Life Science Compliance Update

February 05, 2018

FDA Releases Guidance on IND Sponsors


In December, the FDA issued a guidance describing best practices and procedures for timely, transparent, and effective communications between investigational new drug application (IND) sponsors and FDA at critical junctures in drug development, which may facilitate earlier availability of safe and effective drugs. The guidance applies to communications between IND sponsors and FDA during the IND phase of drug development, including biosimilar biological product development (BPD).


Communications between FDA and industry are often opportunities to share information on clinical trials and for the agency to provide advice on trial design, dose selection, nonclinical study requirements, and manufacturing and facility issues. It is important that agency-industry interactions “be conducted efficiently and consistently, with clear, concise, and timely communication,” FDA says in announcing the guidance.

Pre-IND Meetings

Pre-IND meetings, which can prevent clinical hold issues, can be valuable for understanding proof of concept and initiating dialogue with the agency as the company develops a complete IND submission.

“FDA encourages sponsors to request a pre-IND meeting for the following: a drug not previously approved/licensed, a new molecular entity (NME), a planned marketing application intended to be submitted under the 505(b)(2) regulatory pathway, drugs for which it is critical to public health to have an effective and efficient drug development plan (e.g., counter-terrorism), drugs with substantial early development outside the United States, a planned human factors development program, and drugs with adequate and well-controlled trials to support a new indication,” FDA says.

FDA further says it “encourages sponsors to request pre-NDA/BLA meetings for all planned marketing applications, particularly applications to be reviewed under the PDUFA V Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs.”

Interaction with FDA

The review division regulatory project manager (RPM), who has comprehensive knowledge of the drug and its regulatory history, is the primary point of contact for communications between IND sponsors and FDA during the life cycle of drug development. The RPM is the contact for facilitating the timely resolution of technical, scientific, and regulatory questions, conflicts, or communication challenges between the sponsor and the review team, FDA says.

Other project managers can include:

  • CDER’s Office of Pharmaceutical Quality regulatory business project managers, who manage meeting requests, regulatory submissions, and other inquiries related to chemistry, manufacturing, and controls, including facility and product quality issues;
  • CDER’s Office of Surveillance and Epidemiology safety regulatory project managers, who manage sponsor requests for proprietary name review; and
  • CDER’s Formal Dispute Resolution Project Manager, who manages sponsor requests for resolving scientific and/or medical disputes that cannot be resolved at the division level.

Types of Advice

During the life cycle of drug development, sponsors routinely solicit feedback from FDA on both scientific and regulatory issues. The breadth and frequency of advice sought can vary according to the experience of the sponsor, as well as the novelty and development stage of the proposed drug. During the IND phase of drug development, sponsors often solicit advice at critical junctures in their development programs. These topics include, but are not limited to the following:

  • Regulatory (e.g., plans for submission of proprietary name requests, plans to defer or waive specific studies, development plans with other FDA centers (e.g., the Center for Devices and Radiological Health) for combination products), applicability of an expedited program;
  • Clinical/statistical (e.g., planned clinical trials to support effectiveness, validity of outcomes and endpoints, trial size, enrichment designs);
  • Safety (e.g., safety issues identified in nonclinical studies and early clinical trials, size of the overall safety database, concerns related to particular populations, post-approval pharmacovigilance plans, risk evaluation and mitigation strategies, plans for human factors studies, issues related to evaluation of abuse potential);
  • Clinical pharmacology and pharmacokinetics (e.g., dose selection, use in specific populations, drug-drug interactions);
  • Nonclinical pharmacology, pharmacokinetics, and toxicology (e.g., genetic toxicology, reproductive and developmental toxicology, carcinogenicity, mechanism of action); and
  • Product quality (e.g., proposed shelf life and stability studies, delivery systems, characterization of drug substance/product, facility compliance with good manufacturing practices, comparability of lots used in clinical trials and commercial lots); and
  • The proposed pediatric development plan and dosing.

Complex questions that involve interpretation of regulations and statutes, or the application of existing FDA policy to novel circumstances, can demand additional vetting and response time, FDA says.

More on Communication

FDA notes that the guidance does not apply to communications or inquiries from industry trade organizations, consumer or patient advocacy organizations, other government agencies or other stakeholders not pursuing an IND development program.

