Life Science Compliance Update

April 11, 2017

Senate Holds Confirmation Hearing on Gottlieb

Scott Gottlieb MD WWSG Hi-Res Photo

On April 5, 2017, the Senate Health, Education, Labor, and Pensions (HELP) Committee held a confirmation hearing on the nomination of Scott Gottlieb, M.D. to serve as Commissioner of the Food and Drug Administration (FDA). Members of the committee engaged Dr. Gottlieb on the agency’s role in addressing opioid abuse. Chairman Lamar Alexander of Tennessee said the Committee would vote on Dr. Gottlieb’s confirmation after the Easter recess.

During opening statements, Chairman Alexander called for quickly moving FDA user fee reauthorizations before Aug. 1. He said he is concerned with the Administration’s hiring freeze and its implications for the FDA, especially because the 21st Century Cures Act sought to bolster FDA staffing resources.

Ranking Member Patty Murray called for strong, independent leadership of the FDA and said Dr. Gottlieb has “unprecedented financial entanglement with industry.” She said she is concerned about potential ideologically driven decision-making, citing Bush Administration policy on women’s access to Plan B. She said she wants to hear Dr. Gottlieb’s plans for increasing competition through generics and biosimilars and reducing drug costs.

In his testimony, Dr. Gottlieb noted that he appreciates the agency’s work as both a doctor and a cancer survivor. He emphasized that he respects congressional intent and expressed desire to: assure timely implementation of laws, adhere to scientific rigor, and heed guidance from career staff. He said the agency must “lean forward” in implementing 21st Century Cures and that it is a “false dichotomy that everything is a balance between speed and safety,” adding that both are possible while adhering to “gold-standard regulatory conduct.”

Question and Answer Period

The question and answer period of the hearing was extensive, with conversation about many hot topics, including the hiring freeze, opioids, and conflicts of interest.

Hiring Freeze

In discussion with Chairman Alexander, Dr. Gottlieb said he understands how critical FDA personnel levels are and that it is “incumbent on us to have a world-class workforce.” Dr. Gottlieb said he has spoken out on staffing levels and will make it a priority. Chairman Alexander said he wants to make 21st Century Cures “a reality and [staffing and hiring] is an important part of it.”


Opioid abuse was by far the most frequently raised and discussed issue of the hearing. Chairman Alexander asked about non-addictive painkillers, noting such options might be able to stem opioid abuse. Dr. Gottlieb said the epidemic has “staggering consequences” and will require an “all-of-the-above” approach, including “dramatic action.” He said that includes new alternatives, including device-based interventions and medication-assisted therapy (MAT).

Senator Tim Kaine discussed opioids with Dr. Gottlieb when Dr. Gottlieb said he would have a “bipartisan mandate” on finding the right framework for opioid policies and that opioids would be his “highest immediate priority.”

Conflicts of Interest

Dr. Gottlieb said he had thoroughly complied with Office of Government Ethics procedures and was committed to a “front office” process to mediating any ongoing concerns, including recusals. Senator Murray and other Democrats expressed numerous concerns about Dr. Gottlieb’s role in venture capital and as a board member and investor in various industry entities. Dr. Gottlieb said he is committed to earning the public’s trust.

Dr. Gottlieb has filed an ethics agreement stating that he will recuse himself for one year from any agency decisions that involve more than twenty health companies he has been connected to.


Senator Mike Enzi asked Dr. Gottlieb about the status of approval of biosimilars. Dr. Gottlieb said there is an opportunity for “meaningful savings,” including through interchangeability. He expressed a need to get final interchangeability guidance out.

Competition and Reimportation

Senator Bernie Sanders asked about Dr. Gottlieb’s position on reimportation of drugs from Canada and cited Dr. Gottlieb’s writings on the approach not addressing “core challenges.” Dr. Gottlieb said he has other ideas on how to promote competition and that many of his articles may address subjects falling outside the FDA’s purview.

Trial Design

Responding to Senator Tim Scott, Dr. Gottlieb said he would encourage the use of better tools for getting products to market quickly. He pointed to Cures as a template, including “not just adaptive trial designs but modeling and simulation.” Senator Elizabeth Warren discussed the example of Thalidomide as illustrating the risks of prioritizing treatment over consumer protection. She questioned Dr. Gottlieb about his views on this balance and her concerns.

