On February 15, 2019, the U.S. Food and Drug Administration (“FDA”) finalized two guidance documents regarding regenerative medicine therapies (see FDA’s announcement here). This development comes nearly 14 months after FDA issued both guidance documents in draft form, which also coincided with FDA’s announcement of a new comprehensive regenerative medicine policy framework intended to spur innovation and efficient access to new regenerative medicine products.

FDA Commissioner Scott Gottlieb remarked that the finalization of regenerative therapy guidance documents “demonstrate[s] [FDA’s] continued commitment” to fulfilling the promise of providing a clear and predictable pathway to approval. Moreover, he noted that these guidance documents help stakeholders to “understand our regulatory framework” and, in turn, “may help to more efficiently advance access to safe and effective regenerative medicine therapies.” These guidance documents, which are discussed in further detail below, provide information to product developers about FDA’s current thinking with respect to evaluating devices used with regenerative medicine advanced therapies and provide information on the expedited development programs that may be available.

Guidance for Industry: Evaluation of Devices Used with Regenerative Medicine

The final guidance entitled “Evaluation of Devices Used with Regenerative Medicine Advanced Therapies” (available here) clarifies how FDA will evaluate devices used in the recovery, isolation, or delivery of regenerative medicine advanced therapies (RMATs). This guidance finalizes FDA’s current thinking on how the agency will streamline and simplify its application of regulatory requirements for combination device and cell or tissue products.

In this guidance document, FDA acknowledges that a wide range of devices may be used in conjunction with an RMAT, ranging from simple, low-risk devices to complex, higher risk devices to devices that are constituent parts of an RMAT that is classified as a combination product. FDA reiterates that the primary factor in determining the availability of premarket pathways for a device is the device’s classification (i.e., Class I, Class II, or Class III), followed by the risks associated with the device type and the level of regulatory controls necessary to provide a reasonable assurance of safety and effectiveness.

In addition, FDA discusses the factors it will consider when determining whether a device may be labeled for use with a specific RMAT or class of RMATs. When determining which devices may be suitable for use with a specified RMAT or type of RMAT, FDA will consider the distinct biological and physical characteristics of RMATs, intended use, and conditions for use. With respect to cellular products that are RMATs, FDA intends to review the cellular products’ characteristics, their interaction with different devices, as well as any impact on cell viability, differentiation potential, activation state and ability to respond to stimuli after administration and other similar factors.

Substantively, there were no major or unexpected changes between the draft guidance and the final guidance issued by FDA.

Guidance for Industry: Expedited Programs for Regenerative Medicine Therapies for Serious Conditions

The second final guidance, “Expedited Programs for Regenerative Medicine Therapies for Serious Conditions” (available here), provides information regarding the use of accelerated approval pathways for regenerative medicine therapies that have been granted designation as an RMAT, as well as considerations in the clinical development of regenerative medicine therapies and opportunities for sponsors of such products.

This guidance makes clear that the following therapies could qualify for an RMAT designation: cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except those regulated solely under section 361 of the Public Health Service Act (42 U.S.C. 264) and 21 C.F.R. Part 1271. Notably, the final version of this guidance clarifies that “cell therapies” includes both allogeneic and autologous cell therapies, as well as xenogenic cell products. Products that qualify for an RMAT designation receive all of the benefits of the fast track and breakthrough therapy designation programs, including early interactions with FDA. Although sponsors may apply for and receive both breakthrough and RMAT designation for a product, FDA advised that each designation requires a separate application.

Factors that FDA may consider when determining whether the preliminary clinical evidence is sufficient to support RMAT designation include, but are not limited to, the rigor of data collection; the consistency and persuasiveness of outcomes; the number of subjects and sites contributing to the data; and the severity, rarity, or prevalence of the condition. Unlike the breakthrough therapy designation, RMAT designation does not require a sponsor to produce evidence indicating that the drug offers a substantial improvement over available therapies.

