Summary
R&D organizations are facing big challenges of which the most critical are the reduction of timelines to conduct a clinical trial and associated expenses. This means getting results from clinical trials faster while using fewer resources. In response to these challenges, the structure and functionality of Clinical Operations is changing. Horizontal organizations are replacing long vertical structures but also new areas of specialization are emerging. The focus of these new functional areas are start-up process, recruitment, site selection, regulatory, training, quality oversight and patient retention. Having specialists that are experts in these functional areas have allowed improvements in functionality, and most importantly, speed and process improvements.
Pharmaceutical companies are facing important challenges. Companies should be able to provide information to regulatory authorities that are demanding extensive data not just about the efficacy and safety of products but also about response in subpopulations or ethnicities, long term cardiovascular risk/benefit profiles, intensive pharmacovigilance post-launch and many others. This request for information is having a huge impact resulting in an increase in the number of clinical trials that need to be conducted. The investment needed to develop a product has been duplicated over the past ten years1. How the R&D organizations manage these challenges while maintaining speed and flexibility is critical to how we respond to an environment that becomes more complex every day.
Increasing the number of resources (both internally and externally) has been one of the first responses. Partnerships along all product development processes have become critical to test new molecules faster. This strategy has allowed companies to be able to assess a large number of new molecules among a wide range of therapeutic areas. In some models, co-development is also included to split the cost but also to cover a wide range of indications. CROs, SMOs or central labs, are some of the external key organizations that contribute in a permanent way.
Organizations have worldwide coverage. Maps of disease prevalence are analyzed in advance for an orphan drug or a primary care product to define the optimal geographic deployment to support development. It´s easy to open hundreds of sites, if you are able of include 30 o 35 countries initiated simultaneously. Effective recruitment involves taking advantage of regulatory timelines in some regions or including special populations or diseases with low prevalence.
Large organizations however have high operational costs; therefore companies are looking for new operational models that provide the same flexibility and timelines but generate greater cost efficiency. This challenge can be addressed with different approaches. Companies have become horizontal instead of vertical organizations. This structure allows fast responses to solve problems or risk minimization where quick decisions are critical. As the structure becomes flat, matrix cross-functioning teams need to be assembled to coordinate multiple processes and simultaneous developmental programs. Self-learning, continuous process improvement and innovation are key strategies to include in the organizational culture.
Within R&D, there are new and highly specialized functional structures. Targeted areas include site selection, start up and recruitment, as they are controllable and directly impact study timelines. It is also important to optimize patient retention and quality. Some companies had decided to create centralized/HQ functions while others had established these capabilities on a regional level.
Site selection is a crucial step. Today, 80 percent of the patients come from 20% of the sites participating in a clinical trial. Proposals for improvement include the building of databases to assess a site´s performance (Fig 1). Parameters to score are PI experience, site infrastructure, type of institution (government vs. private), approval timeline, volume of patients and number of subjects recruited by therapeutic area in similar trials. Some companies also, are partnering with Universities, Medical Centers and huge Research Centers all over the world to reduce the number of low enrolling centers.
Specialized functions or teams are collecting worldwide information in order to define what countries or regions are optimal for study deployment. The prevalence of diseases vary from country to country. For instance, diabetes mellitus has a higher prevalence in countries like Mexico or some sub-populations such as Hispanics in the US. In Asiatic countries liver diseases have a higher prevalence. Including countries from different regions (e.g. Northern and Southern Hemispheres) allows enrolling patients at any time for seasonal diseases, as the winter and summer times are not the same. These teams are also collecting information about specific study sub-populations, genotype prevalence or genetic “tracers.” Feasibility surveys are deployed leveraging the internet.
Accelerating the start-up process is also crucial. A first approach is to reduce the time to get an approval from the MOH. To effectively reduce timelines, companies are hiring experts who are familiar with complex worldwide regulatory requirements. Depending of the country size or resources of the company, experts can be located in each of the countries, by region or being centralized. As regulatory environments, are changing every day, it´s critical to implement all new regulations affecting a product´s development faster. In the past, a large number of clinical trials were conducted in the US and Europe; however, these clinical trials are now deployed to over 30 different countries at the same time and companies should have a well-defined MOH submission strategy.
