Life Science Compliance Update

January 13, 2017

FDA Issues Guidance on REMS


With the passage of the long-awaited 21st Century Cures legislation, we saw Senator Mike Lee (R-UT) vote “no” because the bill did not include language that would allow generic pharmaceutical companies to obtain samples of products under the Risk Evaluation and Mitigation Strategies (REMS) program. Senator Lee an others, including Senator Chuck Grassley (R-IA) and Patrick Leahy (D-VT) had supported an amendment to Cures based on a legislative proposal that would improve the REMS process as a method to control drug prices. This is why it is interesting to review a draft guidance from FDA that tries to further explain the application of REMS regulatory paradigm, which can ultimately delay generic drug competition. A REMS can be a medication guide or package insert or communication plan that is required by FDA to ensure that the benefits of a drug outweighs the risks.

40 percent of FDA approvals are subjected to REMS

In a 2014 report, the Generic Pharmaceutical Association (GPhA) wrote that nearly 40 percent of new FDA approvals are subject to REMS, and brand manufacturers have also begun imposing distribution restrictions on non-REMS products. “Government, consumers, and private payors are already missing out on sizeable health care savings from misuse of these programs. Specifically, REMS and non-REMS strategies to restrict access to brand drug samples represent lost savings on small-molecule drugs of at least $5.4 billion annually,” said the GPhA.

FDA Guidance

The 14-page draft, “FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary,” offers some explanation for how it tries to address the burden of the REMS program.

The FDAAA requires FDA to consider the following six factors in making a decision about whether to require a REMS:

  • The seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug;
  • The expected benefit of the drug with respect to the disease or condition;
  • The seriousness of the disease or condition that is to be treated with the drug;
  • Whether the drug is a new molecular entity;
  • The expected or actual duration of treatment with the drug;
  • The estimated size of the population likely to use the drug.

These six factors influence FDA’s decisions with respect to both whether a REMS is required for a particular drug and what type of REMS might be necessary (i.e., what specific elements or tools should be included as part of the REMS). FDA makes decisions about requiring a REMS as part of a benefit-risk determination for a drug after an evaluation that includes integrated consideration of each of the statutory factors. No single factor, by itself, is determinative as to whether a REMS is necessary to ensure that the benefits of a drug outweigh its risks.

The more serious a drug’s known or potential associated risks relative to its benefits, the more likely it is that a REMS will be necessary to ensure a favorable benefit-risk balance, without which the drug could not be approved. In determining whether to require a REMS, FDA considers the source, nature and reliability of available scientific evidence about the adverse events as well as the characteristics of the risks, including the severity, frequency, temporality, preventability, reversibility, background incidence, and likelihood of occurrence of the adverse events.

When assessing a drug’s expected benefits with respect to a specific disease or condition in considering whether a REMS is necessary, FDA may evaluate information about the drug’s effectiveness, whether the drug treats a serious disease or condition, whether it fills an unmet medical need, and whether it can cure the disease or alleviate its symptoms. FDA may also consider the extent to which new dosage forms enhance convenience of administration and/or improve adherence to prescribed regimens, and whether new formulations or delivery mechanisms may extend treatment to patient populations who were formerly unable to use the drug. A drug’s expected benefits, however, are not considered in isolation. In determining whether a REMS is necessary, FDA’s assessment of a drug’s benefit is balanced against consideration of the risks associated with its use.


In the conclusion of its guidance, the agency writes, “FDA understands that REMS, particularly those with ETASU, may impose some measure of burden on patients and/or health care providers. When considering this burden on patient access and the health care delivery system, FDA takes into account existing REMS elements for other drugs with similar risks and whether the REMS under consideration can be designed to be compatible with established medical drug distribution, procurement, and dispensing systems.”

The FDA also looks at patients for whom the drug is indicated currently access health care and whether the REMS may impose additional access difficulties. FDA also takes into account the consequences of potential treatment interruption or delays, particularly where patients have serious or life-threatening conditions and/or have difficulty accessing health care. In such circumstances, FDA claims it takes steps, to the extent possible, to ensure that REMS are designed to minimize delays or interruptions in drug therapy that may have untoward clinical impact.

May 05, 2016

FDA ER-LA REMS Day 2 of the Drug Safety and Risk Management Advisory Committee

Day Two of the Joint Meeting of the Drug Safety and Risk Management Advisory Committee (DSaRM) and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) was lively and full of debate and conversation.

The day started out with comments from the FDA, followed by presentations by Joanna G. Katzman, MD, MSPH, of the University of New Mexico Health Sciences Center and Graham McMahon, MD, the President and CEO of the Accreditation Council for Continuing Medical Education (ACCME).

The bulk of the morning was spent on the "Open Public Hearing" portion, where twenty-three participants, from various walks of life, various viewpoints, and with various reasons for involvement, gave their opinion on modification of REMS. Many of the speakers had positive things to say about REMS and CME, including many who believe that CME should be mandated for prescribers who are trying to obtain or renew their Drug Enforcement Administration (DEA) license, since many physicians and other providers may not voluntarily participate.  The speakers also emphasized the need to expand the current REMS to IR opioids and to expand the scope of the program to target education towards the entire healthcare team and not just prescribers as pain management often requires several layers of help.

Several of the speakers, including Phyllis Zimmer, a board certified nurse practitioner, believe that the current ER-LA Opioid REMS is not an undue burden, nor does it limit patient access to physicians and appropriate care.