To apply for RMAT designation, a sponsor should submit either a new investigational new drug application (“IND”) or an IND amendment, along with a concise summary of information in support of the RMAT designation. The application should include a description of the investigational product; rationale for the investigational new drug meeting the definition of an RMAT; a discussion to support that the disease or condition the product is intended to treat is serious; and preliminary clinical evidence that the product has the potential to address the specified unmet medical need for the serious condition. The requirement to provide a description of the product is new to the final guidance.  No later than 60 calendar days after receipt of the designation request, FDA will notify the sponsor as to whether the regenerative medicine therapy has received the RMAT designation.

Finally, this guidance provides recommendations for clinical trial design. FDA states that it will consider clinical trials in support of a Biologics License Application (“BLA”) that “incorporate adaptive designs, enrichment strategies, or novel endpoints.” This final guidance provides new language indicating that historical controls and natural history data (the course a disease takes from its onset, through presymptomatic and clinical stages, to a final outcome in the absence of treatment) may be considered, if appropriate. Natural history data, however, may only provide the basis of a historical control if the “control and treatment populations are adequately matched, in terms of demographics, concurrent treatment, disease state, and other relevant factors.”

FDA’s continued focus on developing and finalizing guidance in the regenerative medicine space suggests that FDA is serious about helping industry to both navigate the application process in an effort to streamline the premarket approval process and to better understand and address identified regulatory pain points. For these reasons, sponsors of investigational regenerative therapies should pay close attention to and take into consideration the recommendations set forth in these final guidance documents.

On November 26, 2018, the U.S. Food and Drug Administration (“FDA”) announced the process for clearing most medical devices for marketing is being updated to incorporate changes the FDA laid out in an April draft guidance. For over forty years, most medical devices have entered the United States market through the 510(k) clearance process. The 510(k) process offers an expedited approval process available only for products that are substantially equivalent to products already on the market (known as predicate devices). The FDA is considering no longer allowing sponsors to rely on predicates older than ten years and making public information about cleared devices that relied on predicates more than ten years old. In addition, the FDA intends to finalize guidance establishing an alternative 510(k) pathway with different criteria that reflect current technological principles.

In a statement, FDA Commissioner Scott Gottlieb reasoned that newer products relying upon older predicates might not reflect new performance standards or latest scientific and medical understanding. Commissioner Gottlieb believes this change will promote the continual improvement of medical devices. However, the announced change received quick pushback. Many manufacturers argue that reliance upon older predicates can be necessary when no newer predicates are available, and older predicates can provide data that helps sponsors make new devices safer. In addition, many industry-observers believe the FDA’s plans may contradict and exceed its statutory authority, and therefore require additional support from Congress.

If the current proposal becomes law, the implications will include increased costs for manufacturers forced to innovate because of the inability to rely on older predicates. The agency’s statement indicates that new medical devices that utilize the 510(k) pathway should be better than predicates, rather than the applicable legal standard of substantial equivalence. Thus, manufacturers can anticipate increased agency scrutiny when submitting information in the 510(k) summaries. In addition, manufacturers may need to make alternative plans if developing a new device based on an older predicate.

On October 2, 2018, FDA Commissioner Scott Gottlieb released a statement announcing new agency actions to further deter “gaming” of the generic drug approval process through the use of citizen petitions.  Among these actions, the most significant was the issuance of a revised draft guidance on citizen petitions subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act (“FDCA”), published on the same day.  The stated goal of this revision was to create a more efficient approach to 505(q) petitions and to allow the Agency to focus reviewer resources on scientific reviews.

For years, FDA has been addressing allegations that companies have been using the citizen petition process to delay competitor approval, thereby “gaming” the system, while also balancing the value of individuals exercising their First Amendment rights through the citizen petition process.  In 2007, Section 505(q) was added to the FDCA through the FDA Amendments Act (“FDAAA”).  This new statutory provision provided that FDA shall not delay the approval of a pending abbreviated new drug application (“ANDA”) or 505(b)(2) application as a result of a citizen petition (pursuant to 21 CFR 10.30) or a petition for stay of action (pursuant to 21 CFR 10.35), unless the Agency determines that a delay is necessary to protect public health.  Section 505(q) also requires FDA to take final agency action on a petition “not later than 150 days after the date on which the petition is submitted.”  In 2014, FDA issued a guidance document describing the Agency’s interpretation of Section 505(q) and the process by which it determines whether the section applies to a particular petition.

