Talking with JSS Medical’s Dr John Sampalis

Dr John Sampalis, President and founder of JSS Medical Research Inc., is a clinical epidemiologist with graduate training in Clinical Epidemiology and Biostatistics (MSc and PhD) from McGill University. Currently, he is a tenured Associate Professor of Surgery and Epidemiology and Biostatistics in the Faculty of Medicine at McGill University with equivalent appointments in the Faculties of Medicine at Laval University and the University of Montreal. Dr Sampalis has more than 60 peer reviewed publications and 80 presentations to date and over US$6.5 million dollars in federal and provincial research grants awarded. He is recognized as one of Canada’s leading epidemiologists, as well as the top trauma researcher in Canada.

Here, he talks to NGP about the importance of employing scientific rigor right through the clinical trials process – from phase I to post-marketing observational studies.

NGP. What challenges do drug companies currently face in terms of performing successful, cost-effective clinical trials?

JS. There is an increasing demand for healthcare and effective interventions that are aimed not only at prolonging life but improving quality of life. The population of the world is aging while remaining very active and relatively healthy. As a result, the prevalence of individuals alive with chronic diseases is increasing and along with this, there is an increasing demand for better and more effective medications. In consideration of this increasing demand, pharmaceutical companies are faced with the challenge of developing new effective medications, testing them and bringing them to market within a very short time.

While facing the challenge to develop new effective medications, pharmaceutical companies also have the challenge of continuously demonstrating effectiveness and safety of their drugs that are currently on the market. Government and regulatory agencies are becoming much more sophisticated and much more demanding with respect to the quality of the studies used to support and maintain approval of drugs. As a result, pharmaceutical companies have to ensure that they invest in high-quality studies that could withstand scrutiny. Furthermore, patients have evolved from passive recipients of health care to active consumers. Consequently the consumer/patient is now better informed and challenges medical decisions regarding their treatment. Pharmaceutical companies and healthcare providers are also faced with the challenge of accurately disseminating information through mass media and the internet that supports their claims regarding evidence of the safety of their drugs.

In order to meet these demands imposed by the aging population, a more sophisticated regulatory machine and critical patient/consumer, pharmaceutical companies have no choice but to conduct clinical research that is of the highest possible quality. Failing to do so will result in loss of credibility and revenues.

While the demand for high quality research is increasing, a proportional increase in the training of individuals capable of conducting high quality research has not been observed. This is because the graduates of medical school are overwhelmed with a sober specialization, high clinical volume and resource limitations and are therefore prevented from dedicating their valuable time to clinical research. Pharmaceutical companies, especially in Canada, are faced with an astonishing lack of highly trained individuals that could be hired to conduct clinical research. The majority of pharmaceutical companies are constantly actively searching for highly specialized clinical researchers but this demand cannot be met.

NGP. And what role are organizations such as yours playing in helping drug companies meet these challenges?

JS. In order to design and execute high quality clinical studies that could withstand peer-reviewed scrutiny, an academic background in clinical research, experience with the industry, knowledge of the government requirements and strong business management are essential. Our organization combines all of these characteristics. Our core scientific group is comprised of academics, individuals with long-term clinical research experience both in the academia and the industry, biostatisticians, computer programmers and business administrators with knowledge of the healthcare industry. In addition, our involvement in government reviews provides us with valuable insight on the regulatory and approval processes and requirements from a scientific point of view. By collaborating with an organization like ours, pharmaceutical companies benefit from our academic background, industry experience and government knowledge.

NGP. With clinical trials forming the largest single cost for new drug development, how can pharma companies help drive down clinical research expenditure?

JS. In order to minimize clinical research expenditure while meeting the increasing demand for more and better clinical trials, pharmaceutical companies have to become efficient. Establishing alliances aimed at developing research programs with credible organizations will allow them to achieve this. As a result, costs for individual trials will be minimized through volume. As an example, instead of entering a contractual agreement for the execution of a single trial it would be more efficient if the scope included several trials within the same clinical research program. By taking advantage of the similarities between studies within the same program, overall costs and time to complete clinical trials would be reduced significantly.

NGP. Looking specifically at phase IV trials, the life sciences industry is experiencing strong pressure for phase IV to have a more rigorous scientific basis – what does this entail? How would current practices need to change?

