reference product (section 351k of Public Health Service Act). FDA is eager to have an informational discussion on this topic because with the new pathway program, the agency is “essentially launching an entirely new regulatory paradigm” and public needs to understand this, said Sherman.

The BPCI Act adds “protein” to the definition of a biological product which currently includes terms such as a virus, toxin, and blood. Historically, proteins have been approved as drugs under the FD&C Act (505) and under the PHS Act (351). Proteins (except for any chemically synthesized polypeptide) will be regulated going forward under PHS.

FDA can rely on some existing information about the reference product when considering a proposed bisimilar product. Specifically, “biosimilar” means the product has the same mechanism of action as the reference product; the condition of use in proposed labeling has been previously approved for reference product; and has the same route of administration, dosage form, and strength as reference product.

The agency has to decide whether the biosimilar product is highly similar to the reference product and ensure that there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency. A doctor can provide product A or B, for example, and expect the same result. The doctor cannot go back and forth between Product A and B, however (see below), noted Sherman.

The BPCI Act requires FDA to look at three buckets of information for the 351(k) pathway: analytical studies to show that the biosimilar is highly similar to the reference product; animal studies (including toxicity, and as needed); and clinical study(ies) to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed (including, among others, pharmacokinetics and immunogenicity).

A common question: biosimilars are not identical to the reference product but are close—how close? As Sherman explained it, each study adds a piece of information to understand what the biosimilar product is and shows what more is needed to fully understand it. The method is similar to a fingerprint like approach to closely identify the product. There is no one size fits all assessment. Another approach FDA may take is to use the totality of evidence in assessing the biosimilar. Europe has a similar way of evaluating biosimilars. To provide the best advice on required animal and human studies to the biosimilar applicant, FDA should have competed a thorough review of data from structural and functional analyses.

Interchangeability. This term means that the biosimilar product produces the same clinical result as the reference product in any given patient, AND for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater with repeated use of reference product without alternating or switching. An interchangeable biosimilar product may be substituted for reference product without authorization of a healthcare provider. NOTE: Biosimilarity is a prerequisite for interchangeability.

Discussions happening at FDA: The agency is thinking about ways to consider non-US licensed comparator products; the definition of protein (including chemically synthesized polypeptides); standards for interchangeability; naming and tracking standards for biosimilars and interchangeable products; exclusivity issues; and pediatric assessment requirements.

FDA will also be thinking about product class under the Act’s transition provisions. By 2020, every biological product will need to be approved under 351 of the PHS Act versus the FD&C Act.

To date, there have been 35 Pre-IND meeting requests for proposed biosimilars to 11 reference products. 21 PRE IND sponsor meetings held, and 9 INDs received

As for the FDA guidance on biosimilars…. Sherman says it’s still in final stages. No details on timeline specifics.

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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On Jan. 4, 2012, the HealthCare Institute of New Jersey (HINJ) published a press release which evaluated the results of the 2011 biopharmaceutical and medical technology economic impact survey, a study (conducted by Deloitte) which concluded that the life-sciences industry continued to make up a key sector of New Jersey’s overall economy.

Although the responses of five fewer companies—24 in the 2010 survey compared to 19 the following year—generated less meaningful findings for the most recent survey, HINJ President and CEO Dean J. Paranicas pointed to the strong continued growth in New Jersey’s bio/pharmaceutical sector. “Although we had 20% fewer companies participating in this year’s survey, those that did supply data demonstrate that the life-sciences industry continues to be a major economic driver in New Jersey,” said Paranicas. “However, New Jersey continues to face stiff competition from around the world and within the US for our industry’s investment. If anything, this data reinforces the need for our leaders in Trenton and Washington to continue to pursue policies that create a more competitive and attractive business climate here, and we look forward to continuing to work with them to achieve this objective.”

The study also cited (factoring in the decrease in participation) a total economic impact from reporting HINJ member companies of $24.2 billion in calendar year 2010, as compared to $29.3 billion in calendar year 2009.

