EMA Publish Guideline on Clinical Evaluation of Treatments for Hepatitis C
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This guideline provides guidance on the clinical development of compounds for the treatment of Chronic Hepatitis C (CHC), including directly acting antivirals (DAAs) as well as host targeting antivirals (HTA). It should be read in conjunction with updated and recognised clinical treatment guidelines. Various combination regimens, including a DAA or HTA together with peginterferon (pegIFN) and ribavirin, regimens with more than one DAA/HTA in combination with pegIFN + ribavirin, as well as regimens excluding either or both of these agents, are considered.
While the primary investigation of new DAA/HTA in combination with pegIFN + ribavirin in patients with genotype (GT) 1 remains important, it is recognised that other paths of drug development, focussing on wider or alternative populations, or other drug combinations (such as more than one DAA/HTA with or without ribavirin, or 2 DAA/HTAs in combination with pegIFN+ribavirin) are warranted and ongoing.
The guidelines emphasize the importance of new DAA/HTA for usage in special populations including patients with decompensated liver disease, patients pre/post transplantation, HCV/HIV co-infected patients, patients intolerant to pegIFN and/or ribavirin and patients with prior DAA experience.
When studying novel agents in combination with pegIFN and ribavirin, the comparator in pivotal trials should be a licensed first line recommended regimen; notwithstanding this, European regulators recognise the need for licensed DAA/HTAs from several classes, with different side effects profiles and resistance patterns, which is seen as a benefit per se. When studying novel drug combinations without pegIFN, it is recommended that patients previously failing therapy with pegIFN+ribavirin that do not have an immediate treatment need be avoided prior to obtaining proof-of-concept of sustained virological response (SVR), as the consequences of acquired drug resistance in terms of retreatment success has still not been investigated. For drugs to be used in combinations eschewing pegIFN, it is recognised that patients that do not tolerate pegIFN have no presently licensed therapeutic options and a probability of viral clearance close to zero. Thus, for licensure, response rates would be weighed in relation to this fact. Regarding special populations, the need to start trials as early as can safely be done for groups with an important unmet medical need (e.g., patients with decompensated liver disease or HCV/HIV coinfection) is emphasised, Since the previous guidelines were adapted, host IL-28B genotype has emerged as a very important predictor of the efficacy of pegIFN, and it is recommended that stratification by IL28B genotype be employed whenever the studied drug regimen includes this drug.
Regarding future developments, proof-of-concept of SVR with treatment combination excluding pegIFN, as well as data on retreatment of patients that have failed therapy that has selected for DAA-resistant variants, but whose dominant population has subsequently reverted to wild-type, are eagerly awaited. Such data are likely to greatly impact regulatory considerations within the field. It is recognised that this is a rapidly moving therapeutic area, and that a further revision of these guidelines may be mandated within the foreseeable future.
Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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