Life Science Compliance Update

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31 posts from February 2014

February 28, 2014

Study Reveals Significant Practice Gaps for Oncologists Treating Renal Cell Carcinoma

As part of the 2014 ASCO Genitourinary Cancers Symposium, Clinical Care Options (CCO), a Reston-based provider of innovative continuing medical education (CME), presented findings on practice gaps and barriers to optimal care for patients with renal cell carcinoma (RCC). The American Society of Clinical Oncology (ASCO) announced that the presentation was one of the "8 noteworthy studies among more than 500 abstracts" to be presented at the 3-day meeting.

"CCO is honored to have our study named among the most noteworthy presentations at the Genitourinary Cancers Symposium," said Trish Bates Doolin, General Manager, CCO Oncology. "As part of our commitment to improving patient outcomes, we strive to consistently assess and create innovative continuing medical education programs that address key clinical practice challenges."

CCO partnered with the Annenberg Center for the Health Sciences and AXDEV Group for the study, entitled "Professional Practice Gaps and Barriers to Optimal Care of Renal Cell Carcinoma (RCC) Among Oncologists in the United States." The study was supported by an unrestricted grant from Pfizer.

The researchers compared oncologists' responses to treatment case studies with optimal answers based on National Comprehensive Cancer Network kidney cancer guidelines and evidence-based opinions of two RCC experts. The findings revealed clinically relevant practice performance gaps that affect delivery of care and patient health outcomes.

Conclusions

"Not recognizing predictors of poor risk or the importance of evaluating clinical symptoms can result in missed opportunities to change treatment strategy, leading to suboptimal outcomes. These results will support design of educational programs and performance improvement interventions."

As this study shows, CME is critical to healthcare provider's ongoing educational needs as they strive to stay current with the advances of medical science. Cancer treatment options like RCC demand physicians stay on top of the latest breakthroughs. Continuing medical education companies utilize innovative methodologies to offer physicians this information, which leads to better care for patients.

February 27, 2014

ACCME Adopts Changes to Simplify the Accreditation Requirements

The Accreditation Council for Continuing Medical Education (ACCME) announced that its Board of Directors has adopted changes to simplify the accreditation requirements and process. This includes changes to the accreditation criteria for ACCME accredited providers of continuing medical education.

The ACCME had proposed a broad spectrum of changes including changes to the use of logos in disclosing commercial support. At this time has delayed for further discussion changes concerning the use of corporate logos and changes to the criteria for accreditation with commendation.

The purpose of the changes is to streamline the accreditation system while maintaining high standards and continuing to support continuing medical education as a strategic asset to healthcare improvement initiatives. These changes come after the ACCME's formal call for public comment on the accreditation requirements and process. The results of these comments are clear: a significant majority of the respondents agreed with the ACCME's proposals to simplify the Accreditation Criteria, policies, and process.

The changes include:

  • Simplifying and removing some of the Accreditation Criteria and policy requirements
  • Changing terminology from "joint sponsorship" to "joint providership"
  • Offering providers an abstract as an ACCME-approved tool to use when verifying performance-in-practice
  • Simplifying the process for organizations applying for initial accreditation

These changes are designed to remove redundancies while maintaining the continuous improvement model and the high standards that are essential for designing and implementing independent, effective, and relevant CME. The number of criteria required for accreditation is reduced from 15 to 12, one policy is eliminated, and five policies are modified. The changes will simplify the process for accredited providers and offer greater flexibility, while retaining the Plan-Do-Study-Act cycle which is integral to the ACCME's expectations.

These changes apply to all CME providers within the ACCME accreditation system, including providers directly accredited by the ACCME and those accredited by ACCME Recognized Accreditors (state or territory medical societies that are recognized by the ACCME as accreditors of intrastate CME providers).

Implementation of Changes

According to the ACCME, the changes are effective immediately:

  • Elimination of requirements: Accredited providers will no longer be evaluated for compliance with the requirements that have been eliminated.
  • Change in terminology: ACCME does not expect accredited providers to change or reprint any materials that currently exist. ACCME expects accredited providers to use the term "joint providership" for new materials published after January 1, 2015. Please note that this change in terminology applies to accreditation statements for jointly provided activities as well as other materials.
  • Accreditation process: Providers will have the option of using an abstract to verify performance-in-practice or to continue using labels. ACCME is in the process of producing the abstract.
  • Initial applicants: Organizations applying for Provisional Accreditation will no longer be required to have an on-site survey. Surveys are still required; conference calls are the standard interview format the ACCME currently uses. Initial applicants and accreditors continue to have the option of using other survey formats including televideo and face-to-face, if circumstances warrant it.

Accredited Providers: What This Means for You

Regardless of where you are in the accreditation process, you will no longer be evaluated for compliance with any requirements that have been eliminated:

  • If you are in the March 2014 decision cohort, you were not reviewed for compliance with the requirements that have been eliminated and your decisions will not reflect those requirements. For progress reports that had a noncompliance finding in one of the eliminated requirements, ACCME is providing feedback about your effectiveness in meeting those requirements, in support of your continuous improvement and in recognition of the work you did in the progress report process.
  • If you have already submitted materials for reaccreditation, you do not need to resubmit or change those materials. The ACCME will ensure that you will not be reviewed for any requirements that have been eliminated.
  • If you are preparing for reaccreditation, do not change any of the materials you have already prepared or are in the process of preparing. The ACCME will ensure that you will not be reviewed for any requirements that have been eliminated.
  • If you are in a future accreditation cohort, you will not need to submit materials related to compliance for the requirements that have been eliminated.