The revised draft guidance document that was released last week includes much of the same information contained in the 2014 guidance.  However, it also includes substantially more detail and clarification on how the Agency makes a determination that a petition would delay an ANDA or 505(b)(2) application.  For example, the revised guidance states that one criterion in finding a delay is that the ANDA or 505(b)(2) applicant has less than 150 days left on a pending review.  The draft guidance also explains that FDA will apply a “but for” test in evaluating whether a delay is caused, essentially asking, “Would the application be ready for approval but for the issues raised by the petition?”

The revised draft guidance also provides a number of factors that FDA will consider in making a determination that a petition was filed with the primary purpose of delaying approval.  These include factors such as whether the petition was submitted close in time to the expiration of a patent or exclusivity period, or whether the petition raises the same or substantially similar issues as a prior petition to which FDA has already responded.  FDA will also consider whether the petitioner took an unreasonable amount of time in filing the petition based on when the relevant information relied upon in the petition became known (or should have become known).  A full list of the factors can be found on page 16 of the guidance.

If FDA makes the determination that a petition has been submitted with the primary purpose of delaying an application, it will then decide whether the petition can be summarily denied pursuant to Section 505(q)(1)(E).  In addition, if the Agency makes such a determination, it intends to refer the matter to the Federal Trade Commission and notify Congress in its annual report. Such an FDA determination could potentially have serious consequences as it may support causes of action related to unfair competition under the Federal Trade Commission Act, Lanham Act, and various state laws, which can carry substantial penalties.

On September 28, 2018, the U.S. Food and Drug Administration (FDA) released two draft guidances for industry. The purpose, according to FDA Commissioner Scott Gottlieb, M.D., is to modernize the approach to clinical trial design in efforts to (1) make clinical trials more efficient while maintaining patient safety and (2) increase the amount of information concerning product safety and benefits. The two draft guidances are entitled: “Master Protocols – Efficient Clinical Trial Design Strategies to Expedite Development of Cancer Drugs and Biologics” and “Adaptive Designs for Clinical Trials of Drug and Biologics.” This is the second of the two-part blog series describing the updates to the agency’s recommended approach to incorporating master protocols in clinical trials of new drugs and biological products for the treatment of cancer. The first of the two-part blog series described FDA’s recommended considerations to “adaptive designs” used in clinical trials.

In brief, the “Master Protocols Guidance” provides FDA recommendations to sponsors that desire the opportunity to run several related oncology studies concurrently under a master protocol, defined as “a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure.” This would give sponsors the ability to expand the reach of their oncology clinical studies to observe safety and efficacy in multiple subtype populations, disease subtypes, drug combinations and/or dosages.  Master protocols may be utilized to provide data for exploratory purposes or to support a marketing application.

Running an oncology clinical trial with a master protocol potentially benefits the sponsor by allowing the sponsor to concurrently evaluate multiple studies that may have different objectives, thus potentially saving time and costs as compared to running separate clinical trials. However, FDA also acknowledges that a master protocol may introduce challenges that, if not properly addressed, can increase risk to study subjects or delay the development of the product. Therefore, FDA released this guidance to provide recommendations to sponsors that are considering incorporating a master protocol into their clinical trial design to help them avoid unnecessary delay in the IND review process.

In the Master Protocol Guidance, FDA describes two types of master protocol designs: (1) the “basket trial” design and (2) the “umbrella trial” design. The basket trial is designed to test a single investigational oncology drug or drug combination in different populations (e.g., disease subtypes, biomarkers, demographic characteristics, etc.). FDA states that each substudy within a basket trial should include specific objectives, the scientific rationale for inclusion of each population, and a detailed statistical analysis plan that includes sample size justification and stopping rules for futility. In contrast, the umbrella trial is usually designed to evaluate multiple investigational oncology drugs administered as single drugs or as drug combinations in a single disease population. FDA reminds sponsors that appropriate dosages should be established for each investigational drug in Phase 2 studies prior to evaluation of the drug in a master protocol. Because umbrella trials can be used to compare the activity of investigational drug(s) in randomized controlled studies with a common control arm, FDA strongly recommends that the control arm be the standard of care (SOC) for the target population, noting that the SOC may change over time as newer treatments are adopted.

