Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.

Randi Hernandez

	High-throughput methods of identifying host-cell proteins in biotherapeutics will be the focus of a new partnership between SCIEX and Singapore’s Bioprocessing Technology Institute (BTI), according to a press release from SCIEX on Jan. 26, 2016.

	Under the terms of the agreement, SCIEX with provide BTI with analytical mass spectrometry instruments-including the company’s TripleTOF 6600 system, Nano LC system, and proprietary software-to help BTI advance its work on the analysis of contaminating host-cell proteins in biologic drugs. In exchange, BTI will provide SCIEX with data and validation results from their studies.

	Singapore’s BTI has been expanding its presence in the biologic space since early 2015. In May 2015, BTI’s Agency for Science, Technology and Research (A*STAR) division partnered with Visterra to develop a neutralizing antibody for the treatment of dengue fever. In July 2015, BTI announced a partnership with Agilent to develop new methods of glycan analysis for large-molecule protein therapeutics.

Articles

The partnership will focus on the identification and analysis of host-cell proteins in biologics.

SCIEX and the Bioprocessing Technology Institute Announce Partnership

	Of the 45 new molecular entities and new therapeutic biological products approved by FDA in 2015, nine products were monoclonal antibodies (mAbs). And there may be many more of these types of proteins on the horizon-as many as 14 are projected to hit the market in 2016, according to data compiled by EvaluatePharma, in collaboration with 


	Most of the products listed below are in Phase III trials; however, a few are in earlier stages of development. Although the pharmaceutical manufacturers developing these mAbs will likely seek various indications for their products, the preliminary indications include treatments for various cancers, multiple sclerosis, psoriasis, asthma, HIV, and exposure to anthrax. Most of the emerging large-molecule drugs in the asthma pipeline are interleukin inhibitors targeting inflammatory pathways and are indicated for patients who have a reduced sensitivity to corticosteroids, although the specific targets vary somewhat by product.

-Eli Lilly’s ixekizumab is an interleukin-17 drug that works by targeting the IL-17 ligand. This mAb is being developed for the treatment of psoriasis and psoriatic arthritis, and may directly compete with Novartis’ Cosentyx (secukinumab) and AstraZeneca/Valeant’s brodalumab. Brodalumab, however, will work a bit differently-it is an antibody that binds to the IL-17 receptor, whereas secukinumab and ixekizumab focus on the IL-17 ligand. In clinical trials, ixekizumab demonstrated superiority over Enbrel (etanercept) for clearing skin plaques.

-Valeant and AstraZeneca’s IL-17 therapy, brodalumab, for the treatment of psoriasis got some bad press in May 2015 when Amgen dropped out of the co-development project with AstraZeneca after clinical-trial results suggested that the drug was associated with suicidal ideation in patients. In September 2015, however, Valeant stepped in and agreed to be responsible for the commercialization and development of the project. Brodalumab was shown in clinical trials to clear the scaly skin patches associated with psoriasis more efficiently than Johnson & Johnson’s Stelara (ustekinumab)‎.

-Elusys Therapeutics’ mAb, obiltoxaximab, which will go by the trade name Anthim, differs significantly from the rest of the mAb pack. The investigational agent for the treatment of inhalational anthrax infection is supported by the Biomedical Advanced Research and Development Authority (BARDA), which is part of the US Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response (HHS ASPR). Even before the product’s approval by FDA, BARDA 

 Elusys its first delivery procurement order for Anthim so that the agency could add Anthim to its Strategic National Stockpile (SNS) as a countermeasure against a potential bioterrorist attack. Elusys has already received more than $220 million in grants from government agencies to develop the mAb. The drug, meant to be used as both a treatment after anthrax exposure and as an anthrax prophylactic, is being investigated as an intravenous treatment as well as an emergency injectable. Obiltoxaximab was granted Fast-Track status and Orphan Drug Designation by FDA, according to the company.

-This fully humanized mAb immunotherapy (a PD-L1 checkpoint inhibitor) is being investigated for the treatment of various solid tumors, including indications for non-small cell lung cancer (NSCLC), bladder cancer, renal cell carcinoma, and breast cancer. The medication is meant for patients whose tumors express high levels of PD-L1. In clinical trials, treatment with atezolizumab corresponded to an average 7.7 month-extension of life when compared with those who received docetaxel chemotherapy; this represents a 

 survival benefit. If approved, atezolizumab will likely compete with Merck's Keytruda (pembrolizumab), Bristol-Myers Squibb's Opdivo (nivolumab), and AstraZeneca's 

, which is being investigated in Phase II and III trials.

