Practical challenges in conducting respiratory studies.

Respiratory studies are complex on account of specific therapeutic knowledge that is needed and various instruments that are used for the management of this condition. Monitoring a respiratory study requires knowledge of the specific disease and associated guidelines. The intent of this article is to help clinical research professionals understand the technicalities, challenges, and the nuances of performing respiratory studies.

INTRODUCTION

In modern times, the prevalence of respiratory diseases has increased dramatically due to a combination of lifestyle factors and environmental pollution, which has been commensurate with an explosive growth in the knowledge of its epidemiology, etiology, diagnosis, and treatment options. Through this article, we will be highlighting some of the practical challenges in conducting respiratory studies with a particular focus on bronchial asthma and chronic obstructive pulmonary disease (COPD). The overall worldwide prevalence of Asthma ranges from 1% to 18%, affecting 300 million people worldwide[12] and in India the prevalence is 2.4% in adults over 15 years of age.[3] COPD kills more than 3 million people every year (prevalence: 4-10%),[4] making it the 4th largest cause of death in the world.[5] Half a million (prevalence around 8%) people die every year due to COPD in India.[5]

A clinical trial needs a lot of planning, time for execution and resources. When it comes to respiratory disease such as asthma, COPD (obstructive), and idiopathic pulmonary fibrosis (restrictive), it becomes even more difficult as in addition to the knowledge of the therapeutic area, technical knowledge with respect to handling of various instruments for disease management is required.[1678]

The intent of this article is to help clinical research professionals understand the technicalities, challenges, and the nuances of performing respiratory studies.

CHALLENGES AND STRATEGIES

Patient specific challenges and strategies

The profile of respiratory diseases like asthma and COPD is often variable. The disease intensity can vary based on various factors such as environmental factors, smoking history, genetic factors, etc. Education of the patient's with respect to the disease helps in circumventing the factors which influence their disease severity. For example-avoiding cold environment, food allergens, smoking cessation, etc. Therefore, it is imperative to include such educated and well-trained patients in the clinical studies.

Specialized tests such as spirometry, body plethysmography, lung diffusion capacity are required to manage the disease. The results of these tests are highly subjective and depend mainly on cooperation and efforts from patient and technician in performing the test correctly. In clinical trials with spirometry parameters (forced expiratory volume in 1 s, forced vital capacity) as the primary end points, spirometry needs to be performed per the American Thoracic Society (ATS)/European Respiratory Society (ERS) standards.[67] Hence, it becomes imperative to include only such patients who will be able to fulfill these requirements.

Current medical practice specific challenges and strategies

In India, barring a few exceptions, patient's medical records are usually kept with the patients, due to which there is high probability of patient losing these important documents from the date of diagnosis. In addition, patients go hopping from one doctor to another resulting in delinking the new doctor from the past medical management of these patients.

Unavailability of documentation of past medical management, poses a major challenge in assessing patients eligibility to participate in study. Patient may be taking a prohibited medicine, which could have an interaction with the investigational drug, or could have a medical condition in which particular study procedure is prohibited.

To compound the problem, Indian doctors generally do not have a habit of writing detailed notes, which leads to source documentation gaps during clinical trials. Hence, while including these patients in clinical trials, it important for the site to document the negative medical history based on their interview with the patient or their treating physician. Furthermore, detailed medical examination should be performed in all cases to collect complete medical data.

Many a time patients do not remember their exact date of birth (DOB). In studies involving spirometry, exact DOB is needed to calculate the percent predicted values, which determine patient eligibility. Even a small difference in the age can result in a different predicted value [Figure 1].[91011] This may result in including an ineligible patient in the study. This issue can be counteracted by filing age proof documents in source files like permanent account number card, driving license or equivalent or in their absence with a through interview with the patient.