Regarding companies that fail to respond, FDA notes that later drug development can be negatively affected by sponsors’ delay or failure to respond to FDA, though the timing of FDA’s response may also be negatively affected if the review team experiences “an unexpected shift in work priorities or team staffing. In these cases, the FDA project manager will try to keep sponsors apprised of changes to the estimated response timeline.”

Regarding delays in obtaining FDA response, FDA advises the sponsor to contact:

  • The appropriate FDA project manager, typically the review division RPM, for a status update after the expected amount of time (e.g., the timelines described in a MAPP) for a FDA response that has passed;
  • The appropriate FDA project manager, typically the review division RPM, for a status update after the estimated response time has passed (i.e., the estimated FDA-response date communicated to the sponsor previously);
  • The appropriate FDA project manager’s next level supervisor for assistance in eliciting a response from the project manager; and
  • The appropriate division or office management officials for assistance in eliciting a response from the project manager; or
  • CDER’s or CBER’s Ombudsman for assistance in eliciting a response from the project manager.

December 18, 2017

FDA Issues Two Federal Register Notices on Prescription Drug Promotion


On December 11, 2017, the United States Food and Drug Administration (FDA) published two Federal Register notices regarding prescription drug promotion from the FDA’s Center for Drug Evaluation and Research (CDER) Office of Prescription Drug Promotion (OPDP).

Final Guidance on Promotional Labeling

The first notice announces the FDA’s Final Guidance on product name placement, size, prominence, and frequency in promotional labeling and advertisement for prescription drugs (human and animal), including prescription biological products. The FDA believes that the disclosure of the product name in promotional materials is important for the proper identification of the products to help ensure they are used safely and effectively.

The recommendations in this guidance relate to product names in traditional print media promotional labeling and advertisements such as journal ads, detail aids, brochures; audiovisual promotional labeling, such as videos shown in a health care provider’s office; broadcast advertisements (e.g., television advertisements, radio advertisements); and electronic and computer-based promotions such as internet, social media, emails, CD-ROMs, DVDs). In this guidance, FDA further clarifies issues relating to the direct conjunction of the proprietary and established names, as well as the frequency of use of the established name on printed pages or spreads, in running text or columns, in the audio portion of audiovisual promotions, and in electronic media.

FDA recommends that the established name be placed either directly to the right of or directly below the proprietary name. FDA also recommends that the proprietary name and the established name not be separated by placement of intervening matter that would in any way de-emphasize the established name of the product or obscure the relationship between the proprietary name and the established name.

When it comes to the prominence of the proprietary and established names of a product with one active ingredient, the regulations require that “the established name shall have a prominence commensurate with the prominence with which such proprietary name or designation appears, considering all pertinent factors, including typography, layout, contrast, and other printing features.” Generally, FDA considers all methods used to achieve prominence in promotional labeling or advertisements when evaluating whether the established name is presented with a prominence commensurate with that of the proprietary name.

Additional regulations and guidance can be found in the document, including recommendations for products with two or more active ingredients.

FDA’s Proposed Project on Deceptive Presentations

The second notice is related to an FDA proposal to study the ability of consumers and healthcare professionals to spot and report deceptive prescription drug promotion practices. The ability to spot deceptive prescription drug promotion in the marketplace has important public health implications. Patients may use information from drug promotions, such as information about a product’s efficacy and risks, when exploring treatment options and making treatment choices. Likewise, health care professionals may consider information from promotional materials when making prescribing decisions. In cases where such information is false or misleading, consumers may ask for and health care professionals may prescribe specific drugs that they would not otherwise request or prescribe, respectively.

The studies will be conducted concurrently and will focus on different health conditions. Each study will be administered to two separate populations (i.e., HCPs and consumers affected by the condition). HCPs will view mock pharmaceutical websites targeted toward physicians and consumers will view mock consumer-targeted pharmaceutical websites. The goal will be to keep the HCP and consumer-targeted websites as similar as possible, but to include content that is appropriate for the target audience. For example, HCP websites may contain medical terminology, whereas the consumer websites would utilize consumer friendly language. A professional firm will create all mock websites such that they are generally indistinguishable from currently available prescription drug websites.