Senator Bob Casey asked about the role of Phase III trial data, saying Dr. Gottlieb had been critical of reliance on such results. Senator Casey said some safety issues arise only at that juncture. Dr. Gottlieb said it may be possible to compress Phase II and III into a larger adaptive design. He said a “proper clinical program is an essential feature and proper post-market enforcement tools are important.”

Industry Oversight

Senator Tammy Baldwin expressed concern with drug industry attempts to extend market exclusivity and engage in “misleading” direct-to-consumer advertising. Dr. Gottlieb said the FDA is designed to promote public health and not to engage in commercial disputes. He said he wants a “framework that prevents regulatory process’ use as commercial arbitrage.”


As noted above, the vote on whether to confirm Dr. Gottlieb won’t happen until the Senate gets back from Easter recess. However, Gottlieb has been endorsed by the National Consumers League, the National Coalition for Cancer Survivorship (he is a survivor of Hodgkin’s Lymphoma), the Global Healthy Living Foundation, the Alliance for Aging Research and by former FDA Commissioners Margaret Hamburg, Robert Califf, and Mark McClellan. It is likely that he will also be approved by the Senate to run the FDA, though it is likely that his appointment will fall along party lines in highly-partisan Washington, D.C.

April 05, 2017

OPDP Picks Up Steam on Enforcement Letters


After a fairly slow 2016, the United States Food and Drug Administration’s (FDA) Office of Prescription Drug Promotion (OPDP) issued a quick burst of letters in the span of nine days in December. This flurry of activity more than doubled the enforcement letters that had been issued up to that point in the year.

Although there was an apparent increase in enforcement activity in December (perhaps related to the new Administration and the mark the old Administration wanted to leave on the industry), the type of activity and the nature of Draft Guidances issued in 2017 prior to the Trump Administration taking office indicated a dramatic shift in OPDP’s approach from years past. After losing battle after battle in First Amendment cases, OPDP seems to be using more discretion when it comes to enforcement letters, focusing instead on omission and minimization of risk, as well as pre-approval promotion.

The FDA’s First Amendment case losses tended to focus on issues relating to information disseminated about FDA-approved or FDA-cleared prescription products, not addressing communications about investigational products for which there were no approvals or clearances.

Of the 11 letters issued in 2016, four dealt with pre-approval promotion. Given that only four of the 70 total letters issued by OPDP between 2012 and 2015 dealt with pre-approval promotion, this dramatic increase signals a potential sign of things to come in terms of OPDP’s future enforcement activities. 

With regard to already marketed products, there were no letters issued in 2016 dealing solely with efficacy claims. The few letters that addressed efficacy did so briefly, with a focus, primarily, on the communication of risk information. The Draft Guidances issued in early January 2017 also reflect this approach - indicating flexibility in FDA’s traditional “substantial evidence” standard to substantiate certain product claims.  

Celgene Corporation

Celgene, the manufacturer of OTEZLA, received an untitled letter for making “false or misleading representations about the risks associated with Otezla” in a TV ad.

As noted in the letter,

According to the FDA-approved product labeling (PI), Otezla is indicated the treatment of adult patients with active psoriatic arthritis. Otezla is also indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Otezla is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation. Otezla is associated with serious risks. The PI contains warnings and precautions regarding depression, weight decrease and drug interactions. The most common adverse reactions associated with Otezla are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache.

OPDP felt as though some of the visuals presented in the commercial (“compelling and attention-grabbing visuals and SUPERs”) compete for the consumers’ attention, therefore making it “difficult for consumers to adequately process and comprehend the risk information. The overall effect undermines the communication of the important risk information and thereby misleadingly minimizes the risks associated with the use of Otezla.

Sanofi-aventis US

Sanofi-aventis US is the manufacturer of TOUJEO, an insulin injection. OPDP issued an untitled letter to the company for a TV ad that “makes false or misleading representations about the risks associated with Toujeo.”