-Teva is gunning for FDA approval in 2016 for its biologic reslizumab (trade name Cinquil), which targets IL-5. Although the company will first seek an approval for the medication for the treatment of eosinophilic asthma, it is also researching the drug’s efficacy in the treatment of eosinophilic esophagitis. Reslizumab is in the same class as GlaxoSmithKline’s Nucala (mepolizumab). In late 2016 or early 2017, AstraZeneca's benralizumab may also prove to be a competitor to reslizumab; although like mepolizumab, benralizumab will be a subcutaneous injection, while reslizumab is an intravenous drug. According to 

, a decision from FDA on reslizumab is expected by March 2016.

-Sanofi and Regeneron’s dupilumab is currently in late-stage development for asthma and eczema/atopic dermatitis. The drug is promising because of its 

ability to inhibit the biological effects of both IL-4 and IL-13

. It will compete with GlaxoSmithKline’s Nucala (mepolizumab), which was approved by FDA in November 2015, although Nucala works by another mechanism (through IL-5). Other competitors to dupilumab will likely include AstraZeneca’s Xolair (omalizumab), which was approved in the US in 2003 and works by another mechanism as well (by binding to the Ce3 domain of immunoglobulin E). Teva’s IL-5 inhibitor Cinquil (reslizumab, currently in Phase III trials), Roche’s IL-13 inhibitor lebrikizumab (in Phase II trials), and AstraZeneca’s IL-13 inhibitor tralokinumab (in Phase III trials for asthma) may also compete for market share in this crowded uncontrolled asthma mAb market. Sanofi/Regeneron will also seek approval for dupilumab for the treatment of eosinophilic esophagitis.

-Farletuzumab is an investigational humanized IgG

 antibody targeting tumor cell surface protein folate receptor alpha (FRA), which is typically overexpressed in epithelial tissue-derived cancers. Farletuzumab works by blocking the function of FRA. The mAb, which is a radiotherapeutic that is bound to a cytotoxic radioisotope, received Orphan Drug designation in the US, European Union, and in Switzerland for its potential to treat platinum-sensitive ovarian cancer. Although the investigational agent is being developed by Eisai subsidiary Morphotek, the precursor to farletuzumab was originally developed by Dr. Lloyd Old from the Ludwig Institute for Cancer Research.

 it entered into an agreement with the Targeted Alpha Therapy Group (TAT Group) at the University of Gothenburg in Sweden to collaborate on the research and development of  farletuzumab as an alpha therapy vector.

-The medication ibalizumab is believed to be a promising treatment for HIV, as it represents a treatment alternative to traditional antiretroviral therapies (ARTs) and HIV vaccines. It represents a therapy for those who have become resistant to ARTs. Known as a viral-entry inhibitor, the anti-CD4 human mAb of murine origin works by blocking HIV-1 entry 

	Clinical-trial supplies of ibalizumab were manufactured at WuXi's biologics manufacturing facilities in China for its partner, developer TaiMed Biologics, according to a WuXi 

. The drug received FDA’s Breakthrough Therapy designation, according to WuXi, but curiously, the drug is not mentioned on the fda.gov website, perhaps because 

 say the drug received this status more than 12 years ago. EvaluatePharma cites Roche, Biogen, and The Aaron Diamond AIDS Research Center as co-developers of the drug.

-Pfizer’s drug candidate for the treatment of acute lymphoblastic leukemia (ALL) is the only antibody-drug conjugate on the potential approval list for 2016. The drug received a Breakthrough Therapy designation from FDA in October 2015

 on the results of the drug’s performance in clinical trials compared with long-term chemotherapy for patients with relapsed or refractory CD22-positive ALL. Current treatments for ALL include Gleevec (imatinib) and Sprycel (dasatinib), but these are both examples of treatments for patients whose leukemia cells have the Philadelphia chromosome. According to the American Cancer Society, other mAbs that are now being studied for use against ALL include Rituxan (rituximab) and Campath (alemtuzumab). Inotuzumab ozogamicin originated from a collaboration between Pfizer and Celltech, which is now UCB-but Pfizer 

 has sole responsibility for all manufacturing and clinical development activities for the medication.

