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

Randi Hernandez

	Beyond challenges related to expansion and persistence of T-cell therapies, there are also challenges related to overall toxicity, specificity, and safety of T-cell therapies. Advances have been made to arm T-cell therapies with suicide switches or marker genes to prevent on-target, off-tumor activity. Bispecific T-cells, which often have an inhibitory CAR recognizing antigens on normal tissues and an activating CAR to recognize tumor antigens, are also in development.

	A new, locally effective CAR-T construct was the focus of a 

. Researchers from Cellectis engineered T cells to respond to variation in oxygen levels, enabling the immune cells to remain inactive in normoxic conditions and become active in low-oxygen (hypoxic) settings, such as the conditions that are characteristic of the tumor microenvironment.

	The cells were created to contain an oxygen-sensitive subdomain of hypoxia-inducible factors 1-alpha (HIF1α), a protein that degrades in normal oxygen environments and stabilizes (i.e., becomes active) in the presence of low oxygen levels. The subdomain acts as a sensor to control T-cell response, making the construct safer to normal tissues. Thus, the construct’s cytolytic ability is directly tied to level of oxygen in the local environment.

	Although off-the-shelf, gene-edited chimeric antigen receptor T-cell therapies (CAR-T therapies) are ideal for the manufacture of cell therapies at large scale, and are 

associated with a lower risk of graft-versus-host disease in patients upon adoptive transfer

, there hasn’t been much action on the regulatory front for these universal cell therapies-until now. Cellectis 

 that an investigational new drug application (IND) for its T-cell candidate targeting CD123 was filed with FDA, and according to the company, it is the first allogeneic CAR-T being investigated in human clinical applications in the United States.

	The universal CAR-T (UCART) UCART123 will enter into Phase I trials during the first part of 2017. Cellectis will test the agent’s efficacy to target CD123, the membrane biomarker that is typically overexpressed on the cells of patients with acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), and other hematologic malignancies.

Articles

Researchers from Cellectis investigate how external signals in the tumor microenvironment could control the cell-surface expression and specificity of engineered CARs.

Cellectis Describes Novel CAR-T Design in New Paper

	On Jan. 23, 2016, the Federal Trade Commission (FTC) announced it had reached an arrangement with Endo to resolve the FTC’s complaint that Endo entered into reverse-payments settlements for Lidoderm and Opana ER that eliminated generic competition. Under terms of the agreement, Endo will be prohibited from entering into future reverse-payment agreements, and FTC will release the company from liability surrounding these agreements for the branded drug AndroGel (testosterone gel), which is made by AbbVie.

	The refiled complaint, which was originally issued in March 2016 but dismissed in November 2016, names Allergan, Watson, and Endo as defendants. It challenges the agreements between Watson and Endo for the lidocaine patch Lidoderm, wherein Endo "bought off" Watson and Watson agreed to abandon the patent challenge. In the agreement, Endo agreed to hold their generic version of Lidoderm off the market and allow Watson to market its version for up to 7.5 months. Endo also agreed to provide Watson with samples of Lidoderm for free, which Watson could sell at profit through its distribution arm, Anda.

	FTC said in its complaint that because Lidoderm was such a unique product, other branded products to relieve pain that were similar (such as Qutenza, Horizant, and Gralise), “had no discernible impact on Lidoderm prices or unit sales.” As a result of Watson and Endo’s deal, by 2014, Endo had captured more than 40% of the lidocaine patch market.

	The agency wrote the pay-for-delay agreement hurt consumers and harmed competition, namely because Watson could have had its generic enter the market prior to September 2013, but “abandoned” its plan to enter the market before this time because it received a payment from Endo and free product to sell.

	FTC filed a related complaint against Impax Laboratories as well, claiming it illegally entered into a reverse-payment agreement with Endo for $112 million that kept Impax’s version of Opana ER off the market.

	Endo agreed to the terms of the stipulated order for permanent injection, effectively resolving the disputes with FTC on Opana ER and Lidoderm. In a press release, Endo also said that the agreement resolves the FTC’s claims against Endo subsidiary Par Pharmaceuticals in the action 

In a recent deal with the Federal Trade Commission, Endo agreed to refrain from entering into future pay-for-delay agreements for ten years.