Study 1 will sample consumers who self-report chronic pain that has lasted at least 3 months and HCPs whose primary medical specialty is either primary care or internal medicine and whose responsibilities involve direct patient care at least 50 percent of the time. Study 2 will sample consumers who self-report obesity, defined as body mass index greater than or equal to 30 and include the same types of HCPs as study 1.

Once completed, the proposed studies will provide data on whether consumers and health care professionals can identify claims as false or misleading, and whether they would be willing to report deceptive drug promotion to the FDA. Although both studies will assess consumers and health care professionals, the first study will focus on the degree of deception in an ad while the second study will focus on implied versus explicitly deceptive claims.

Any comments should be faxed to the Office of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, Fax: 202-395-7285, or emailed to All comments should be identified with the OMB control number 0910-New and title “Consumer and Healthcare Professional Identification of and Responses to Deceptive Prescription Drug Promotion.” Also include the FDA docket number: FDA-2016-N-4487.

December 13, 2017

FDA Issues Guidance on Real-World Evidence for Medical Devices


Earlier this year, the United States Food and Drug Administration (FDA) finalized guidance on the use of real world evidence to support regulatory decision-making for medical devices. The final guidance follows a July 2016 draft guidance on the topic in which the FDA discussed potential uses of real world data and the various factors evaluated to determine whether that data can support a regulatory decision. The FDA believes that this guidance is a “cornerstone” of its strategic priority to build a national evaluation system for health technology.

The final guidance includes clarity as to what it means for companies moving forward, “While FDA encourages the use of relevant and reliable real-world data, this guidance neither mandates its use nor restricts other means of providing evidence to support regulatory decision-making.”

In the final guidance, FDA recognizes that “traditional” clinical trials may sometimes be impractical or overly challenging, and appropriate real world data can sometimes provide comparable information. While clinical trials are controlled and require monitoring and data auditing, they may be narrow in scope. Real world data may be able to generate information on a broader patient population, but studies must be carefully designed, regardless of whether the real world data has already been collected or will be collected in the future. Protocols and analysis plans for real world data “should address the same elements that a traditional clinical trial protocol and statistical analysis plan would cover.”

The final guidance also notes that due to the “rapidly advancing methodology for generating and interpreting real world data, this guidance will not elaborate on the methodological approaches that can be used.”

The FDA believes that real world data drawn from clinical practice settings can provide greater insight into the benefits and risks of medical devices, including how they’re used by health care providers and patients, and how they perform under the conditions of routine medical practice. The guidance does not change the evidentiary standards that are required to make those decisions.

Given the expansion in the availability and use of health data derived from registries, billing claims, and electronic health records, the FDA is taking these steps in hopes of clearly describing the appropriate characteristics of real world evidence that meet the agency's standards of evidence to support regulatory decisions.

To assess reliability of data, the FDA is primarily concerned with how the data were collected (data accrual), and whether there were people and processes in place to provide “adequate assurance” that the data quality and integrity are sufficient. The real world data source should have an operational manual (or similar document) in place specifying the methods and extent of data collection and aggregation. FDA provides a list of factors that it will consider the when assessing data accrual, many of which are also considerations for any clinical trial.

Several weeks after the release of the guidance, FDA Commissioner Scott Gottlieb stated that the agency will need to work with the healthcare system to change the way clinical information is collected.

"We need to close the evidence gap between the information we use to make FDA's decisions and the evidence increasingly used by the medical community, by payers, and by others charged with making healthcare decisions," Gottlieb told attendees of the National Academy of Sciences' workshop on the impact of real world evidence on medical product development.

While noting the current uncertainty among sponsors on the role real world evidence plays in regulatory decision making, Gottlieb said FDA needs to think of itself as an information curator, rather than an arbiter of information, "where a single truth standard is secured to a fixed orthodoxy."

Rachel Sherman, principal deputy commissioner at FDA, added later in the day, "We want a better evidence base to make product approval decisions" and she noted that more guidance will be forthcoming on real world evidence and real world data. "The goal is not to define real world evidence and real world data but to get better information and in a more sensible way," she added.

For more information, we encourage you to read the final guidance and access the FDA webinar on the topic here.


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