	The success of inotuzumab ozogamicin may not be easily gauged until Phase III trials conclude, however. In 2013, Pfizer ended its Phase III study of inotuzumab ozogamicin for the treatment of relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) patients due to futility.

-Roche’s ocrelizumab is a mAb being developed to treat relapsing multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS). In clinical trials, ocrelizumab was shown to be superior to interferon beta-1a, also known as Pfizer/EMD Serono’s Rebif, a widely used treatment for relapsing forms of the disease. There are currently no approved treatments for the progressive form of the disease. Ocrelizumab is designed to selectively target immune cells-CD20-positive B cells-that are thought to contribute to myelin and axonal damage. Ocrelizimab works by binding to CD20 cell-surface proteins on B cells, blocking their action. Roche’s Chief Medical Officer and Head of Global Product Development Sandra Horning, MD, stated in a company press release that ocrelizumab is the "first investigational medicine to slow a clinically meaningful and statistically significant effect on the progression of disease in primary-progressive MS."

-This IL-6-receptor inhibitor from Sanofi and Regeneron-meant to treat rheumatoid arthritis-was originally projected by some sources to gain regulatory approval in 2015, but is now expected to have a potential approval and launch in late 2016.  The mAb works by blocking the binding of IL-6 to its receptor and interrupting the cytokine-mediated inflammatory signaling cascade. Clinical trials with the investigational compound revealed x-ray data that showed 90% inhibition of structural damage to joints.

	The drug is being tested in clinical trials as a first- and second-line therapy in combination with methotrexate or other disease-modifying anti-rheumatic drugs (DMARDs) and also as a monotherapy. Regeneron said in its 2015 

 that EULAR guidelines support the use of an IL-6 inhibitor as a monotherapy. Sarilumab is likely to compete with such first-line therapies as Bristol-Myers Squibb’s Orencia (abatacept), Genentech’s IL-6 inhibitor Actemra (tocilizumab)‎, and AbbVie’s tumor necrosis factor (TNF)-blocker Humira (adalimumab). The company said it will have clinical trial results comparing sarilumab’s efficacy to adalimumab by 2016.

- Another psoriasis drug, you say? This mAb from Merck is in Phase III clinical trials for the treatment of plaque psoriasis and is yet another psoriasis medication that is expected to gain regulatory approval in 2016. Merck 

 the product to Sun Pharma in September 2015; Sun will be responsible for the funding of the molecule through regulatory approval, but Merck will perform the clinical and regulatory duties leading up to approval. Post-approval, Sun will take over all subsequent regulatory duties. Potential competitors that target IL-23 include J&J’s Stelara (ustekinumab) and Janssen’s guselkumab, which is currently in Phase II trials.

-Tremelimumab is an immune checkpoint inhibitor that prevents the blocking of the action of cytotoxic T-lymphocytes, allowing the immune system to more effectively destroy cancer cells. The fully humanized mAb binds to the protein CTLA-4 on the surface of activated T-lymphocytes, turning off inhibitory immune signals.

	The molecule has had somewhat of a troubled developmental past, however, as Pfizer got to Phase III trials with it for the treatment of metastatic melanoma, but failed in this phase to demonstrate the drug’s superiority over chemotherapy. In 2011, AstraZeneca’s MedImmune arm gained worldwide development and commercialization rights to the molecule (although Pfizer will retain rights to tremelimumab for certain combinations of therapies). In the ARCTIC, MYSTIC, and NEPTUNE trials, MedImmune is 

 the drug's efficacy in combination with investigational agent durvalumab for the first-line treatment of metastatic non-small cell lung cancer and head and neck cancers. FDA has also granted 

 to tremelimumab as a monotherapy for the treatment of malignant mesothelioma, an aggressive rare form of cancer that affects the lining of the lungs and abdomen.

-Daclizumab will join Roche’s ocrelizumab as another treatment for multiple sclerosis that could gain regulatory approval in 2016. Daclizumab, under the trade name Zenapax, was actually approved by FDA in 1997 to prevent organ rejection after transplantation. The drug would be listed under trade name Zinbryta for the treatment of multiple sclerosis, and according to a press release from co-developers Biogen and AbbVie, it 

 “superior outcomes” in clinical trials when compared with Biogen’s Avonex (interferon beta-1a). The superior outcome was defined as 45% better relapse reduction than was observed with Avonex. Although daclizumab successfully reduced the relapse rate of disease, it did not significantly improve disease progression after three months when compared with treatment with Avonex.

