Life Science Compliance Update

February 10, 2016

BioSimilars: FDA Panel Overwhelming Recommends Approval of Remicade BioSimilar, Congress Asks Tough Questions of FDA and CMS

Yesterday an FDA Advisory panel overwhelmingly recommended the Celltrion/Pfizer biosimilar Remsima 21-3 for approval for all the clinical indications for Jannsen's Remicade including (RA, AS, PsA, PsO, adult CD, pediatric CD, adult UC). The discussions were straight forward outlining just how similar the two products really were.

This is only the second biosimilar to get an advisory committee. But given the FDA's staff enthusiastic analysis of the clinical program and the advisory panels whole hearted validation for all the questions before the panel we can expect to see the flow of biosimilar applications and approvals start to accelerate.


While Martin Shkerli was busy making fun of congress for discussing his Wu Tang album at the Government Oversight committee hearing. The real work to reduce drug prices was being held at the same time in the Committee on Energy and Commerce Subcommittee on Health, entitled, "Examining Implementation of the Biologics Price Competition and Innovation Act." The hearing was an opportunity for the Congress and the general public to get an update from the Food and Drug Administration (FDA) on the regulation and approval of biosimilars, as well as an update from the Centers for Medicare and Medicaid Services (CMS) on the recent reimbursement policy.

In 2010, the Biologics Price Competition and Innovation Act was enacted to establish a new and abbreviated approval pathway at the FDA for biological products that are determined to be "biosimilar" to or "interchangeable" with an already-FDA licensed product. In 2012, the Biosimilar User Fee Act was enacted to support the FDA's work related to the development, review, and approval of biosimilar products. The FDA has continued to issue guidance documents on key policy considerations, and in March 2015, the FDA approved the first biosimilar in the United States. CMS, in preparation for biosimilars entering the market, has published final rules that set the stage for how Medicare will reimburse for biosimilar products.

The Contentious Hearing

Throughout the hearing, members of Congress were fairly critical about the pace at which the FDA is approving biosimilars and how Medicare plans to reimburse for them. Committee members asked Janet Woodcock, MD, the Director of the Center for Drug Evaluation and Research, and Sean Cavanaugh, Deputy Administrator and Director of CMS' Center of Medicare, whether the two agencies had ever discussed the differences between generics of small-molecule drugs and biosimilars of large-molecule biologics.

Throughout the hearing, the subcommittee reviewed the ways that differentiate biosimilars and their regulation. Congress was concerned that the unique qualities of biosimilars are not being properly considered by CMS, and that the existing payment policy could negatively impact biosimilars that enter the market in the future, or even ultimately, wind up limiting beneficiary access and negating program savings.

Congressman Joe Barton, for example, one of the authors of the Biologics Price Competition and Innovation Act, seemed troubled that the CMS payment system for biologic drugs may discourage competition and that the FDA has not moved quickly enough to finalize a naming convention or issue guidance to manufacturers of biosimilar medications. His comments sounded a bit like a disappointed teacher, "As to how you've been doing with biosimilars, I would give FDA a C plus, maybe a C minus, and CMS a D. The only reason I haven't given you an F is because you're trying, you got something out there."

He further commented that, "today, we sit as a subcommittee with numerous concerns about the implementation – or more appropriately, the lack thereof – of this important piece of legislation. Only one biosimilar has been approved, and numerous products are waiting to proceed through the approval process, and many physicians, patients, and concerned individuals like myself are concerned with the lack of progress."

CMS Reimbursement Policy

The current CMS policy, published in November 2015, allows for biosimilars to be paid for, depending on the average sales price, using six percent of the reference product price as the add-on, and also groups all biosimilars that share the same reference product, with each product being reimbursed under the same code.

This creates concern because, as Rep. Frank Pallone, Jr., stated, it "treats biosimilars like generic drugs" and runs the risk of "disincentiviz[ing] manufacturers from entering the biosimilars marketplace." Pallone also reminded Congress and the witnesses that Medicare Part D and Medicaid both acknowledge the difference between biosimilars and generics in their own programs.

Congressman Joe Barton also asked Sean Cavanaugh whether or not the agency has plans to revisit how biosimilar drugs are priced. Cavanaugh simply stated that, "From a clinical perspective, CMS knows that biosimilars are not the same as generics. From a regulatory perspective, there are similarities. Consequently, we created similarities as to how biosimilars and generics are priced," and that CMS will be monitoring the market closely and that rulemaking could be possible in the future.