FTC Bars Endo from Future Pay-for-Delay Agreements

	Merck announced late last Friday, Jan. 20, 2016, that it will settles a patent infringement case with Bristol-Myers Squibb (BMS) and Ono Pharmaceutical regarding the use of the PD-1 inhibitor for the drug Keytruda (pembrolizumab). Merck will pay a one-time fee of $625 million to the companies, as well as percentage of sales through 2026.

	BMS and Ono, who own the patent showing that the PD-1 antibody is efficacious in treating cancer, had previously said that Merck’s sale of Keytruda infringed their patents that are used to make Opdivo (nivolumab). The companies signed a global license agreement allowing Merck to continue to make and market Keytruda, and in return, BMS/Ono will end the patent litigation pertaining to Keytruda.

	Opdivo was the first immune checkpoint inhibitor to receive regulatory approval “in the world” (AKA in Japan) in 2014, according to BMS-although 

, Merck’s checkpoint inhibitor, was actually approved before 

 that Merck started developing Keytruda after BMS and Ono started making Opdivo, and that Merck had knowledge of the family of patents used for Opdivo.

	Importantly, the royalties will likely span across all future indications in cancer for Keytruda. The drug is currently under investigation for the treatment of at least 15 other types of cancers. Wrote BMS, “Under the agreement, the companies have also granted certain rights to each other under their respective patent portfolios pertaining to PD-1. The royalties will be shared between Bristol-Myers Squibb and Ono in a 75/25 percent allocation, respectively.”

Merck will pay a one-time fee of $625 million and additional royalties to BMS and Ono Pharmaceutical to settle the patent infringement case related to Keytruda.

Merck Settles Litigation with Bristol-Myers Squibb on Use of Antibody Targeting PD-1

	Pharmaceutical companies are retaining a smaller share of the prescription drug spend than is typically reported by outside agencies, according to a new report conducted by the Berkeley Research Group (BRG) and commissioned by industry trade group PhRMA. The study concludes that the share of gross drug expenditures realized by brand manufacturers has declined since 2013 (from 41% in 2013 to 39% in 2015). Meanwhile, the share realized by all the other non-manufacturer entities, such as participants in the supply chain, has increased, say report authors.

	Increases in drug list prices have been offset by increases in retrospective rebates and discounts that manufacturers granted to other industry stakeholders, the report claims. Historical calculations of gross drug spend (such as those that are presented in IMS Health and similar reports) do not take rebates into account, so they are misleading, according to BRG. BRG says that payers are increasingly demanding higher rebates so that a product remains on a formulary, contributing to outgoing funds. The growth of the 340B drug discount program for hospitals, as well as increases in mandatory rebates in Medicaid, are also contributing to pharma’s lower returns. In 2015, manufacturers retained less than half (47%) of total United States spending on prescription drugs, cites the BRG report.

	PhRMA's President and CEO Stephen J. Ubl implied in a company press release that the other stakeholders in the supply chain are to blame for increasing costs to patients, and the discounts and rebates that manufacturers award to those in the supply chain should be passed down to patients. Ubl commented in the release, “The study begs an important question: Are we doing enough to ensure the growing amount of rebates and discounts flow to the patient?”

 spoke to one of the BRG study authors, Aaron Vandervelde, to gain a bit of insight into how the data were calculated for the study and how information on manufacturer rebates-which is typically not public information-was collected.

 How were these data calculated (i.e., did the sample size ‘n’ include distribution to both specialty pharmacies and commercial pharmacies)?
	

 The analysis was done comprehensively for the entire market (i.e., we did not use a sample). We started with IMS data and then categorized drugs into four buckets: retail brand, retail generic, non-retail brand, and non-retail generic. We then applied a category-specific reimbursement formula to each of the four categories to determine total initial gross drug expenditures made by health plans and patients. We then allocated total gross drug expenditures across the supply chain based on various data, industry reports, and government publications available to us.

 I know the operational costs from a supply chain perspective are typically higher with specialty pharmacies because of the additional costs associated with special handling (cold chain, special storage, etc.). How do the costs of distribution play into your report calculations?
	