	Unlike investigational agent ocrelizumab, which binds to CD20, daclizumab binds to IL-2 subunit CD25, modulating the activity of IL-2 against abnormally activated T-cells that attack myelin. Zinbryta is believed to modulate the function on IL-2 without disrupting general immune system responses.


	Please click the image to the left for a chart listing all of the aforeentioned mAbs.

	Other notable mentions of mAbs to watch in 2016: AstraZeneca's benralizumab, Merck’s 

The forecasted approval dates are drawn directly from company-disclosed information (e.g., press releases, company presentations, etc.). As such, there may be products that are filed or in Phase III that are not included in these reports, due to the lack of information regarding approval/launch dates from either of these sources. Similarly, the original data were requested by and provided to 

by EvaluatePharma in August 2015; therefore, some of the original submissions have been excluded and/or modified by 

 to reflect regulatory changes. As examples, although daratumumab, elotuzumab, and idarucizumab were originally included in EvaluatePharma’s list as mAbs that would gain regulatory approval in 2016, these three molecules actually gained US FDA approval in 2015.

BioPharm highlights the monoclonal antibodies that may gain United States regulatory approval in 2016.

mAbs to Watch in 2016

	Perhaps in an effort to renew its soiled image following a problematic distribution arrangement with Philidor Rx Services and questions from Congress about its drug pricing activities, Valeant 

 on Dec. 15, 2015 that it will enter into a direct distribution agreement with Walgreens. The agreement may also allow Valeant to reclaim a portion of the 20% of scripts that the company lost as a result of its separation with Philidor.

	The arrangement will authorize Walgreens to “host” Valeant’s products on its pharmacy shelves, without the obligation for the pharmacy to purchase the drug inventory from Valeant. This means that Walgreens will not make its money on pharmacy spread, but will instead receive a flat distribution and dispensing fee from Valeant, according to Pembroke Consulting’s Adam J. Fein on his website, 

. In essence, Valeant will hold title to products, and Walgreens will provide a storefront in which the drugs can be purchased.

	Although J. Michael Pearson affirmed in an 

 that Valeant’s drugs will be available for purchase in most other pharmacies, other chain competitors will not enjoy some of the same discounts, which are said to be about 10% off a branded drug’s wholesale list price. These discounts will be reserved for Walgreens and “other independent pharmacies;” the press release from Valeant did not specify which community pharmacies would be included. Valeant did, however, note in a slide deck on Dec. 16, 2015 that its new, decentralized model would “empower local leaders to make decisions that are right for their business.”

	While Valeant plans to also offer 30 of its branded products at “generic prices”-representing discounts of an average of 50% or higher from its branded drug prices-the company did not specify how those discounts will be calculated. Pearson did not elaborate if Valeant will price-match its products to the lowest-priced generic equivalents or if it will choose generic drug prices that are at the higher end of the spectrum. According to Valeant, it alone will be responsible for setting prices to the patient. Additionally, it is unclear how much less patients will pay for Valeant drugs at Walgreens than they will at other pharmacies.

 showed that medication prices vary widely by pharmacy location and chain. This variation is partially due to existing distribution contracts with manufacturers, but can also be influenced by payer reimbursements. Whether a patient pays for his or her prescription in cash or not can also influence what a medication’s final price will actually be.

	It is also ambiguous what a Walgreens pharmacist may be expected to do if there are cheaper alternatives to some of Valeant’s products. Because Walgreens Boots Alliance does not own a pharmacy benefit manager (PBM), its pharmacists may not face as much pressure from outside parties to substitute the least costly generic alternative. In fact, as Fein points out, Valeant may make more money from dispensing and distribution fees than it would from spread alone.

 with PBMs is that a PBM could potentially steer a patient towards a more expensive medication to increase manufacturer rebate payments for said prescription, a phenomenon that was known as “drug switching”. A similar problem could emerge at the pharmacy level if pharmacists are instructed to steer patients to Valeant’s products over less expensive generic medications with spreads that would be smaller than the dispensing fee the pharmacy would get for Valeant products.