Additionally, FDA provides specific design considerations that sponsors are strongly recommended to address in their master protocols:

  • If sponsors are investigating a novel combination of two or more investigational drugs, the master protocol should summarize available safety, pharmacology, and preliminary efficacy data for each investigational drug; the biological rationale for use of the drugs in combination instead of individually; and evidence, if any, the interaction of the drugs when used together.
  • If sponsors are investigating drugs that target multiple biomarkers, the master protocol should include a prespecified plan for allocating patients who are potentially eligible for more than one substudy.
  • If sponsors seek to potentially add, expand, or discontinue treatment arms, sponsors should ensure that the master protocol and its associated statistical analysis plan (SAP) describe the conditions that would result in making such adaptations.
  • If sponsors anticipate utilizing the results from one or more of the substudies in support of a marketing application, the master protocol should describe and provide the charter for an independent radiologic review committee to perform blinded tumor-based assessments, a charter for an independent data monitoring committee (IDMC) to monitor efficacy results and safety results or alternatively an independent safety assessment committee (ISAC). The charter should authorize these committees to conduct prespecified and ad hoc assessments of efficacy, safety, and futility and recommend protocol modifications or other appropriate actions (i.e., adjusting sample size; discontinuing the substudy based on futility or substantial evidence of efficacy).
  • If sponsors are utilizing master protocols to evaluate biomarker-defined populations, the master protocol should explain why the use of the biomarker is appropriate and also include a validated in vitro diagnostic (IVD) test.

According to the Master Protocol Guidance, each sponsor will need to submit each master protocol as a new IND. When submitting an IND with a master protocol, the sponsor should consider the following:

  • The master protocol should be the only trial conducted under the IND;
  • The master protocol should be submitted to either CDER or CBER for review of the primary indication(s). If more than one indication is being investigated, the IND should be submitted to the most appropriate clinical review division within the Office of Hematology and Oncology Products in CDER or CBER, taking into account the population to be studied.
  • In addition to the elements required to be included in an IND submission under 21 CFR Part 312, the master protocol should include:
    • A detailed description of the trial design as text and as a visual illustration;
    • Procedures for sample acquisition, handling, and testing of biomarkers, if appropriate;
    • Identification of all substudies;
    • A description of all committee groups responsible for patient safety monitoring;
    • A description of the plan for submitting interim safety and efficacy results; and
    • The proposed informed consent document.

* * *

As mentioned above, incorporating master protocols into a clinical development program may have advantages, as these studies may reduce burdens associated with conducting separate studies and increase product speed to market.  If these benefits are realized, the end result may be improved patient access to therapeutic oncology interventions and lower costs of drugs through reduced development costs and greater competition.  However, concurrent evaluation of multiple oncology drugs and/or disease populations within a single trial is complex. Therefore, it is important that the trials are well-designed and well-conducted to ensure research subject safety and obtain quality clinical study data in support of drug or biological product approval. This guidance provides a glimpse of FDA’s approach to modernizing product development. Sponsors and stakeholders with an interest in developing their products under a master protocol are strongly encouraged to review this guidance and submit comments to FDA by November 30, 2018.

Two draft guidances issued together late last month seek to increase both clinical trial efficiency and the amount of information that is available about a drug’s safety and benefits.  The two draft guidances address, respectively, adaptive designs and master protocols.  This blog post discusses FDA’s recommendations for adaptive designs; master protocols will be addressed in a subsequent blog post.

An adaptive design is a “clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on the accumulating data from subjects in the trial.”  The ability to make changes to a study in progress allows investigators to take into account new information that was not known when the study began.  According to FDA, adaptive designs can both provide a greater chance to detect a true drug effect and reduce the number of patients exposed to ineffective investigational treatments (since effectiveness will be more easily detected earlier in the trial).  Because adaptive designs allow for greater flexibility, they also may be more acceptable to those conducting and those participating in clinical trials. For sponsors in particular, adaptive designs can potentially both save time and reduce costs.  Adaptive design can also have ethical advantages by facilitating early termination of trials once it becomes clear that a trial is unlikely to demonstrate effectiveness, thereby minimizing risk to participants.

