Opioid painkiller benefits fall short of abuse risks

The benefits derived from the use of Endo International Plc’s opioid drug no longer outweighs its risks, according to an FDA advisory panel. As opioid abuse, overdose and addiction have reached epidemic proportions in the United States, partly due to unrestricted prescription of narcotic painkillers, as well as the paucity of access to substance-abuse treatment programs, the FDA has undertaken review of the uses of the painkiller in a variety of settings. Eighteen panelists recommended that the risks of the reformulation eclipse the benefits, while eight disagreed and one member abstained from voting. The FDA generally follows advisory panel recommendations, but is not required to do so.

The FDA advisory panel reviewed the abuse rate of Endo’s Opana® ER – a long acting painkiller similar to oxymorphine and other oxymorphone drugs. Opana was approved in 2006, and in 2012, the drug maker introduced a new formulation to attempt to deter abuse of the drug. Although the reformulation (in nasal form) reduced abuse rates, intravenous abuse increased in the same timeframe. The panel was unable to conclude whether this rise was related to the reformulation, but noted that the trend was observed before the reformulation. Additionally, abuse rates for similar oxymorphone drugs are as high as Opana.

One factor that triggered the advisory panel’s review was the increased rate of rare blood disorders and human immunodeficiency virus (HIV) linked to the IV abuse of the reformulation.

Some advisory panel members expressed concerns that the voting question posed did not permit consideration of the risk-benefit profile for an intended user versus use by an addict. Others questioned whether withdrawing the product would stop an addict from abusing other opioids, or whether oxymorphone was still an integral part of the arsenal of treatments for chronic pain.

 

User fee program reauthorizations necessary for product development

The House Energy and Commerce Subcommittee on Health focused its attention on the FDA’s generic drug and biosimilar user fee programs by inviting the FDA and industry leaders to a hearing to discuss how the programs have been implemented to date and recommendations on reauthorization. Both the Generic Drug User Fee Amendments of 2012 (GDUFA) and the Biosimilar User Fee Act of 2012 (BsUFA) expire in September 2017 and must be reauthorized for the Fiscal Years 2018 to 2022. The hearing also discussed H.R. 749, the Lower Drug Costs Through Competition Act, which seeks to increase generic competition through a shortened review cycle of six months.

Background

Since 1992 and based on the Prescription Drug User Fee Act (PDUFA), Congress has authorized the FDA to collect fees from regulated industry to supplement congressional appropriations. Revenues generated from these fees have been used on specific activities related to the review and regulation of medical products. In exchange for industry agreeing to pay fees, the FDA agrees to meet certain performance goals, such as completing product reviews within specified timeframes. Industry concerns about the length of time it was taking the FDA to review generic drug applications, known as abbreviated new drug applications (ANDA), and the backlog of such applications pending at the agency led Congress to pass GDUFA as part of the Food and Drug Administration Safety and Innovation Act (FDASIA).

Likewise, the Biologics Price Competition and Innovation Act (BCPIA) of 2009, as passed with the Patient Protection and Affordable Care Act (ACA) (P.L. 111-148), established a new regulatory authority for the FDA to create an abbreviated approval pathway for biological products demonstrated to be “highly similar” to, or “interchangeable” with, a previously licensed biological product. As part of FDASIA, Congress passed BsUFA to authorize FDA to collect user fees from biosimilar product manufacturers.

Pew Charitable Trusts

Allan Coukell, Senior Director of Health Programs, The Pew Charitable Trusts presented testimony on rising pharmaceutical costs, within and beyond the user fee context. He noted the rising cost of new medicines—especially high-cost specialty drugs, which are only used by 1 to 2 percent of the population, but account for more than one-third of drug spending. Although the FDA’s approval processes outlined in the generic and other user-free agreements offer some potential to address drug spending, he stressed that competition via generic drugs.

As such, the Lower Drug Costs through Competition Act (H.R. 749) would award a generic priority review voucher to any manufacturer that brings a generic drug to market in cases of limited competition or a drug shortage. It would also establish a six-month timeline for FDA review of priority applications, faster than the GDUFA review. In addition to accelerated review, the Pew Charitable Trusts called for Congress to consider requiring greater transparency of contract terms and definitions between payers and pharmacy benefit managers (PBM), as well as mandating the ability to audit these deals, and ensuring that entities that advise purchasers on PBM contracts do not also have financial relationships with the PBMs themselves.

