Tag: FDA

Will Approval of an Interchangeable Biosimilar Mean that Others Are Inferior?

In terms of the biosimilar market and utilization, the US has been at least one full decade behind Europe in every respect but one. Yes, we have the EU beat in a game they avoided playing: The interchangeability gambit. The Europeans never defined interchangeability as a separate concept for biosimilars, thus leaving the individual countries to decide whether to allow unencumbered switching of biosimilars for their originator drugs.

As in other areas of biosimilar policy and regulation, the US started very slowly. Leah Christl, PhD, Associate Director for Therapeutic Biologics, OND Therapeutic Biologics and Biosimilars Team, Food and Drug Administration (FDA) stated last week at the Drug Industry Association’s annual meeting in Chicago that she expects the first interchangeable biosimilar to be approved within about 2 years. This is probably realistic, based on the timeline of the adoption of the agency’s interchangeability guidelines. Comments on the draft guidance are being read by the FDA at this time. Seven years after the passage of the legislation calling for the biosimilar approval pathway. If there were competitors in this game, we’d be desperately trying to catch up!

It seems unlikely that the FDA has any active 351(k) applications seeking the interchangeability designation, although Dr. Christl did not reveal whether this was the case. The application process is confidential; a submitted application is publicized only if the drug maker issues a press release on its ownDeck 1.png. It would seem premature to seek the interchangeability designation before the FDA’s own guidance on what the review entails is released. This may not prevent a biosimilar manufacturer that has already received approval from taking the quick step towards interchangeability, especially if they have conducted a series of switching studies that meet the FDA’s criteria (e.g., NOR-SWITCH).

Payers are chomping at the bit for an interchangeable product in the 36 states (and 3 pending) that have signed legislation allowing pharmacies to automatically substitute a biosimilar for an originator biologic.

Others have pointed out that the interchangeable biosimilar may be a boon to its manufacturer, but it may have negative effect on competitive markets. For example, a noninterchangeable infliximab may be considered by prescribers or patients somehow inferior to the interchangeable version, devaluing this biosimilar. On the other hand, the maker of “infliximab-int” could experience increased demand and boost prices (or avoid decreasing prices in the face of other noninterchangeable biosimilars coming to the market). And this may be justified. No one really knows the manufacturer’s incremental cost of achieving this designation, based on:

  • The cost of conducting additional switching studies
  • The potential cost of responding to FDA requirements for more data
  • The opportunity cost in marketing time, resulting from a delay in the application or approval

The race for a product with this extremely valuable designation drags on at a snail’s pace. I hope I’m still writing about it by the time someone reaches the finish line.

 

FDA Stuns With Rejection of Pfizer’s Retacrit

Following a 14-1 vote by its Oncology Drug Advisory Committee last month to recommend approval for Pfizer’s biosimilar version of Epogen®, the Food and Drug Administration (FDA) on June 22 sent the drug maker a complete response letter outlining its decision to reject the product.

It is unusual for the FDA to decide against a clear majority recommendation by its Advisory Committee, but the agency pointed to potential manufacturing issues at one of Pfizer’s facilities. Pfizer stated, “This [complete response letter] relates to matters noted in a Warning Letter issued on February 14, 2017 following a routine [FDA] inspection of the company’s facility in McPherson, Kansas in 2016. This facility was lisfdated as the potential manufacturing site in the BLA for the proposed epoetin alfa biosimilar. The issues noted in the Warning Letter do not relate specifically to the manufacture of epoetin alfa.” Although Pfizer responded to that notification by submitting a corrective and preventative action plan the following month, apparently, the FDA is not yet confident in the drug maker’s plan. According to Pfizer’s statement, the agency did not request that additional clinical data be submitted.

The FDA had cited this particular plant for several issues regarding the presence of foreign matter in medications being produced there. In its Warning Letter, the agency suggested there was “a significant loss of control in your manufacturing process” that represents a “severe risk of harm to patients.” The plant was one that Pfizer acquired in its purchase of Hospira in 2015.