For more information, please see this Ask ACCME Q&A.

Webinar

The ACCME will hold a free webinar on March 11, from 1-2:30 PM CST, to discuss the changes and answer questions. This webinar is open to all stakeholders; however enrollment is limited. For more information about the webinar, including connection instructions, visit the Event Page on the ACCME website. The webinar will be recorded and published on the website.

Changes to ACCME Requirements and Process

The ACCME has updated its Accreditation Requirements and Descriptions document to reflect these changes and is in the process of updating the ACCME website and other accreditation materials to incorporate these changes.

Accreditation Criteria

The purpose of the changes to the Accreditation Criteria is to remove redundancies and streamline the Criteria while maintaining the continuous improvement model and the high standards that are essential for designing and implementing independent, effective, and relevant CME. These changes reduce the number of criteria required for accreditation from 15 to 12. They will simplify the process for accredited providers, while retaining the Plan-Do-Study-Act cycle, which is integral to the ACCME's expectations. For the purposes of visually seeing the changes the deleted items are struck out in this article.

1.       Edit Criterion 1: Mission Statement

FROM

The provider has a CME mission statement that includes all of the basic components (CME purpose, content areas, target audience, type of activities, expected results) with expected results articulated in terms of changes in competence, performance, or patient outcomes that will be the result of the program.

TO

The provider has a CME mission statement that includes 'expected results' articulated in terms of changes in competence, performance, or patient outcomes that will be the result of the program. 

2.       Eliminate Criterion 4: The provider generates activities/educational interventions around content that matches the learners' current or potential scope of professional activities.

3.       Eliminate Criterion 14:  The provider demonstrates that identified program changes or improvements, that are required to improve on the provider's ability to meet the CME mission, are underway or completed.

4.      Eliminate Criterion 15 The provider demonstrates that the impacts of program improvements, that are required to improve on the provider's ability to meet the CME mission, are measured.

Policies

These changes remove requirements that predate the current accreditation criteria and are no longer necessary due to the evolution of CME and technology.

5.       Eliminate Organizational Mission and Framework: The accredited provider must have an organizational framework for the CME unit that provides the necessary resources to support its mission including support by the parent organization, if a parent organization exists.

6.       Eliminate some special requirements for enduring materials

Because there is no direct interaction between the provider and/or faculty and the learner, the provider must communicate the following information to participants so that they are aware of this in-formation prior to starting the educational activity

1. Principal faculty and their credentials;

2. Medium or combination of media used;

3. Method of physician participation in the learning process;

4. Estimated time to complete the educational activity (same as number of designated credit hours);

5. Dates of original release and most recent review or update; and

6. Termination date (date after which enduring material is no longer certified for credit).

Providers that produce enduring materials must review each enduring material at least once every three years or more frequently if indicated by new scientific developments. So, while providers can review and re-release an enduring material every three years (or more frequently), the enduring material cannot be offered as an accredited activity for more than three years without some review on the part of the provider to ensure that the content is still up-to-date and accurate. That review date must be included on the enduring material, along with the original release date and a termination date.

Sometimes providers will create an enduring material from a live CME activity. When this occurs, ACCME considers the provider to have created two separate activities – one live activity and one enduring material activity. Both activities must comply with all ACCME requirements, and the enduring material activity must comply additionally with all ACCME policies that relate specifically to enduring materials.

7.       Eliminate some special requirements for Internet CME (retaining 3 that support the Standards for Commercial Support)

There are special requirements for Internet CME because of the nature of the activities:

Activity Location: ACCME-accredited providers may not place their CME activities on a Web site owned or controlled by a commercial interest.

Links to Product Web sites: With clear notification that the learner is leaving the educational Web site, links from the Web site of an ACCME accredited provider to pharmaceutical and device manufacturers' product Web sites are permitted before or after the educational content of a CME activity, but shall not be embedded in the educational content of a CME activity.

Transmission of information: For CME activities in which the learner participates electronically (e.g., via Internet, CD-ROM, satellite broadcasts), all required ACCME information must be communicated to the learner prior to the learner beginning the CME activity.

Advertising: Advertising of any type is prohibited within the educational content of CME activities on the Internet including, but not limited to, banner ads, subliminal ads, and pop-up window ads. For computer based CME activities, advertisements and promotional materials may not be visible on the screen at the same time as the CME content and not interleafed between computer windows or screens of the CME content.

Hardware/Software Requirements: The accredited provider must indicate, at the start of each Inter-net CME activity, the hardware and software required for the learner to participate.

Provider Contact Information: The accredited provider must have a mechanism in place for the learner to be able to contact the provider if there are questions about the Internet CME activity.

Policy on Privacy and Confidentiality: The accredited provider must have, adhere to, and inform the learner about its policy on privacy and confidentiality that relates to the CME activities it provides on the Internet.

