Life Science Compliance Update

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35 posts from March 2017

March 31, 2017

CDER 2017 Guidance Agenda


In January, FDA’s Center for Drug Evaluation and Research (CDER) released its annual guidance agenda, announcing the new and revised draft guidances that the Center plans to publish during the 2017 calendar year. CDER’s 102-part agenda is organized by category and touches on a variety of topics, giving us a glimpse of what to expect throughout the year. This year’s agenda follows a similar pattern to the Center’s 2016 agenda, placing an emphasis on the clinical aspects of drug development, pharmaceutical quality, generics, and procedural activities. However, CDER is not bound by this list of topics, required to issue a guidance on every topic included in the list, or precluded from developing guidance on topics not included in the list. According to Regulatory Focus, several items on the 2017 list were also listed in 2016.

Delayed by Trump Executive Order?

Maybe, but it is not entirely clear. Additionally, the items in CDER’s announcement reflect only draft and revised draft guidances under development as of the date of FDA's posting. So there is still the potential for modifications, even more potential guidances.

Recent reporting from Regulatory Focus indicates the “Two Out, One In” Executive Order may have been clarified through OMB guidance to offer “wiggle room” for the FDA in issuing guidances. OMB notes that “significant guidance or interpretive documents will be addressed on a case-by-case basis.” Rachel Sachs, an associate law professor at Washington University in St. Louis, argues the OMB document "significantly restricts" and "walks back" the reach of the EO because it exempts classes of regulations required by law and appreciates that regulations may be deregulatory in nature so the costs and issuance of such regulations will be considered accordingly.

“Emergencies addressing critical health, safety, or financial matters, or for some other compelling reason, may qualify for a waiver from some or all of the requirements of Section 2,” the guidance also notes, which may further allow the FDA room to move on these issues.

The 2017 Agenda

A few interesting items that stood out:


  • Drug and Device Manufacturer Communications with Payors, Formulary Committees and Similar Entities


  • Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations; Revised Draft


  • Considerations in Demonstrating Interchangeability With a Reference Product
  • Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity


  • Guidance for clinical Investigators and Sponsors Natural History Studies for Rare Disease Drug Development
  • Pediatric Oncology Product Development; Revised Draft
  • Rare Diseases: Drug Development Safety Data Considerations

Clinical Pharmacology:

  • Clinical Drug Interactions Studies: Study, Design, Data Analysis, Implications for Dosing and Labeling Recommendations, Revised Draft
  • Clinical Lactation Trials – Trial Design, Data Analysis and Recommendations for Labeling; Revised Draft
  • Exposure-Response Relationships – Study Design, Data Analysis, and Regulatory Applications; Revised Draft
  • Population Pharmacokinetics; Revised Draft


  • Adaptive Design Clinical Trials for Drugs and Biologics; Revised Draft
  • Meta-Analysis of Randomized Controlled Clinical Trials to Evaluate the Safety of Human Drugs or Biologic Products

Drug Safety:

  • Format and Content of a REMS Document, Revised Draft
  • Postmarketing Safety Reporting for Human Drugs and Biological Products Including Vaccines, Revised Draft

Electronic Submissions:

  • Standardized Format for Electronic Submissions of NDA and BLA Content and Planning and Conduct of Bioresearch Monitoring Inspections for Submissions to CDER
  • Providing Regulatory Submissions in Electronic Format – Submission of Manufacturing Establishment Information
  • Providing Regulatory Submissions in Electronic Format – Bioanalytical Methods Data Standards
  • Providing Regulatory Submissions in Electronic Format – Standardized Bioanalytical Data


  • 180-Day Exclusivity: Questions and Answers
  • ANDA Submissions – Amendments to Abbreviated New Drug Applications Under GDUFA
  • ANDA Submissions – Content and Format of Abbreviated New Drug Applications; Revised Draft
  • ANDA Submissions Refuse to Receive Standards: Questions and Answers
  • Controlled Correspondence Related to Generic Drug Development; Revised Draft
  • Changes That May Be Included in a Single Prior Approval Supplement for an ANDA
  • Determining Whether To Submit an Application Under 505(b)(2) or 505(j)
  • Issuance of ANDA Complete Response Letters Before Completion of Review by One or More Disciplines
  • Meetings With Applicants of Complex Generic Drug Products
  • Pre Submission Facility Correspondence for Priority ANDAs in GDUFA II
  • Three-Year Exclusivity Determinations for Drug Products
  • Variations in Drug Products (ANDAs) Guidance


  • Drug Abuse and Dependence Section of Labeling for Human Prescription Drug and Biological Products – Content and Format
  • Indications and Usage Section of Labeling for Human Prescription Drugs and Biological Products – Content and Format

Pharmaceutical Quality/CMC:

  • GDUFA II Priority ANDA Pre-Submission Communications
  • Harmonizing Compendial Standards with Drug Application CMC Approval Requirements Using the USP Pending Monograph Process

Pharmaceutical Quality/Manufacturing Standards (CGMP):

  • Current Good Manufacturing Practice for Medical Gases; Revised Draft
  • Expiration Dating of Unit-Dose Repackaged Solid Oral Dosage Form Drug Products; Revised Draft