JS. The recognition that phase IV studies continue to be clinical research studies and not marketing programs is an important one that has been long overdue. Governments, regulatory agencies and editors of high-ranking reputable clinical journals recognize the importance of phase IV studies in the ongoing evaluation of effectiveness and safety of market interventions. However, the same stakeholders have become weary of phase IV studies being used for the sole purpose of directly increasing market shares of a specific branded drug. As a result, several phase IV studies have come under severe scrutiny and may never be published. In order to prevent this from happening, pharmaceutical companies have to engage individuals with appropriate clinical research training and experience to design and conduct these studies. These individuals have to be capable of not only designing and executing the study but also appropriately analyzing the results and disseminating information in a way that it would receive scientific peer reviewed acceptance. Engaging market-based or distribution organizations to conduct these kinds of studies would be counterproductive and could result not only in the loss of the investment but of the credibility of the sponsor.

In the recent years, a large number of pharmaceutical companies have realized the importance of conducting properly designed and executed phase IV studies and engage or hire well-trained clinical researchers. Current practices would have to change, not only from the point of view of the pharmaceutical company, but also from the perspective of regulatory and government agencies. To be more specific, from the societal point of view, the single most important objective of a phase IV or post-marketing observational study is to ensure that the intervention is safe and effective when applied in the real-life setting. In fact, phase IV studies are often mandated to confirm or further assess important safety signals or evidence that may suggest therapeutic ineffectiveness of the intervention.

Regulatory agencies such as Health Canada and the US FDA often require the results of the studies to make final decisions about approval of a specific drug or specific drug formulation. Changes in labeling or ‘Dear Dr’ letters are often based on results of the studies. However, despite the importance of these studies, there is no regulation on how they are conducted or who is involved in the execution of the study, the data analysis and the interpretation. These government agencies react to badly conducted studies and often request from the sponsor another study or intervene with label changes or even removal of the drug from the market. This could have been prevented if the studies were properly conducted. Establishment of accreditation, ensuring that individuals with academic training and experience in clinical research are ‘licensed’ to conduct the studies, would be an appropriate solution. It is fascinating that in our society we demand licenses for mechanics and permits to build homes or to renovate backyards, however, there are no license requirements for those conducting clinical trials – the results of which could affect the safety of millions. Nearly all Canadian medical schools provide graduate training in clinical research. Establishing training requirements for those that conduct clinical research and sign clinical study reports should be an easy process.

NGP. There are a number of important considerations involved in the development, design and conduct of a large-scale phase IV or post-marketing trial. What should drug companies and clinical research organizations bear in mind when conducting a phase IV trial, and what are the various methods and opportunities available for addressing these issues?

JS. What is important to keep in mind when designing and conducting phase IV studies is that the studies do not have lower requirements from the point of view of scientific quality and rigor when compared to phase II or III studies. The only thing that is different in phase IV studies is the patient population and the fact that the study protocol must involve treatment methods that resemble, although are not identical, to that of real-life routine clinical practice. From the point of view of study design, adherence to good clinical practices, statistical analysis, accuracy of the results and interpretation, there is no difference between these studies and those of earlier phases. One important distinction of phase IV studies is that they are aimed at demonstrating ongoing effectiveness and safety in the target population or patient subpopulations. Consequently, we have very good estimates of effect size and expected results. Properly designed phase IV studies could also identify new indications and special patient populations that could benefit from the interventions.

NGP. What is a post-marketing observational study (PMOS) and where does it fit in with regard to the drug production cycle?

JS. A post-marketing observational study is a truly epidemiological study aimed at assessing the effectiveness and safety of an intervention in a non-controlled, real-life setting. In these studies, we observe the effect of the intervention without interfering with its application. These studies are not necessarily part of the drug development cycle but are essential in many cases for ongoing accumulation of evidence regarding effectiveness and safety. It is important to keep in mind that in post-marketing observational studies the interventions are not provided to the patient by the sponsor but are acquired or paid for through usual channels. In addition, sponsor involvement in selecting patients or even investigators in post-marketing observational studies is unacceptable. Patients and physicians participating in the studies should be randomly selected from the target population in order to ensure that valid generalization of the results could be established.

NGP. How does it improve upon the results gained from phase I-IV trials? What are the benefits of using a PMOS?

JS. The post-marketing observational study, if properly conducted, provides valid data on how the drug works in real life without interference from the investigators or researchers. Phase II and III studies cannot be easily generalized to the target population in a real-life setting because of the strict protocol and highly selected patient samples. Phase IV studies imitate real-life settings better than phase II and III studies but because of the implementation of patient selection and treatment schedule that adheres to the study protocol and because the intervention is provided at no cost to the patient, the generalization to real-life setting is not complete. Post-marketing observational studies do not follow protocol-defined treatment schedules and patient selection is limited to those patients that will receive the intervention regardless of the study. Therefore, these observational studies are the only source of real-life effectiveness and safety evidence.