Figure 1

Predicted values for forced expiratory volume in 1 second by sex and ethnic group[10]

In the clinical practice, asthmatics are treated based on their disease severity. There is no need for the clinician to know exact difference between high, medium and low dose of inhaled corticosteroid (ICS). However paradoxically in clinical trials the differentiation in the ICS doses determines the severity of asthma per Global Initiative for Asthma (GINA) guidelines and hence the investigators need to be trained on GINA guidelines.[1]

To counteract the challenges posed due to incomplete or unclear medical history it is important to lay basic expectations for source documentation in respiratory clinical studies. This can be done through a source documentation workshop at investigators meeting wherein expectations can be set by the sponsor regarding the minimum requirements, which need to present in the medical history and patient notes to determine eligibility and also continuing documentation throughout the clinical study. This is needed to ensure compliance not only to the study requirements, but also to ensure compliance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP),[12] regulatory,[13] and legal requirements.[13]

Another issue which is predominantly seen in trials involving COPD patients is with pack year calculation for bidi/cigar/cheroot/pipe tobacco/hookah smoking. There is a great variability in published articles,[141516] which give differing formulas for calculating pack years for above-mentioned smoking types. A pack year for cigarettes is calculated as 20 cigarettes smoked every day for 1 year (pack years = number of cigarettes per day × years of smoking/20).

In case of bidi smokers, the number of pack years was further divided by four, as some articles suggest four bidi's are equivalent to one cigarette.[1415] However, data from other articles suggest that bidi is more harmful or at least as equally harmful as cigarette.[17] Considering the references[141516] and until research on this topic evolves further, we can consider one bidi as equivalent to one cigarette for pack year calculation, as it takes into consideration more factors than merely grams of tobacco in bidis and cigarettes such as nicotine, tar, carbon monoxide, etc.[16]

The article from Lange et al.[17] provides clear information about content of tobacco in cigar, cheroot, and pipe tobacco. Per this article one plain/filter cigarette and 1 g of pipe tobacco is equivalent to 1 g of tobacco, one cigar is equivalent to 5 g of tobacco, one cheroot or cigarillo is equivalent to 3 g of tobacco. Further it provides formula for calculation of pack years based on grams of tobacco content (Pack years = number of gram per day × years of smoking/20).

Hookah/narghile/shisha/goza is different names of waterpipe smoking. Waterpipe smoking is associated with many of the same risks as cigarette smoking, and may, in fact, involve some unique health risks. In 2007, Dr. N. J. Masters and Catherine Tutt, designed a simple web based smoking pack years calculator for detection of asymptomatic COPD patients.[18] This web based tool is specially recommended for use to calculate smoking pack years for waterpipe smoking (which is based on TobReg's Advisory Note[19]) as no other currently published research provides information about how to calculate pack years in waterpipe smokers.

Site specific challenges and strategies

In India, the diagnosis of respiratory airway diseases is mainly based on patient's history and radiological tools such as X-ray, computed tomography scan etc. Very rarely tools like pulmonary function test are used other than in specialist pulmonology centers. Barring few organizations, there is a lack of awareness about spirometry with others. Hence, the need of the hour is to create mass awareness about the use of spirometry through such organizations for the management of respiratory disease. While selecting investigators, in clinical trials one has to therefore ensure that site is using spirometry on a regular basis, has a trained spirometry technician, is well-versed with ATS/ERS 2010 requirement, understands the need for calibration and performs and interprets acceptable, reproducible graphs. High level of oversight is needed during the trial to ensure good quality spirometry reports. Retraining of site staff is the key to avoid major spirometry quality issues.

It is a requirement per ICH GCP E6[12] that the equipment's (sphygmomanometer, thermohygrometer, weight scale, etc.) used in clinical trials should be calibrated/validated per the manufacturers standards, so that they provide accurate readings. Since spirometer needs inputs about room temperature, atmospheric pressure, height and weight of the patients, it is even more important for clinical researcher to ensure that the machines used for calculating the same are calibrated and deliver accurate values. Sites should have a standard process to ensure calibration/validation of equipment's used in clinical trials throughout the studies and wherever required the clinical monitor should provide assistance to sites to ensure the same.

In studies in which the sponsor employs a vendor for an independent assessment of spirometry results, the spirometry machines are provided by the external vendor. During such studies, sites need to regularly transfer data through analogue fax lines to spirometry vendors. This requirement needs to be assessed during the site qualification visit else there will be data transmission errors or failures subsequently. Successful test transfers at the time of initiations are the best way to avoid these issues. Even after this, there are chances of technology failure, to which multiple other solutions are available. Monitor needs to discuss the same with the spirometry vendor to find an acceptable resolution.

When the spirometry data is transferred centrally, it is reviewed by independent central expert for quality of spirometry graphs per the ATS/ERS 2010 standards. When any of the best peak expiratory flow value loop is rejected and second best is chosen for quality issues a “Best test review report” (BTR) is generated. These reports are faxed to investigators and they are expected to approve/reject it, based on their assessment. Disregarding the first best and using second best loops at the time of enrolment because of quality issues can result in ineligible patients participating in the study. This can be avoided by proper oversight from sponsors monitoring team and requesting the central spirometry vendor to send a copy of this BTR to study monitor too, so that the later can remind the site about the BTR/s.