	Although potential problems could arise with the novel distribution model, some experts believe the scheme could end up being beneficial to patients. "In general, this could be a positive move for patient access, since it moves away from the more traditional PBM model,” Ron Lanton III, Esq., president of True North Political Solutions, told 

. “We would have to see how this agreement will play out, but usually pharmacists are more concerned with providing their patients with the best healthcare options and value.”

	The announcement from Valeant may not deter large PBMs, however. "There will be no changes to our formularies or protocols as a result of the Walgreens/Valeant announcement, and we will continue to focus on making medicine more affordable for those we serve," wrote David Whitrap, senior director of corporate communications and public affairs at Express Scripts, in an email to 

. "The contracts that we have with pharmacies in our network require that the pharmacies adhere to the plan design that our clients have established."

*Update from the National Community Pharmacists Association on inclusion of independent pharmacies:

	If the distribution network proposed by Walgreens is restricted to just Walgreens pharmacies, the direct distribution model could have major repercussions on patients ‎and pharmacies, said John Norton, director of public relations at the National Community Pharmacists Association, an industry trade group that represents community pharmacists, in an email to this publication.	
	"This is the first attempt at restricting common prescription products to certain pharmacies. If the network is broad (23,000 independent and regional chain pharmacies and Walgreens) then [direct distribution] could be a cost-saving move that allows patients to get brand products at generic prices and reduces some of the PBM middleman cost additions," Norton wrote. "If the network is narrow (Walgreens plus a small number of their pharmacies), then [the deal] could be very restrictive to patient access and [could] exponentially bump the hassle factor for getting prescriptions." Norton added that a small network could also be a "slippery slope"-subsequent price hikes on Valeant drugs could end up costing consumers more in the long run. Additionally, for states that require generic substitution, the new Valeant model could be problematic. Ultimately, a patient's payer or PBM may "reduce or refuse to provide any insurance benefit if the patient does not do what the PBM tells them to do," Norton asserted. 

The new arrangement draws from a consignment approach, in which Walgreens will sell-but not directly own-Valeant’s products.

Valeant Strikes Novel Drug Distribution Deal with Walgreens

	
	The drug industry flooded the regulations.gov website with comments on FDA’s 

, with many of the comments coming in the form of concern over how manufacturers will report their data to the agency and how the data will be used by the agency to guide further regulatory action. Further, many commenting companies questioned who in the supply chain would ultimately be responsible for reporting to FDA-as well as what specific data would be necessary, how these data would be interpreted to assess overall product quality, and how to determine whether a quality program was successful or not. Questions were also raised about the methods of reporting that would be required and the overall burden to the industry as far as adding resources to perform quality testing, which Sanofi said in a comment could “increase the potential for drug shortages because some companies may make choices based on FDA metrics to the detriment of the drug supply, by discontinuing products, increasing drug prices, or diverting resources from other quality activities.” Sanofi even questioned FDA’s legal authority to collect metrics and the agency’s ability to take enforcement action if a site does not submit a quality metrics report.

	Approximately 15 pharmaceutical manufacturers submitted formal comments to FDA, and numerous trade groups-including the Pharmaceutical Research and Manufacturers of America (PhRMA), the Generic Pharmaceutical Association (GPhA), the Biotechnology Industry Organization (BIO), the Parenteral Drug Association (PDA), the Pharma & Biopharma Outsourcing Association (PBOA), and the International Society for Pharmaceutical Engineering (ISPE)-voiced their concerns as well. ISPE itself submitted a nearly 60-page response to FDA’s request for comments.

	Many stakeholders called for a phased approach to the submission of quality metrics to allow companies to alter processes to meet requirements, if necessary. Celgene specifically requested that the initial phase of implementation be optional. Additionally, as Grifols pointed out in a comment, although the draft document says that manufacturers of blood and blood components for transfusion are exempt from submitting quality reporting metrics, Grifols says it is unclear if the guidance will include biologic manufacturers in general.

PhRMA: The draft requires “significant revisions”


	Industry trade group PhRMA is concerned that FDA is grossly underestimating the burden that manufacturers will encounter in the collection and reporting of data, the group said in a comment.

	Both PhRMA and GPhA agree that guidance should not govern such quality issues. Instead, the quality efforts FDA presents in its guidance should be a product of formal rulemaking activity, especially if the rules therein are expected to be mandatory, rather than voluntary, the trade groups noted.