Association for Accessible Medicines

David Gaugh, Senior Vice President for Sciences and Regulatory Affairs at the Association for Accessible Medicines (AAM), which was previously known as GPhA—the trade association representing the manufacturers and distributors of generic prescription drugs, manufacturers and distributors of bulk pharmaceutical chemicals—testified that the best way of achieving the goal of providing patients access to generic alternatives is through the development of policies that promoted competitive markets. The AAM stressed that the best way to control drug costs generally was through policies that incentivize competition, such as GDUFA.

The user fee program supports small business by exempting them from a facility fee until the first ANDA in that facility is approved. The proposal also provides for a tiered structure of annual ANDA program fees based on small, medium, and large companies. Designing GDUFA to spread fees across industry to keep individual amounts as low as possible, the AAM believed the program would help assure that patients continue to receive the significant cost savings from generics alternatives.

Biotechnology Innovation Organization

Kay Holcombe, Senior Vice president, Science Policy, Biotechnology Innovation Organization (BIO), offered testimony to the Subcommittee on reauthorization of BsUFA and H.R. 749. BIO supported the reauthorization of BsUFA, as well as expressed its support for competition in the prescription drug marketplace not only between innovator biologics and biosimilars, but also between innovator drugs and generic drugs, which is the subject of H.R. 749. BIO urged the FDA to lay out its thinking on interchangeability and believed it was crucial for the FDA to clarify its expectations for the data needed to determine that a biosimilar product is interchangeable with its reference biological product. Such a determination could serve to encourage greater prescribing and use of biosimilars as the availability of biosimilar products increases, provided the determination is sufficiently rigorous.

As for H.R. 749, BIO did not adopt a position on the question of timelines for generic drug review or awarding certain generic drug applicants with priority review vouchers under the proposed legislation. BIO did note that it supported policy intended to lower drug prices through the promotion of competition in the drug marketplace, including the timely entry of generics and biosimilars once patents and exclusivities for innovator drugs have expired.

Biosimilars Council

Bruce Leicher, Senior Vice President and General Counsel at Momenta Pharmaceuticals, and Chair of the Biosimilars Council Board of Directors, a division of AAM, noted that the BsUFA reauthorization user fees were now tied to the level of resources needed and adjust with resource demand. As such, it was vital that Congress understood that the funding provided by user fees is in addition to, not a substitute for, congressional appropriations.

Biosimilars Forum

Juliana Reed, Vice President of Government Affairs for Coherus BioSciences, stated that the Biosimilars Forum entered into the BsUFA reauthorization negotiation process with four primary goals: (1) ensuring solid financial support for the program; (2) improving communication between the FDA and biosimilars product sponsors during the approval process to improve efficiency; (3) increasing transparency during the approval process and regarding the spending of user fees; and (4) preventing the expenditure of BsUFA funds on extraneous policy issues or activities that are not exclusive to biosimilars. The Biosimilars Forum was pleased to see that the BsUFA draft met these goals.

In addition, the Biosimilars Forum urged Congress require CMS to review its current reimbursement policy for biosimilars and make it consistent with FDA biosimilar policies. Specifically, it noted that the FDA policy on biosimilars acknowledges the unique nature of each biosimilar, and CMS should align its policy by assigning unique, individualized billing codes to each biosimilar.

FDA

Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER) at the FDA, discussed both GDUFA and BsUFA during her testimony before the Subcommittee. GDUFA achieved a number of notable goals during the course of its five-year authorization. The FDA approved or tentatively approved 835 ANDAs—the most approvals in the history of the agency—in fiscal year (FY) 2016 alone. The previous high was 619. In addition, approximately 25 percent of all currently approved generic drugs were approved over the past four years. Prior to GDUFA, ANDAs were approved in one review cycle less than one percent of the time. Now, approximately nine percent of ANDAs are approved in the first review cycle.

The FDA did note some challenges to GDUFA, namely submission completeness and volume of applications. Historically, it has taken on average about four review cycles to approve an ANDA as a result of deficiencies by generic drug sponsors in submitting complete applications. More work by both the FDA and industry will be necessary to have the filings be accurate the first time. Moreover, in FYs 2012, 2013, and 2014, the FDA received over 1,000, nearly 1,000, and nearly 1,500 applications, respectively, which taxed the agency’s ability to timely process the ANDAs.

