Clinical Trials – A Timely Matter
We investigate action being taken to conduct trials in a timelier manner.
No one would argue the fact that the costs of clinical trials are rocketing – especially in the US. The cost of developing a drug is rising faster than the rate of inflation due to the length and complexity of clinical trials.
Sonal Singh, M.D., M.P.H, Assistant Professor of Medicine, Health Policy and Management, and International Health, at John Hopkins University, shared some thoughts on reducing the length of clinical trials. He says, “Focus on trials that maximize pharmaceutical profit with societal good. We can get away from a lot of ‘me too’ clinical trials that are non-informative by relying on previous systematic reviews.” Indeed, Singh believes systematic reviews help achieve focus.
Currently, the concern seems to be the one-off nature of clinical trials, which, on the whole, could be more efficiently coordinated. There is also the concern that pharmaceutical companies may have one main agenda (to secure FDA approval) while society has another agenda (to find answers to their questions about suitable treatments). Finances are another issue of concern regarding clinical trials – funding may be available for one type of trial while another, which may be of more importance to potential patients, is not addressed.
Comparative Effectiveness Research (CER) was jumpstarted in 2009 with the allocation of $1.1 billion by Congress in order for federal agencies to determine the effectiveness of various medical treatments for patients in certain circumstances. The aim was also to supply information on the costs and benefits of one treatment compared to other treatments. This marked the start of an effort to coordinate and prioritize research in order to streamline delivery.
The length of a clinical trial can have an enormous impact on the data received. If it is too short, you may miss vital information regarding the efficacy and side-effects of a drug. If it is too long, you may waste time and money gathering redundant data and delay the release of a potentially important treatment. Companies are now looking at ways of encouraging patient-centricity during clinical trials in an effort to improve dialogue and be more responsive to what the patient actually needs, thereby decreasing costs, reducing the length of trials, and lowering risk.
Consider patient endpoints and new methods
Methods for active patient engagement in designing trial endpoints are few. If we agree that patient driven endpoints are relevant then trials can be designed for the optimal duration - neither too short nor too long".
It is the necessity to narrow the divergence between patients’ needs and financial viability that has made ‘patient-centricity’ the buzzword in clinical trials. There is a potential that the adoption of this approach will lead to a streamlining of the clinical trial endpoints.
“Patient-centricity is the cliché, but methods for active patient engagement in designing trial endpoints are few. If we agree that patient driven endpoints are relevant then trials can be designed for the optimal duration - neither too short nor too long,” says Singh.
Daniel Rubin, PhD., of the FDA mentions in a presentation (HABP/VABP Patient Outcomes from Previously Conducted Trials) that endpoints need to be, “well-defined and reliable,” with a “standardized definition for multicenter trials,” and that endpoints must be a “direct measure of patient benefit.” Too often, the actual benefit to patients is not the focus as researchers become involved in the scientific complexities of bringing a new drug to the marketplace.
Singh points out, “New methods are being developed - Bayesian adaptive designs can shorten time in clinical trials.” Bayes theorem allows for calculating the actual probability of an outcome based on the results of certain tests. As Scott Berry and associates pointed out in, ‘A Bayesian dose-finding trial with adaptive dose expansion to flexibly assess efficacy and safety of an investigational drug’, the trial of an investigational drug for patients with diabetes was terminated after Stage 1 based on the “low probability that the tested doses had efficacy greater than the active control.” This eliminated the time and cost of proceeding to Stage 2 of this two-part trial.
Different phases, different costs
Of the four phases involved in clinical trials, it is Phase 3 that is currently the most expensive and prolonged part. During this phase, the drug or treatment on trial is administered to groups of between 1000 to 3000 people in order to monitor side-effects, confirm effectiveness and compare it with equivalent treatments. The collected information can then be used to determine how the experimental drug or treatment may be safely used.
During Phases 1 and 2, the groups involved are smaller – in Phase 1 the experimental drug or treatment is administered to around 20 to 80 people to identify side-effects and evaluate safety. This is only done after laboratory trials and animal testing. Phase 2 involves a larger group of between 100 to 300 volunteers. During this phase, the drug is compared with equivalent treatments, and information on how the drug may be safely used is collected. After Phase 3 is completed, the drug goes through the process of approval by the FDA and can then be publically distributed. Finally, Phase 4 involves researchers tracking safety and compiling information on risks, benefits, optimal usage and safety.
Tufts Center for the Study of Drug Development at Tufts University estimate a length of around 15 years for an experimental drug to go from lab to patient as patients in each of the first three phases may be involved for up to a year. Prior to this, preclinical testing is completed and additional time is also required to recruit a sufficient number of suitable study participants. Another study indicated a time frame of around 7.5 years, however, this looked at the time frame from the start of clinical testing to marketing and did not consider development during the pre-clinical phase.
Technology and centralized coordination to the rescue
Centralized co-ordination and technology are contributing to reducing study time frames. A global database by country of, for example, diabetes mellitus type 2 patients, pre-screened by doctors and recommended for trials of a new treatment, once established would significantly reduce time as web-based portals facilitate speedy patient recruitment. At the present time, there is a need to manage the disconnect between protocols for clinical trials and the actual process of patient recruitment. Through web-based portals, researchers gain a better understanding of potential participants and their backgrounds in order to allocate them correctly into an appropriate trial.
Systems such as goBalto, Comprehend Clinical, and ClinCapture, enable clinical operations teams to share, visualize (through graphic representations), and analyze data. This expedites study completion times as data is in real-time and the critical path can be configured and tracked efficiently, resulting in time-savings of around 30%, compared with paper-based methods.
Functional Service Providers are providing companies with access to trained and experienced personnel through Contract Research Organizations (CRO’s), enabling them to scale studies as the need arises and avoid the costs of creating teams from scratch. This is resulting in a reduction in length of trial times of up to 20%.
Careful patient follow-up
Careful patient follow-up in foreign countries avoids delays. Many trials are now taking place in countries such as India and Russia because the cost savings run into millions of dollars due to the salaries of physicians being lower compared to the US. In countries such as these, there is no lack of volunteers for new drugs or treatments as people seek to obtain better quality of life. Also, there are claims that clinical trials conducted in foreign countries are of higher quality because of strict adherence to the protocols required and to careful patient follow-up. This translates to mitigation of potential problems and helps to avoid costly delays.
The use of digital media, patient registries and social media can streamline the time required to complete patient recruitment. Another recruitment strategy is to work with patient advocacy groups, where researchers are able to target patients with rare diseases. Concerns relating to privacy and data protection as well as regulations must be addressed; however, the requirements for various countries are already built into systems like goBalto.
When considering costs in the region of $2 billion to bring a new drug onto the market, it is necessary to try to reduce the length of time spent on the clinical trial period. The adoption of innovative measures in conducting clinical trials, while ensuring safety protocols are maintained, especially in the case of life-threatening diseases, could considerably reduce the mortality and morbidity of patients.
For more information on Patient-Centered Clinical Trials 2015 in Philadelphia, click here.