Is Clinical Research Inclusive Or Extractive?

By Eduardo F. Motti, MD GFMD, founder, Trials & Training

This past October, the Royal Swedish Academy of Sciences announced the winners of the 2024 Nobel Prize in Economics. Daron Acemoglu, Simon Johnson, and James A. Robinson received the prize for their 2001 work “The Colonial Origins of Comparative

Development: An Empirical Investigation.” In the succinct description of the work, published in The Economist¹, “…they developed a schema for institutions, dividing them into ‘inclusive’ (those which shared prosperity) and ‘extractive’ (those where a small group took from the rest). Inclusive institutions encourage investment in human and physical capital. Extractive ones discourage it.”

The authors explain that some countries are more economically successful than others because their institutions are more inclusive and foster wealth distribution, while others are poorer because their institutions have an extractive character, favoring the transference of wealth to central power. In the first group, the authors include the English-colonized United States, Australia, and Canada and, in the latter group, the Iberic-colonized countries of South and Central America.

The work of the Nobel Prize economists is much more complex than that, but for the present article, that simple central idea may be enough to start discussing the question posed in the title: Is clinical research inclusive or extractive?

Clinical research has been among us for almost a century. It gains momentum every time new knowledge opens new possibilities for the development of newer and better drugs. That happened in the 1950s and 1960s with antibiotics, in the 1970s and 1980s with enzyme inhibitors, and later with biotechnology leaps leading from monoclonal antibodies to mRNA vaccines. According to IQVIA, more than $138 billion was spent on R&D by the 15 largest pharmaceutical companies in 2022².

Research regulation has become ever more rigorous. The creation and expansion of the International Council of Harmonization (ICH) has successfully standardized many aspects of pharmaceutical development and paved the way for the globalization of clinical trials.

The pharmaceutical industry has reached a point where it cannot absorb the number of studies necessary to develop so many drugs with its internal resources. CROs fill this gap and have thrived to become the leading force in clinical research operations. They are present in various capacities in around 75% of clinical trials³, with revenue estimated at $56.7 billion in 2022, with an estimated compound revenue growth of 6.9% per year until 2033⁴.

Patient recruitment is a global challenge, resource and timeline planning is difficult, and costs are soaring. The fast growth in the number of projects has led to shortages of trained personnel in CROs and research sites. As a result, many projects have been delayed or failed, causing instability. The pharmaceutical industry and CROs have adopted different strategies to cope with these challenges. In general, they have become more risk-averse and cost-conscious. They have centralized decision power and placed increased pressure on outside stakeholders, such as investigators and suppliers.

For this discussion, let’s use Brazil as an example of what happens in most emerging countries. In the 1980s, a few multinational pharmaceutical companies started bringing a small portion of their Phase 3 trials to Brazil. Academic research has been widespread, but drug development studies for regulatory purposes are not. Most of the expertise for those studies was brought to Brazil by American and European companies and, although the process was not exactly formal and regulated as it is now, investigators responded to that endeavor with quality work and very good patient recruitment and retention. In the 1990s, we witnessed new international regulations taking place, while in Brazil a new national regulatory agency — ANVISA — was created. More pharmaceutical companies felt confident in expanding their clinical trial programs to South America, and many research sites with technical capabilities and financial help from trial sponsors were opened. Investigators saw the potential to conduct large studies. Brazil could contribute significantly to development programs in HIV, osteoporosis, cardiovascular medicine, infectious diseases, and other areas. Global CROs also noticed that growth potential and started to open offices in Brazil. It is fair to say that during that period research institutions were inclusive.

More recently, the research landscape started to change. Pharmaceutical companies increased outsourcing of clinical operations to CROs. Technology was more intensely absorbed by pharma and CROs than by research sites, mostly for obvious economic reasons. Productivity, combined with cost containment, took the front row. This scenario led to an asymmetry that continues to grow today, placing increasing pressure from enterprises on clinical sites. They are required to deliver more complex studies on time and budget while struggling to maintain their own staff.

Under this new environment, both pharma and CROs shifted decision power from subsidiaries to headquarters. Country allocation decisions were not always shared with local country teams, making them more operational and less strategic. In a way to contain costs even further, the presence of CRAs at the sites was drastically reduced in favor of remote activities. Tasks like project management, contracting, payments, and start-up were passed to global teams located in international hubs, located in places where labor costs were lower. That might have created a gain in process scale but with a loss of local country expertise. Clinical research thus turned to become more extractive.

The Nobel Prize economists explain that extractive institutions, defined in a broader sense, do not foster progress and wealth distribution. They may be effective in producing short-term gains, but in the long course, they end up hindering market growth. Local CRO and pharma teams now have less influence in decisions that directly affect their operation. Investigators complain of poor support from CROs and of excessive pressure. Sponsors have demonstrated concern about the performance of large CROs⁵, and some started returning monitoring and site feasibility functions in-house⁶.