The FDA was also supportive of and fully engaged with the development and approval of biosimilar and interchangeable products. One of the first steps in the development and review process for a biosimilar is for an applicant to join the FDA’s Biosimilar Product Development (BPD) Program. As of February 2017, 64 programs were enrolled in the BPD Program and CDER has received meeting requests to discuss the development of biosimilars for 23 different reference products. Moreover, the FDA finalized six guidances and issued four draft guidances during the timeframe in question. The FDA’s challenge, however, was a result of staffing shortages. Without additional staffing to handle the increased workload for biosimilar review, the FDA warned that review performance would be impacted.

Feds snare 16 hospice providers in $60M Medicare fraud scheme

Sixteen individuals were charged with offenses related to a health care fraud scheme in a federal court in Texas. The scheme alleges that from July 2012 to September 2016, Novus Health Services, owned and operated by the 16 individuals, billed Medicare and Medicaid more than $60 million for fraudulent hospice services, of which more than $35 million was paid to Novus. The individuals submitted false claims for hospice services and continuous care hospice services, recruited ineligible hospice beneficiaries via kickbacks to physicians and health care facilities, and falsified and destroyed documents to conceal these activities. The grand jury indictment was the result of an investigation into Novus by the Federal Bureau of Investigation, HHS Office of Inspector General (OIG), and the Texas Attorney General’s Medicaid Fraud Control Unit (MFCU).

Scheme

Novus and Optim Health Services, Inc. were operated and co-owned by one of the individuals, a certified public accountant without any medical licenses. Licensed physicians who were paid Novus medical directors provided little to no oversight of Novus’s hospice patients. Some of the indicted individuals were not physicians and they would determine whether a beneficiary would be certified for, recertified for, or discharged from hospice; whether they would be placed on continuous care; and how and to what extent they would be medicated with drugs. These decisions on medical care were often driven by financial interest rather than patient need.

The scheme also involved directing that beneficiaries be placed on continuous care, whether the beneficiaries needed the service or not, and often without any consultation with a physician. Continuous care physician’s orders were falsified and uploaded into Novus’s electronic medical records database. When a beneficiary was on continuous care, the Novus nurses would unnecessarily administer high doses of Schedule II controlled medications such as morphine or hydromorphone. The Schedule II medications were obtained with prescription forms unlawfully pre-signed by medical directors. The investigators found instances when these excessive dosages resulted in serious bodily injury or death to the beneficiaries.

If convicted, each count of conspiracy to commit health care fraud and substantive health care fraud count carries a maximum statutory penalty of 10 years in federal prison and a $250,000 fine.

Bloodstream infection detection test approved for marketing

In a first of its kind, the FDA has approved the marketing of the PhenoTest BC Kit, which is the first test to identify organisms that cause bloodstream infections. The test kit, manufactured by Accelerate Diagnostics Inc., can provide information to health professionals about which antibiotics the organism is sensitive to and potentially reduce the amount of time to provide this information. As a result, antibiotic treatment recommendations can be formulated much quicker. Unlike traditional identification and antibiotic susceptibility tests that may take 24 to 48 hours after detection in a positive blood culture to provide test results, the PhenoTest BC Kit can identify bacteria or yeast from a positive blood culture in approximately 1.5 hours. The test can identify 14 different species of bacteria and two species of yeast that cause bloodstream infections, while also providing antibiotic sensitivity information on 18 selected antibiotics for a subset of the identified organisms as appropriate.

Bacterial or yeast blood infections can occur in individuals of all ages, but are particularly severe in infants, the elderly, and those with weakened immune systems. If not treated rapidly, such bloodstream infections can lead to severe complications, such as septic shock and death. The PhenoTest BC Kit can also provide treatment recommendations within 6.5 hours of organism detection in blood cultuers.

The FDA reviewed the data for the PhenoTest BC Kit through its de novo premarket review pathway, a regulatory pathway for devices of a new type with low-to-moderate-risk that are not substantially equivalent to an already legally marketed device and for which special controls can be developed, in addition to general controls, to provide a reasonable assurance of safety and effectiveness of the devices. Although some risks with the kit included false positive findings, the FDA’s decision was based on Accerlerate’s clinical study of 1,850 positive blood cultures.  In the study, bacteria or yeast in positive blood culture was identified correctly more than 95 percent of the time.