FDA's Delay

The Subcommittee was also displeased with the way the FDA has worked to implement the BPCIA, since only one biosimilar has been approved. The FDA has been dragging its feet on implementation, but Dr. Woodcock claimed that, "We've seen a lot of progress since 2010, although most of it has been under the hood. We did approve the first biosimilar in 2015, and on Feb. 9, 2016, FDA's Arthritis Advisory Committee is scheduled to hold a meeting to discuss a biosimilar to Remicade (infliximab), a biological product licensed by FDA to treat conditions such as rheumatoid arthritis, ulcerative colitis and Crohn's disease."

Woodcock emphasized that for biosimilars, it is important to her that the FDA applies "rigorous standards" and that while biologics are life-changing and cost-saving, "we don't intend to sacrifice on their performance with biosimilars."

Woodcock also placed a bit of blame back on Congress for the slow pace at which biosimilars and biologics are being approved, highlighting the fact that "Congress didn't appropriate any additional funding to the FDA to implement BPCIA. We took money from other activities." She did mention that the FDA has begun to collect more money under the user fee program, and that she is hopeful that the FDA will have more "robust funding" for biosimilars. Dr. Woodcock further expressed concern that "as more biosimilar applications come in, … we will not have the staff because we always seem to be waiting to catch up."

February 09, 2016

An Update on the Nomination of FDA Commissioner Robert Califf

An increasing number of senators are threatening to block Dr. Robert Califf's nomination to be the next Commissioner of the U.S. Food and Drug Administration. The story illustrates an unusual coalition of right and left-leaning members of the Senate, and common refrains about "industry ties" in government and medicine. Ultimately, arcane Senate rules allow the entire process to be stalled by these individual members of the body.

The U.S. Senate: Where things go to die (slowly)

Members threatening to block Califf's nomination include Senator Joe Manchin of West Virginia. He cited Califf's ties to the pharmaceutical industry and concerns over opioid abuse. He is joined by "Democratic Socialist" Bernie Sanders of Vermont. Presidential ambitions likely play some role in his decision to place a hold on Califf—a procedure that prevents the nomination from even coming to the Senate floor in the first place—and Sanders cites industry ties, along with Manchin.

The theatrics on the Senate floor could possibly include Manchin reading letters from West Virginia families dealing with opioid abuse, if the nomination ever gets past the hold stage. Senator Edward Markey of Massachusetts, also cites opioid concerns, along with Senator Ayotte of New Hampshire.

Not to be out done, Senator Murkowski of Alaska, a Republican, says she will hold up the vote unless the FDA changes its position on the voluntary labeling of genetically modified fish.

Califf helped establish Duke University's clinical research center and has acknowledged that his studies have received funding from pharmaceutical companies. But he insists that they had no ability to change or hide the results, and the Senate Health, Education, Labor and Pensions Committee approved his nomination with no dissenting votes earlier this year.

In Califf's corner against the unlikely alliance of diverse interests stands, President Obama.

"Obviously, the president and the administration have full confidence in the ability of our nominee to make the kinds of decisions that are in the best interest of the health and safety of the American people," White House press secretary Josh Earnest recently said at a briefing. "The president would not have nominated him to the job if he didn't think that he would be able to effectively look out for the interests of middle-class families in that role."

According to Senate rules, one senator is allowed to block a nomination vote unless 60 Senators vote to overrule the hold. And while it is not likely Califf's nomination will be held up indefinitely, the efforts of the senators to block Califf from moving forward highlight lawmakers' concerns over the approvals process at the FDA.

Positives of industry ties

A recent Medscape article addresses Califf's ties to industry and the Senate procedural hurdles facing the nominee. Although the industry ties are cited by politicians as a negative, a number of clinicians and medical professionals disagree. In the article, Medscape notes that a large group of doctors and organizations have publicly declared their approval of Califf as FDA commissioner, including the American College of Cardiology (ACC), the American Heart Association (AHA), and the American Psychiatric Association. The American College of Cardiology's president, Dr. Kim Williams, cited Califf's vast knowledge as a cardiologist and investigator which will be beneficial when dealing with a variety of conditions.

Dr. Jeffrey Drazen, editor of the New England Journal of Medicine stated that Califf's interactions with pharmaceutical companies is a strength instead of a weakness because Califf will be able to illustrate the intricacies of the relationships.

"The ability to know how the pharmaceutical industry works is probably key for a person in the position of an FDA commissioner or leader. You need someone who knows the issues . . . and can give some guidance," Dr. Williams said in the Medscape article.

It was further reported that the AHA's CEO, Nancy Brown, stood by her organization's support of Califf as she "cannot think of a better person" to lead the FDA, despite his ties to industry. This work, she notes, has been focused on clinical research and innovation—ultimately a positive for patients.

