Christina Mattina

The high cost of bevacizumab can impede access to this anticancer agent, particularly in emerging markets. A recent survey of physicians around the world found that a majority of them would be willing to prescribe a biosimilar if it became available, which could potentially lower costs and expand access.

Currently, there is no approved biosimilar for bevacizumab, a monoclonal antibody used to treat advanced solid tumors, including metastatic colorectal cancer (mCRC) and advanced or metastatic non-squamous non-small-cell lung cancer (mNSCLC). In the United States, it is approved for treating glioblastoma (GBM) and metastatic ovarian cancer (mOC), and in the European Union (EU) it is indicated for patients with metastatic breast cancer (mBC). Bevacizumab has been shown to prolong survival in patients with these cancers when combined with chemotherapy.

A survey of 510 oncologists in the United States, the EU, and emerging markets (Brazil, Mexico, and Turkey) has, however, revealed interesting disparities in rates of prescribing and perceptions of access, according to a study recently published in the journal 

Of the surveyed physicians who did not frequently prescribe bevacizumab, those from emerging markets were more likely to cite access as a barrier to prescribing across all tumors types. Further, physicians in the United States and EU found it easier to access the drug when treating patients with mCRC, mNSCLC, and mOC than physicians in emerging markets. US physicians could readily access bevacizumab for treatment of GBM than physicians in the 2 other markets, while EU physicians found it easier to access the drug for mBC.

The predominant reasons for the perceived barriers to access were that the drug’s costs were “not reimbursed by healthcare system/private insurance,” and the “high out-of-pocket (OOP) costs to the patient.” These barriers were most commonly cited by physicians in emerging markets, although 67% of American respondents said lack of reimbursement was a barrier to prescribing the drug for mOC, compared with 55% of physicians in emerging markets and just 24% in the EU.

Roughly 50% of respondents agreed that reducing the amount of bevacizumab cycles would likely or very likely impact patient quality of life and survival, yet some found it necessary to do so. Of the physicians who had to reduce the number of cycles prescribed, the most common reason across all markets and tumor types was the lack of reimbursement. A significantly higher number of physicians in the US (40%) reported they had to reduce the number of cycles for GBM treatment because of high OOP costs to patients, compared with physicians in the EU (18%) and in emerging markets (19%).

Considering these cost-related barriers, it comes as no surprise that 42% to 92% of physicians across all tumor types and markets would definitely or probably prescribe a biosimilar for bevacizumab if it became available. Physicians in all regions cited efficacy and cost as the main reasons they would be willing to prescribe the biosimilar, although the most common rationales against biosimilar prescribing were concerns about efficacy and a lack of clinical trial data. The physicians who probably or definitely would not prescribe a biosimilar indicated that they might change their minds upon seeing more efficacy and safety data and substantial cost reductions compared to the originator.

“Overall, these data demonstrate that access-related issues create a barrier to bevacizumab use worldwide, but particularly among physicians in the EM [emerging markets],” the study authors concluded. “A bevacizumab biosimilar could offer the same opportunity to address the needs of patients with cancer by increasing access to bevacizumab, and generating cost savings that could be redistributed to expand patient access to other biologic therapies.”

Monk BJ, Lammers PE, Cartwright T, Jacobs I. Barriers to the access of bevacizumab in patients with solid tumors and the potential impact of biosimilars: a physician survey. 

. 2017;10(1). pii: E19. doi: 10.3390/ph10010019.

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Bevacizumab Biosimilar Could Address Global Barriers to Access

An industry-sponsored survey of specialty physicians in America revealed that their awareness and perceptions of biosimilar drugs can be lacking in some areas, but they would be interested in learning more about the concept.

Researchers from the Biosimilars Forum surveyed 1201 American dermatologists, gastroenterologists, rheumatologists, nephrologists, hematology-oncologists, and medical oncologists who reported prescribing biologic drugs, and published the findings in the journal 

The study was conducted from November 2015 to January 2016, which could contribute to the seemingly low levels of knowledge among the participants, since the first FDA-approved biosimilar had just entered the market in September 2015.

Some participants were seemingly confused about what defines a biologic, despite the fact that all participants reported they prescribed biologic drugs. Medical oncologists, for instance, correctly identified a given drug as a biologic 62.8% of the time. Similarly, the vast majority said they have heard about biosimilars, but knowledge of specifics was low.