Paranicas went on to laud the recent actions taken by Governor [Chris] Christie and the state legislature to make New Jersey more competitive and attractive for life-sciences investment. They include an aggressive and competitive business recruitment and retention program, adopting the single sales factor as the basis for calculating New Jersey’s corporate business income tax, and enhancing the Business Employment Incentive Program (BEIP) to promote greater private sector collaboration with New Jersey’s universities and colleges.

However, every rose has its thorn. The study pointed out that the number of full-time employees decreased from 55,366 in 2009 to 51,619 in 2010, and capital spending dwindled from $1.5 billion to $0.9 billion during that same span of time. The Whitehouse Station, New Jersey-based Merck & Co. announced the elimination of approximately 13,000 jobs following the second quarter of 2011 as part of a cost-cutting initiative. This continues a workforce-reduction trend for Merck in recent years. According to a July 30, 2011, article from The Wall Street Journal, “[Merck] will have eliminated about 30% of the work force it had at the end of 2009, in the wake of its $41.1-billion acquisition of Schering-Plough.”

This reflects the long-growing trend among the industry’s financially dominant companies. Expansion in the form of mergers and acquisitions (M&A), without a focused emphasis on R&D to maintain and add to a workable pipeline, will enable access to only a finite amount of prosperity constructed on a delicate foundation of borrowed time. Paranicas pointed out that global R&D spending increased by $6.1 billion—one of the factors that has contributed to the continued success of New Jersey’s biopharmaceutical sector, despite some overexpansive M&A miscalculations, and the consequences as a result.

Aside from the keynote speakers, there was also a poster session bringing together some 30 sets of research from British universities. Topics ran from small-scale chromatography resin development for the purification of Japanese encephalitis virus to a biotechnology-based platform to optimise the expression of monoclonal antibody (MAb) sequence variants in CHO cells. University College London was extremely well represented, contributing almost a third of all posters. There was a competition for best poster and the winner was Rhian Grainger from the University of Sheffield with the title “Cell line specific control of recombinant antibody N-glycosylation.”

Howard Levine, president of BioProcess Technology Consultants, discussed the changing landscape of mammalian cell culture manufacturing capability and presented some very interesting data. He noted that MAbs are driving biopharmaceutical revenue and predicted that commercial antibody demand could double by 2016. But what about manufacturing capacity to cope with increasing biopharm demand? The main take away point was that while utilisation currently stands at 43%, this figure is expected to increase to 64% in five years and because much of the capacity (around 75%) is controlled by only 10 companies, access to manufacturing could become difficult. Are CMOs readying themselves?

Research Centre Jülich’s Peter Rohe stepped up the technical detail with his research into boosting bioprocess optimisation through the use of an automated micro-titer plate cultivation system. The system aims to hit the middle ground between controlled conditions and high throughput.

Aidan Courtney from Roslin Cells gave a thought provoking talk on scaling up cell manufacture from the point of view of translating research protocols into GMP processes. He noted that “the destination defines the journey” meaning that, depending on the application of a particular cell therapy, the quantity of cells required for treatment becomes a crucial parameter. Courtney went on to provide numbers for a couple of example scale-up scenarios; ischemia therapy would probably require 100000000 cells per treatment, so estimating perhaps 10,000 treatments per year, the numbers start multiplying faster than the cells… He concluded that GMP translation and scale-up are challenges best addressed in tandem.
There were several more presentations during the first day including an introduction to the “Kymouse” from Kymab’s Tom Shepherd. Watch this space. The final lecture was given by this year’s recipient of the Peter Dunnill Award, Professor Mike Hoare from University College London. It was an inspiring presentation and almost a supplication for companies, funding organisations and academic institutions to continue working together to facilitate breakthroughs in bioprocessing. Focusing on ultra scale-down for enhanced bioprocess discovery, Hoare concluded “Design for manufacture; design for lower cost.”

Regrettably, I couldn’t make the second day of the conference, but I hope that PharmTech will be able to deliver some of that content through contributions from some of the speakers in 2012. You can find more information about BioProcess UK conference here.

