By David Hufner, Traci Kruckmeyer, and Peggy Schrammel, UBC
Post-approval studies are typically initiated to gather additional product safety information, comply with a postmarketing requirement (PMR), or support overall market access. Many times, these studies require enrolling very large numbers of patients at often research-naïve investigative sites to address pressing study objectives. Many sponsors and CROs erroneously believe that a phase III operational approach will meet all needs of a postapproval study. However, applying phase III processes can result in study delays, astronomical budgets, and dissatisfied study investigators. Streamlining all aspects of postapproval studies is key to overall success.
Drug Development — Phase III Studies
Phase III studies involve randomized and blind testing of a drug or device in several hundred to several thousand patients. This large-scale testing, which can last several years, provides the pharma company and the FDA with a more thorough understanding of the effectiveness of the drug or device, the benefits, and the range of possible adverse reactions. Seventy percent to 90% of drugs that enter phase III studies successfully complete this phase of testing. Once phase III is complete, a pharmaceutical company can request FDA approval for marketing the drug.
Hallmarks of phase III trials include:
A priori hypotheses centered on clinical efficacy and short-term safety
Phase III clinical trials clearly define study objectives up front in a study protocol and seek to answer the questions “Can it work?” and “What is the short-term safety profile of the drug?” Questions of effectiveness and efficiency are delayed until the post-approval phase of the drug.
Homogeneous patient populations with few comorbidities and concomitant medications
Phase III clinical trial participants are carefully screened in order to enroll a population that is as free as possible of any factors that may bias or confound study results. For example, it is well known that type II diabetic patients are often treated simultaneously for cardiovascular-related illnesses (hyperlipidemia, hypercholesterolemia, hypertension, etc.). Phase III clinical trials for new antidiabetic agents often seek to exclude patients with these comorbidities in order to evaluate the true outcome associated with the investigative drug, and not those associated with an accompanying illness or treatment regimen.
Protocol-mandated visits with numerous procedures that do not typically mimic normal clinical practice
Phase III clinical trial participants are subject to many visits and procedures, not typically conducted in the “real-world” setting. For example, physicians typically diagnose hypertension using a simple blood pressure reading before prescribing antihypertensive medication. Treated patients are then seen monthly until the blood pressure stabilizes and then on a yearly basis, as part of routine clinical care. However, in a phase III clinical trial for a new antihypertensive, a prospective patient might be subject to the following procedures necessary for study inclusion:
- many blood pressure readings at different times of the day, in different positions (supine versus standing) and often collected in a patient diary
- full lab workup
- pregnancy test.
Additionally, once enrolled, the patient can often expect monthly, sometimes weekly, study visits, additional periodic lab work and EKG, nonclinical questionnaires assessing health-related quality of life, treatment satisfaction, compliance and persistence, collection and reporting of serious adverse events, changes to concomitant medications, and concomitant illnesses. Consequently, phase III trial execution requires a high level of rigor and oversight that often includes the following elements:
- a prolonged investigative site selection process that relies on research-savvy investigators, often at major academic-based research centers
- completion of many up-front forms necessary for site enrollment, including FDA 1572 forms, CVs, medical licenses, protocol signature pages, financial disclosure agreements, W-9s, lab certifications
- reliance on many local IRBs (institutional review boards) and individually negotiated site contracts specifying substantial per-patient compensation
- extensive data collection requirements, often with mandated 100% clean data
- close supervision of study staff by routine clinical monitoring and verification of source data.
It comes as no surprise then that per-patient costs for phase III clinical trials can run from $3,000-$50,000 depending on complexity, study duration, and investigative site setting.
Drug Development — Post-approval Studies
A phase IV study from a pharmaceutical, biotechnology, or other sponsor is typically conducted as a postmarketing commitment and may be a commitment that has been required by the FDA or other regulatory authority. Oftentimes, these studies seek to gather “real-world” data from community-based physicians using their product. These studies focus on capturing safety and treatment data in large numbers of specific patients under study. In phase IV trials, sample sizes tend to be larger and study duration may be longer than the phase I-III studies in comparison.
Many sponsors apply phase III operational processes to phase IV studies. However, this often leads to study delays and overinflated budgets. By streamlining the approach to phase IV trials, these trials are most successful, are executed on time, and save the sponsor unnecessary funds.