	Many industry players voiced concerns about how quality reports will shape further action by FDA. BIO wrote, “We understand that regulatory relief (e.g., less frequent inspections, post-approval manufacturing change categories) may be granted based on positive high-quality metrics; however, it is unclear whether FDA would use low-quality metrics as an indicator to increase inspections at a particular entity.” BIO also wrote that phasing FDA’s changes over a two-year period (or even a period of two-three years, as suggested by other commenters)-in which FDA would have open dialogue with industry on quality data metrics-may be necessary to properly define and identify the data that are of most value in the decision-making process. The agency adds, “An assessment period will also allow FDA and industry to identify any unintended consequences that may arise from the collection of these metrics.”

Data disclosure from the outsourcing community


	Cook Pharmica, a contract and development manufacturing organization (CDMO), said it had "considerable concerns about providing information outside of the scope of what is currently provided within the Annual Product Review," mostly because in its role as a CDMO, Cook does not own the license or production rights to the medications produced at its locations. Because of this technicality, Cook suggests sending its data on each product to the license holder for the license holder to submit to FDA; it says that this approach “ensures each license holder has appropriate visibility and accountability for their products' data.” Cook said it would be a major burden to its business to have to submit data to FDA directly. 

	BIO noted that the application holder should be responsible for submitting quality information to FDA. In contrast with this view, Sanofi wrote in a comment that it favors site-by-site metrics reporting, and said that contract companies, such as contract manufacturing organizations (CMOs) and CDMOs, should be required to submit their own data to FDA. PBOA, however, said that site-based metrics for “variable product types, lifecycle, or frequency/volume of manufacture” would create inaccurate, unbalanced ratings across sites.

	Cook added that although FDA says it will not make quality information public, it asked that FDA take extra measures to guarantee that the information not be made public-even under the Freedom of Information Act (FOIA) -to protect “trade secrets and commercial or financial information which could harm the competitive posture or business interests of a company.”

	Cook also pointed out that differences between foreign and domestic production sites would create inconsistencies, saying that reporting requirements would have to be the same regardless of plant location, else it may put an undue burden on US-based manufacturers and would “create a skewed or incomplete risk-ranking model.”

Who in the supply chain should be required to report quality metrics?


	Concerns also swirled about assigning out-of-specification (OOS) rates, how they will be calculated (i.e., with what mathematical equations), and the scope of tests that would be required to determine if something is OOS. Another CDMO, Hovione, said in a comment that while it generally supports FDA’s quality initiative, quality for finished dosage forms (FDFs) and APIs must be assessed in the same way. Sanofi specifically requested that FDA exclude API manufacturers from reporting requirements, and Baxter disagreed with FDA that the FDF manufacturer be responsible for providing quality data on both the FDF and API. Teva said that if CMOs were to be required to report quality metrics, manufacturers should not be in charge of managing those entries or serving as a conduit to the data reporting. Teva added, “It is unlikely that CMOs and other suppliers would agree to this level of involvement in their operations.” Perrigo, as a company that manufactures APIs, argued that API manufacturers should be required to submit their own quality data on quality, as the API manufacturer won’t always know if the finished product sponsor used its API in drugs headed to the US or to international markets and in which drug their APIs were ultimately used. Gilead asked specifically how FDA plans to assess quality when there is an API used by a manufacturer for different products (i.e., should there be one report for the supplier of the API or multiple reports for each different combination product that uses that API?).

	Baxter also requested removal of the requirement to report the number of lot release and stability tests conducted per product and asked FDA to consider final product testing only, as some products are more complex by nature (such as gene therapies) and may require more tests than other products.

A call for less frequent, more tailored reporting


	Reporting requirements may be more difficult to fulfill for complicated supply chains, Novartis claimed in a comment, and FDA is underestimating the effect quality reporting requirements will have for those working with various interconnected partners. Teva estimated in its comment that for a product that uses contract services, up to 120 data points per product may be required per year. For Teva’s more than 500 active product applications, the number of data points that would be required for the year for these products alone could exceed 18,000.

	Baxter called for less frequent reporting when "there is evidence that the establishment is operating in an ongoing state of control," and suggested that manufacturers be able to design their own reporting programs based on their products in question, provided these metrics are within FDA parameters.