 The analysis did not consider operational costs at all. The goal was to understand the volume of total initial gross drug expenditures and the allocation of those expenditures throughout the supply chain. Each individual stakeholder has its own unique cost structure and that was not accounted for in this analysis.

 The report acknowledges that rebate info is not public knowledge and as a result, is not always disclosed. If this is the case, how did you calculate that 20% of gross drug expenditures are transferred from manufacturers to other entities via rebates?
	

 Commercial rebate information is not publicly available but aggregated rebate information for Medicare Part D is made available by The Centers for Medicare & Medicaid (CMS). We utilized that data to determine the rebate percentage in Part D and then applied the same percentage to the commercial channel.

 The report excludes ‘fees and costs in the pharmaceutical supply chain, such as dispensing fees paid to pharmacies, manufacturer payments to specialty pharmacies, and claims administration fees paid to PBMs [pharmacy benefit managers] by health plans and employer groups.’ How do you think the overall calculations would have changed if these fees had been included?
	

 We excluded any fees or costs that were not tied directly to the gross, net, or list price of a drug. So, for example, a rebate is included because rebates are structured as a percentage of the list price, but we excluded dispensing fees because those transactional costs are not tied to a pharmacy’s ingredient costs. If we were to include these costs, it would have departed from the original goal of the paper, which was to allocate the initial gross drug expenditures-and transactional costs are not part of the initial gross drug expenditure. It is unclear to us how or whether it would have changed the findings of the report. My suspicion is that inclusion of all of these transactional costs would not have meaningfully changed the results.

 The analysis says it does not take supply chain operating expenses into account that could ‘further reduce margins and realized net revenue.’ Does this mean the ‘final cut’ that supply chain stakeholders take in the end could be much smaller than reported if operating expenses were taken into account?
	

 From a whole dollars perspective, yes, but from a percentage perspective, not necessarily. Each entity in the supply chain (including manufacturers) has various operating costs that were not included in the analysis. If we had attempted to include all of these, the percentage retained by each individual stakeholder may have stayed the same because all stakeholders’ numbers are being reduced at the same time.

 There are differences in payer reimbursement schemes for branded vs. generic drugs. So, why are branded and generic manufacturers included in the same pie charts (Figure 2 and Figure 3 in the BRG report)? Wouldn’t it be more illustrative to present a graph of total drug expenditures for brand manufacturers and a separate graph for generic-drug manufacturers to show how these two types of manufacturers have different returns in the pharmacy space?
	

 I understand the point and we did show a brand-only table in the Appendix of the report. But, it is important to include brand and generic manufacturers together in the same pie chart for a different reason. Historical IMS figures-which most media outlets rely on to report US drug spending-reflect the acquisition cost to pharmacies. Generics discount directly to pharmacies because they are competing with each other for space on the pharmacy’s shelf. Manufacturers, however, rarely discount to pharmacies. Instead they provide retrospective rebates to health plans because they are competing for a position on the health plan’s formulary. As a result, their ‘acquisition cost’ from the pharmacy’s perspective is much higher and the IMS reported figures make it appear that brand manufacturers are a much bigger percentage of ‘US drug spend’ than they really are. For example, IMS reports indicate that brand manufacturers account for approximately 75% of US drug spend, whereas our analysis, which is a more accurate apples-to-apples comparison, reveals that brand manufacturers actually account for approximately 67% of total net drug spend retained by either a generic or brand manufacturer (see Figure 3 in the report).

A new report says that failure to account for rebates, discounts, and price concessions leads to an “overstatement of payments realized by manufacturers” in most annual industry drug spend reports.

Pharma Manufacturers Say Supply Chain Stakeholders Now Getting a Bigger Cut

	The Reproducibility Project: Cancer Biology has been working to confirm the results in five prominent cancer biology experiments, and just released the results of its preliminary findings on Jan. 19, 2017. The researchers were only able to validate the findings in two of the five initial studies. The researchers could not replicate the findings in one study, and deemed another two studies “uninterpretable” because the tumor cells under investigation either grew too quickly or too slowly to measure whether the cancer drug had the predicted effect.

