Click here for Part 1 of our two-part series on innovative and alternative trial design in heart failure research.
In the 1990s the unmet medical need related to heart failure treatment was quite substantial. This unmet medical need was inversely proportional to the clinical trial size in previous years, using the conventional cardiovascular outcomes trial design. With the advent of the Angiotensin-Converting Enzyme Inhibitors (ACE-I) and aspirin (ASA) regimens as standard of care therapy, combined with the development of new diagnostic techniques, modern-day cardiac care units and cardiac catheterization/ revascularization techniques and strategies, there has been a reduction in this unmet medical need.
Should We Keep Pushing the Boulder Uphill?
While the unmet medical need has continued to decrease, the trial size has not followed. The sizes of typical cardiovascular outcomes clinical trials have become unmanageable, untenable, and very expensive. The vorapaxar program with its two sister trials, TRA-2P and TRACER, at the time they were conducted were the largest trials in chronic coronary heart disease and acute coronary syndrome with > 26,000 and almost 13,000 patients enrolled respectively (1-2).
So if we think of Sisyphus rolling that large boulder up the hill and watching it come back to hit him for all eternity, we can imagine the concept of insanity as continuing to do the same thing over and over again within cardiovascular clinical research , while expecting a different result.
Innovation and Novelty Needed in HF Clinical Trial Design
To avoid this frustrating recurrence in heart failure clinical trials, we will want to look at inserting novelty into our cardiovascular drug development plans to achieve drug approval quicker – but with the same if not better evaluation of efficacy and safety as in the conventional trial design – and when possible, with reduced costs.
Health authorities recognize the need to reduce cardiovascular outcome trial size and are thus open to new and innovative trial designs that will demonstrate efficacy and evaluate for safety. Collaborating with academic research organizations (AROs) and clinical research organizations (CROs) can prove beneficial in the development of trial designs. These groups will have trialists who are well versed in designing trials of all types and styles, and who are familiar with what regulatory agencies are looking for related to efficacy, safety evaluation and labeling.
Taking a New Look at Phase 2 and 3 Trial Designs
The conventional cardiovascular drug development program employs a large, cumbersome, Phase 3 cardiovascular outcomes trial after completion of a Phase 2 clinical trial. Yet, it has become more the rule than the exception that the Phase 2 trial is discordant with the results of the Phase 3 trial. Therefore, reducing the risk of a negative Phase 3 result is no longer a prescient rationale for a Phase 2 trial. This has been demonstrated numerous times within the cardiovascular therapeutic area. For example, instead of a conventional Phase 3 outcomes trial, the PARADIGM-HF trial employed a long run-in period for safety with stopping points at completion of a certain number of patients in the run-in period. The Drug and Safety Monitoring Board (DSMB) then evaluated for safety and a hold was placed on continued enrollment until the DSMB had determined that there was no significant safety signal to be addressed. After a number of patients were enrolled without significant safety signals, the trial was allowed to continue enrolling unfettered (3).
Another alternative trial design is to combine a Phase 2 and Phase 3 program into one fluid clinical trial, with continued enrollment held between the Phase 2 and Phase 3 periods for evaluation of data for safety and efficacy as well as a re-evaluation of sample size based on the Phase 2 period treatment effect. This design reduces the amount of downtime between the Phase 2 and 3 trials, with the intervening health authority discussions as well as time lost to start-up of a new trial. This can save costs, decrease the overall duration of the trial, and reduce the total number of patients needed between the Phase 2 and 3 trials.
Heart Failure Research: Partner with the Experts to Improve Your Trial Design Strategy
It is important to have the academic research organization (ARO) and the contract research organization (CRO) partnering with the sponsor throughout the trial design process to define and refine the strategy. For instance, the ARO can guide the trial design by helping to define what type of patient population will be most readily accepted. If the eligibility criteria defines patients that don’t benefit from treatment, then the ARO can help to define a patient population with a greater medical need. However this must be taken with a caveat: academics that are brought in on a consulting basis should not only be experts in their own fields, but are also trialists, skilled in the design of the type of trial appropriate for the investigational product.
This is an important distinction because subject matter experts who do NOT have clinical trial design experience can derail a trial and ultimately a drug development program. This can happen because their choices may not be restrictive enough, thus enrolling a patient population that doesn’t have high enough cardiovascular risk to generate a reasonable number of events over a certain time period. Or, their choices may be too restrictive, excluding the right patients, or worse, so restrictive that it becomes an unenrollable clinical trial.
Choosing the Right ARO and CRO Partners
As you can see, selecting the right academics and/or ARO to work with on a clinical trial is extremely important. They also must be easy to work with and have enough experience that they can be an effective partner in designing your cardiovascular clinical trial (such as having access to unpublished or to-be-published, yet non-proprietary information that can assist the current trial in defining the right patient population). Involving the wrong academics in the design process can make or break a trial, pushing the company to use the wrong endpoints found to be poorly associated with risk, and more.
One of the academic research organizations that Worldwide frequently collaborates with is the Antithrombotic Trials Leadership and Steering (ATLAS) group. In addition, there are other premier AROs working on cardiovascular clinical trials around the world, including the TIMI Study Group (US), Duke Clinical Research Institute (US), Harvard Clinical Research Institute (US), Cleveland Clinic Coordinating Center for Clinical Research (US), Population Health Research Institute (Canada), and Green Lane Coordinating Center (New Zealand).
Choosing the right CRO is also important, if not more so. Many clinical research organizations have different expertise and capabilities that set them apart. For instance, some have their own imaging and laboratory analysis, while others have the internal experience to help in identifying sites and anticipating challenges with recruitment and retention. Some CROs employ a highly skilled physician group, who are used as consultants, similar to the type of consultation available from academic trialists. An in-house physician team, when used in concert with a skilled operational group, can add significant know-how to a sponsor’s strategic advisory team. Finally, including an ARO can not only provide the scientific and trialist expertise needed, but can also support a clinical trial with a lead investigator or study chair, as well as provide recommendations for the Clinical Events Committee (CEC) and DSMB committee.
I’m proud to be a member of the physician team at Worldwide Clinical Trials, where we are committed to helping our sponsors avoid pushing the same boulder uphill again and again by supporting the development of innovative trial designs in cardiovascular disease research, and beyond.
References
1. Morrow DA, Braunwald E, Bonaca MP, et al for the TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404-13.
2. Tricoci P, Huang Z, Held C, et al for the TRACER Investigators. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366:20-33.
3. McMurray JJ,Packer M, Desai AS, et al. for the PARADIGM-HF investigators. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004.
