The FDA recently released a new draft guidance with recommendations on how sponsors of analgesic painkillers should develop products in preparation for future marketing authorization.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 This draft guidance is intended to serve as a focus for continued discussions on relevant issues among the Division of Anesthesia, Analgesia, and Addiction Products,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.