At the same time, the draft guidance recognizes that adaptive designs increase the risk of “Type I” (false positive) errors, i.e., concluding that a drug has a beneficial effect when it does not.  To mitigate this risk, the draft guidance recommends sponsors employ methods to determine appropriate statistical thresholds for interim and final analysis to ensure that the overall Type I error is controlled at 2.5 percent.  Similarly, the draft guidance acknowledges the risk of bias that can result from early unblinding of a study, and recommends limitations on who may access such data to mitigate this risk.

A key element of adaptive design is pre-specification (i.e., planning in advance), including pre-specification of the number and timing of interim analyses, what statistical methods will be used to interpret the interim data, and how the study design will be changed depending on the results of such analyses.  Failure to pre-specify can result in the introduction of bias and thereby put the quality and integrity of study data at risk. Therefore, FDA strongly recommends that prespecified protocols are included in the clinical study design to ensure that access to comparative interim results are limited to individuals with relevant expertise who are independent from personnel involved in conducting or managing the trial.

Because adaptive designs introduce certain added complexities, FDA recommends that sponsors provide additional information when submitting a protocol for FDA review, including a detailed description of the monitoring and adaptation plan, information on who will be responsible for implementing the adaptive design, pre-specification of the statistical methods to be used, and a comprehensive written data access plan to maintain data integrity and quality.

The new adaptive designs draft guidance supersedes an earlier draft guidance issued in 2010.  At that time, adaptive designs were in their infancy, and proponents of adaptive designs viewed FDA’s initial guidance as a first step in considering how best to integrate them into clinical trials to support FDA regulated products and recommended that FDA guidance evolve in response to greater experience with the use of different adaptive study designs.  The new draft guidance reflects such evolution in FDA’s thinking; for example, in acknowledging the potential adverse impact arising from Type I error and in eliminating confusing categorization of “well understood” and “not well understood” adaptive design methods in favor of a more focused assessment of factors, such as unblinding, that can increase risk of bias.

FDA encourages sponsors to consider and discuss prospective design options with FDA.  Clinical trial sponsors and other stakeholders may want to consider the potential impact of the new guidance on their approach to clinical trials, and to submit comments to the FDA.  The deadline for submitting comments is November 30, 2018.

On September 20, 2018, the U.S. Food and Drug Administration (“FDA”) released draft guidance “Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank” (“Guidance”). The purpose of this Guidance is to explain FDA’s protocol in (1) determining how the centers will identify whether responsible parties failed to comply with submission and certification requirements to the ClinicalTrials.gov or submitted false or misleading documents to the data banks and (2) deciding when, why, and what civil monetary penalties will be assessed against the responsible parties or submitters. The new guidance seeks to address requirements of responsible parties involved in the performance of clinical research and submission of applications for marketing authorizations to register their trial, submit clinical results information and make certain certifications regarding their compliance with these requirements.  In order to mitigate their risk of civil money penalties in accordance with this guidance,  sponsors and researchers should (1) have policies and procedures that ensure correct clinical trial information is submitted to the ClinicalTrials.gov data bank, (2) have policies and procedures that ensure routine monitoring for missing or inaccurate clinical trial information in the data bank, (3) make timely submissions of the required information, and (4) remain responsive to any inquiries by FDA concerning clinical trial data and/or certifications to FDA.


Under section 801 of the Food and Drug Administration Amendments Act of 2008 (the “FDAAA”), which amended section 402(j) of the Public Health Service Act (42 U.S.C. 282(j)(5)(B)), responsible parties engaged in certain clinical research activities are required to submit registration and results information to the ClinicalTrials.gov data bank. Additionally, submitters of certain applications and other items to FDA regarding drug, biological, and medical device products are required to certify to FDA that all requirements of section 402(j) have been met. Similarly, the FDAAA amended section 301(jj) of the Food Drug and Cosmetics Act (the “FD&C Act”) to prohibit: (1) the failure of submitting or knowingly submitting a false certification to FDA, (2) the failure to submit required clinical trial information, and (3) submitting false or misleading clinical trial information to the ClinicalTrials.gov data bank. Further, the FDAAA amended section 303(f)(3) of the FD&C Act, authorizing FDA to assess civil monetary penalties against the person committing the prohibited acts.

