Drug Regulators, EMEA, Publish Guidance of the Development Of Medicinal Products for The Treatment of Cystic Fibrosis

Full Text Here

The aim of this guideline is to provide guidance on the clinical development of compounds for the treatment of cystic fibrosis, a systemic chronically debilitating disease, mainly paediatric up to now, with a regularly increasing adult population as life expectancy improves (47% adults in 2006 according to ECFS, mean-aged 16-22 yrs).
Because up to now cystic fibrosis cannot be cured, currently the goal of therapy is to delay disease progression.
In the context of insufficient long-term efficacy of available treatments, and high level of associated non-compliance, morbidity and considerably shortened life expectancy, there is a need for new medicinal products to treat pulmonary disease and infections and exocrine pancreatic insufficiency and associated malnutrition. Both conditions affect > 90% CF patients and are the major responsible for morbidity and mortality.

Efficacy in pulmonary disease

As a rule, the goal of therapy is to maintain/restore respiratory function, as assessed by FEV1. However, a microbiological primary endpoint at 28 days is acceptable for confirmatory trials in the treatment of early lung colonisation or of chronic infection exacerbations. For almost all other pulmonary indications, FEV1 will be the primary endpoint:
• For prophylaxis and treatment of chronic PA infection, it is recommended to stratify the patients population at inclusion according to the severity of the pulmonary impairment based upon Respiratory Function Tests, and to age in paediatric studies. An at least 6-month clinical primary endpoint assessing the respiratory function through FEV1 measurement is recommended in confirmatory trials, with a 12-month follow-up for safety. Corresponding secondary endpoints should include a microbiological endpoint documenting the potential to select resistant strains and colony density, from an efficacy as well as from a safety viewpoint.
• For slowing/stopping pulmonary disease progression, a 12-month FEV1 endpoint is recommended. Microbiological secondary endpoints such as the “number of exacerbations’ are necessary to document efficacy , while enabling ruling out a negative effect on the most relevant pathogens in CF patients. Randomised active-controlled confirmatory trials are mandatory when a reference treatment exists. When no reference treatment exists, a placebo-controlled study in mild to moderate patients on top of
best supportive care is recommended. When the claim is to treat the underlying chronic obstructive disease by improving airway clearance, either by altering the thick mucus or by enhancing mucosal hydration, currently approved mucoactive drugs should be used as an active control, in the frame of a superiority trial or a 3-arm non inferiority trial. The standardisation of concomitant therapy (including bronchodilators, physiotherapy and mechanical therapy) is strongly recommended.

Efficacy in exocrine pancreatic disease (replacement therapy)

Standardisation of the patient’s specific diet (on a patient per patient basis) is mandatory:
• When the claim is for a ‘Global improvement in nutritional status’ dependent on nutrient digestion and absorption, placebo-controlled superiority confirmatory trials in the frame of add-on studies are mandatory (on top of standard therapy). The primary efficacy criterion should allow demonstrating a clinical benefit: target height at 12 months and normal weight at 6 months in children, weight gain or nutritional status at 6 months (changes in body weight, weight/height and Lean Body Mass) in adults.
Corresponding secondary efficacy criteria should be biological and investigate pancreatic enzymes activity (steatorrhoea and protein synthesis).

• When the claim is a pharmacological claim (e.g. for a ‘me too’ PEP), active-controlled-trials are mandatory and non inferiority trials are accepted. A biological endpoint (steatorrhea or protein synthesis) can be accepted as a short-term primary endpoint in confirmatory trials, preferably in the frame of cross-over design due to the high level of inter individual variability.

Efficacy in improving CFTR function

A therapy aiming at improving CFTR function (protein therapy or protein modulator) may be expected to translate into a clinical improvement in pulmonary disease. The disease improvement through assessment of another organ function would be also an acceptable endpoint. The translation of disease improvement into improved organ function may be limited by the level of irreversible damage at the time of treatment initiation, and may be unlikely in pancreas. That is why the greatest expected benefit of such therapy would be expected in young children. Since we have no data in that field, the primary endpoint in confirmatory trials should be clinical to evidence that the CFTR default correction actually translates into a long-lasting clinical benefit. The clinical endpoint used will be based on the target organ. Because of the associated specificity of disease features, trials should rely on a stratification of patients at inclusion, based on the characterisation of the class of mutation. Alternatively, it may be
more appropriate to conduct trials in patients with specific mutations or mutation class. Further recommendations to this regard are premature.

Safety

Influence on growth and development should be systematically addressed in paediatric studies. The emergence of resistance to an ATB should always be assessed, and cross-resistance between different ATB used in the treatment of PA infection should be addressed. Regular assessment of good aerosol technique is needed. Also rare, a definite dose-dependent lipase-induced fibrosing colonopathy has been found in young children, which should be monitored and taken into account when establishing the initial dosing of PEP and maximal Pancreatic Enzyme Replacement Therapy (PERT).

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our 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.

Avoid Expensive Mistakes, Keep On Top of New and Changing Regulations for Free.

As you know this website is a great resource for keeping up to date with developments and regulations, why not get our FREE monthly regulatory and market round up. You can un-subscribe at any time and we do not share your details with anybody.

Turn your Business Into an Investor Magnet

How to Write a Business Plan – Free E-Course

Get the secrets that turns your project into an investment magnet, 100% of our clients raise the finance they need to take their projects to the next stage, we will share these secrets with you. – Sign up for Free

“Please note that the pages on this website are designed to provide you with general information only. We make no warranties, representations or undertakings about any of its content. This includes the completeness, accuracy and fitness for any particular purpose, or the content of any third party site referred to or accessed through it. You are personally responsible for ensuring that the information is correct and we will not be held liable or accountable for any mistakes that occur.”