This is Pfizer’s second rejection for Retacrit™, a product that was developed and brought to market in Europe by Hospira. Pfizer had resubmitted the 351(k) application in 2016.

The manufacturer stated that it is seeking to clear up any remaining issues at the plant cited by FDA. However, it is not clear whether Pfizer will have to resubmit its application entirely, as the rejection does not seem to be related to safety or efficacy issues involving the agent.

Pegfilgrastim: 0 for 3 on Biosimilars at FDA

On June 12, Coherus Biosciences received word of the Food and Drug Administration’s (FDA’s) rejection of its biosimilar pegfilgrastim. Manufacturers have now taken 3 swings and misses, striking out in their quest for a biosimilar version of another blockbuster product.

In 2016, Sandoz whiffed on its version, after having the nonpegylated version approved in 2015 (Zarxio®). Although details of the FDA’s complete response letter were not released, Sandoz decided to withdraw its application to the European Medicines Agency as well. In December 2014, Apotex was the first to submit its pegfilgrastim application to the FDA, but it was similarly rejected.

The remaining biosimilar version of Neulasta® awaiting its turn at bat in the US is from Mylan/Biocon. Submitted in February of this year, the FDA decision is due October 9, 2017. Pfizer is working on its own version of pegfilgrastim (HSP-130), which is in phase 2 study. Apotex’s Apobiologix unit is still seeking approval of its biosimilar, according to its website. In Europe, 2 pegfilgrastim applications are currently awaiting decisions, but none have been approved to date.Image result for pegfilgrastim (neulasta)

On the bright side, the FDA’s complete response letter to Coherus did not indicate that the game is over. Apparently, the agency asked for a re-analysis of specific data and requested further information regarding manufacturing its biosimilar agent. The drug maker indicated its willingness to work with FDA to resolve these concerns.

There seems to be something about the pegylated version of filgrastim that makes it more difficult to obtain an approval during the first plate appearance. It may well be that Mylan’s application hits it out of the park in October. However, the batting average of drug makers pitching their other biosimilars is far better—Pfizer’s second try at approving epoetin seems to have been a hit (with a 14-1 margin by the FDA Advisory Committee).

With $4.5 billion in US sales of Neulasta last year, there will be no shortage of hitters willing to come to the plate.

US Supreme Court Strikes Down 180-Day Waiting Period

In a unanimous decision, the Supreme Court rejected Amgen’s oral arguments—a biosimilar manufacturer can meet the 180-day notification period requirement by notifying the originator’s manufacturer before receiving approval. In other words, biosimilar launches can occur immediately after approval by the Food and Drug Administration (FDA).

The 180-day notification period was seen as giving the originator a further 6 months of exclusivity, not allowing newly approved products to reach the market until after the period had expired. The argument by biosimilar manufacturers has been that notification of its intention to commercialize the drug can be given prior to approval (e.g., at the time the application is sent to the FDA), without any disadvantage in terms of an examination of whether patents had been infringed.

Sandoz v. Amgen involved Sandoz’s filgrastim biosimilar Zarxio®, which has since launched, but this decision, written by Justice Clarence Thomas, will clear one barrier out of the way to faster access to biosimilars.Image result for justice clarence thomas

The justices decided to punt on a ruling of whether the patent dance is necessary to the states, where unfair business conduct laws may take precedence. The patent dance involves a protocol where the biosimilar applicant must provide to the reference drug maker information on how it plans to manufacture the agent and its actual 351(k) application. The reference drug manufacturer can then evaluate which of its patents it believes will be infringed, and must respond (and counter) within a specific timetable. According to Justice Thomas’ opinion, “There is no dispute about how the federal scheme actually works, supreme-courtand thus nothing for us to decide as a matter of federal law. The mandatory or conditional nature of the [Biologics Price Competition and Innovation Act] requirements matters only for purposes of California’s unfair competition law, which penalizes ‘unlawful’ conduct. Whether Sandoz’s conduct was ‘unlawful’ under the unfair competition law is a state-law question, and the court below erred in attempting to answer that question by referring to the BPCIA alone.