Identifying Noncompliant Responsible Parties and Submitters

In this Guidance, FDA states its intention to utilize evidence collected during FDA’s Bioresearch Monitoring Program (“BIMO”) inspections to assess compliance with registration and results reporting requirements as described in Form FDA 2438 – Chapter 48 – Bioresearch Monitoring (Apr. 19, 2017). FDA also intends to identify violations as a result of complaints received by the Agency, which may entail reviewing public and non-public information, including, but not limited to information submitted to the ClinicalTrials.gov data bank and to FDA.

It is in the best interest of sponsors, researchers, and other parties subject to an obligation to submit clinical trial registration, information, results, and/or certifications to FDA to have policies and procedures in place to ensure correct information is submitted to ClinicalTrials.gov data bank. Policies and procedures should also include periodic review of the data bank to monitor for any missing or inaccurate clinical trial information. Developing and implementing these policies and procedures will mitigate the risk of enforcement for noncompliance with registration and clinical trial results reporting requirements, as outlined in the Guidance.

Determining When to Seek Civil Monetary Penalties

Under Guidance, FDA intends to provide the responsible parties with an opportunity to remedy any prohibited acts under section 301(jj) of the FD&C Act and corresponding regulations (42 CFR Part 11) before initiating an action to recover penalties. Pursuant to the procedures detailed in the Guidance, when FDA determines that when submissions are not timely filed or inaccurate, FDA will generally send the responsible party or submitter a Preliminary Notice of Noncompliance Letter describing the potential violation. The responsible party or submitter will have thirty (30) calendar days to remedy the violation. Should FDA conduct further review and find further or continued noncompliance with the applicable clinical trial requirements, the agency will then issue a Notice of Noncompliance, giving the responsible party or submitter another thirty (30) days to remedy noncompliance after receipt of the notice.

It is in the best interest of sponsors and researchers to promptly respond to any FDA inquiries and notices concerning registration, clinical trial information or certification issues related to the ClinicalTrials.org data bank. Failure to comply within the thirty (30) days of receipt of Notice of Noncompliance will result in FDA escalating regulatory action, including civil monetary penalties, of up to $10,000 for all violations adjudicated in a single proceeding.  Additional penalties of up to $10,000 each day may be included if the violation continues and if said violation is not corrected within thirty (30) days following notification. FDA may also pursue injunction and/or criminal prosecution.

In determining monetary penalties, the FDA will evaluate the circumstances, nature, extent, and gravity of the violation(s) with respect to the individual.  Other factors will include the violator’s ability to continue conducting business, any prior history of such violations, and the degree of culpability in the matter.

Responding To Civil Monetary Penalties by FDA

If FDA seeks civil monetary penalties, according to 21 CFR Part 17, the responsible party or submitter has the opportunity to either: (1) pay the penalty prescribed in the complaint or (2) file an Answer, contesting the allegations either in part or in whole, within thirty (30) days of date of service.

Should the responsible party or submitter contest the allegations by submitting an Answer, generally settlement discussions with FDA are entered into, providing the responsible party or submitter to present mitigating evidence to FDA for purposes of reducing the penalty amount. If a settlement is not reached before a decision on appeal, a presiding officer will make an initial decision, followed by the usual administrative appeal process (e.g., Department of Health and Human Services Departmental Appeal Board and then the U.S. Court of Appeals for the District of Columbia or any other circuit in which the responsible party or submitter resides or conducts business), should either party appeal the initial decision.


* * *

A recent BMJ article, “Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource,” reported that for approximately half of the clinical trials, the responsible person did not report results on the EU register while a 2015 New England Journal of Medicine article, “Compliance with Results Reporting at ClinicalTrials.gov,” reported that approximately 20% of industry trials did not report results when required to do so, and 50% of NIH-sponsored research went unreported. While the registration, reporting, certification requirements, and the penalties for noncompliance are not new, FDA’s release of this Guidance should be taken as a signal to sponsors and researchers of its plan to enforce those requirements more rigorously. Therefore, sponsors and researchers should take this opportunity to evaluate the sufficiency of their policies and procedures for compliance with registration and reporting requirements and audit their submissions to ensure they are up-to-date.  Comments are due by November 20, 2018.