Regulatory aspects are not limited to country requirements. There are multiple regulations that change every day. Specialists in this matter need to have a deep understanding of all related subjects that impact IRBs/ECs, labeling, licenses to import/export supplies and samples, etc. A validated translation processes (including requirements of forward, back forward and validations) for core documents among different countries and languages should be handled as a priority. Diversity demands supports from highly specialized vendors to support each unique part of the process.
Accelerating patient recruitment is a common objective across all companies. Effective recruitment strategies to booster recruitment require the assignment of resources both inside the company and at the site level. Use of media, advertisement and web pages is now very common to inform patients about clinical trials. Looking for barriers that preclude the enrollment of patients like differences in the standard of care, access to pre-study medications or a diagnostic test is necessary to avoid recruitment delays. Including a plan at the onset of the study will allow assign adequate resources and optimize costs. Companies are hiring services that allow direct messaging to patients and advocacy groups to inform on investigational medicines.
Retention strategies must address the potential causes of attrition and should be tailored to the particular patient profile. Strategies must also meet appropriate regulatory and ethical guidelines. A satisfied patient is generally a retained patient. It is critical to treat each individual with honesty and respect, provide good quality medical care and provide psychological support to the patient and his/her family.
Specialists in retention are experts in the use of media and campaigns. Communication with key stockholders is a core activity for Influencing retention of patients, for instance, the Advocacy Groups. Close communication with patients in long term trials can be reinforced via newsletters, motivational e-mails, etc. It is important to support sites in contacting “patient influencers” like family members, physicians and study coordinators. Sites should define how they will interface with influencers. Sites should also be informed about worldwide performance regarding retention.
SMOs are involved in several steps along these processes. Some of these companies provide support from site selection to patient retention. They handle worldwide databases for all therapeutics areas. They have available Information about doctors, hospitals, medical societies and research clinics by country or region. Filtering the information to include only sites that have previous experience in clinical research could be added to complex protocol designs or pathologies. Some companies are focused on contacting sites or patients to reinforce recruitment or retention.
Training is a core for both productivity and compliance. Technical training is just a piece of the full scope of abilities that should be promoted within organizations. Creating awareness about organizational dynamics and promoting soft skills is mandatory to face a diversified environment. Interactions with authorities, vendors, sites or partners should be focused on removing barriers and looking for synergies and positive interactions. Competencies to understand diverse cultural values and motivations need to be developed globally. Outside investigators and site staff should also develop also soft skills to enable better communications with patients and authorities. Recruitment or retention programs should be amongst different populations, each with unique social and cultural backgrounds. They should share much more information about safety risks on new investigational product like biologics within a new clinical research setting.
Worldwide environments are changing very fast. Each company is facing the new challenge with different strategies, one of them is to development highly specialized departments or resources that allow them manage growth while simultaneously maintaining flexibility and speed.
References
- Pharmaceutical Research and Manufacturers of America, PhRMA Annual Membership Survey (Washington, DC: PhRMA, 1996– 2012); National Institute of Health Offi ce of Budget, “History of Congressional Appropriations,” http://offi ceofbudget.od.nih. gov/pdfs/FY08/FY08%20COM PLETED/appic3806%20-%20 transposed%20%2090%20-%2099.pdf (for 1995-1999), http:// offi ceofbudget.od.nih.gov/pdfs/FY12/Approp.%20History%20 by%20IC)2012.pdf (for 2000-2011)[accessed 5 March 2012].
Matilde Damian is a graduate of the Medicine Faculty from “Universidad Nacional Autonoma de Mexico (UNAM)”and is an internal medicine physician, from Mexican Institute of Social Security. She has held positions of increasing responsibility during her 20 year pharmaceutical research career at BMS, Boheringr Ingelheim and Zeneca Pharmaceuticals. Her experience spans clinical research, medical, training and data quality management where she primarily focused in development and improvement. During her last 12 years at BMS she has been focused in development, innovation and strategic deployment. She was professor of the UNAM at Medicine Faculty for five years and currently is working with “Instituto Politecnico Nacional” in educative activities related to GCPs and protocol design. She is an active member of the Mexican national pharmaceutical chambers of Canifarma, AMIIF and also Grupo Unificado de Investigacion.