“We decline to resolve this particular dispute definitively because it does not present a question of federal law. The BPCIA, standing alone, does not require a court to decide whether §262(l)(2)(A) is mandatory or conditional; the court need only determine whether the applicant supplied the sponsor with the information required under §262(l)(2)(A).”

Justice Stephen Breyer suggested, in a concurring opinion, that the FDA may play a greater role in deciding the outcome of the patent dance. He stated, “[If FDA], after greater experience administering this statute, determines that a different interpretation would better serve the statute’s objectives, it may well have authority to depart from, or to modify, today’s interpretation.”

Pfizer’s Epogen® Biosimilar Gets FDA Advisory Committee Backing

Pfizer purchased Hospira in 2015, and one of its prizes was a biosimilar version of Epogen® and Procrit® that was already being reviewed by the Food and Drug Administration (FDA). The FDA rejected that 351(k) application and issued a complete response letter. Pfizer’s Hospira unit resubmitted its application for its Retacrit™ version of epoetin alpha in 2016. They received good news this week from the agency.

According to the FDA’s staffers’ summary released ahead of the May 25th Oncology Advisory Committee review, Retacrit fulfilled the requirements for biosimilarity. Today, the Advisory Committee added further support to this conclusion by voting 14-1 to recommend approval for all extrapolated indications, despite some safety concerns expressed by committee members.

According to the staff review, “The totality of analytical data support the determination that ‘Epoetin Hospira’ is highly similar to US-licensed Epogen/Procrit notwithstanding minor differences in clinically inactive components.” Nor were any clinically meaningful differences in immunogenicity risk found. The FDA staff review documents also concluded that Retacrit’s biosimilarity evidence supports extrapolation across its intended indications.

Last month, the Food and Drug Administration removed the Risk Evaluation and Mitigation Strategy (REMS) on the originator product, indicating that it is no longer necessary to “ensure that the benefits of Epogen/Procrit and Aranesp® outweigh the risks of shortened overall survival and/or increased risk of tumor progression or recurrence, for the treatment of anemia associated with myelosuppressive chemotherapy.” The originator agent has been linked with cardiovascular safety concerns, which has affected utilization of epoetin alpha over the years.

The first epoetin biosimilars were approved for use in Europe in 2007; a tremendous amount of real-world data have accumulated on their use. However, the FDA Oncology Advisory Committee cannot consider this in their decision.

Members of the FDA Committee expressed “residual concerns with immunogenicity and safety.” For example, patients with chronic kidney disease who require hemodialysis may have a reduced response to Retacrit.

The rather unique “dual” originator products (Epogen/Procrit) resulted from a duel in the 1990s between Amgen and Johnson & Johnson. Amgen originally manufactured the product in the late 1980s and licensed it to J&J’s Ortho Biotech unit. A stormy relationship developed, with lawsuits passed back and forth. The result was a licensing agreement that the drug would be manufactured under license (sounds a bit like a biosimilar, doesn’t it?) by each company for different indications.

Will the Final Guidance on Biosimilar Naming Be Reversed?

Judging from the comments at the Academy of Managed Care Pharmacy’s (AMCP’s) annual meeting March 27–30 in Denver, there is some hope and expectation that the Trump Administration will review and possibly revoke the naming convention for biologics and biosimilars that was finalized just recently.

The Academy’s position on the naming convention has not changed, according to Mary Jo Carden, VP of Government and Pharmacy Affairs. She characterized the naming convention chosen by the Food and Drug Administration (FDA) as unnecessary and confusing. Therefore, AMCP is still in favor of using the government-approved name and international nonproprietary name to biosimilars (and no new suffixes to existing originator products). In previous comments to the FDA, the Academy wrote, “AMCP supports a biosimilar naming convention using the same INN that has proven safe and effective globally for small molecule drugs and for biological products in Europe, and therefore it should be the standard in the United States. Using the same INN for biosimilars would also alleviate the need for multiple product identifiers in biosimilar labeling and therefore eliminate the potential for confusion by health care providers and patients.”