Our colleagues James A. Boiani and John S. Linehan at Epstein Becker Green wrote an advisory on the U.S. Food and Drug Administration’s (“FDA”) introduction of new plans to constrain animal drug compounding with the release of its Draft Guidance for Industry (GFI) #230, Compounding Animal Drugs from Bulk Drug Substances. In this advisory, the parameters of the Draft Guidance are outlined, which suggests that a dramatic shift in the FDA’s enforcement approach may be underway and provides insight into the FDA’s enforcement priorities and its interpretation of the applicable regulatory regime.

Read the full alert online.

Earlier today, FDA published guidance, for immediate implementation, effectively delaying the effective date of the product tracing requirements for manufacturers, wholesale distributors or repackagers until May 1, 2015.  This guidance appears to be a continuation of FDA’s efforts to address industry’s concerns about the implementation of the DSCSA product tracing requirements that are effective January 1, 2015.

It is unclear whether the ghosts of FDA past, present or future had anything to do with today’s announcement, but this Dickens-esque change of heart should ensure the product tracing requirements do not cause supply chain issues or drug shortages.

As a result of this guidance, manufacturers, wholesale distributors, and repackagers will have until May 1, 2015 to implement a process for providing and capturing transaction information, transaction histories and transaction statements.  This guidance does not have much impact on dispensers who are still required to capture, and if necessary, provide this information beginning on July 1, 2015.

On November 13, 2014, the Food and Drug Administration (“FDA”) announced a proposed study on spousal influence on consumer understanding and responses to direct-to-consumer prescription drug advertisements.  FDA notes that consumers are often thought of as individual targets for prescription drug advertisements, without considering the social contexts in which many treatment decisions are made.  For example, FDA notes that when spouses view an ad together a spouse “may influence their partner by expressing concern about risk and sides effects that might occur, or pressuring their partner to consider the drug despite the risks and side effects.”  The FDA proposes to examine the influences spouses may have on the consumer’s memory and understanding of risks and benefits information, intention to seek more information about the product, and variables pertaining to the consumer-spouse relationship (such as closeness and communication style).

FDA’s proposed study recognizes the strong influence that spouses have on shaping treatment decisions. Studies have shown that married people are generally healthier than unmarried people, and that “a spouse may play an important role in monitoring and encouraging healthy behaviors… as well as discouraging unhealthy ones.”  How a spouse shapes the consumer’s perceived risks in relation to the benefit of the advertised drug is important not only to regulators but to the drug manufacturers as well.

FDA Guidance for Industry on Presenting Risk Information in Prescription Drug and Medical Device Promotion describes how advertisements should present information about effectiveness and information about risk in a balanced manner. Specifically, “[i]f the benefits information is easily understood and maintained through repetition or other reinforcing techniques, and risk information is not similarly reinforced, the net impression may not be appropriately balanced.” (emphasis added)   FDA is concerned with whether, as a whole, the communication provides an accurate and non-misleading impression of the product.

It remains to be seen whether FDA intends to use the results of the study to expand its review of promotional materials to include consideration of the potential influence of the promotional materials on a spouse, who will ultimately influence the consumer’s treatment decisions. It’s common to see drug advertisements showing a happy, healthy couple walking down a beach or playing in a back yard with grandchildren. If this touching scene causes a spouse to press his or her partner to seek more information about product will that make an otherwise balanced communication misleading?  Companies should be mindful of this proposed study and the possible impacts upon their product marketing.


Earlier this week the Department of Health and Human Services (“HHS”) published its long awaited notice of proposed rulemaking regarding the registration of clinical trials.  The most significant change that would result from implementation of the proposed rule, and the one getting the most press, is the new requirement that results data be submitted for all applicable clinical trials, even those evaluating unapproved drugs and devices.   Although we agree that this new requirement is likely to have significant ramifications for drug, biologic and device manufacturers, here are five other issues you may want to focus on as you review the proposed rule:

1.   All combination product clinical trials will be considered drug clinical trials regardless of the product’s primary mode of action. 

