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When completed, this form should be sent to the European Medicines Agency electronically, in Word format (not PDF). 1. General comments
(To be completed by the Agency)
General comment (if any)
Outcome (if applicable)
(To be completed by the Agency)
The new draft guidelines are considered to describe acute pain more clearly and provide helpful guidance in the design of clinical programs. However some of the proposed study requirements for acute pain could be considered unnecessarily rigorous and some clarifications are needed.
The guidelines appear to dismiss the possibility of pure chronic nociceptive pain and suggest that examples of chronic pain may initially be nociceptive but evolve into mixed pain in time. The bar for chronic pain indication is then made impossible to achieve as therapies must have effect on both nociceptive and neuropathic pain. This risks excluding a large patient population that could potentially benefit from relief of an element of their mixed pain.
Limitation of the indication to specific pain models that have been studied is reasonable but should be extended to subgroups of patients whose mixed pain condition e.g. CLBP is predominately nociceptive/neuropathic as appropriate to the therapeutic agent studied.
In this second draft guidance we apparently see a redefining of the distinction of chronic from acute pain, from duration of the pain disorder, to the presence of “maladaptive characteristics”, which over time have developed. In addition previously chronic pain conditions appear to have been reclassified as “long-standing” and in Section 6.2.3, Neuropathic Pain it is not clear if the term “chronic” is in any way now applicable. A reading of the guidance in the current draft suggests that only mixed pain disorders are now suitable to retain the chronic label.
As stated in line 517-8, the contribution of nociceptive and neuropathic components in patients with chronic pain is not routinely evaluated in general clinical practice, and it is for this reason that we would strongly urge the committee to retain/clarify the link between persistence of a pain condition and the term chronic, to avoid confusion in the label for the physician, for whom the distinction between repeated acute insults (example in a “long-standing” nociceptive pain disorder), and a chronic pain condition (in which the initial pain of nociceptive origin has maladapted into an apparently mixed pain condition) is a moot point.
The second draft introduces to the guideline multiple concepts referred to as “maladaptive”: maladaptive pain (pain that is not useful as a signal of injury to the person), maladaptive functioning of a damaged pain processing system (i.e., the pathophysiology underlying a neuropathic lesion), and the maladaptive characteristics of “long-standing” nociceptive pain conditions. It is not clear if this latter concept (“maladaptive characteristics of…”) refers to neuropathy as narrowly defined (damage to neurons in pain sensory pathways) or to neural plasticity (e.g., central sensitisation), or to both. More detailed operational descriptions are needed to allow for a complete reading and understanding of the agency’s views.
In Chapter 6 “specific Considerations for clinical development” it is proposed to discuss the specific cases of:
Specific paragraphs to cover these additional cases can be considered to be included in this Chapter.
It seems that EMA is calling ‘chronic mixed pain’ as ‘chronic pain’ in this guidance. Please describe why it is considered separate from pure neuropathic pain, nociceptive pain and cancer pain.
It appears that more specific and limited labels/ licences are encouraged, recognizing that every type of pain may not respond to a given mechanism. This is great a step forward vs. the “one size should fit all” generalisation. However, this also raises questions on requirements to show that a mechanism/compound works across pain types. This applies not only to CLBP but also very much to cancer related pain. For cancer pain- will one need to demonstrate all components of cancer pain or will they consider subtypes for labelling?
With respect to e.g. OA, but also CLBP, neuropathic pains (and FM), current evidence suggests that all types of pain that is long-lasting have a central component. However, it does not mean that you cannot block a component of that pain by a peripheral mechanism. (For reference e.g. Haroutounian S, et al. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 2014;155:1272–1279. doi: 10.1016/j.pain.2014.03.022.). The draft guidance is eluding to this evolving science but this could be explained with a bit more clarity.
In general the guidance in this draft has improved since draft 1. However, the section regarding Nociceptive Pain now appears to raise a number of important questions for developers which are not answered in this version of the guidance. While appreciating that the guidance may wish to raise some of the issues surrounding clinical studies in this area it would still be helpful to understand what type of clinical development pathways in nociceptive models could result in an indication either for broad chronic pain or indeed chronic nociceptive pain. This appears to be absent in this version.
The following general comments are supplied in relation to the content regarding Nociceptive Pain, focussing on section 6.2.2.
The only nociceptive pain model discussed is OA, and the requirement for maladaptive changes to be present is also stated. We consider that the presence of a centralised (maladaptive) component of the pain is not necessary to show that OA patients are suffering from chronic pain and therefore should not be a requirement to use OA, with associated structural damage at any stage, as a model of chronic nociceptive pain.
In addition, this is not a requirement for development of medicinal products for the treatment of OA pain in the US for example and consequently this inclusion in the EU guideline could present problems in defining a global development plan.