Around half of respondents from each specialty correctly said that biosimilars had just become available in the United States within the past year, with the exception of rheumatologists, 55.5% of whom thought that biosimilars were not yet available in the country. While 62.3% of respondents knew that biosimilars must be equally efficient as the original drug and 57.2% said the biosimilar must be comparable in safety, over half (55.2%) disagreed that biosimilars were safe.

There was some confusion regarding the term “interchangeable,” which indicates that a biosimilar has demonstrated its safety and efficacy for back-and-forth switching with the original biologic. Four out of 5 respondents did not know that interchangeability would let pharmacists switch between the originator biologic and its biosimilar products.

Respondents also reported concerns about the approval process. Half were knowledgeable of the concept of “totality of evidence” used to assess biosimilars, and just 12% were comfortable with the concept of extrapolation to approve a biosimilar for other indications based on the originator biologic, although this could be due to knowledge gaps on what the term actually means.

Despite these apprehensions, 91% of respondents said they would be open to prescribing biosimilars to their patients after seeing sufficient evidence on switching and indications. They also indicated they would like to learn more about key biosimilars concepts and their potential impact on drug costs and access.

The study authors wrote that the survey results “highlight a significant need for evidence-based education about biosimilars for physicians across specialties.” They plan to conduct a follow-up survey in 2 to 3 years to examine whether awareness and perceptions about biosimilars have improved as new drugs continue to enter the US and European markets.

Cohen H, Beydoun D, Chien D, et al. Awareness, Knowledge, and Perceptions of Biosimilars Among Specialty Physicians. 

Biosimilar Knowledge Gaps Identified Among US Specialty Physicians

Beginning this month, the European Medicines Agency (EMA) will offer biosimilar manufacturers a chance to receive tailored scientific advice on their drug’s development prior to submission of a formal application. These meetings will resemble some stages of the FDA’s recommended biosimilar development process.

, will give drug makers individualized feedback on data submitted to the agency’s Scientific Advice Working Party before the final marketing authorization application. The pilot differs from the standard scientific advice procedure in that it allows for an in-depth assessment of trial data and offers specific recommendations for future tests and next steps, not just suggestions on the general development strategy.

The pilot will accept 6 participants after reviewing the applications’ suitability. Only 1 request for the tailored advice will be granted per month, and the process will take a month longer than the traditional scientific advice procedure.

In the announcement, the EMA wrote that this pilot aims to “provide developers of biosimilars with advice on the studies/tests they should be conducting” based on the submitted data. It noted that submissions that undergo this enhanced process are not guaranteed acceptance of their final authorization applications.

As the extent of advice offered by the EMA will vary depending on the evidence submitted, the pilot can be compared to 2 stages of the FDA’s biological product development (BPD) process as outlined in 

, “Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants.” In these guidelines, the FDA explains the 5 types of formal meetings that may occur between drug makers and FDA representatives before the drug approval application is submitted.

A BPD Type 2 meeting can be arranged by a drug maker seeking targeted advice to answer a specific question on an issue like study design. This type of meeting can encompass “substantive review of summary data, but does not include review of full study reports.” A Type 3 meeting, meanwhile, offers in-depth data review of full study reports and guidance from the FDA on the proposed drug’s similarity to the reference drug and any further tests needed.

Applicants can request as many of these meetings as necessary throughout the drug’s development, though the FDA does charge a one-time fee to participate in the program. Drug makers are not required to participate in each meeting stage.

According to the draft guidance, the FDA encourages drug makers to use these meetings “to optimize product development and facilitate submission of marketing applications.” The FDA’s 

website on the biosimilar approval process

 notes that manufacturers should take advantage of this opportunity to obtain input at an earlier stage, especially as FDA officials may determine during this review process that an element of the required information to be submitted with the application is unnecessary for that particular drug.

These feedback efforts by the EMA and FDA, therefore, can be invaluable to drug makers preparing to submit biosimilar applications, as the input may expedite the approval process and reduce the number of rejected submissions.

EMA Pilot Will Provide Tailored Advice to Biosimilar Developers, Similar to FDA Process

Sandoz has pulled its pegfilgrastim biosimilar application from consideration by the European Medicines Agency (EMA) after the agency’s Committee for Medicinal Products for Human Use (CHMP) responded to the initial submission with a list of questions. Zioxtenzo, which was intended as a biosimilar for Amgen’s Neulasta, was rejected by the FDA in July 2016.