Copyright: The accredited provider must be able to document that it owns the copyright for, or has received permissions for use of, or is otherwise permitted to use copyrighted materials within a CME activity on the Internet.

8.       Eliminate some special requirements for journal-based CME

A journal-based CME activity includes the reading of an article (or adapted formats for special needs), a provider stipulated/learner directed phase (that may include reflection, discussion, or debate about the material contained in the article(s), and a requirement for the completion by the learner of a pre-determined set of questions or tasks relating to the content of the material as part of the learning process.

The ACCME considers information required to be communicated before an activity (e.g., disclosure information, disclosure of commercial support, objectives), CME content (e.g., articles, lectures, handouts, and slide copies), content-specific post-tests, and education evaluation all to be elements of a journal-based CME activity.

The educational content of journal CME must be within the ACCME's Definition of CME. ACCME Accreditation Requirements

Journal CME activities must comply with all ACCME accreditation requirements. Because of the nature of the activity, there are two additional requirements that journal CME must meet:

The ACCME does not consider a journal-based CME activity to have been completed until the learner documents participation in that activity to the provider.

None of the elements of journal-based CME can contain any advertising or product group messages of commercial interests. Disclosure information cannot contain trade names. The learner must not encounter advertising within the pages of the article or within the pages of the related questions or evaluation materials.

9.       Eliminate some special requirements for Regularly Scheduled Series (RSS)

The ACCME defines a regularly scheduled series (RSS) as a course that is planned as a series with multiple, ongoing sessions, e.g., offered weekly, monthly, or quarterly; and is primarily planned by and presented to the accredited organization's professional staff. Examples include grand rounds, tumor boards, and morbidity and mortality conferences. ACCME-accredited providers that offer regularly scheduled series must describe and verify that they have a system in place monitor these activities' compliance with ACCME accreditation requirements. The monitoring system must:

1. Be based on real performance data and information derived from the RSS's that describes compliance (in support of Accreditation Criteria 2-11), and

2. Result in improvements when called for by this compliance data (in support of ACCME Criteria 12-15), and

3. Ensure that appropriate ACCME Letters of Agreement are in place whenever funds are contributed in support of CME (in support of the ACCME Standards for Commercial Support: Standards to Ensure Independence in CME Activities).

Also, the provider is required to make available and accessible to the learners a system through which data and information on a learner's participation can be recorded and retrieved. The critical data and information elements include: learner identifier, name/topic of activity, date of activity, hours of credit designated or actually claimed. The ACCME limits the provider's responsibility in this regard to "access, availability and retrieval." Learners are free to choose not to use this available and accessible system.

10.   Edit "joint sponsorship" to "joint providership" throughout the requirements, including in the accreditation statement, as shown in the examples below. The purpose of the change is to support consistency within our own terminology and with the terminology used by other accreditors.

Accreditation Statement for Jointly Provided Activities

"This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of (name of accredited provider) and (name of nonaccredited provider). The (name of accredited provider) is accredited by the ACCME to provide continuing medical education for physicians."

Joint Providership Policy

"The ACCME defines joint providership as the providership of a CME activity by one accredited and one nonaccredited organization Please note: the ACCME does not intend to imply that a joint providership relationship is an actual legal partnership. Therefore, the ACCME does not include the words partnership or partners in its definition of joint providership. One accredited provider must take responsibility for a CME activity when it is presented in cooperation with other accredited providers or with a nonaccredited organization and must use the appropriate accreditation statement. "

Accreditation Process

These changes are designed to simplify the process and increase flexibility.

11.   Add a Performance-In-Practice Structured Abstract as a tool for documentation review.

12.   Eliminate the requirement for on-site interviews for initial applicants.

Public Comments

On December 17, 2013, the ACCME issued a formal call for public comment about its proposal to simplify the accreditation requirements and process, in accordance with its Rule-Making Policy. The comment period ended January 31, 2014. Overall, the responses to the formal call for comment were consistent with the responses to the spring 2013 survey. Most of the respondents agreed with the ACCME's proposals to simplify the Accreditation Criteria, policies, and process.

Formal Call for Comment Data

Respondents agreed with the changes to the Accreditation Criteria by an overwhelming margin of 214-11. This set of changes includes simplifying Criterion 1 and removing Criteria 4, 14, and 15.

The respondents who agreed with the changes to the Accreditation Criteria said that the changes reduce redundancy, enhance clarity, increase flexibility, and will allow providers to focus more on continuous improvement. The respondents who disagreed were concerned that providers might need more direction and offered suggestions on how expectations for fulfilling the mission should be even more explicitly emphasized.

Respondents were mixed on the proposed Changes to Standards for Commercial Support, 142-85, but those organizations who commented the numbers were significantly different 29 supporting the change and 77 against. This set of changes is about changing the Standards for Commercial Support so as to prevent the use of commercial interest logos in the disclosure of commercial support.

Submitted Comments

Changes to SCS

ACCME Accredited Provider

State Accredited

Provider

State Medical Society

ACCME Member Organization

Healthcare Provider

Other

ACCME Commercial

Interest

Total

Agree

12

12

1

1

2

1

0

29

Disagree

39

8

3

0

2

23

2

77

Those in support said the changes would minimize any possibility of conflict of interest, eliminate any ambiguity, decrease participants' perception of real or perceived bias, and strengthen the perception of the value of the Standards for Commercial Support. Those opposed to the changes said that the current Standards were sufficient and expressed concerns that prohibiting commercial interest logos would decrease transparency and disclosure, and make it more difficult to distinguish between commercially supported CME and CME that is not commercially supported.