	Other issues that stakeholders tackled included the definition of lot and what to do about partial lot rejections (Allergan); how to handle/register alternate sites of manufacture that are on file but not used and the logistics of reporting on a facility when there are multiple facilities in the supply chain (Amneal); the fact that product complaint rate does not consider lot volume (Takeda); the fact that product complaints do not account for patient error or unsubstantiated claims (Celgene); and the concern that submitted data may not be evaluated in context (Novartis).

	Celgene notes that although metrics have the potential to provide benchmarking opportunities for the industry, it says that reporting measurements should come “with the understanding that the metrics may not be direct indicators of quality itself.” The industry generally supports the introduction of a free text field in reports, although a few commenters mentioned that the 100-character text field may not be long enough to include additional information that could be relevant to a quality assessment.

While stakeholders generally welcome improvements to quality initiatives, they are concerned with how the new requirements will be implemented for more complicated supply-chain models.

Overwhelming Response from Industry on FDA’s Guidance on Quality Metrics

Pfenex is making a name for itself in the news headlines as of late. The company’s CEO, Bert Liang-who is also chair of the Biosimilars Council, a division of the Generic Pharmaceuticals Association (GPhA)-has been an outspoken opponent of the Centers for Medicare & Medicaid’s (CMS) proposal to assign common Healthcare Common Procedure Coding System (HCPCS) J-codes to all biosimilars for a given innovator product, saying that linking reimbursement for all biosimilars under the same separate code from the reference product is “illogical”. Liang has said in media reports that the current CMS proposal is not in accordance with the Biologics Price Competition and Innovation Act (BPCIA) as it was originally written and argues that the current reimbursement decision from CMS for Medicare Part B drugs would hinder biosimilar uptake (1).

	While biosimilars to a common reference product may not clinically be analogous, CMS believes that, for payment policy purposes, biosimilars can and should be treated like generics. The agency notes it did not consider any special circumstances with the products when making this conclusion. Plainly stated, “CMS’ proposals and related discussion about how biosimilar product ASPs [average sales prices] would be grouped did not encompass clinical interchangeability, substitution of biosimilar products, or clinical decision making when prescribing these products” (2). Should future changes occur-such as the commencement of the use of interchangability status designations-CMS notes that the “proposed revised regulation text would not preclude CMS from separating some, or all, of a group of biosimilars for payment (and the creation of one or more separate HCPCS codes).”

	The US Federal Trade Commission (FTC) also recently weighed in about biosimilar policy, specifically on the issue of biosimilar naming (3). The FTC says the addition of a suffix to a nonproprietary name (as is proposed by the US Food and Drug Administration) may lead physicians to conclude the naming differences equate to clinically meaningful differences. The FTC adds that FDA’s naming scheme conflicts with the World Health Organization’s (WHO’s) proposal to employ biological qualifiers, hence, FDA’s proposal “risks undermining international harmonization efforts.” Additionally, FDA’s proposed naming convention would, according to FTC, hinder price competition, and price competition is a necessary element of patient access to and uptake of biosimilar products.

	Biosimilar manufacturers like Pfenex have skin in the game when it comes to crucial naming and payment decisions, as the biologics company is developing a number of biosimilar products, with one of its most prominent being its biosimilar to Lucentis (ranibizumab injection). Pfenex’s product candidate, PF582, is licensed to Hospira (now Pfizer) and is in Phase I studies. Aside from pricing and naming issues, manufacturers of biosimilars will also face significant hurdles when it comes to intellectual property-although Phase III trials for PF582 are due to commence in 2016, the patents for Lucentis do not begin to expire until 2019. In addition, according to analysts at Evercore ISI, Pfenex also faces first-to-market competition with Formycon, which announced in October 2015 that it began Phase III trials for its own Lucentis biosimilar.

 interviewed Liang to learn more about Pfenex’s development strategy and how the company’s expression technology platform for recombinant protein production could give the company a manufacturing competitive advantage over other biosimilar sponsors. 

 Prior to the interest in the development of biosimilars for Lucentis, some physicians have used Avastin off-label to treat age-related macular degeneration, the main indication of Lucentis. What is Pfenex’s view on the off-label use of Avastin as a more affordable substitute for Lucentis?

 With the current draft guidance from the US FDA, compounded products that are biologics will need to be used within five days after compounding. The process of compounding is required to be performed in strict accordance with cGMP requirements. This includes specific testing for purity and sterility. As a result, those companies that compound products will need to evaluate if it is within their business model to continue such activities within the biologics realm.