The steady growth in clinical research globally requires opening more sites in non-traditional countries, exactly the opposite of what has been done so far. Those who have adopted this alternative have had good experiences. The downside of this option is that it requires more resources on the ground.⁷

What else may help to decrease the asymmetries and boost performance?

1. Clinical research sites need more support.

From site identification until study closure, many sites need more guidance from CROs and sponsors with greater experience to help them deal with the complexities of trial designs, risk assessment, etc.⁶

Caitlin Ciavarro, head of clinical operations from the Bill & Melinda Gates Medical Research Institute, wrote an excellent summary of how to engage with new sites and get good results in low- and middle-income countries⁸. She advises sponsors to be more present, to visit sites early and more often, and to customize instructions, taking into account site characteristics, experience, and culture.

2. Form strong country teams and trust them.

Pharma companies have largely decimated their clinical operation teams in the countries and outsourced the functions to CROs. In emerging regions where research activities are relatively new, CROs have filled their ranks with very junior and insufficiently trained professionals. That is likely the main cause of poor CRO performance and investigators’ dissatisfaction. This must be corrected quickly. Yes, it takes more investment and may hurt the bottom line initially, but long-term results will compensate. Once a good country team is in place, they should be listened to, empowered, and trusted. Engaged and trusted teams have lower turnover rates.

3. Engage investigators in best management practices sessions.

Pharma companies have many management training activities for their managers. Investigators come from the scientific and medical fields without developing sound management skills. They learn on the job and, until they get there, they may place sites and studies at risk. Support and guidance given early in the investigator’s career has long-lasting positive effects and a positive reputation for sponsors.

4. Payments

Commonly, the whole study budget is transferred from sponsors to CROs, who manage it with variable degrees of independence and oversight. Budget negotiations with sites are consistently tough, and CROs have typically pressured sites and investigators to receive payments every quarter, and only after visit data are monitored. Considering calendar periods and fewer site visits from monitors, that may delay payments for many months. This is a big killer for sites, which must pay their expenses continually and personnel monthly or more often. Many investigators give up on clinical research for this reason. Sites are unable to invest in new personnel or recruitment and retention tactics. Sponsors must listen to investigators about how study payments are being handled. It is not fair that CROs increase their margins at the expense of site budgets.

In conclusion, the troubles we face in delivering studies and bringing new drugs faster to the patients who need them so much is common knowledge. We need more patients enrolled in the studies and more good sites performing at a higher standard. We can achieve this if we dare to break some paradigms and make clinical research more inclusive.

References:

1. An economics Nobel for work on why nations succeed and fail. Published in the October 24, 2024 issue of The Economist, available at: https://www.economist.com/finance-and-economics/2024/10/14/an-economics-nobel-for-work-on-why-nations-succeed-and-fail . Accessed on Nov 11, 2024.
2. Global Trends in R&D 2023, ACTIVITY, PRODUCTIVITY, AND ENABLERS. Available at: www.iqviainstitute.org
3. The Growing Role of CROs in Clinical Trials. Available at: https://www.ppd.com/blog/growing-role-of-contract-research-organizations-in-clinical trials/
4. How Many Clinical Trials Are Run by CROs? Available at: https://vial.com/blog/articles/how-many-clinical trials-are-run-by-cros/?utm
5. Industry Survey: Pharma and Biotech Firms Increasingly Concerned About the Stability of Large CROs Amid Industry Consolidation. Available at: https://www.worldwide.com/newsroom/pharma-and-biotech-firms-incre…d-about-the-stability-of-large-cros-amid-industry-consolidation/
6. As The Pendulum Swings, More Sponsors Initiate Site Identification And Feasibility. Available at: https://www.clinicalleader.com/doc/as-the-pendulum-swings-more-sponsors-initiate-site-identification-and-feasibility-0001.
7. Lumis Life Science Consulting – Comprehensive Overview. Available at: https://lumisinternational.com/trends-in-outsourcing-clinical-tr…imated%20that%20the,need%20more%20full%2Dservice%20outsourcing.
8. Clinical Trial Operations In Low- And Middle-Income Countries: 5 Keys To Clinical To Success. Available at: https://www.clinicalleader.com/doc/clinical trial-operations-in-low-and-middle-income-countries-keys-to-success-0001.

Acknowledgment: I am deeply grateful to Dr. Maria Lucia Pecoraro, who made valuable contributions to the present article.

About The Author:

Eduardo Motti graduated in medicine and completed residency and a mastership in infectious disease at the University of Sao Paulo, Brazil. In 1984, Dr. Motti began working in the pharmaceutical industry for Merck Sharp & Dohme until 2001, and then started the activities of Eurotrials in Brazil. He also worked for Schering AG, now Bayer, and Pfizer, where he was the regional director of clinical operations for Latin America. In 2012, he started Trials & Training, a consulting company, and became a certified executive coach from Royal Roads University, in Victoria, BC, Canada. Dr. Motti has worked on more than 500 clinical research projects and provided technical training, coaching, and mentoring for hundreds of health care professionals. He is also a global fellow in medicines development from IFAPP Academy.