	Erkki Ruoslahti, a cancer biologist at the Sanford Burnham Prebys Medical Discovery Institute, is an author of one of the original papers that was included in the Reproducibility Study. The replication authors could not reproduce the findings from Ruoslahti’s original study. Ruoslahti told 

 that a least a dozen other labs have successfully replicated his findings, and there are more studies in the pipeline confirming his original conclusions. He told the publication that he worries that the findings released on Jan. 19, 2017 could influence the future funding of his research.

 accompanying the research findings asserted that it would be virtually impossible to directly replicate all of a study’s findings. Thus, rather than strive for statistical significance in their replication studies (citing a less than 50% chance that all three experiments would yield a significant 

 value), the authors focused on whether or not they could see effects that were similar to those demonstrated in the original studies following the methodology in the original studies. Although 100% reproducibility is an unrealistic expectation, the authors were seeking to come to some of the same conclusions as the original study authors.

	The replication team interviewed original study authors in an effort to avoid errors due to discrepancies in samples and materials. The team “undertook authentication of key biological materials (such as STR profiling of cell lines)” and asked the authors of the original studies to “share any original reagents, protocols, and data in order to maximize the quality and fidelity of the replication designs.”

	The takeaway? Small changes in experimental design, such as buffer conditions, pH, slight differences in cell line, reagents used in studies, cell culture changes, and even differences in tubing and labware suppliers could theoretically change the outcomes of experiments. Although it was difficult to draw conclusions from some of the results in the five featured reproducibility studies, replication study authors deduced while conducting these experiments that too little information is typically included in the “materials and methods” sections of most scientific studies. And, the fact that the Reproducibility Project authors could not produce many of the same results in their experiments highlights the inherently complex nature of living cells and how they react to different manipulations and variables.

	The accompanying editorial acknowledged that replication efforts could be affected by inadequate expertise of the contract labs performing the replication studies, and this could be a disadvantage: “the contract research laboratories performing the replications may not have the same level of expertise or motivation as the original laboratories.” Elizabeth Iorns of the Reproducibility Project, however, 

 that the contract labs used for the replication experiments were proficient at running these types of experiments.

	The Reproducibility Project has 24 more experiments that it hopes to try to reproduce, and will publish its findings throughout 2017.

	Leonard P. Freedman, PhD, who has written on the crisis of reproducibility and is president of the Global Biological Standards Institute (GBSI), tells 

 that he is not surprised with the results from the first five replication studies, adding that irreproducibility in biomedical research is already a well-established concept. He notes that transparency on methodologies, reagents, data analysis, and other key variables has not been common in science. "The significance of the RP:CB project [Reproducibility Project] is how transparency is a central feature of the effort. While reproducibility in biology is difficult because of the inherent variabilities at play in biological systems, the RP:CB project hopes that transparency in how experiments are carried out-precisely so that the work can be effectively scrutinized and then repeated-will become the norm."

	Freedman says these studies prove that reagent variability "is a huge contributor to variability in published results." He adds, "GBSI’s work in firming up standards and validation guidelines for, in particular, cell lines and research antibodies, can go a long way to addressing irreproducibility of experiments, including several of the problems highlighted in the five RP:CB papers."

	Incomplete disclosure affects all aspects of scientific research

	Irreproducibility is also a problem for the patents that are meant to support and protect innovation in pharma, as Jacob S. Sherkow recently wrote in

He wrote that patents, which disclose the details of an invention or method, are supposed to describe a scientific result that can be verified and replicated by scientists. "To the contrary, the availability of patents for the products of clinical research appears to hamper or even actively dissuade reproducibility,” Sherkow wrote. “Since pharmaceutical manufacturers often structure drug development and clinical research around patent protection, patent law’s deficiencies with respect to disclosure encourage manufacturers to engage in research-often, irreproducible research-that satisfies the bare minimum needed to obtain protection. This failure of patent law exacerbates the current real-world reproducibility crisis.”

*Editorial note: This article has been updated to include comments from Leonard P. Freedman of GBSI.

Researchers were not able to replicate all of the findings in five highly-cited cancer biology papers.