Respondents agreed by a significant margin, 183-24, in favor of changes that remove some of the policy requirements for CME activity types, introduces the term "joint providership" to replace "joint sponsorship," and removes an organizational structure policy that pre-dates the current requirements.

The respondents who agreed said that the policy changes would simplify the process and accurately reflect the current CME environment and the evolution of technology. They also suggested that the change in terminology should alleviate the misunderstanding created by the use of the word sponsorship and create a more consistent nomenclature. The respondents who disagreed said that the policy requirements were still important for promoting good practices and providing a framework for compliance.

Finally, by a large margin, 185-17, respondents supported two changes including the elimination of on-site survey requirements for organizations seeking initial accreditation, and introducing an abstract for accredited providers to use when verifying performance-in-practice.

The respondents who agreed said the change to the initial applicants' process would provide greater flexibility and reduce cost and burden without degrading the process. Those who disagreed said that the requirement for on-site surveys provided value that other survey formats could not replace. Respondents said the abstract would greatly simplify the process; some who agreed and who disagreed provided important suggestions for improvements.

Several organization letters were included in the comments.

Council of Medical Specialty Societies (CMSS) letter to ACCME

Norman Kahn, MD, Executive Vice President & CEO of CMSS addressing corporate logos:

"The issue of the use of corporate logos is a complex one. Corporate logos are clearly associated with the company providing the support. That's both bad and good news. If the ACCME's intent is to decrease the appearance of a relationship between the commercial supporter and the CME activity, then prohibiting the use of corporate logos may make sense. If the priority, however, is clearly communicating to learners that the event has received commercial support, then prohibiting the use of corporate logos may be counterproductive. Identifying corporate supporters in regular type font may very well get lost in the administrivia associated with announcements of CME activities, and thus be functionally invisible to learners. Learners look for the corporate logos to see if there is commercial support.

CMSS values open and transparent disclosure. Given the binary options between corporate logos or not, we recommend that open and transparent disclosure to learners of the corporate support is best achieved by including corporate logos which will be immediately recognizable by learners. At the same time, we agree with prohibiting corporate slogans, product group message, tag lines, trade name, areas of therapeutic focus, or any other message that appears promotional on the part of the company.

Finally, there is the issue of timing. ACCME has been successful in obtaining national recognition for the Standards for Commercial Support, particularly by CMS through the new Open Payments program, the current iteration of the Physician Payments Sunshine Act. As the Open Payments program is in its first year, now is not the time to make any changes in this critical set of standards that have been adopted as is by CMS. It is not time to threaten the whole by tinkering with a part. It's just too risky right now.

We strongly recommend not changing the CME community's self-regulatory standards right now, which could put the standards and the CME community at risk in the current political environment."

Society for Academic Continuing Medical Education (SACME) letter to ACCME

Deborah A. Samuel, MBA, FACEHP, President, Society for Academic CME writing in support of simplifying the accreditation requirements and process:

"SACME wholeheartedly endorses the idea of simplifying the accreditation requirements and process. We believe simplification will benefit everyone and will facilitate accredited CME offices' efforts to apply their resources to enhance the performance of physicians and other healthcare providers, while still ensuring the scientific integrity of CME activities.

We are pleased to inform you that the responses reported from our member survey, as well as those developed in the Board's discussion, reflected overwhelming approval of every item submitted for comment. The responses reached or exceeded 90% on items 1, 2, 3, 6, 7, 8, and 12. The positive response on the rest of the items exceed 80% with the sole exception of item 11 (eliminating the requirement to have on-site initial accreditation interviews), which received approval by 75%."

Regarding corporate logos:

"There was a significant minority opinion expressed by some of our members regarding the use of Corporate Logos that we believe is worthy of your consideration. Their position was as follows:

'The ACCME position should 'reflect the principles outlined in the CME Coalition's Responsible Logo Use Guidelines, rather than eliminate ACCME-defined commercial interest logos as outlined in the proposed changes.' As another member stated, 'When commercial support is acknowledged to participants, greater transparency can be shown by showing the corporate logos, which are recognizable, with size limitations and restraint.' "

Analysis

The ACCME has taken a strong leadership role in helping to streamline the accreditation system and adopting to criteria that is important. It is also encouraging that they are going through a deliberative process before making any additional changes.

 

FDA Draft Guidance Analgesic Indications: Developing Drug and Biological Products

The FDA recently released a new draft guidance with recommendations on how sponsors of analgesic painkillers should develop products in preparation for future marketing authorization. The draft, "Analgesic Indications: Developing Drug and Biological Products", is intended for sponsors of analgesic products intended to treat acute, chronic and breakthrough pain.

All three types of pain—acute, chronic and breakthrough—are characterized by the need for long-term, regular treatment with analgesics. FDA notes that while it is important to understand how a single dose of the drug works, it's even more interested in understanding how the drug functions as part of a long-term regimen.