This will have a significant impact on clinical trials involving unapproved or uncleared combination products that are subject to FDA regulation as medical devices.  Because these clinical trials will be considered drug clinical trials, NIH will publish the full registration information within 30 days of the information being submitted.  However, if these clinical trials were regulated as device clinical trials, the majority of the registration information would not be published until the combination product was approved or cleared.

2.   The bright line rule between a clinical trial evaluating a new use of an approved, cleared or licensed product and a clinical trial evaluating a new product that is unapproved, unlicensed or uncleared is not so bright.

The determination of which side of the line a clinical trial sits on will depend on the type of submission the clinical trial is intended to support.  If the clinical trial is intended to support a new application (i.e., NDA, ANDA, BLA, PMA) or premarket notification (i.e., 510(k)) for a new product, the clinical trial is evaluating a new product under the proposed rule.  However, if it is intended to support a supplement or a 510(k) for a new indication, then it is evaluating a new use.

Not only is it unclear how a manufacturer is supposed to parse whether a 510(k) is for a new indication or for a new device, but the “application = new product; supplement = new use” formula suggested by the proposed rule is not always applicable to approved devices.  Current FDA guidance states that, at least, certain changes to an approved device’s indications for use require the submission of a new PMA.  Additionally, the proposed rule fails to explain whether a clinical trial evaluating an unapproved or uncleared combination product would be considered a clinical trial of a new product if one of the constituent parts was previously approved or cleared.

As this distinction plays an important role the ability of a sponsor to delay reporting the results of a clinical trial, this could be a significant issue requiring clarification.

3.   The length of time a sponsor can delay publication of results is the same regardless of whether the clinical trial evaluates the new use of an approved, cleared or licensed product or it evaluates a new product.

The length of time sponsors can delay submission of clinical trial results is subject to statutory limitations with respect to clinical trials evaluating the new use of an approved or cleared product (i.e., up to two years following submission of notice certifying qualification for delayed publication).  The same is not true for clinical trials evaluating the use of a new product.  Yet, HHS decided to impose the same limitation after determining that the benefits of publication outweighed the potential competitive disadvantages this may cause to manufacturers that are developing new products.

4.   HHS found a creative way around the requirement that it not publish most applicable device clinical trial registration information prior to approval or clearance of the device.

By requiring results data from all applicable device trials to be submitted regardless of whether the clinical trial evaluated an unapproved or uncleared medical device, HHS created the problem that results data could be published before it is permitted to publish the registration information for the clinical trial.  Recognizing the results data would be of little value without the accompanying registration information, HHS got creative. 

Instead of “publishing the registration data” HHS now requires the submission of the same information provided in the registration as part of the results data from these clinical trials.  However, to avoid repetitive data entry, HHS permits sponsors to certify to certify that the same information included in the registration information has been verified and updated, and is ready to be posted along with the results.

Device manufacturers may want to consider using the need for this creative work around to support comments requesting the ability to delay submission of results from clinical trials evaluating unapproved or uncleared devices.

5.   HHS has imposed additional requirements regarding the frequency at which submitted data must be corrected or updated.

The proposed rule expands the number of data elements, from two to ten, that must be updated within 30 days of the sponsor becoming aware of the need to update the data.  Additionally, the proposed rule requires sponsors to update data within 15 days in the event it becomes aware, either on its own or upon notification by NIH, of errors in the data.  Sponsors may want to consider whether these timing requirements are too burdensome or are impracticable. 

It is important to note that these deadlines apply to data updates and error corrections regardless of whether the original data was required to be submitted because it relates to an applicable clinical trial or the data was voluntarily submitted. 

In light of this and other obligations imposed on sponsors who voluntarily submit data, it is important to consider whether these obligations are likely to discourage sponsors from voluntary submitting information about, and reporting results from, clinical trials that are not applicable clinical trials.

HHS is accepting comments on the proposed rule, through February 19, 2015. 

* I would like to thank Ryan Benz, Shilpa Prem and Bonnie Scott for their help in reviewing and analyzing the proposed rule.