Caroline Hroncich was associate editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International from 2015 to 2017.

Caroline Hroncich

 to members of US House and Senate committees citing concerns with FDA’s decision to make changes to a section of the 

FDA and NIH Workforce Authorities Modernization Act. 

The organizations, including the American Pharmacists Association (APhA), Academy of Managed Care Pharmacy, American Society of Consultant Pharmacists, American Society of Health-System Pharmacists, Biosimilars Council, International Academy of Compounding Pharmacists, National Alliance of State Pharmacy Associations, National Community Pharmacists Association, and National Council for Prescription Drug Programs, signed the letter, which was submitted on August 1, 2016.

	The organizations noted concerns about Section 11 of the Act, which may exempt certain biological products from abiding by 

standards for quality. The main concerns voiced in the letter are related to issues that may arise from biosimilars with different nonproprietary names than reference products. 

	“We are concerned that any naming approach which would assign a unique non-proprietary name to each biological drug, including biosimilars, would create unclear and complex naming conventions that could lead to unintended consequences and barriers to access for biologic and biosimilar medications,” the letter notes. The authors also indicate that this would impact interchangeability, and potentially create confusion for prescribers and patients. Having separate nonproprietary names for biosimilars may "perpetuate the notion that biosimilars are not comparable to the reference biologic drug," the letter asserts.  

FDA and NIH Workforce Authorities Modernization Act 

say “except that (1) a product for which a license has been approved under this section shall not be required to have an approved application under section 505 of such Act; and (2) those provisions of the Federal Food, Drug, and Cosmetic Act that refer to an official compendium as defined under section 201(j) of such Act shall not apply to a biological product subject to regulation under this section.” The letter notes 

is currently the primary entity establishing nonproprietary names. These proposals would represent a significant diversion from the established processes that could “jeopardize the supply chain and make medications less safe,” the authors write.

	In the letter, the organizations reiterate their concern for standardized naming of biosimilars, requesting FDA to not move forward with the current proposal. “We believe that biologics and biosimilars should be required to have the 

nonproprietary names based on existing standards and mechanisms,” the letter states.

	This is just the latest in the long debate over biosimilar naming, for which FDA has yet to provide clear guidance. In a 

 released in June 2016, FDA said it would require applicants to submit up to 10 proposed four-letter suffixes for biological products licensed under the Public Health Service Act. The agency later withdrew this notice, and has yet to release anything further on the topic. FDA’s draft guidance on 

Nonproprietary Naming of Biological Products 

noted that the agency was asking for comment on whether or not a biosimilar name should contain the same suffix as its reference product.

Articles

Nine public health organizations submitted a letter to US House and Senate committees citing concerns about Section 11 of the FDA and NIH Workforce Authorities Modernization Act.

Public Health Organizations Pen Letter to House and Senate Committees

	In Phase III clinical trials, Merck’s Keytruda (pembrolizumab) proved to be superior to chemotherapy for progression-free and overall survival of patients with non-small cell lung cancer whose tumors express high levels of PD-L1. An independent data monitoring committee recommended the trial be stopped and patients receiving chemotherapy switch to treatment with Keytruda, the company said in a June 16, 2016 

. Data from the Phase III KEYNOTE-024 trial has yet to be released.

	The most recent study results may present Keytruda as a first-line treatment for lung cancer, and represents an important step for the company, which has seen significant return in its immuno-oncology program. Merck is currently involved in multiple clinical trials to investigate the likelihood that Keytruda will be effective for the treatment of other types of cancers. 

 indicates the drug is currently being investigated in more than 30 tumor types of cancers.

, Keytruda is the first check-point inhibitor for the treatment of first-line lung cancer that has “demonstrated superiority” to standard care. In a June 16, 2016 note to investors, Mark Schoenebaum of Evercore ISI noted that Keytruda may have some competition in the near future with the release of results from Bristol-Myers Squibb’s (BMS) Opdivo (nivolumab) trial, CHECKMATE-026, at the conclusion of the third quarter. Opdivo is also being tested for the treatment of patients with first-line lung cancer and is a PD-1 inhibitor. Schoenebaum pointed out that Merck’s trial was performed on PD-L1 high expressers, approximately 25â30% of the first line population, in comparison to the BMS trial which also includes low expressers, approximately 70% of the first line population. This could create a differentiation in the first line label, if BMS is successful with low expressers, Schoenebaum said.