 Is the assignment of an interchangeability status a real possibility within the next 10 years? What additional evidence does Pfenex think will be required by FDA to call a product interchangeable?

 It has been noted by FDA that switching studies may be required for the development of interchangeable biosimilars. Our understanding is that draft guidance on this important issue will likely be released by the end of 2015.

 You have mentioned in previous interviews that Hospira is a good partner for Pfenex because of Hospira’s strong legal infrastructure. Will this type of protection be increasingly important for biosimilar manufacturers? What kind of specific protections can a company like Hospira offer?

 We have a partnership with Hospira, now Pfizer, which will control the clinical studies of PF582, our biosimilar candidate to Lucentis. The partnership is overseen by an executive steering committee, with equal representation of both companies, although our partner will control the execution of the clinical study. 

	As has been seen in the variety of cases filed by reference product sponsors, clarification of the BPCIA will require litigation for interpretation of the statute. Companies like Hospira, now Pfizer, which has extensive experience in biosimilars, as well as in generics, provide an experience base to move the programs forward [through litigation] in such a milieu.

 Can you discuss some of your other biosimilar development projects (partners, targets, etc.)?  

 We have a total of 12 programs in our pipeline. The most advanced programs-in addition to PF582, a biosimilar candidate to Lucentis-include PF530, a biosimilar candidate to Betaseron (interferon beta-1b); PF708, a generic candidate to Forteo (teriparatide [rDNA origin] injection); and PF529, a biosimilar candidate to Neulasta (pegfilgrastim). In addition, we recently received a contract from the Biomedical Advanced Research and Development Authority (BARDA) of up to $143.5 million to develop the next-generation anthrax vaccine. This is a recombinantly produced vaccine that has the potential to fulfill the Strategic National Stockpile of 75 million doses, which has been articulated by the government as a targeted need to ensure biodefense preparedness.

 How is the Pfenex Expression Technology platform unique compared with other available platforms on the market?

 The Pfenex Expression Technology is a high-throughput, robotically enabled parallel process that allows us to obtain a production strain in nine weeks, compared with up to a year or longer in traditional settings. This strain is produced at launch scale, which creates savings on real and opportunity costs in strain development. Integrated into this strain development technology is a world-class bioanalytical capability built by the Dow Chemical Company, [which was developed] when Pfenex was part of that firm. This combination of accelerated expression and bioanalytics allows us to create biosimilar product candidates with low costs and demonstrate high quality that satisfies regulatory body concerns about quality and similarity.

 produces higher yields than traditional 

expression. Could the high yield produced upstream in 

 create a downstream product purification bottleneck?

 The Pfenex Expression Technology and downstream purification has been developed over the past 15 years and has been tech-transferred to all major CMOs [contract manufacturing organizations]-as well as client sites-without difficulty. Given the fact that every one of our biosimilar products is expressed soluble and properly folded, we avoid the entire refold step. The removal of these unit operations enables a more streamlined production process, increases overall yield, and avoids significant costs driven by raw materials and subsequent waste streams.


	1. Pfenex, “Statement on Final Coding Rule for Biosimilar Reimbursement under
	Medicare Part B,” Press Release, www.pfenex.com/statement-on-finalcodingrule-for-biosimilar-reimbursement-undermedicare-part-b/, accessed 3 Nov., 2015.
	2. 

, “Medicare Program: Revisions to Payment Policies under the Physician Fee Schedule and Other Revisions to Part B for CY 2016,” https://federalregister.gov/a/2015-28005, accessed 9 Nov., 2015, prior to the official publication date of Nov. 16, 2015 (file date 30 Oct., 2015).
	3. The Federal Trade Commission, comment in response to FDA’s 

Guidance for Industry, Nonproprietary Naming of Biological Products

, www.ftc.gov/system/files/documents/advocacy_documents/ftc-staffcomment-submitted-food-drug-administration-response-fdas-request-comments-its-guidance/151028fdabiosimilar.pdf, submitted on 27 Oct., 2015.

 When referring to this article, please cite it as R. Hernandez, "Litigation and Manufacturing Hurdles Block US Biosimilars Market Success," 

The CEO of a US-based biosimilar manufacturer explains the legal and intellectual property issues of bringing a biosimilar to market in the United States.