Many of the senators opposing Califf implicitly call into question his ability to act ethically having "ties" to industry. This is a foolish argument, at best, as noted by Dr. Robert Harrington, one of Califf's former colleagues at Duke who cited Califf's "highest level of integrity and honesty," according to Medscape. "He believes passionately in providing evidence for people to practice medicine. And he has been unfailing in his quest for the truth about what works and doesn't in a clinical setting."

Dr. Harrington's defense continues and serves as an important reminder of the positive outcomes from industry-physician collaboration: "I can't imagine there's someone who better understands the complexities of the issues, especially around the healthcare side of the FDA." Harrington added that many of the concerns brought up by the senators revolve around politics "and don't actually speak to his qualifications or suitability for the job."

And regarding talk about too-close pharma ties, "the reality, from a research perspective in cardiovascular medicine, is that to understand therapeutics, then one is almost certainly going to be doing collaborative research with industry," he said. Califf "does have a lot of relationships with industry. But they've always been appropriately managed and been very strict about their independence."

Medscape's article continues with a quote from AHA chief science officer Dr. Rose Marie Robertson, noting that Califf's experience over the years "gives him a broad view not only of the science of the drugs and devices used in his trials, but lets him understand and be critical of study design in a way that people who haven't had that experience would find very difficult to do."

FDA Changes Course

One of the objections to Dr. Califf's nomination is around the approval of opioids. Califf and others at the FDA recently called for a far reaching plan to reassess the agency's approach to opioid medications. The plan will focus on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief. Including requiring an advisory committee for the approval of new opioids, additional warnings to immediate release labeling, and updating REMS.

Tide is moving against Hold

Recent editorials seem to suggest there is a growing interest in seeing an up-or-down vote on Califf—one he would surely win. In an editorial, several papers wrote:

Senators are entitled to object to White House nominees, but Ms. Murkowski and Mr. Markey have gone further and placed a hold on the appointment. A hold is a maneuver permitted by Senate rules that allows a single lawmaker to block a measure from receiving a floor vote.

It is often used as a partisan weapon, in which a senator from one party can hold hostage the appointment of a president from the other party. Last month, no fewer than 28 Obama nominees — for judgeships, ambassador posts, terrorism finance specialist, and high-level state department positions — were on ice in the Republican-led Senate, some of them via individual holds.

The holds on this nomination aren't partisan payback, but they're just as insidious because they deny the full Senate a chance to vote.


January 28, 2016

FDA CDER Update 2016

We recently reported that 2015 resulted in the highest level of newly approved U.S. drugs in nineteen years. This reflects an industry-wide desire to research and develop drugs for rare and hard-to-treat diseases. As has been reported, while speaking at a recent meeting in Washington, D.C., the U.S. Food and Drug Administration's Director of the Center for Drug Evaluation and Research (CDER), Janet Woodcock, noted the agency has moved to address the backlog of abbreviated new drug applications (NDA). Woodcock added that CDER is working to prepare for the emerging biosimilars market. Additionally, John Jenkins, Director of the Office of New Drugs at CDER, outlined drug approval statistics, particularly as CDER has seen a steep rise in orphan drug approvals.

CDER in 2016

In 2016, Woodcock stressed the need to fill vacancies at the agency's drug offices as of critical importance. CDER will also be engaged in the re-negotiations of the generic drug, prescription drug, and biosimilar user fee programs—the programs expire in 2017, adding to FDA's focus. Other areas of focus for CDER include issuing draft guidance on generic versions of abuse-deterrent opioid formulations, streamline clinical trial monitoring and data cleaning practices, develop and standardize electronic submissions to CDER, and reevaluation of drug advertising and promotion regulations in light of recent court decisions.

Woodcock's comments on promotional activity come as it has been reported in 2015 the Office of Prescription Drug Promotion (OPDP) issued a record-low nine letters to companies for advertising and promotion violations. Four of the letters involved inadequate or omitted risk information and other common citations involved unsubstantiated or misleading statements. FDA has still not finalized its guidance on social media, although the agency has issued several guidances that deal with the issue.

Legislation Stalled

As FDA grapples with staffing concerns and regulatory developments, Congress continues to debate the 21st Century Cures legislation. It easily passed the House, but for months has been stuck in the Senate. Now, news comes that the Senate Health, Education, Labor and Pensions (HELP) Committee will not take up the bill as it marks up legislation on neurological diseases research and electronic medical records. The measure has stalled in the Senate, mostly because Republicans and Democrats have failed to agree on how to pay for the bill. The House bill included more than $8 billion in new funding for researchers at agencies like the National Institutes of Health and provisions seeking to overhaul the FDA.