	Keytruda was granted marketing authorization by the 

 in July 2015, following a September 2014 

 The drug is also indicated for the treatment of patients with unresectable or metastatic melanoma. Keytruda is administered to patients through a 30-minute intravenous infusion every three weeks.

Keytruda was shown to be superior to chemotherapy in the treatment of patients with non-small cell lung cancer.

Keytruda Proves Superior to Chemotherapy in Phase III Trials

 presented on June 10, 2016 at the European League Against Rheumatism Annual Congress (EULAR 2016) suggest that rheumatic patients with anti-infliximab (IFX) antibodies may have a cross-reaction with infliximab biosimilars-notably Remsima (infliximab) and Inflectra (infliximab)-leading to a loss of clinical response. However, the study also confirms these patients will also experience a similar loss of response with the branded product if anti-IFX antibodies are present. A EULAR 

 promoting the data, titled “Biosimilar Switching Not Suitable for All Patients,” seemed to suggest that switching to a biosimilar of infliximab compounded the adverse effects associated with taking the branded medication.

	Hubert Chen, MD, chief medical officer at Pfenex, told 

that patient use of either branded infliximab or biosimilar infliximab would most likely lead to a similar clinical outcome. Biosimiliars are highly similar to their reference products and do not have any clinically meaningful differences from their reference products in terms of safety, efficacy, potency, or purity, Chen noted. In fact, a 

 also presented at EULAR showed that switching to biosimilar infliximab did not change the number of flare ups experienced by patients. According to the study, approximately 10% of patients with rheumatoid arthritis experienced a flare-up both before and after switching to a biosimilar.

	According the Chen, the EULAR announcement "seems to imply that patients who develop antibodies against branded infliximab should not switch to a biosimilar version of infliximab, because such a transition may potentially accelerate the loss of response. In reality, the continued use of either branded or biosimilar infliximab would have the same clinical effectâ¦[H]ence, if a patient were to develop antibodies when treated with a reference product, it should not be a surprise to expect those antibodies to cross-react against a biosimilar product that is highly similar,” said Chen. In fact, evidence of cross-reactivity may actually serve to confirm the similarity of a biosimilar to a reference product. Chen added, “It is reassuring, though, that such antibodies have not been associated with safety or tolerability issues in switching studies performed with branded and biosimilar infliximab, to date.”

 “If antibodies are formed against Remicade, or the patient does not respond, it does not make sense to switch to the biosimilar or to stay on Remicade, but [they instead should switch] to another drug (e.g., adalimumab or etanercept).” Therefore, patients who experience a loss of response using a drug sharing a mechanism of action with infliximab may want to look into other treatment options, he clarified. The 

 research was originally published in March 2016.

	Debate over the safety of biosimilar switching came to a head earlier this year when FDA released its 

. The agency indicated that biosimilar labels should contain reference product information. Some groups, including the American College of Rheumatology, 

 saying they are concerned displaying reference product clinical trial information on biosimilar labels and not designating unique names for biosimilars may imply interchangeability. The college released a statement to FDA on the draft guidance encouraging FDA “to continue to apply distinct names for future biosimilars, and to maximize clarity in the labeling of biosimilars, specifically with respect to their interchangeable status and origins (reference drug versus biosimilar) of clinical data upon which FDA approval is based.” FDA has yet to make any comment on its view of the interchangeability of biosimilars and reference products.

A study published in BMJ indicates that rheumatic patients with anti-infliximab antibodies may have a similar cross reaction to infliximab biosimilars.