Comments on the guidance should be submitted to FDA by April 7, 2014.

I. Introduction

This guidance provides recommendations to sponsors on the development of prescription drugs that are the subject of new drug applications (NDAs) for the management of acute and chronic pain as well as the management of breakthrough pain (hereafter analgesic development). Specifically, this guidance focuses on clinical drug development and trial design issues and chemistry, manufacturing, and controls (CMC) concerns that are unique to the study of acute, chronic, and breakthrough pain and the labeling considerations for analgesic drugs. This draft guidance is intended to serve as a focus for continued discussions on relevant issues among the Division of Anesthesia, Analgesia, and Addiction Products, pharmaceutical sponsors, the academic community, and the public. This guidance does not discuss nonclinical drug development, because FDA has not identified nonclinical concerns unique to analgesic development.

II. Background

Pain can be categorized according to its duration, acute or chronic, as well as based on other characteristics, such as breakthrough pain, acute episodes of pain that occur on a background of well-controlled, chronic pain. Pain is subjective in nature and is measured by patient self-reporting of its intensity, and other subjective qualities.

Acute pain is defined as pain that is self-limited and generally requires treatment for no more than up to a few weeks (e.g., postoperative or acute musculoskeletal pain). Chronic pain is defined as either pain persisting for longer than 1 month beyond resolution of the underlying insult, or pain persisting beyond 3 months. Breakthrough pain is defined as a transient flare of pain occurring in opioid-tolerant patients experiencing persistent pain otherwise controlled with around-the-clock maintenance opioid therapy consisting of an equivalent of at least 60 milligrams (mg) of morphine per day or an equianalgesic dose of another opioid for 1 week or longer.

III. Establishing indications and claims for analgesics

FDA encourages sponsors to state the indications being sought for their analgesics before phase studies are initiated, and to discuss these indications with the FDA as early as feasible. Suggested approaches for establishing analgesic indications are provided in the guidance, which is divided into sections that discuss procedures for: (1) new molecular entities (NMEs); (2) reformulations of approved drugs; (3) add-on or adjunctive indications; and (4) additional claims.

For the purposes of establishing an analgesic indication, the severity of the expected pain intensity based upon the underlying cause should be taken into consideration and weighed against the risks of the drug. Therefore, drugs associated with greater risks may be indicated for pain of great enough severity to warrant those risks and that may not be expected to be adequately treated by drugs or drug dosages used for pain of lesser severity (e.g., cancer pain or postoperative pain following major abdominal surgery).

A. NMEs

NMEs should have development programs that explore the analgesic drug's safety and effectiveness in a variety of clinical situations. FDA encourages sponsors to explore the efficacy of these drugs to best assess in which settings the drug may be useful. Resulting information may inform the indication and ensure that safety information is gathered in studies of patient populations likely to be exposed to the drug after approval. The final proposed indication should reflect the safety and efficacy of the drug based on appropriately designed clinical studies. The INDICATIONS AND USAGE section of labeling should be supported by language describing the specific conditions studied in the CLINICAL STUDIES section. In general, a finding of efficacy for an NME analgesic that is to be used to treat a specific pain condition should be supported by at least two adequate and well-controlled studies, depending on the condition.

FDA encourages sponsors with analgesic drugs for which they are seeking general pain indications (e.g., treatment of the pain of peripheral neuropathy, treatment of the pain of neuropathy, or treatment of musculoskeletal pain) to discuss those development programs with the review division early in development. This is particularly important for sponsors whose drugs fall within well-recognized analgesic drug classes such as opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), or local anesthetics, because additional flexibility and individualization of the development programs may be possible.

B. Reformulations of Approved Drugs

For reformulations of approved analgesics, if an NDA is intended to be submitted as a 505(b)(2) application that references an analgesic listed drug, reliance on the FDA's previous finding of safety and effectiveness for the listed drug and one adequate and well-controlled trial (in addition to comparative bioavailability studies against the listed drug) may be sufficient to support the change from the listed drug. This includes modified-release reformulations of a drug previously approved as an immediate-release product. For proposed products that include a new route of administration, a new indication, or a new population, sponsors should conduct two adequate and well-controlled trials to support a finding of efficacy, but consideration may be given to alternate proposals with adequate justification. In general, whether the finding of analgesia should be replicated in specific patient populations (i.e., subjects with particular types of pain) versus across patient populations depends on how much is known about the pharmacology of the drug under development.

C. Add-On or Adjunctive Indications

There may be situations in which drugs are studied as add-ons or adjunctive therapy in subjects receiving concomitant treatment with an existing standard of care. This situation may be appropriate for drugs expected to have an effect only in conjunction with concomitant treatment or in patient populations that cannot be studied without the underlying therapy. In cases where the efficacy data come from such adjunctive use, the drug would likely receive an indication as an adjunctive therapy in the setting under which it was studied).