According to Sen. Lamar Alexander (R-Tenn.): "Senators and staff on our committee have been working together throughout 2015 to produce a number of bipartisan pieces of legislation that are ready for the full committee to consider". "The House has completed its work on the 21st Century Cures Act. The president has announced his support for a precision medicine initiative and a cancer 'moonshot.' It is urgent that the Senate finish its work and turn into law these ideas that will help virtually every American," he said.

GAO: FDA Lacks Reliable and Accessible Postmarket Data

When there is an unmet need for the treatment of a serious condition, FDA may use one or more of its expedited programs, such as fast track and breakthrough therapy designation, which are intended to bring drugs to market more quickly. FDA is also responsible for monitoring the safety of drugs and reporting on those efforts.

With this in mind, the GAO was tasked with providing information about FDA's expedited programs and its postmarket monitoring of expedited and nonexpedited drugs. The report examined (1) the number and types of requests for fast track or breakthrough therapy designation, (2) the number and types of FDA-approved drug applications that used an expedited program, and (3) the extent to which FDA's data on tracked safety issues and postmarket studies allowed the agency to meet its reporting and oversight responsibilities.

The GAO looked at FDA data on requests for fast track or breakthrough therapy designation and approved drug applications that used an expedited program from October 1, 2006, to December 31, 2014. It also reviewed FDA information on tracked safety issues and postmarket studies, including FDA internal evaluations and guidance, and interviewed FDA officials. In its findings, the GAO recommends the FDA develop plans to correct problems with its postmarket safety data and ensure that these data can be easily used for oversight. HHS agreed with GAO's recommendations, according to the report.

Rep. Rosa DeLauro (D-CT), who commissioned the GAO report, said in a statement: "The GAO report confirms my greatest fear, that FDA lacks fundamental resources and leadership in ensuring that drugs brought quickly to market are truly safe and effective." She added: "If FDA is shifting more of the safety risk to consumers by allowing fewer and shorter clinical trials on expedited drugs, adequate tracking of drug safety issues and review of post market studies are absolutely vital."

The GAO's report was especially critical of FDA's CDER office. According to the report, FDA lacks reliable, readily accessible data on tracked safety issues and postmarket studies needed to meet certain postmarket safety reporting responsibilities and to conduct systematic oversight. CDER's internal evaluations of data in its database revealed problems with the completeness, timeliness, and accuracy of the data. These problems have prevented FDA from publishing some required postmarket safety reports in a timely manner, and have restricted its ability to perform systematic oversight.

CDER's data on tracked issues was not complete, indicating that 144 issues had not been formally entered into its database. The time consuming nature of data entry was cited by FDA as a potential reason. GAO reports FDA officials acknowledged that staff were not following CDER's policies and procedures for tracking and documenting potential safety issues, but said that given the high workload of its review staff it had prioritized identifying, assessing, and addressing potential safety issues over administrative tracking. CDER's information on postmarket study status was found to be outdated and inaccurate, also related to staff delays in reviewing submissions.

Additionally, tracked safety issue and postmarket study data were not readily accessible to the GAO for analysis. FDA officials told the GAO much of the information has to be manually reviewed and cannot be accessed electronically. FDA reported to GAO that some information about postmarket studies, such as the date FDA requested or required a study, must be manually collected from the text of letters to sponsors; these letters are not automatically linked to information about the study in internal systems, which can make them challenging to locate.

GAO concludes the FDA's lack of reliable and accessible postmarket safety data prevents the agency from publishing required reports in a timely manner and restricts the FDA's ability to conduct effective oversight. As of October 2015, GAO notes that FDA had not published required annual reports containing data on postmarket studies for fiscal years 2013 and 2014. FDA officials told GAO that the agency had decided to delay publication of the reports primarily due to CDER's internal evaluation of the postmarket study data and subsequent efforts to address the data problems that were identified.

However, to its credit, GAO reported that FDA has taken some steps to address the problems identified with the postmarket safety data, although the agency is not currently announcing any comprehensive plans with goals and time frames. FDA said it intends to address its incomplete data on tracked safety issues by revising and streamlining its processes for reviewing and tracking these issues. FDA officials said that CDER has formed a workgroup that is considering options to clarify which potential safety issues should be centrally tracked, and how the tracking and review processes could be streamlined. Additionally, FDA intends to increase the timeliness and accuracy of its postmarket study data by improving tools for oversight and data collection. FDA officials said the agency is aiming to facilitate more timely review of sponsor submissions that contain information on postmarket studies by improving internal oversight.



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