Doug Long, MBA, VP of Industry Relations at QuintilesIMS, in answer to a question from the audience, said he “might mention it to Scott Gottlieb,” newly nominated FDA Commissioner, to revisit it after his confirmation. Image result for Doug Long IMSEspecially in light of the present administration’s statements to streamline the drug approval process and improve public access to less-expensive medications, this would seem to make sense. Mr. Long also said that he had difficulty fathoming the reasons behind the decision making on biosimilar naming.

Drug consultant C. Douglas Monroe, RPh, MS, pointed out that there is hope. The Office of Management and Budget has asked the FDA to postpone implementation, and public comments from numerous organizations railed against the policy. Mr. Monroe cited publisher Wolters Kluwer as saying that the “…FDA’s proposed naming approach is a solution in search of a problem.” And several organizations, such as NCPDP and drug manufacturers, complained of the time and billions in cost of applying suffixes to all existing biologics.

Although it may be appealing for the Trump Administration to simply scrap the existing final guidance on naming. If they do not simply revert to the basic INN nomenclature for biologics, do we really want to start the entire process of considering a new system from scratch again?

Interchangeability Guidance Released, FDA to Require Switching Studies

On January 10, the Food and Drug Administration (FDA) released its long-awaited draft guidance on the interchangeability standard for biosimilar manufacturing.

It’s been quite a while since we have been able to discuss progress on interchangeability, so as a reminder, the practical differentiator between a product designated as biosimilar versus interchangeable is that the latter “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Not surprisingly, the critical mandated addition in clinical studies of an interchangeable biosimilar is the conduct of a sufficient number of switching studies; that is, studies where patients are alternatively given the originator product, switched to the biosimilar, and possibly back to the originator, without any measurable risk to patient safety or efficacy. Or as the FDA puts it “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.”

Interestingly, the FDA does restrict switching studies to between the biosimilar and the US-licensed reference product only (i.e., no EU versions with bridging studies). The reason is related to slight, nonclinically meaningful differences that may be introduced in the EU version that is not present in the US originator product.

The draft guidance is subject to a 60-day public comment period. For those interested in commenting on the guidance, they can visit https://s3.amazonaws.com/public-inspection.federalregister.gov/2017-01042.pdf for instructions.

Are 2 Biosimilars to the Same Originator Product Biosimilar to Each Other?

In Europe, several manufacturers are marketing approved biosimilars to the same originator product. In fact, 7 manufacturers compete for the biosimilar filgrastim market, 5 biosimilar versions of epoetin are sold, and 3 biosimilars of infliximab seek marketshare from Remicade®. In the US, this situation is not a reality yet. It will be one day, however, and it raises a couple of important questions.

We know that the biosimilars are not exactly the same structurally as the originator products, but how similar may they be to each other? In other words, at some point, payers will prefer one biosimilar version of filgrastim over another one, as some do currently with Zarxio® versus Neupogen®. We can assume that with 3 filgrastim biosimilars sold in the US, payers will seek to leverage 1 against the others and make it their preferred or only available form of filgrastim available. However, is another manufacturer’s version of filgrastim biosimilar to Zarxio? We can also assume that the new manufacturer’s product has received US Food and Drug Administration approval through testing for comparability only with the originator product—not against Zarxio. How about compared with Teva’s product tbo-filgrastim (a follow-on biologic, not a biosimilar according to the regulatory and statutory rules)?

What does this mean for switching products, much less interchangeability? Is one biosimilar interchangeable with another? Based on what we know about the FDA, the answer is likely no, as the agency seems to be having difficulty devising interchangeability guidelines for a biosimilar and its originator product.

Why is this important? Consider the patient with Crohn’s disease in 2019 who changes health plans. The patient was receiving biosimilar A, and the new plan covers only biosimilar B. Maybe he or she needs to enroll in a new plan in 2020, and the reverse is true. Regardless of whether we like it, that patient may be unintentionally providing real-world evidence of interchangeability.