Study: Patients Who Have Reactive Responses to Infliximab Should Not Switch to Biosimilar Versions

 from FDA addressed comments on the guidance on 

Proprietary Naming of Biological Products 

and the agency’s decision to require applicants to submit up to ten proposed, four-letter suffixes for biological products licensed under the Public Health Service (PHS) Act. In the notice, FDA reiterated its earlier decision to require applicants to “propose a suffix of four lowercase letters for use as the distinguishing identifier included in the proper name designated by FDA at the time of licensure for biological products under the PHS Act.”

	Responses to FDA’s guidance, which was initially released in August 2015, indicated that applicants were concerned about the time burden that may encompass coming up with, and providing analysis for, the proposed suffixes. Many respondents commented that FDA’s estimate of two hours per suffix (six hours for three suffixes and analysis) was considerably low. One commenter indicated it would exceed 720 hours per suffix to complete an analysis and submission, totaling 2160 hours. FDA said that while it found this estimate “rather high” it revised its estimate to account for “burden associated with creating and submitting up to 10 proposed suffixes for designation.”

	In addition to the time consideration, FDA also mentioned commentary on suffix meaning. Several respondents indicated the importance of selecting a suffix that would help improve pharmacovigilance, enhance safety, and effectively identify a biological product. By comparison, others voiced support for a random suffix, or no suffix at all. FDA did not indicate its preference, and it is still unclear how biosimilar makers should select suffixes.

	This lack of clarity triggered responses from organizations including the Biosimilars Forum, which admitted to finding the guidance’s current language confusing. The Biosimilars Forum also indicated that it did not support the suggestion of a random four-letter suffix. Instead, the Forum suggested the implementation of a suffix that is “unique to the original product license holder, and will be affixed to all biological products developed by that license holder.” The Forum also commented on the potential need to change biosimilar labeling information throughout a products lifecycle, specifically mentioning pregnancy and lactation requirements. The Forum indicates that it may not be feasible for biosimilars to adhere to the pregnancy and lactation final labeling rule, since the biosimilar maker does not have access to reference product data. 

The agency reiterated its earlier decision to require suffixes in biosimilar naming, but was unclear on suffix meaning.

FDA Reiterates Decision to Require Suffixes in Biosimilar Naming

	On May 18, 2016 FDA approved Genentech’s atezolizumab injection, a monoclonal antibody for the treatment of urothelial carcinoma, or bladder cancer. Atezolizumab an anti-PDL1 cancer immunotherapy, Genentech said in a 

	The drug was granted accelerated approval by FDA, based on a clinical trial of 310 patients with locally advanced or urothelial carcinoma. Results of the trial indicated that atezolizumab reduced tumor size in 14.8% of patients, 5.5% of those patients showed complete response to the drug. Genentech says it expects the drug will be available for patients in the US in one to two weeks. 

, FDA notes the drug appeared to be most effective for patients that had high levels of PD-L1 expression in tumors during treatment. While testing for PD-L1 is not required for treatment with atezolizumab, FDA continued, it might help “guide patient selection.”

, there will be an estimated 76,960 new cases of bladder cancer in the US during 2016 alone. Bladder cancer is the fourth most common cancer in men, but is less common in women. Urothelial carcinoma accounts for approximately 90% of all cases of bladder cancer in the US, according to the 

	Immuno-oncology is new territory for pharmaceutical companies, many of which have been rushing to enter the market over the past several months. Companies like Merck and Bristol-Myers Squibb have seen 

 on their investments in immunotherapies. Merck received 

 (pembrolizumab), its treatment for lung cancer in tumors that express PD-L1, in early October 2015. Bristol-Myers Squibb’s Yervoy (ipilimumab)/Opdivo (nivolumab) combination drug to treat metastatic melanoma 

 from FDA in September 2015. Both Keytruda and Yervoy/Opdivo are expected to be competitors with atezolizumab, since all three drugs work as PD-L1/PD-1 inhibitors. Other biopharma companies are also announcing plans to invest in R&D in immuno-oncology; Celgene 

 on May 17, 2016 that it will pay Agios Pharmaceuticals $200 million in a collaboration focused on metabolic immuno-oncology.

Genentech received accelerated approval for its immunotherapy atezolizumab for the treatment of bladder cancer.