There is currently no guidance on how the maladaptive characteristics could be demonstrated in a clinical trial setting and the guidance itself indicates that in clinical practice it is difficult to characterise these different pathophysiological aspects in individual patients (line 544). If this requirement remains in the final guideline some additional guidance on this topic would be needed.
Support of chronic pain indication:
It is not clear from the draft guideline what would support an indication for chronic pain in the nociceptive component. For neuropathic pain, in section 6.2.3, this is made very clear, for example that both central and peripheral neuropathic pain should be studied or the indication restricted accordingly, and some examples of suitable models for both are given. Conversely, the only model discussed for chronic nociceptive pain is OA. In line 523, categories of somatic and visceral nociceptive pain are mentioned, but no further guidance is given on the expectation to study these types of pain. Is this intended to mean that studies in OA alone will support a claim for chronic nociceptive pain? And will this then support a broader chronic pain indication in conjunction with studies in neuropathic pain models? If OA alone is not sufficient to support an indication for chronic nociceptive pain and a model of visceral pain is required, we suggest that it would be useful to consider including some examples in the guideline. We consider that the following examples are likely to be considered for selection by companies: Interstitial Cystitis, pain due to Crohn’s disease.
In section 6.2.4 it is stated that CLBP typically begins as a nociceptive pain and then develops into a mixed pain due to maladaptive processes. Line 585 states that CLBP is an appropriate specific target population. While this clarification of the possibility of a specific CLBP indication is very welcome it is less clear whether this model would make a suitable model to support a broader chronic pain claim? It is also welcomed that a statement has been included that the inclusion of predominantly neuropathic CLBP would be supportive of a chronic neuropathic indication (line 575). However, it is our position that a predominantly nociceptive (early) CLBP population would be suitable to support a claim for chronic nociceptive pain and this is not made clear in the guidance.
Additionally, it is our position that an indication for specifically nociceptive or neuropathic CLBP (where the population is predominantly one type) is an appropriate chronic pain target, as an improvement in one of two pain mechanisms would still lead to a benefit for the patients and is therefore valuable. We request that this is clarified in the guideline.
6.2.4. Mixed Pain
Mixed pain is common and CLBP is the example most commonly encountered in clinical practice. CLBP refractory to currently available treatments is a substantial healthcare problem and may therefore be considered as an appropriate specific target population. Multiple and complex factors are typically involved in the evolution of mixed pain, which in the case of CLBP generally starts as a primarily nociceptive pain condition with or without nerve compression in addition. Due to maladaptive processes further neuropathic characteristics develop over time. As the typical chronic mixed pain picture develops, the underlying structural damage correlates poorly with the pain experience. Appropriate studies of a mixed CLBP population would lead to a CLBP indication: however if the population studied consists of the predominantly nociceptive or neuropathic components of CLBP, then the indication could be restricted accordingly.
We would like to acknowledge the work of the CNS Working Party and other involved stakeholders that has considerably helped to advance the draft of the Guideline on the clinical development of medicinal products intended for the treatment of pain, while ensuring that new results in basic science and pharmaceutical research as well as current medical practice are much more adequately reflected as compared to the previous draft. The current guideline emphasizes the difficulties and limitations in categorizing pain, clearly acknowledging that for example the classification of pain based on the suspected underlying mechanism into nociceptive and neuropathic may make sense from a theoretical point of view, but that in practice many patients feature mixed pain including both nociceptive and neuropathic characteristics. This cannot be ignored when designing relevant clinical trials. Importantly, while a target indication of chronic mixed pain still is currently not encouraged because of unclear relevance to prescribers, studying mixed pain models is not explicitly discouraged any longer. Moreover we welcome the fact that cLBP, the most common example of mixed chronic pain is recognized as a major healthcare problem and therefore now considered as an appropriate specific target indication. The updated draft also allows for a more targeted development of drug candidates for particular subgroups of patients for whom the mechanism of action of the new medicine seems most suited, rather than focusing only on a concept of medicinal products with a very broad effectiveness which may be outdated.
The updated draft, while providing a general framework for the development of medicinal products for the treatment of pain, encourages applicants to engage in specific, detailed discussions with national competent authorities or the EMA with respect to the specific requirements related to their development products, which is considered crucial for designing meaningful clinical development programs.
The guidance does not reflect the current medical body of evidence that identifies three pathophysiologies of chronic, non-cancer pain and must include all three.
There are different ways to classify pain but the correct way to classify by pathophysiology is nocio, neuropthic and sensory hypersensitivity. Mixed pain is when nocio and neuropathic exist together and is not a separate pathophysiologic entity. Examples of sensory hypersensitivity pain is irritable bowel syndrome, interstitial cystitis. There is often a lot of overlap in patients and FM patients can have neuropathic pain but it is not a requirement for a diagnosis.