  • Annual Reporting by Prescription Drug Wholesale Distributors and Third-Party Logistics Providers: Questions and Answers
  • Civil Monetary Penalties for Failure to Meet Accelerated Post marketing Requirements
  • Compliance Policy Guide: Marketed Unapproved Drugs Section 440.100; Revised Draft
  • Content of Human Factors Submissions for Evaluation
  • Designated Delivery Services for 505(b)(2) or ANDA Applicants Sending Notices of Paragraph IV Patent Certification
  • Enforcement Policy Regarding Ingredients Nominated for Inclusion on the Bulk Drug Substances List Pursuant to Section 503B
  • Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products
  • National Drug Code (NDC) Assignment of CDER-Regulated Products
  • Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations; Revised Draft
  • Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Regulatory Considerations; Revised Draft
  • Public Disclosure of FDA-Sponsored Studies
  • Refuse to File: NDA and BLA Submissions
  • REMS Assessment: Planning and Reporting
  • Standardization of Data and Documentation Practices for Product Tracing
  • Survey Methodologies to Assess Risk Evaluation and Mitigation Strategies (REMS) Goal Related to Knowledge
  • Use of a Drug Master File for Shared System Risk Evaluation and Mitigation Strategies (REMS)
  • Verification Systems Under the Drug Supply Chain Security Act for Certain Prescription Drugs

User Fees:

  • User Fee Waivers, Reductions, and Refunds for Drug and Biological Products
  • Fees Incurred Under the Drug Supply Chain Security Act

Access Problems Persist with Open Payments…


With less than two days left to submit and attest to data for the June 30, 2017, publication, manufacturers and group purchasing organizations (GPOs) continued to have problems with the CMS Open Payments Portal. (Today is the deadline – we received notice that the site was down late Wednesday night).

Seen below is a screenshot we were sent from one of our sources, which notes that the “CMS Enterprise Portal is currently not available due to an outage. We apologize for any inconvenience. Please try back later.”


CMS has sent several “reminder” emails this week about the upcoming deadline, but nothing about the consistent problems we have heard from several sources. CMS helpfully reminds applicable manufacturers and applicable GPOs that they can “complete the data submission and attestation activities by logging into the Open Payments system through the EIDM Portal, but leaves off any information for help other than “Contact the Help Desk.”

Our question to CMS is, how do they expect companies to fully comply with these onerous requirements when they cannot even get the site up and running well enough for manufacturers and GPOs to input their information in the most efficient way possible?

March 30, 2017

Bristol-Myers Squibb Settles Off-Label Promotion Case for $19.5 Million


Late last year, Bristol-Myers Squibb (BMS) settled with the government to resolve allegations that spanned several states that it improperly promoted a schizophrenia treatment for uses not approved by the United States Food and Drug Administration (FDA).

The agreement, with a whopping forty-two states (including California, New York, and Texas) and the District of Columbia, focuses on charges that BMS promoted Abilify (an anti-psychotic drug) for use in children and elderly patients with dementia and Alzheimer’s disease. The FDA approved Abilify in 2002 for treating schizophrenic adults. Since then, it has since approved various forms of the drug for other uses. When the alleged improper marketing occurred, such uses were not approved by the FDA. In 2006, Abilify received a “black box” warning stating that it could increase the risk of death for dementia patients.

The states further alleged that BMS misrepresented risks that the drug posed to patients, such as weight gain and metabolic side effects, violating consumer protection laws.

The agreement prohibits BMS from promoting Abilify for off-label use, making false or misleading claims about it, paying health care providers for merely attending a promotional event for the drug, using medical education grants to promote the drug and rewarding health care providers with grants based on prescribing habits, among other restrictions.

“Drug companies should not market their drug for off-label uses or make claims that are not supported by scientific evidence,” New York Attorney General Eric T. Schneiderman said.  “Consumers must be able to rely on their doctor’s advice for medication without having to worry about drug companies manipulating their advertising to promote their products at the expense of patients.” 

“We allege that Bristol-Myers Squibb improperly marketed this drug to encourage prescriptions to children and seniors and misled the public about its safety for those populations,” said Massachusetts Attorney General Maura Healey. “Companies cannot use deceptive practices and unfair marketing to increase their sales at the expense of patients’ health and well-being.”

The settlement allows each state to receive hundreds of thousands of dollars, with some getting over $1 million. For example, New York will receive $788,774, Texas will rake in $1 million from the settlement and California will come away with $1.3 million. The only eight states that were not part of the settlement, and therefore will receive no part of the settlement funds, were Alaska, Idaho, Mississippi, New Mexico, South Carolina, Utah, Virginia, and Wyoming.

The settlement will finally lay to rest over a decade of allegations about Abilify marketing. In 2015, a United States judge tossed federal court claims that BMS and its Abilify partner, Otsuka, paid kickbacks to boost prescriptions of the drug. Similar to this state settlement, that whistleblower suit cited promotions to pediatric psychiatrists as evidence of off-label marketing. At the time, the judge allowed the whistleblowers to pursue claims that BMS fired them to retaliate for their off-label accusations.

This settlement follows a 2007 settlement at the federal level, where the company agreed to pay $515 million to settle an off-label investigation involving Abilify, along with other drugs.

BMS notes that it has not marketed the drug since 2013 and did not admit to any wrongdoing and denied all allegations against it. 


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