Study specific challenges and strategies

During the management of respiratory disease like COPD and bronchial asthma, in addition to the standard treatment, patients also need rescue medication (such as salbutamol and/or ipratropium bromide through pressurized meter dose inhalers [pMDI]) to give immediate symptomatic relief. In clinical studies a similar treatment paradigm needs to be followed. It is very important to ensure that the patient uses sponsor provided rescue medication as the doses taken from this are accounted for and used to evaluate need for rescue, symptomatic relief, health condition, and effectiveness of study treatment, which could be the efficacy or safety endpoints.

Some of the studies mandate serial pulmonary function tests. In such situations site staff are needed to stay back for a long time, sometimes even overnight at the site. Our experience is that sites usually agree to the requirement after the scientific rationale is explained to them and an adequate provision is made in the investigators site budget. Such studies are time consuming and it is important to remember these factors while making enrolment expectations/projections. Furthermore, these studies need day care or inpatient facilities, for which appropriate set up has to be ensured.

There are multiple calculations available and used by Indian doctors while calculating spirometry predicted values.[2021] However, majority of chest physicians across the world use and most of the published literature refers to European Committee of Coal and Steel (ECCS) calculations.[21] Race is an important parameter for calculating percent predicted values by ECCS formula. While using these formulas one has to ensure correction factors for Indian race (North Indian-0.9% predicted and South Indian 0.87 of percent predicted).[2122] In our experience, the most common error which happens with respect to this is selection of Caucasian or Asian as the race instead of South/North Indian race. Hence, adequate training has to be ensured at the time of site initiation for capturing and maintaining adequate source notes for case report form and spirometry entries.

In most of the asthma and COPD studies “asthma monitors” (combo device which has an electronic diary + peak expiratory flow rate monitor [PEFR]) are used to capture patient's study medication compliance, rescue medication usage, symptoms, PEFR, etc. Since this device has questionnaires validated for self-administration only, care has to be taken to include literate patients in the study who can complete these questionnaires. Better compliance can be ensured by explaining patients about the benefit of proper and timely use this equipment, in the management of their disease.

The ICS doses recommended in GINA guidelines[1] and study protocols are based on chlorofluorocarbon (CFC) formulation. However, all CFC-propelled formulations have been replaced by pMDIs containing hydrofluoroalkane (HFA) propellants. Since CFC and HFA formulations are not equivalent there is a conversion factor involved. Therefore, medication inserts (and SPCs) for HFA preparations should be carefully reviewed by the investigator for the equivalent correct dosage and conversion factor. In India, package inserts do not contain information about HFA to CFC conversion. Hence, decision on conversion factors has to be taken carefully based on the formulations available in other countries and discussion with investigator and/or sponsor in case of doubt.

Other challenges and strategies

To execute high quality respiratory study, in addition to GCP training,[12] respiratory therapeutic area training to the study monitor/s is must. Through these therapeutic area trainings the study monitor/s should also be trained on basics of spirometry. They should also be trained on handling of above-mentioned challenges and to ensure adequate corrective and preventive actions for these challenges.

CONCLUSION

As we continue to gain expertise in doing high quality respiratory research, more and more challenges will be seen. To keep up with the pace of change in this discipline and the ever increasing expectations of the regulators, we need to plan in advance, check, plug the gaps, and recheck.

To conclude studies in respiratory disease like asthma/COPD are logistically difficult to execute. There is an increasing need for experienced sites and study monitors. Since modern clinical research involves a lot of documentation, setting up expectations with respect to source documents upfront and having dedicated coordinators is the need of time. Lessons learnt from past experience should be discussed with the monitoring team before the start of the study and an experience sharing can be done with the investigators during the Investigator's meeting and site initiation visits [Figure 2].

Figure 2

Success strategy

Creating awareness about the best GCP practices and continuous retraining during the conduct of the study based on the learning's from monitoring/co-monitoring visits will be essential in ensuring good quality respiratory research in India. Since the pool of trained respiratory research sites is limited, there is an urgent need of using some of the abovementioned points to promote the development of new sites and investigators in respiratory research in India.