D. Additional Claims

Additional claims of treatment benefit based on clinical domains relevant to analgesia may be appropriate for some clinical populations that are defined by those domains. Claims of treatment benefit should represent findings that are not directly a result of a change in pain, but if subjects sleep better merely because they have less pain, the improved sleep is not a direct positive effect of the drug. For example, fibromyalgia is a syndrome that includes pain as well as fatigue and trouble sleeping. A properly designed evaluation of sleep during a clinical trial in subjects with fibromyalgia may demonstrate positive effects for pain as well as sleep. In contrast, subjects treated with a sedating analgesic may sleep more, but this may not represent improved sleep, and these subjects may experience the sedating effects during the day as well. Replicated findings from adequately designed studies incorporating instruments demonstrating substantial, clinically meaningful improvement can support such claims.

Early in drug development, sponsors seeking treatment benefit claims in addition to analgesia (e.g., improved physical or emotional functioning) should determine whether a well-defined and reliable patient-reported outcome (PRO) measure exists to assess and measure the concept of interest and context of use or whether a new measure should be developed. The guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims delineates the evidentiary standards by which the FDA reviews a measure for its adequacy to support labeling claims. If additional treatment benefit claims are sought, it is important to also assess the drug's effect on pain (i.e., its analgesic effect) in the same studies, because it is not possible to interpret the effect of treatment on distal concepts (e.g., less constipation) without also evaluating the core symptom under investigation (i.e., pain). FDA recommends that sponsors pre-specify the analysis of endpoints to support additional claims, including methods to address multiplicity

IV. Development program

Analgesic development involves important concepts that sponsors should consider during drug development, such as the duration of drug exposure for the treatment of acute and chronic pain and the subjective nature of pain intensity measurement. It is important that the spectrum of clinical studies planned during analgesic development provide an adequate characterization of the clinical, pharmacological, and, when feasible, pharmacodynamic behavior of the drug.

When developing drugs to treat acute and/or chronic pain, the anticipated duration of exposure to the drug, not other accepted definitions of acute and chronic pain that may appear in medical literature, should define the duration and extent of safety and efficacy data needed to support the marketing application. For the purpose of determining whether nonclinical and clinical safety data support only acute use or support chronic use, FDA considers drugs intended for chronic use as those that may be used for a total duration of 6 months or longer, continuously or collectively, over the course of an individual's lifetime. FDA considers drugs intended to treat acute pain as drugs that do not meet the duration of exposure criterion for chronic pain.

The anticipated context of use should be used to determine how much data would be considered necessary to support the application. Applications for drugs intended for repeated intermittent use in patients with recurring conditions, such as chronic low back pain, should be supported by a larger, long-term safety database. Applications for drugs that could be used more than once in an individual for multiple, independent episodes of pain, where the total lifetime duration of treatment is less than 6 months, would not need as extensive a safety database. As the number of anticipated intervals of short-term use increases, the distinction between acute and chronic use becomes less clear. In such cases, the sponsor should discuss the size of the safety database with the FDA early in development.

A. General Considerations

1. Early Phase Clinical Development

Generally, early analgesic development should be consistent with the standard phase 1 and phase 2 development objectives. Pharmacokinetic characteristics and tolerability should be explored in appropriate volunteers or stable, relatively healthy patient populations. One special consideration to keep in mind when planning early trials of analgesics when dosing is less certain is that pain is a highly activating stimulus. Doses of central nervous system (CNS) active drugs that are tolerated in subjects with pain may be overly sedating or may depress respiratory drive in healthy volunteers. Although subjects in some early studies of opioids can be protected from oversedation and respiratory depression with the use of opioid antagonists, there are no reversal or blocking agents currently available for other existing analgesic drugs or NMEs under development. Sponsors should monitor subjects for early signs of CNS or respiratory depression and appropriate interventions should be planned and specified in advance of initiating clinical

FDA strongly recommends that sponsors include in the protocol detailed information for managing adverse events along with documentation of the immediate availability of staff capable of managing emergencies (e.g., trained in airway management). In general, reliance on transport to an emergency room as the primary support for emergency events may not be appropriate. Stopping criteria for ending further dosing of a dose level, or for discontinuing an individual from the study, should be included in all study protocols. Criteria should be based on the toxicity findings from nonclinical studies, as well as basic vital signs, physical exam, or laboratory parameters as appropriate to the situation. As always, but especially in the absence of any potential benefit for healthy volunteers, risks should be clearly and carefully delineated in the informed consent document. See 21 CFR parts 50 and 56.

2. Drug Development Population

The intended target population for an analgesic indication depends on whether the drug is intended for use in acute or chronic pain, the severity of pain suitable for management with the drug, and the overall risk-benefit balance of the drug. For example, a drug intended for intrathecal use may be indicated for a patient population with pain that is severe and intractable and suitable for the inherent risks of an implantable pump. In contrast, a topical analgesic associated with minimal risk and indicated for the management of local pain may be indicated for a broader population.

3. Efficacy Endpoint Considerations

Because pain is a subjective experience, the choice of an adequate instrument to measure the primary endpoint is critical to demonstrating the efficacy of an analgesic. Therefore, it is important to consider whether a well-defined and reliable instrument exists or can be developed. It is also important that measures be based on scales or instruments that have been adequately developed for use in the population to be studied, and that the instruments be appropriate for use in the setting of a clinical trial to measure change over time. Novel instruments should have documented development and assessment of measurement properties available before use in phase 3 efficacy trials. The development of novel instruments should be discussed with the FDA early in drug development.