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.

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.

ICH Q6B, approved in 1999 by the three ICH regions, outlines specifications, test procedures, and acceptance criteria for biotech products. Q6B specifically calls for structural characterization and confirmation of the amino acid sequence and composition, terminal amino acid sequences, peptide map, sulfhydryl group and disulfide bridges, and the carbohydrate structure. With the more recent passage of the ICH quality guidelines, Q8, Q9, Q10 and the pending Q11, industry has even more information (as well as more expectation) on how to conduct a risk- and quality-based analysis of these products to ensure their safety.

A series of presentations on how to conduct biopharmaceutical characterization in detail was given yesterday in Valley Forge, Pennsylvania, by SGS Life Science Services and its recently acquired M-Scan Group, which focuses on mass spectrometry and gas chromatography for chemical analysis of both small and large molecule products.

Also discussed were biosimilars, which while making headway in Europe (14 have been approved since 2006), are still awaiting an implementation plan for approval in the US. Once that plan is in place—FDA continues to promise that it will be soon—bioequivalence, interchangeability, and comparability tests will become more commonplace. In the meantime, fully understanding and characterizing one’s product—down to the tiniest and most random chromatographic peak—remains a crucial part of the process and an expectation that is here to stay.

As the unemployment rate hovers around 9.1%, the federal government needs to find ways to create jobs. Congress is debating whether a tax break on repatriated money would prompt companies to hire more workers, as I mentioned last week. Meanwhile, the Obama administration is eyeing another potential means of stimulating job growth: investing in biological research.

When he signed the America Invents Act in September, President Obama committed to developing a National Bioeconomy Blueprint by January 2012. The blueprint will describe ways to manage investment in biological research to improve the nation’s health and create the “jobs of the future.” Aside from identifying potentially productive investments in R&D, the blueprint will also describe regulatory reforms to reduce burdens on biopharmaceutical manufacturers.

Illustrating the maxim that great minds think alike, FDA is already seeking to identify and reform burdensome and inefficient regulations as part of its own initiative to stimulate biomedical innovation. At the same time, the agency plans to establish a common understanding among stakeholders to clear the approval pathway for exceptionally promising therapies. These goals are included in the agency’s recent report titled Driving Biomedical Innovation: Initiatives to Improve Products for Patients.

Biological research is the foundation of a significant portion of the American economy, as the White House website notes. The combined efforts of the president and FDA could help discover and develop new therapies. If they also encourage biopharmaceutical companies to hire new employees, they will help mitigate an urgent problem that has not yet been addressed sufficiently.

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.

The Senate’s Foreign Earnings Reinvestment Act, like a related bill in the House of Representatives, would reduce tax rates for CROs and biopharmaceutical firms that repatriated money earned overseas. With the money they saved, companies could hire staff and invest in research, ACRO argues.

WinAmerica, an interest group supported by various firms, says that the bill would repeat the success of a 2004 repatriation tax break. Citing information from the Bureau of Labor Statistics, the group observes that average annual private-sector employment increased by 4,385,000 jobs from 2000 through 2007, and that 98% of the increase occurred during the years when the tax break was in effect (2004 through 2006).

The tax break did not benefit the entire private sector, however. It primarily helped pharmaceutical and technology companies, according to a report by Senator Carl Levin (D-MI). Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Pfizer were among the top 15 repatriators that time around. After bringing $155 billion in overseas earnings back into the country, these 15 firms reduced their overall US workforce by about 21,000 jobs and spent slightly less on R&D. Instead of creating jobs, the companies used the extra money to repurchase stock and raise their top executives’ pay by about 28%—despite express prohibitions against using the money for these purposes.

The increase in employment that WinAmerica cites seems to have occurred in industries other than those that benefited from the tax break—and for other reasons. The law that granted the previous tax break did not include a means of monitoring compliance. Unless the Foreign Earnings Reinvestment Act can do this, and can impose penalties for noncompliance, it will not create jobs for those who need them. I hope Congress takes heed of Senator Levin’s report as it considers the new bills.