Last February, Sandoz—a Novartis subsidiary&mdash;presented study results to the CHMP aiming to show that Zioxtenzo could treat neutropenia in cancer patients with the same safety and effectiveness as Neulasta, but the committee was not convinced. After evaluating the documentation, 

 that it could not approve the drug as a biosimilar based on 2 primary concerns.

First, the trial results failed to show that Zioxtenzo produced comparable blood levels of pegfilgrastim, the drug’s active substance that works similarly to the human protein granulocyte-colony-stimulating factor that fights neutropenia by encouraging bone marrow to make more neutrophils. Neutropenia is common in patients receiving chemotherapy and can result in fever and serious infections.

The second concern of the CHMP was that the drug’s manufacturing site did not have a certificate of Good Manufacturing Practice, which is awarded to manufacturers that meet certain standards of quality assurance, personnel qualifications, accurate documentation, labelling practices, and clean premises and equipment. The CHMP said that it would need to inspect the site before Zioxtenzo could be approved.

However, Sandoz chose not to prepare for this inspection and instead withdrew its application completely. 

 to the chair of the CHMP explaining the decision, the company said that it would “not be able to provide the additional information required by the CHMP within the regulatory timeframe for this procedure.” The letter indicated, however, that Sandoz would continue its ongoing clinical trials and left the door open for future resubmissions after it had addressed the committee’s concerns.

The withdrawal followed a similar disappointment in July, when Sandoz received a complete response letter from the FDA indicating that Zioxtenzo had not been approved. Novartis said 

 that it was “working with the agency to address remaining questions,” though it did not elaborate on the nature of the FDA’s concerns.

Sandoz, the generic subsidiary of Novartis, became the first to enter the 

 when the FDA approved its filgrastim biosimilar Zarxio in 2015. It has vowed to launch 4 additional biosimilars by 2020, including Zioxtenzo.

EMA Concerns Prompt Sandoz to Withdraw Neulasta Biosimilar Application

President Donald Trump's executive order freezing hiring for federal jobs could apply to the already-understaffed FDA, which would extend the waiting time for biosimilar approvals.

The hiring freeze order issued January 23, 2017, specifies that federal agencies can exempt any positions it deems necessary to meet “public safety responsibilities,” but it remains unclear whether drug reviewer positions at the FDA would fall under this category. Bob Pollack, former acting deputy director of the FDA Office of Generic Drugs (OGD), wrote in 

 after the announcement that he did not anticipate the exception would apply to FDA staff, grimly noting that “we could be in for a long, unpleasant haul.”

There are currently around 850 vacant positions within the FDA Center for Drug Evaluation and Research, 150 of which are for generic drug reviewers. This dearth of staff combined with a backlog of over 4000 pending generic drug applications has 

 that approvals of new generics and biosimilars could slow to a crawl. OGD expects to receive a record-high 1600 abbreviated new drug applications in the 2017 fiscal year.

“A fully-resourced FDA is critical to reducing the backlog and making sure that patients have timely access to medicines,” the Generic Pharmaceutical Association (GPhA) said in a statement. “The agency itself has recognized the need for more resources to expedite the approval of generics and biosimilars.”

 reported that 8 congressional Democrats sent a letter on Monday to acting FDA Commissioner Stephen Ostroff, cautioning of the potential ramifications of a hiring freeze at the FDA. A main concern was that the freeze could thwart a component of the recently passed 21st Century Cures Act that would fund the hiring of new drug reviewers.

“A hiring freeze at the FDA would conflict with and do significant damage to these bipartisan efforts to fill vacant positions and expand the scientific and technical workforce needed for a robust review of drugs and medical devices,” they wrote.

If the freeze does in fact stall the review and approval of biosimilars, it will eliminate a promising avenue for controlling the cost of prescription drugs. 

 suggests that biosimilar competition can drive down prices across an entire class of drugs, resulting in cost reductions of up to 60%. A slowdown of biosimilar approvals in the United States would prolong the financial struggles experienced by many patients facing skyrocketing drug prices.

FDA Hiring Freeze Could Slow Down Biosimilar Approval Process

The House of Representatives has approved the bipartisan 21st Century Cures legislation, which includes funding for innovative research and provisions to speed up the drug approval process.

By a vote of 392-26, the House approved the 21st Century Cures Act. The House had passed an earlier version of the bill in July 2015 but continued to revise and update it, releasing the most recent draft of the bill last week. These updates included provisions for mental health, substance abuse, and child and family services.