Efficacy endpoints in an analgesic trial should reflect a direct rating of pain intensity by the subject for all settings in which subjects can communicate in a reliable manner. FDA recommends the use of a well-defined and reliable PRO measure of the subject's pain intensity. FDA discourages an assessment that requires the subject to report on the concept of pain relief because the subject must compare their current state to a previous state, requiring additional mental processing of the overall experience. Additionally, pain relief scales can take into account not just a difference in pain intensity, but also consideration of how efficacy may be affected by adverse effects; therefore, the scales may represent a rating of a different concept for different subjects.

4. Safety Considerations

The safety evaluation should reflect the fact that analgesics treat the symptom of pain, rather than cure or significantly modify an underlying disease or have a direct effect on survival. The size of the safety database needed to support approval for an acute or chronic pain indication depends on a number of factors, including whether the drug is an NME or a reformulation of a known drug substance, the nature of the safety findings from the clinical trials, and the nonclinical data for the drug under development. In addition, safety monitoring should address drug class-related concerns for new drug substances in existing analgesic drug classes. Clinical trials for development of opioids or other new drug substances that are capable of CNS depression should include monitoring of oxygen saturation and vital signs at appropriately frequent intervals.

B. Specific Efficacy Trial Considerations

1. Trial Design

All analgesics have characteristics that create a challenge for clinical trial design. Pain is a subjective phenomenon. Pain often fluctuates over time. For example, acute pain in the postoperative period typically decreases over days; chronic pain of osteoarthritis can wax and wane over weeks. In addition, it is common to see a fairly substantial placebo effect in analgesic trials. There are known instances of failed clinical trials of analgesic drugs later found to be effective. As a result, noninferiority designs cannot provide definitive evidence of efficacy in analgesic trials. In an analgesic trial, if there is no difference between two active treatment groups, it may be because both treatments are successful in managing pain or because neither treatment was successful in managing pain. Another way to describe this is that the trial lacked assay sensitivity. Therefore, trials intended to support a finding of efficacy for an analgesic should be designed as superiority trials. The comparator can be a lower dose of the investigational drug, a placebo, or an active comparator.

2. Single-Dose Characteristics

To fully characterize the efficacy of an analgesic, FDA recommends evaluating single-dose characteristics including changes in pain intensity assessments following one dose, time to onset of pain relief, and time to rescue or re-medication. Whereas a specific single-dose trial can accomplish this goal, these characterizations can be assessed around the first dose in a multiple dose trial. Onset of effect has most commonly been evaluated using two stopwatches. To avoid overestimating a placebo effect, as can occur with the use of just a single stopwatch measured endpoint, sponsors are encouraged to measure both time to onset of detectable pain relief and to meaningful pain relief. Repeated measures of pain intensity and pain relief over the trial period should establish the time of maximal effect of the drug. The duration of analgesia generally is defined by the median time to a request for rescue or re-medication. It is important that onset of analgesia, duration of effect, and magnitude of effect be determined in clinically relevant patient populations.

3. Multiple-Dose Data

Unless the drug under study is intended for single-dose use, multiple-dose trials should be conducted to confirm efficacy over time.

4. Trial Population

FDA encourages sponsors to apply the following principles to subject selection in analgesic clinical trials. Patient populations in phase 3 clinical trials should represent as much as possible those patients reasonably expected to use the drug after it is marketed. This is particularly important for drugs that may have general pain claims. As a general rule, the characteristics of the population should not be unnecessarily restrictive. In some clinical development programs, it may be useful for one phase 3 clinical trial to have entry criteria that are more narrowly defined, allowing for enrichment where appropriate, while a second clinical trial for the same indication may have broader entry criteria, the results of which can help address generalizability.

5. Entry Criteria

The inclusion and exclusion criteria should describe characteristics of the trial population that support its ability to provide appropriate data for the proposed indication. Some criteria are important to assess when designing analgesic efficacy trials. One criterion is whether individuals with a prior history of substance abuse can be included in the trial. If this is to be permitted, specific monitoring of substance abuse or misuse should be incorporated into the trial. Another criterion is whether individuals are involved in activities that can provide secondary gain that may interfere with assessments. Defining a population as refractory to other analgesic treatments or as opioid tolerant are other criteria that may be important to consider.

6. Randomization, Stratification, and Blinding

Randomization ensures balance between arms on important prognostic factors, whether measured or not. It is important to document the method of randomization in the protocol and the outcome of randomization in the final report. Stratification, adaptive allocation, or other schemes to reduce variance between arms can be used as needed. If employed, FDA recommends that a discussion of how the analyses will account for such schemes be included in the protocol.

There are a few important considerations for randomization, stratification, and blinding specific to analgesic trials. Stratification can be considered for important baseline characteristics or concomitant medications. As noted earlier, analgesics such as opioids that have known withdrawal syndromes are not suitable for randomized withdrawal designs that do not incorporate an adequate period to taper the drug. The outcome measures for analgesic trials are subjective assessments. Therefore, a double-blind design is highly desirable to reduce bias in the measurement of efficacy outcome measures. Consideration should be given to assessing the success of blinding in the trials (e.g., asking subjects at the end of treatment which assignment they believe they received).