Case Study: Physician Recruitment — Lowering the Hurdles to Participate
UBC recently completed physician recruitment for a 500-site post-approval study for an internationally marketed nonsteroidal anti-inflammatory drug (NSAID). The target physician populations were busy family and general practitioners, not research-savvy investigators. A streamlined recruitment approach was employed, with fast, broad outreach and collection of limited essential documents from each physician. Nearly 10,000 physicians were contacted within a few days of the start of recruitment through the use of a couriered physician recruitment brochure, which was professionally printed and contained an invitation from a “key opinion leader,” and all the information and documentation necessary for a physician to participate in the study, including a protocol synopsis and the streamlined essential documents. The streamlined essential documents collected included an abbreviated study contract (four pages with confidentiality language), a one-page CV summary form for the lead physician (i.e. the principal investigator), a central IRB submission form, protocol signature page, and W-9 tax form. An FDA form 1572 and financial disclosure form were not required to participate in the study. The brochure also contained a preaddressed courier envelope to return the documents to UBC. Response from the interested sites was immediate, with almost 15% of the contacted physicians returning their completed essential documents or calling UBC for study information within two weeks of the outreach.
Compared with the traditional phase III approach, the streamlined approach required physicians to complete less documentation, both in terms of amount and complexity (i.e. no FDA form 1572) to register as an investigator. The Physician Recruitment Brochure provided critical study information to these generally research-naïve sites and allowed them to consider participation in the study without having to interrupt their normal practice to answer an invitation phone call from a clinical research associate (CRA). Although there were additional initial costs to print and courier the brochures, the use of the brochures and simplified documents dramatically reduced the review time and number of CRA calls to resolve documentation questions. The streamlined approach costs approximately 60% less to execute than the traditional phase III approach.
“Streamlining” does not mean “sloppy research.” Rather, it means developing study processes that balance scientific and regulatory rigor with the ultimate end use of study data. From protocol development, to site start-up, to data collection, thoughtfully applying streamlining techniques in post-approval studies can save time and money and result in increased levels of investigator satisfaction.
Case Study #2: Site Management and Monitoring – Saving Time and Money
Traditional phase III site management and monitoring requires CRAs to travel to sites on a frequent basis to review source documentation and data collection forms. This approach works well for small, controlled studies with research-savvy investigators with office space and staff accustomed to such time consuming visits. When research naïve physicians are the target investigators population, or the number of sites is large, these visits can be costly, disruptive to a busy practice, and at times viewed as a punishment for participating in research. Understanding the time and space constraints on the average physician participating in post-approval studies, UBC has streamlined the site management and monitoring activities implemented in post-approval studies over the last 30 years to be centralized and less intrusive to the practice.
UBC is currently conducting a dermatological study that is employing our streamlined approach to site management. The participating physicians are practicing dermatologists, most with limited research experience and little to no research staff. Routine monitoring visits would shut most of the sites down for day, interrupting the practice and their patients. UBC employed a centralized monitoring approach to site management, to fit the study into the normal office practice activities.
Sites were permitted to choose their selected method of contact that best suited their needs, including telephone, email, fax, or communicating via the dedicated study portal. Allowing sites to select a communication preference added flexibility for the site and ensured critical access to the busy physicians. Outreach to the sites occurred weekly during the patient recruitment period and the bi-weekly or monthly thereafter, depending on the preference of the site. In addition to data management staff, CRAs and site manager (in-house CRAs) review completed data collection forms remotely to ensure data quality and generate queries or questions that are resolved during the next routine contact with the site. Sites were also informed during training that sample monitoring visits would be performed during the study. These “for-cause” monitoring visits are conducted based on predefined triggers, such as high frequency of SAEs or unresolved queries, at up to 10% of the site. Sites also receive monthly study newsletters and have access to a study portal, where they can find study related materials, resources and site specific reporting, which allows the sites to compare their performance with sites across the study. Considering the high costs of onsite monitoring visits combined with the monthly site management costs involved with a traditional phase III study, UBC’s centralized site management and monitoring approach ensures data quality and limited physician impact for nearly 85% less costs.