According to the letter, OPDP took issue with the fact that

[t]he TV ad communicates the “major statement” of serious risks through the audio and onscreen SUPERS. At the same time, the TV ad presents fast-paced visuals that feature a man continuously dancing to music from the song “Let’s Groove” throughout multiple scene changes. Specifically, the man dances while cooking, working in an office, mowing his lawn, picking tomatoes with his children, and walking his dog. The presentation of these compelling and attention-grabbing visuals, all of which are unrelated to the risk message presented in the audio and on-screen SUPERS, in addition to the frequent scene changes and the other competing modalities such as the background music, compete for the consumers’ attention. As a result, it is difficult for consumers to adequately process and comprehend the risk information. The overall effect undermines the communication of the important risk information and thereby misleadingly minimizes the risks associated with the use of Toujeo. The presentation in the video is especially problematic from a public health perspective given the serious and potentially life-threatening risks associated with the drug.

United-Guardian, Inc.

United-Guardian is the manufacturer of RENACIDIN, irrigation solution. The manufacturer submitted a professional email under cover of Form FDA 2253, however, the email makes “false or misleading claims and/or representations with regard to the risks and benefits associated with Renacidin.”

As noted in the warning letter,

According to the FDA-approved product labeling (PI), Renacidin is indicated for dissolution of bladder calculi of the struvite or apatite variety by local intermittent irrigation through a urethral catheter or cystostomy tube as an alternative or adjunct to surgical procedures. Renacidin is also indicated for use as an intermittent irrigating solution to prevent encrustations of indwelling urethral catheters and cystostomy tubes.

The e-mail includes the following claims regarding benefits of Renacidin:

  • “Simplifies long-term catheter care”
  • “Easy 30 mL dosing and delivery”

No references are cited to support these general claims that Renacidin simplifies long-term care of in-dwelling catheters or is easy to use, and we are not aware of supporting evidence. In addition, the unsupported and thus misleading assertion that Renacidin has “Easy 30 ml dosing and delivery” is exacerbated by the failure of the e-mail to reveal specific information from the approved physician labeling about how the drug should be dosed and administered. Specifically, the DOSAGE AND ADMINISTRATION section of the PI states, “Instill 30 mL (one container) of Renacidin into the urethral catheter or cystostomy tube. Clamp the urethral catheter or cystostomy tube for 10 minutes. Remove the clamp and drain the bladder. Repeat the instillation procedure 3 times a day” (emphasis added). This omission of material information further exacerbates the misleading characterization of dosing and delivery in the e-mail.

Spriaso, LLC

Spriaso is the manufacturer of TUXARIN ER, indicated for the relief of cough and symptoms associated with upper respiratory allergies or a common cold in adults 18 years of age and older. Spriaso created a webpage, “Product Pipeline: Tuxarin ER” that OPDP determined made “false or misleading claims and/or representations about the risks associated with Tuxarin ER, and inadequately communicates the full indication for the drug.” As such, in December 2016, OPDP sent Spriaso a warning letter, asking the company to immediately cease misbranding Tuxarin and submit a written response, complete with a comprehensive plan of action.

According to the letter,

Tuxarin ER contains codeine phosphate, an opiate agonist antitussive. This product is associated with a number of serious risks. The PI for the drug contains a boxed warning regarding respiratory depression and death which have occurred in children who received codeine following tonsillectomy and/or adenoidectomy. Tuxarin ER is contraindicated in postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy, and in patients with known hypersensitivity to codeine, chlorpheniramine, or any of the product’s components. The PI also contains warnings and precautions regarding death related to ultra-rapid metabolism of codeine to morphine, respiratory depression, drug dependence, head injury and increased intracranial pressure, activities requiring mental alertness, obstructive bowel disease, acute abdominal conditions, and use in special risk populations. In addition, the PI indicates that common adverse reactions associated with Tuxarin ER include nausea and vomiting, constipation, abdominal distension, abdominal pain, blurred vision, diplopia, visual disturbances, confusion, dizziness, depression, drowsiness, sedation, headache, euphoria, facial dyskinesia, feeling faint, lightheadedness, general feeling of discomfort or illness, excitability, nervousness, agitation, restlessness, somnolence, insomnia, dyskinesia, irritability, and tremor.

The webpage makes representations and/or suggestions about Tuxarin ER such as the following:

  • “First Long Acting Tablet, Schedule III, Codeine Antitussive Combination with Chlorpheniramine Antihistamine”
  • “No spills or taste issues”

However, the webpage fails to communicate any risk information about the product. By omitting the risks associated with Tuxarin ER, including serious and potentially fatal risks, the webpage fails to provide material information about the consequences that may result from the use of the drug and creates a misleading impression about the drug’s safety.

