Life Science Compliance Update

January 19, 2017

Interim FDA Commissioner Announced

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Dr. Robert Califf’s tenure as commissioner of the United States Food and Drug Administration (FDA) is slated to come to an end ahead of the January 20th inauguration of Donald Trump as president. Deputy commissioner Dr. Stephen Ostroff is expected to take over on an interim basis after the inauguration. Ostroff has previously been acting commissioner – from April 2015 to February 2016 he served as acting commissioner. Once Califf was sworn in, Ostroff became the FDA’s deputy commissioner for foods and veterinary medicine.

Califf Permanent Replacement

Scott Gottlieb

The leading candidate to replace Califf is said to be Dr. Scott Gottlieb, an Obamacare opponent who’s also a former deputy commissioner at the federal safety watchdog. Gottlieb, currently a fellow at the American Enterprise Institute, is also an assistant professor at the New York University School of Medicine and a former practicing physician and hospitalist.

While at the FDA, Gottlieb served as a senior advisor for medical technology, director of medical policy development and deputy commissioner for medical and scientific affairs. Before that, he was a senior policy advisor at the Centers for Medicare & Medicaid Services (CMS).

Jim O’Neill

Mr. Trump is also expected to be considering Jim O’Neill, a libertarian and Silicon Valley investor with no medical experience (a fact that has some healthcare experts concerned). O’Neill has also previously made controversial statements about the federal safety watchdog, including when he said the FDA should no longer evaluate whether medical devices or drugs are effective when considering them for approval. That 2014 statement was viewed harshly by experts, with some thinking that it demonstrates O’Neill’s lack of medical experience and the problems that come with that.

Peter Pitts, a former FDA associate commissioner under President George W. Bush, said it’s nearly impossible to separate safety and efficacy when considering pharmaceuticals. “People need to understand that safety doesn’t exist without the balance of risk,” Pitts noted while explaining “every drug has risks,” providing the example of side effects that might be acceptable for lung cancer drugs, but not aspirin.

Experts have also expressed shock and concern over O’Neill’s interest in anti-aging products, and his claim that immortality could be a possibility within the next forty years. O’Neill has said, “You can tell a lot about an era by listening to what people whine about. If we invest wisely in life extension technologies, in 40 years, we’ll all be able to annoy our friends with complaints like ‘immortality almost never works.’”

O’Neill has also made suggestions that donors should be permitted to be paid to donate their organs, a concept largely rejected by healthcare experts.

O’Neill also served as principal associate deputy secretary of the Health & Human Services Department under Bush 43. In that position, he was responsible for the FDA, the National Institutes of Health, the Agency for Healthcare Research and Quality, the Office of Public Health and Science, the Biomedical Advanced Research and Development Authority, and global health.

Such experience prompted Dr. Michael Carome, director of Public Citizen’s health research group, to say, “He is stunningly unqualified in terms of his understanding of medicine.” However, Carome also noted that he was “just stunned” when he heard Mr. Trump was considering O’Neill as FDA chief.

January 18, 2017

FDA Releases Draft Guidance for Medical Product Communications Consistent with FDA-Required Labeling

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The United States Food and Drug Administration (FDA) released a new draft guidance that provides information for medical product manufacturers, packers, and distributors, on how FDA evaluates firms’ medical product communications – including promotional materials – that present information not contained in the FDA-required labeling for the product, but that is consistent with such required labeling.

Various medical product firms have told the FDA that they would like to communicate data and information about the approved/cleared uses of their products, including information not contained in their products’ FDA-required labeling. As a result, the FDA issued this draft guidance for all drugs and devices, including those that are licensed as biological products, and animal drugs.

Because a communication that is consistent with a product’s FDA-required labeling could nonetheless misbrand the product and subject a firm to enforcement action if the representations or suggestions made in the communication are false or misleading, this guidance also provides general recommendations for conveying information that is consistent with the FDA-required labeling in a truthful and non-misleading way, as well as examples to illustrate these concepts. Interestingly, missing from the guidance document is any mention of off-label communications.

If a firm’s communication is consistent with the FDA-required labeling, that communication alone is not viewed by FDA as providing evidence of a new intended use. Further, FDA does not view a communication that is consistent with the FDA-required labeling as failing to comply with the Federal Food, Drug, and Cosmetic Act’s (FD&C Act) requirement that a medical product’s labeling bear adequate directions for use, based solely on the fact that it presents data and information that are not reflected in the product’s FDA-required labeling.

Examples of Information that Could Be Consistent with FDA-Required Labeling

The following examples are listed as some of the examples the FDA provides of information that could be consistent with the FDA-required labeling.