NGP. One of the complaints often leveled at these types of trial is that companies are often motivated by promotional rather than purely scientific reasons. Is this a fair criticism? How can companies assure the trial has significant scientific value?

JS. This is in fact a valid criticism. There have been many post-marketing studies initiated by the marketing divisions of pharmaceutical companies and conducted by marketing or distribution organizations. The studies, although they should not be called studies but programs, better resemble marketing surveys and promotional/advertising campaigns and not epidemiological studies. In order to assure that post-marketing observational studies are conducted according to accepted scientific standards they should be designed and conducted as true epidemiological observational studies. The studies should therefore be initiated by medical divisions of pharmaceutical companies, although they could be mandated and supported by marketing divisions. In addition, the execution of these studies should be delegated to organizations with appropriate training, experience and credibility. This will ensure that the studies not only have high scientific value and gain peer acceptance from the scientific community and governments, but also answer important questions.

If properly conducted, the studies can be beneficial to the sponsor by providing evidence of continuous evidence real-life effectiveness and safety. On the other hand, safety signals may be detected early and appropriate actions taken to minimize risk and consequences to the sponsor. Finally, in the long term, the results of the studies could support increased market access to the dissemination of the results in a scientific and lay media. It is important for pharmaceutical companies to realize that their investment in post-marketing observational studies will be recovered not during the study but during the following two or three years through improved public image, enhanced evidence of benefits and prevention of risk.

 

According to a recent survey, pharmaceutical companies sink 71 percent of their total R&D budget into drug development. Of that, a whopping 45 percent of total R&D spending is devoted solely to clinical trials, whilst half the time it takes to move a drug through the development pipeline to the marketplace is spent in the clinical trial phase.

 

Clinical trials backgrounder

Clinical trials are essential in order to demonstrate that a new medication or surgical intervention is safe, efficacious and effective in treating the disease for which it has been developed. Clinical trials are classified into four different phases. Each one of these phases has a specific purpose and answers different questions.

Phase 1 studies are aimed at demonstrating that the intervention is safe, with studies primarily conducted in healthy volunteers.

Phase II studies are aimed at demonstrating that the intervention is efficacious in treating the condition for which it has been developed. In phase II studies, safety is also evaluated. The studies are conducted on patients with the target condition. Usually in phase II studies the new intervention is compared against a placebo.

Phase III studies are aimed at further evaluating efficacy and effectiveness as well as safety in patients with the target condition. In these studies, patients are treated with the new intervention or with an alternative that is typically a comparator treatment. Placebo-controlled phase III studies could also be conducted. In addition to providing information on efficacy and safety, phase III studies also provide some information regarding effectiveness. In phase III studies, subgroup analyses may also be conducted to identify subpopulations of patients with various levels of response to treatment or safety concerns.

After phase III studies have been completed, the intervention is typically accepted and approved for use in routine clinical practice.

After the drug has gained regulatory approval for use in the general population, there is an ongoing need to demonstrate effectiveness in real life as well as safety. Phase IV studies are used to address these needs. These studies are required because controlled clinical trials that are typically conducted during the previous phases are based on highly selected patient populations that are treated according to strict protocols. In addition, the majority of the studies do not have large enough sample sizes to detect important safety signals as indicated by the occurrence of rare but important adverse events. Phase IV studies are also used to compare several interventions or to assess the effectiveness and safety of intervention in clinically important patient subpopulations. Although phase IV studies represent the real-life situation better than phase I to III studies, they continue to have an element of control especially since they are conducted according to well-developed protocols and the intervention is provided by the sponsor free of charge to the patient. Therefore issues of adherence and access to care that could affect real-life effectiveness do not factor into the results of phase IV studies.

Post-marketing observational studies are conducted after the intervention has been approved and is routinely used in practice. As the name implies, these are purely observational studies that essentially preclude any interference of the investigator on how the intervention is applied. In other words, in these studies the investigator only observes what happens to patients that are treated with the target interventions. The outcomes assessed include measures of effectiveness that are routinely used in clinical practice and safety. In these studies, the intervention is paid by the patient or insurance company in the same way as it is paid in real life. Therefore, in these studies issues of access to care, compliance and adherence to treatment become very important potential predictors of effectiveness.