Furthermore, the webpage contains the following claims:

  • “Minimize serious risk of over dosing”
  • “Issues with Hydrocodone and Chlorpheniramine commercial products
    • Current market is dominated by liquids prone to serious risk of dosing errors.”
  • “Issues with Promethazine (antihistamine) plus Codeine commercial products.
    • Current market is dominated by short acting liquids that are prone to dosing errors.
    • FDA requires boxed warning added to all promethazine containing products
    • Unlike promethazine no known serious safety issues with Chlorpheniramine”

These claims are misleading because they suggest that Tuxarin ER is safer than its competitors based on differences in dosage formulations and the safety profiles of individual ingredients. No references were cited in support of these claims and we are not aware of evidence to support the suggestion that Tuxarin ER is safer than its competitors because of its tablet formulation or because it is not associated with “dosing errors” or “serious safety issues.” On the contrary, according to the WARNINGS AND PRECAUTIONS section of the PI for Tuxarin ER, overdose of codeine has been associated with fatal respiratory depression. This section of the Tuxarin ER PI also discusses several serious safety issues such as the risk of death related to ultra-rapid metabolism of codeine to morphine, dose-related respiratory depression, and drug dependence. Furthermore, similar to the products containing promethazine referred to in the claims above, the PI for Tuxarin ER also contains a boxed warning as discussed in the Background section above. Comparing the safety profile of a single ingredient in a combination product to another single ingredient in a competitor combination product (i.e., promethazine versus chlorpheniramine) is misleading as it fails to take into consideration the overall safety profile of the entire combination product.

Such statements raise considerable public health concerns and are particularly alarming with respect to an opiate agonist product, as these controlled substances can lead to overdose, dependence, abuse, and death.

Zydus Discovery DMCC

OPDP sent an untitled letter to Zydus Discovery, the manufacturer of Saroglitazar, an investigational drug for which there is no marketing authorization in the United States. However, according to the letter, Zydus has published a video on YouTube suggesting that Saroglitazar is safe and effective for the purposes for which it is being investigated or otherwise promotes the drug.

According to the letter,

These claims and presentations promote an investigational new drug by suggesting that Saroglitazar is safe and effective for the treatment of patients with diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes. For example, the claims and presentations, which refer to Saroglitazar by the proprietary name, “Lipaglyn”, make conclusions that the drug is “indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes mellitus,” is “superior” to other molecules, and is not associated with many serious risks that are generally attributed to these other molecules with similar mechanisms of action, when Saroglitazar has not been proven to be safe and effective within the meaning of the FD&C Act and has not been approved as a drug under that authority for any use. Although we acknowledge that Saroglitazar is approved for use in another country, the claims and presentations, including the broad statements regarding the drug’s approval as the “world’s first,” furthermore are misleading, suggesting that the drug is approved throughout the world, including in the United States, when that is not the case. The video does not include any specific information regarding Saroglitazar’s approval status in the world or any information to indicate that Saroglitazar is an investigational new drug that has not been approved for commercial distribution in the United States.

Chiasma, Inc.

Chiasma is the manufacturer of octreotide capsules, an investigational new drug. This is another case of a YouTube video suggesting that the investigational drug is safe and effective for the purpose for which it is being investigated, or otherwise promotes the drug. There is no marketing authorization in the United States.

According to the untitled letter, there are several claims that make

numerous positive and conclusory statements about the safety and effectiveness of octreotide capsules, such as suggesting that “the drug is safe” and “the effectiveness of the drug was proven in the clinical trials.” Thus, these claims suggest in a promotional context that octreotide capsules, an investigational new drug, is safe or effective for such uses, when FDA has not approved octreotide capsules for any use. We acknowledge that the statement “Product is an investigational new drug and not available for commercial distribution,” is included as a SUPER on the screen for eight seconds at the end of the video. However, there is no disclaimer that would sufficiently mitigate the extensive claims and presentations throughout the majority of this video that suggest in a promotional context that octreotide capsules, an investigational new drug, is safe or effective for such uses, when FDA has not approved octreotide capsules for any use.

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


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