Some of the recommendations for updating REMS included: increase transparency for patients; develop a blueprint for patient information; increase the available range of activities, so that physicians and other practitioners can help close their personal gap, not a predetermined gap that may or may not benefit them individually; standardize REMS while allowing for increased flexibility; educate entire healthcare teams, not just physicians; include in the education other treatments that may reduce overall need for opioids; make REMS more comprehensive, including IR; provide education for providers on how to manage "at risk" patients; launch a public health campaign so the entire country is involved; and focus on education that emphasizes fewer patients, shorter duration of prescribing patterns, and lower dosages. Several speakers also mentioned the idea that REMS should include some screening for mental disorders, and provide education to providers on how to handle patients who may suffer from such illnesses.

The afternoon was full of questions to the committee and committee discussion. The committee did not hold a formal vote, but several members of the committee recommend that the FDA should update its education materials to incorporate the new CDC guidelines on opioid prescribing and other material on alternative pain treatments. There was a real concern that the learners were engaged and to do more work to show changes in clinical practice.

The committee also agreed with many morning presenters in recommending the continuing education component be mandatory and tied to DEA licensure, not voluntary, in order to be most effective.

Earlier in the day Graham McMahon, CEO of ACCME outlined how mandatory CME often is not effective in changing clinical practice and called for continuing education for physicians who prescribe opioids to be voluntary.

The committee also urged the FDA to update REMS to include shorter acting opioids, which have the potential to be more dangerous than ER/LA opioids. Critics of that idea believe that opioid manufacturers have too much control and influence over strategy but several of those who expressed concern applauded the REMS Program Committee for their work in supporting this effort.

While the FDA is not required to follow the recommendations of its panelists, history reflects that the opinions and recommendations of panelists have a large effect on the eventual rules.

March 09, 2016

Endo New York Settlement Announcement

New York Attorney General Eric T. Schneiderman announced an agreement with Endo Health Solutions, Inc. and Endo Pharmaceuticals, Inc. (collectively, "Endo"), which make and sell Opana ER, a long-acting opioid.

Opana, one of Endo's prescription drugs, was long abused in New York State. In May 2011, for example, after a spike in opioid prescribing and abuse, Nassau County issued a Public Health Alert on the increasing use and abuse of Opana ER, warning both the public and law enforcement of the dangers associated with the prescription drug. In July 2012, USA Today reported that Opana ER was actually the drug of choice for people seeking narcotics, and that in Nassau County, hundreds of people each month were seeking treatment for addiction to Opana ER.

As a result of concerns regarding both Opana ER's role in the larger opioid abuse epidemic and Endo's marketing practices, the Office of the Attorney General opened an investigation into Endo, focusing on Opana ER. The Attorney General found that Endo improperly marketed Opana ER as designed to be crush resistant, when Endo's own studies actually showed that the pill could be crushed and ground up. While this may have bolstered Opana ER sales, it also may have provided a false sense of security to healthcare providers and their patients. The Attorney General also found that Endo improperly instructed its sales representatives to diminish and distort risks associated with Opana ER, including serious dangers involving addiction.

Endo also claimed that Opana ER was distinguishable from its main competitor, OxyContin, because patients who take Opana ER need less rescue medication than those who take OxyContin. This claim, made by sales representatives in sales calls, was not supported by any clinical evidence or study.

The Attorney General's investigation found that Endo had no meaningful program in place to ensure that its sales representatives were not encouraging healthcare providers who are engaged in abuse and diversion to write more prescriptions for Opana ER. This was of particular concern because multiple New York healthcare providers who were heavily "detailed" by Endo were subsequently convicted of illegally prescribing prescription opioids (see p. 10-12 of Settlement).

According to Attorney General Schneiderman, "The public health crisis created by improper opioid prescribing in New York remains pervasive and extremely dangerous. My office is committed to ensuring that prescription drugs are marketed and prescribed responsibly – and that consumers get the information they need about the serious risks associated with painkillers, such as addiction."

The Office of the Attorney General has compelled Endo to change its practices in light of their "deceptive and unlawful conduct."

Endo must implement the following corrective measures:

  • Provide truthful and complete information regarding addiction risks associated with Opana ER;
  • Stop improperly marketing Opana ER as crush resistant;
  • Create an Abuse and Diversion Detection Program that requires Endo's sales representatives to report to the company any healthcare providers they suspect of engaging in abuse and illegal diversion of opioids;
  • Post results of clinical studies on Endo's website; and
  • Provide healthcare providers with information about addiction treatment resources for their patients.
  • Inform NY providers both in writing and orally to participate in the FDA ER-LA REMS Prescriber Education each year

Attorney General Schneiderman also imposed a $200,000 penalty on Endo for its unlawful conduct.

Settlement Specifics

In addition to the aforementioned items, the Settlement went through the findings that Attorney General Schneiderman found, including that in addition to an annual salary, Endo's sales representatives were eligible for a bonus based partly on the number of Opana ER prescriptions written by healthcare providers they were permitted to call upon. Attorney General Schneiderman felt as though such a bonus scheme may create an incentive to encourage more Opana ER prescribing.

The Settlement also mentions that Endo neither admitted nor denied Attorney General Schneiderman's findings in the Settlement and that Endo did cooperate with the Attorney General investigation.

The Settlement also laid out specific plans and requirements for the aforementioned Abuse and Diversion Detection Program, including the filing of a written report with Endo's Legal Department when sales representatives or medical liaisons observe or learn of situations that may suggest that a healthcare provider whom they contact for the purpose of promoting Opioid Medications may be involved in the abuse or diversion of opioids.

This settlement is not the light at the end of the tunnel for Endo. Earlier this month, they said they are still facing other regulatory probes and lawsuits related to its opioid sales and marketing practices.


Preview | Powered by FeedBlitz


February 2017
Sun Mon Tue Wed Thu Fri Sat
1 2 3 4
5 6 7 8 9 10 11
12 13 14 15 16 17 18
19 20 21 22 23 24 25
26 27 28