  • Information based on a comparison of the safety or efficacy of a medical product for its approved/cleared indication to another medical product approved/cleared for the same indication (e.g., a firm’s communication provides information from a head-to-head study indicating that its drug that is approved to treat high blood pressure in adults has superior efficacy to another drug that is also approved to treat high blood pressure in adults);
  • Information that provides additional context about the adverse reactions associated with the approved/cleared uses of the product reflected in the product’s FDA-required labeling (e.g., the FDA-required labeling for a product identifies nausea as a potential adverse reaction and further indicates the product can be taken with or without food. A firm’s communication about the product provides information about how taking a product with food might reduce nausea);
  • Information about the long-term safety and/or efficacy of products that are approved/cleared for chronic use (e.g., a firm provides post-marketing information for its product, which was approved/cleared for chronic use based on 24-week study data, regarding persistent safety and/or efficacy over 18 months);
  • Information concerning the effects of a product that comes directly from the patient (i.e., patient-reported outcomes) when the product is used for its FDA-approved/cleared indication in its approved/cleared patient population (e.g., a firm’s communication provides information concerning patient compliance/adherence, or a firm’s communication provides information about patients’ perceptions of the product’s effect on their basic activities of daily living); and
  • Information that provides additional context about the mechanism of action described in the FDA-required labeling (e.g., the FDA-required labeling for a drug product indicates it exerts its effects by binding to a certain receptor, and a firm’s communication provides additional information about the product’s selectivity for that receptor).

Examples that Are Not Consistent with FDA-Required Labeling

The FDA also included some general types of information that they do not consider to be consistent with FDA-required labeling, some of which are below.

  • Information about the use of a product to treat or diagnose a different disease or condition than the product is approved/cleared to treat or diagnose (e.g., a product is approved/cleared to treat cardiovascular disease, and a firm’s communication provides information about using the product to treat diabetes);
  • Information about the use of a product to treat a different stage, severity, or manifestation of a disease than the product is approved/cleared to treat (e.g., a product is approved/cleared only to treat severe asthma, and a firm’s communication provides information about using the product to treat patients with mild asthma);
  • Information about using a product through a different route of administration or in a different tissue type than the product is approved/cleared for (e.g., a product is approved only for intramuscular injection, and a firm’s communication indicates the product can be injected intravenously); and
  • Information about the use of a product in a different dosage form than what is set forth in the FDA-required labeling (e.g., the product’s approved dosage form is a capsule, and a firm’s communication provides information about use of the product as an oral solution).

FDA Consideration Recommendations

The way a firm presents information that is consistent with the FDA-required labeling (including the express and implied claims made and the overall impression created by the communication as a whole) affects how the information is understood. The following are some high-level recommendations for firms to consider when developing their presentations of information that is consistent with the FDA-required labeling to help ensure the presentations do not mislead the applicable audience(s):

  • Any study results or other data and information that are relied upon to support a firm’s communication should be accurately represented in the communications. Moreover, material aspects of study design and methodology for any studies relied on should be clearly and prominently disclosed in firms’ communications to allow audiences to accurately interpret the information (e.g., type of study, study objectives, product dosage/use regimens, controls used, patient population studied), and material limitations related to the study design, methodology, and results should also be disclosed in a clear and prominent manner.
  • The communication should accurately characterize and contextualize the relevant information about the product, including by disclosing unfavorable or inconsistent findings. For example, if a firm presents efficacy results from a post-marketing study of its product that evaluated the effect of the product on two different endpoints, such as overall survival and progression-free survival, and the product failed to demonstrate an effect on one of these two endpoints, the firm should disclose this in the communication, rather than selectively presenting only the positive efficacy results.
  • For communications that present data or information that is not in the FDA-required labeling, but where the FDA-required labeling contains other data or information related to what is being represented/suggested in the communication, the communication should also include the data or information from the FDA-required labeling to provide the audience with appropriate context. For example, if a communication provides post-marketing information about the types and rates of occurrence of adverse events that have been observed in practice, the communication should also include information from the FDA-required labeling about the types and rates of occurrence of adverse reactions observed in clinical trials to provide context.

The guidance document also provides several examples for applicable audiences to review, and to determine if their situation is similar. The examples also provide a bit of extra insight into FDA’s thought process and goal with the guidance document. In general, guidance documents do not establish legally enforceable responsibilities. Instead, they describe the Agency’s current thinking on a topic and should be looked at only as recommendations, unless there are specific regulatory or statutory requirements cited.  

January 13, 2017

FDA Issues Guidance on REMS

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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.

Conclusion

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.

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