Reproducibility Project only Partially Able to Validate Findings of Prominent Cancer Studies

	A draft guidance covering biosimilarity is finally here-in 2017-even though it was originally on the guidance agenda for 2016. The guidance relies heavily on switching studies between a reference product and a biosimilar and proving that such switches remain safe and clinical results remain unchanged. A product must first be deemed a biosimilar, and an interchangeability determination can follow, according to the documents. The agency supports switching studies because it believes these studies most accurately reflect how an interchangeable product will be used in clinical practice.

	To support an interchangeability designation, product sponsors must submit data on the critical quality attributes, analytical differences, mechanisms of action, pharmacokinetics, immunogenicity risk, differences in potential toxicities, and any other safety information that is relevant for both a reference product and a biosimilar product.

	Differences between products related to their specific mechanisms of action, such as any differences in glycosylation profiles, will need to be presented to the agency. These product differences should not confer any significant differences in clinical benefit or safety. FDA admits that not all current analytical methodologies may characterize all relevant structural differences between products, so data sets should include information around things such as charge variants and glycoforms to “reduce the residual uncertainty about interchangeability.” Additionally, the agency notes that postmarketing surveillance data from the licensed biosimilar product may be necessary for a sponsor to make its case that there are no clinically meaningful differences between a reference product and a biosimilar.

	A sponsor may seek interchangeability licensure for fewer indications than for which the reference product is licensed, which could prove to be challenging when it comes time to label said product with a meaningless suffix.

	If patients in switching studies experience an adverse immune response, FDA acknowledges that “carryover effect” may make it difficult to tell if the reference product or the proposed interchangeable was the cause of the adverse event. Although it may be difficult to prove the cause, FDA says the appearance of an adverse event would still “raise concerns” about the interchangeability of a biosimilar. Thus, relevant pharmacodynamics data may help illustrate domains of activity and help a sponsor’s case.

	Lead-in periods should be sufficient to ensure a patient has seen the effect of a medication before he or she is switched to the biosimilar, and there should be at least three switching events to the alternate product, with the last switch being from the reference product to the alternate product. The agency also suggests using a non-switching proposed product arm through the duration of the switching studies to serve as a control.

	No reference product data from other countries allowed

	FDA said it expects that switching studies be included in applications for interchangeable products; however, the “originator” products that will serve as controls may not be sourced from outside of the United States. Although biosimilar sponsors can use data from non-US sources to prove biosimilarity, they may NOT use these data to support an interchangeability designation. Because of small structural differences in products, such as acidic variants or deamidations, the overall immune response could be increased as a result of multiple exposures to different products, the agency notes.

	Plus, the agency says, establishing interchangeability with a product that would primarily be used outside of the US “would generally not be appropriate,” as it would not be representative of a real-life clinical option for patients. But, FDA did not elucidate how originator manufacturers would provide product to biosimilar applicants or if originator companies would be required to provide enough samples to biosimilar applicants for comparability purposes.

	FDA also says that a product should “generally” not be considered for an interchangeability status if the method of drug delivery differs from that of the originator product. Thus, a drug made in a prefilled syringe cannot be considered for auto-injector packaging, unless the changes do not negatively impact patients nor require additional training for proper use. If the packaging design differs for the biosimilar, FDA may require additional studies showing that the design differences won’t impact administration of the medication.

	What about the switching studies done for Inflectra?

	Although interchangeability was not proposed nor requested in Celltrion’s biologics license application (BLA) for Inflectra (called Remsima in Canada and other regions), the company did present some preliminary switching data in its BLA. FDA wrote in a 

 on that data, “the single transition from EU-approved Remicade to CT-P13 during the long-term extension studies in RA and AS did not result in worse safety or immunogenicity profile. This would support the safety of a clinical scenario where non-treatment naïve patients undergo a single transition to CT-P13.” Despite the fact that the agency acknowledged at the time of Inflectra’s review that Celltrion’s switching data could theoretically support an interchangeability status, it would appear that the agency has backtracked on this statement-the EU-approved Remicade could not actually be used in switching studies because of its origin of manufacture. More than 30 distinct orthogonal methods were used to evaluate the analytical similarity of Inflectra to Remicade, so sponsors should expect to present results for numerous types of analytical tests.

“Considerations in Demonstrating Interchangeability With a Reference Product.”

FDA released a long-awaited draft guidance to help sponsors seeking to demonstrate interchangeability for biosimilar products.