Patient-Reported Outcome Measures for Cystic Fibrosis

Dr Nicola Davies explores the utility of PROMs in pharma, with a focus on cystic fibrosis.

Dr Anoushka de Almeida, Head of Research at the Cystic Fibrosis Trust, London, UK.



“The advances seen in clinical research regarding patient-reported outcomes (PROs) and patient-reported outcome measures (PROMs) have been mirrored in research on cystic fibrosis. A large number of instruments have been used for both therapeutic and non-therapeutic clinical research for many chronic conditions,” says Christopher Goss and Alexandra Quittner in their study on ‘Patient-reported Outcomes in Cystic Fibrosis.’

According to the FDA, “A PRO is any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else.” PROMs refers to the specific instruments designed to gauge a patient’s response – usually through carefully designed questionnaires. The former is frequently discussed in relation to pharma, but how can the latter be better utilized within the industry?

PROMs for disease prevention and symptom relief

With cystic fibrosis, the main aim of treatment is symptom relief, as well as the prevention of comorbidities that might impact quality of life. In particular, cystic fibrosis leads to the production of exceptionally thick mucus, which can cause obstructions of the bronchi, often resulting in respiratory infections as well as intestinal and pancreatic duct hindrances. The pancreas is responsible for the production of insulin so cystic fibrosis can increase the risk of developing diabetes, which currently stands at almost 20% of cystic fibrosis sufferers. Given that diabetes is reaching epidemic proportions worldwide, one focus of pharma is on conducting clinical trials and gaining data on the efficacy of various medications aimed at stemming the tide of diabetes.

The over-production of mucus hinders the passage of digestive enzymes from the pancreas to the small intestine, resulting in the body being unable to absorb all the necessary nutrients from food. This can cause constipation, poor growth, and malnutrition unless a specific diet is followed to help ease these problems. Through careful reporting of these symptoms especially in pediatric patients, pharma will be able to design treatments that can assist in alleviating the symptoms.

Cystic fibrosis has no cure, but through early diagnosis, correct medication and changes in lifestyle the symptoms and complications can be reduced. This is where early intervention through PROMs and closely monitored patient reports can assist pharma in developing medications. By using PROMs from patients who are at risk of this hereditary disorder, symptoms that are observable can be taken into account, as can the unobservable, such as how the patient feels with regard to pain or difficulty in breathing or whether the patient is feeling depressed.

Using PROMs in clinical trials

The various ways PROMs can be used to improve the lives of people with cystic fibrosis are through clinical trials to establish primary or secondary outcomes; evaluation of new pharmaceutical interventions and comparison of treatments available; assessment of the effect of cystic fibrosis on patients' daily functioning; and, to aid in establishing the cost-effectiveness of different treatments.

Dr Anoushka de Almeida, Head of Research at the Cystic Fibrosis Trust, London, UK, explains how early detection of the gene that causes the disease in children can improve life expectancy and quality of life. She says, “Early diagnosis of cystic fibrosis has been improved by the practice of newborn screening. Studies have suggested that early diagnosis can prevent problems such as severe malnutrition, and, in turn, protect against any negative effects in cognitive function. An improvement in long-term growth is also apparent. Other trials have concluded that pulmonary benefits from cystic fibrosis newborn screening are likely in early childhood, but we need to bear in mind that effects on long-term pulmonary prognosis are more difficult to assess due to factors such as infection and pancreatic status.”

It was through clinical trials utilizing PROMs that Lynovex® was developed. The results of the Novartis Phase IIa clinical trial, comprising 10 patients, found that Lynovex® could be absorbed and processed in concentrations shown to minimize the impact of outbreaks of lung infection for people with cystic fibrosis. Through close collaboration with patients, the Cystic Fibrosis Trust and pharma, what has been hailed as a breakthrough drug has been developed by Novartis.

“We are delighted to see the encouraging results from the Phase IIa clinical trial, which confirms earlier findings that Lynovex® has the unique properties suited to minimize the impact of pulmonary exacerbations (lung infections) in cystic fibrosis. The promising data takes us a step closer to realising the positive impact Lynovex® will have on the lives of people with cystic fibrosis,” says de Almeida.

She adds, “This project is an excellent example of the Cystic Fibrosis Trust collaborating with pharma companies; an important area highlighted in our research strategy. We look forward to the next stage in the development of this ground-breaking treatment.” Through organizations such as the Cystic Fibrosis Trust, pharma can access patients willing to participate in clinical trials and through the use of PROMs all stakeholders gain more insight into the efficacy of medications.

The complexity of cystic fibrosis PROs

The goal of cystic fibrosis treatment is to deal with lung infections through prevention and control, to loosen and remove mucus from the lungs, to prevent and treat intestinal blockage, and to make sure nutrition is adequate. Managing the disease through collaboration between pharma, healthcare, and patients provided with PROMs has already proved worthwhile in terms of early diagnosis and preventative measures to slow the progression of the disease.

Despite the usefulness of PROMs for pharma, there remain some important considerations. In particular, the complexity of the symptoms of cystic fibrosis,which may vary depending on the severity of the disease, means that the end point for PROMs need to be carefully considered. They must be reliable, valid and meet “rigorous psychometric criteria,” according to Goss. Among these would be considerations of the time frame – if patients have to remember how they felt a month ago there could be memory bias, for example, but if they have to describe how they feel within a few minutes of a treatment the results would be more accurate.

The FDA has published a set of guidelines on the use of PROMs and states, “Generally, findings measured by a well-defined and reliable PRO instrument in appropriately designed investigations can be used to support a claim in medical product labeling if the claim is consistent with the instrument’s documented measurement capability.”

They also highlight that, “The conceptual framework of a PRO instrument may be straightforward if a single item is a reliable and valid measure of the concept of interest (e.g., pain intensity). If the concept of interest is general (e.g., physical function), a single-item PRO instrument does not provide a useful understanding of the treatment’s effect because a stand-alone single item does not capture the domains of the general concept.”

Collaboration is the key to PROMs success

The pharma industry is working with institutions like the Cystic Fibrosis Foundation (US) and Cystic Fibrosis Trust (UK) to develop medications that take into consideration PROMs data.

“There are a number of pharma companies with drugs in the pipeline which will benefit those with cystic fibrosis,” says de Almeida, “One successful example is the approved drug, Ivacaftor (aka Kalydeco), developed by Vertex Pharmaceuticals, in conjunction with the Cystic Fibrosis Foundation (CFF) in the US. Ivacaftor is the first drug that treats the underlying cause rather than the symptoms of the disease, and improves lung function in people with cystic fibrosis with certain mutations.”

Recently, Vertex/CFF carried out a phase 3 clinical trial which used this drug in combination with another, Lumacaftor, again showing some improved lung function, but this time this combination treatment (Orkambi) is effective in a much larger cystic fibrosis population. “Orkambilooks set to be an important additional treatment option that could improve the lives of many more people with cystic fibrosis,” says de Almeida.

So, it appears that PROMs could be the future of healthcare and that pharma will increasingly be required to report on patient-reported outcomes. Goss and  Quittner said in their article, “We believe that the future of cystic fibrosis research will incorporate a more diverse selection of PRO outcome measures; these outcome measures ultimately may be incorporated into clinical care to standardize symptom assessment and provide information regarding the need for specific clinical interventions to improve the quality of care delivered to these patients.”

Through PROMs it would seem that pharma can achieve confirmation of the benefits of a treatment while at the same time maintaining the integrity of the trial. PROMs create a win-win situation for patients and pharma.


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