7. Specific Populations

The usual assessments of specific populations appropriately apply to analgesic development. However, pediatric pain is considered an unmet medical need because few analgesics carry pediatric indications or specific pediatric dosing recommendations based on clinical data. The suitability of pediatric studies should be considered early in development. Sponsors are encouraged to begin discussions about their pediatric clinical development plan early in development because applicants submitting NDAs (or supplements) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration of a drug are required to submit pediatric study plans no later than 60 days after an end-of-phase 2 meeting, unless another time has been separately agreed upon For further information about required pediatric studies, FDA recommends sponsors refer to the Pediatric Research Equity Act as amended by the Food and Drug Administration Safety and Innovation Act.

8. Dose Selection

Dose selection for analgesic trials should take into consideration the nature of the drug and likely concomitant medications. For CNS depressants, concomitant use of other CNS depressants should be minimized in early trials and explored cautiously later, if such use is expected in the clinical setting. Protocols should include an adequate titration period with monitoring for CNS depression. NMEs should be evaluated for possible withdrawal syndromes, and whether known or expected, adequate tapering periods should be incorporated at the end of the trial. In NSAID trials, sponsors should consider dosing with respect to renal function.

9. Choice of Comparators

As previously noted, efficacy trials for analgesics should be superiority trials. The comparator can be placebo, a lower dose of the investigational drug, or an approved drug if the investigational drug can be expected to be superior. For an approved drug, consideration can be given to a trial design with a dose control as comparator (i.e., a dose lower than known to offer full efficacy). Care should be taken to avoid drawing comparative claims about superiority to an approved drug if the dosing of the approved comparator drug was at or below the lower range of effective dosing.

10. Efficacy Endpoints

There is a broad spectrum of information that should be collected to understand the effects of an analgesic drug and to adequately inform the prescriber. In general, the outcome measures for acute pain and chronic pain studies are similar. When selecting instruments to measure study outcomes, it is important to take into consideration whether the trial population is representative of the population in which the instrument was developed and its measurement properties were demonstrated. It is also important that instruments be sensitive to change over the time period of the trial.

11. Statistical Considerations

The statistical analysis of analgesic trials has two related but distinct goals. First, it should be demonstrated, at an acceptable level of confidence, that the investigational drug has a beneficial effect. Second, it is important to describe the drug's efficacy in some detail. The first goal normally should be addressed by significance testing, which controls the probability of falsely finding that an ineffective drug is effective. As the probability of such false findings is multiplied when there are multiple tests, it is important to specify in advance a single, primary analysis without whose success the trial will not be claimed to provide evidence of efficacy.

There should be a multidimensional description of the drug's efficacy. Questions to be answered can include: How large were the effects? How did the effects vary from subject to subject? How soon after dosing did the effects appear, and how long did efficacy last? The answers to these questions will certainly involve measurements at multiple time points, and they may involve different kinds of measurements as well.

 C. Other Considerations

1. Risk Management Considerations

Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) grants the FDA the authority to require a REMS for certain drug products, IF FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks. FDA may determine that a REMS is necessary to support approval of a drug application or may require a REMS after a drug is approved, on the basis of new safety information.

FDA views drug risk management as an iterative process encompassing the assessment of a drug's risks and benefits, and developing and implementing tools to minimize the risks while preserving the drug's benefits. It is important in developing any REMS to begin by defining the serious risks specific to the drug that must be managed. For example, FDA has determined that a REMS is required for ER/LA opioid analgesics to mitigate the serious risks of overdose, abuse, and addiction.

FDA encourages sponsors to discuss the potential need for a REMS for their analgesic drugs with the division as early as possible during the clinical development program. If FDA advises a sponsor that a REMS is required, the proposed REMS should be complete at the time of submission of the application. Sponsors should refer to the draft guidance for industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications for information on how to format and submit a proposed REMS to the FDA.

2. Skin Studies for Topical Products

Topical products, either those intended for local drug delivery or those intended to provide transdermal systemic drug delivery, should be evaluated for dermal toxicity. Topical safety studies can be most useful if they are conducted with the final to-be-marketed formulation.

3. Fixed-Combination Drug Products

New fixed-combination drug products composed of two analgesics, such as an NSAID and an opiate, are expected to be supported in accordance with the FDA's combination policy 1265 regulations (21 CFR 300.50). This expectation applies to any fixed-combination drug that has not been previously approved by the FDA (i.e., where the particular active moieties combined represent a new combination, even if the components have been previously approved separately). To satisfy 21 CFR 300.50(a), the application for a new combination of two or more analgesic drug substances must provide data that demonstrate that "each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug."

4. CMC Considerations

Analgesics encompass a variety of dosage forms including solid and liquid oral dosage forms, transdermal and iontophoretic patches, parenterals, and liquid and semisolid topical formulations. General guidance pertaining to the CMC of drug development can be found on the FDA Drugs guidance Web page.

The usual criteria for developing a dissolution method are applicable and a robust dissolution method is a necessary tool for assessing in vitro drug release profiles and abuse deterrent properties.

5. Specific Labeling Considerations

For transdermal products, the DESCRIPTION section should include the total drug content of the transdermal system along with the release rate (in mg per day). Also, several categories of analgesic drugs have class labeling in one or more sections.

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