The Research Protocol

Abstract

The research protocol is defined as the most important document in clinical research which helps the researchers and the scientists to understand the necessity of the study and the way of execution and completion.

The protocol outlines the rationale for the study, its objective, the methodology used, and how the data will be managed and analyzed. It highlights how ethical issues have been considered, and where appropriate, how gender and minority issues are being addressed.

An additional step, after writing the protocol, particularly in large studies with teams of investigators, is to develop what may be called the operations manual for the study.

The full research protocol development takes usually 4 months, but is variable depending on the complexity of the research.

Barriers to Research in Developing Countries and Possible Steps to Overcome Them

The rise in the number of cancer cases, 14 million new cancer cases globally every year, with the majority of cases occurring in developing countries [1], has a great impact in those countries and must be addressed. Additionally, treatment options are both limited and expensive, and trial participation is an opportunity for better cancer care.

There are four key components to cancer control and, therefore, areas in need of research: prevention, early detection, diagnosis and treatment, and palliation, as stated by WHO [2]. In each of these areas, developing countries face major challenges, not only in dealing with the ongoing problems, but also with research opportunities.

The International Agency for Research on Cancer (IARC) uses the term “developing country” for less-developed regions such as: all regions of Africa, Asia (excluding Japan), Latin America and the Caribbean, Melanesia, Micronesia, and Polynesia [1].

In order to overcome barriers to doing research, and so that the results will have a chance to impact on local problems, some points have to be taken into consideration:

Choose a Relevant Topic to Your Community

Make sure that the many pressing problems in developing countries are being addressed, so local patients are able to see direct benefits. The research question has to be relevant for the population where it is tested. This is an ethics question, as well as a question that will improve accrual.

There is a broad consensus that efforts and scarce resources in developing countries should focus first and foremost on prevention and awareness rising, and secondly on early detection, treatment, and research. However, this should not prevent the progress and improvement of research capabilities in these countries.

Will the Protocol Be Feasible?

If the issue being looked at is technology, it should be noted that most health equipment used in developing nations is manufactured in the first world. Sometimes the equipment does not work on arrival, with lack of parts or trained technicians to fix it or do maintenance. Technical, social, cultural, and economic factors must be considered when looking at new technologies for these countries.

Researchers should also remember that in some countries there is limited access to radiotherapy, so research questions involving concurrent or sequential treatments may not be the best research option.

According to the International Atomic Energy Agency (IAEA) [3], although the developing world constitutes 85 % of the world’s population, it only has 2200 radiation therapy machines compared with the 4500 in the developed world. Those developing countries that have access to radiotherapy face considerable financial investment constrains and for up to 5 years are required to provide the necessary training, equipment set-up and maintenance, protocols, and quality control. Therefore, even if budget is not a concern for a specific study, creating a Radiotherapy Service for research purposes in a developing country would take a lot of planning, resources, and time.

In order to do the scans as planned in a protocol, radiologists with RECIST knowledge and time to do proper comparative reports are also needed and are not always available. Even with a central review, the delay in getting the images as planned could result in wrong clinical decisions and protocol violations.

The same applies to health workers, where it is sometimes necessary to train locals and adapt to the capabilities of the country. Obviously, if feasible, the improvement in capabilities would be welcome, as in addition to the research they could offer new treatments to patients and open the way for further research.

Funding and Economic Incentives

The challenges are many and substantial such as insufficient political priority and funding among donor agencies and governments of developing countries that have many competing priorities.

However, the local investigator must be familiarized with potential local and international sources: universities, government incentives, international for-profit initiatives, and creative not-for-profit partnerships.

Involvement in research with pharmaceutical companies, which can be lucrative to the institutions where it is done, is an obvious way to start, but usually some capabilities must already be in place to attract this kind of research. A pressing challenge is getting industry partners to invest in the clinical development of drugs that offer limited commercial opportunities. Despite the fact that the cost to approve drugs is lower in developing countries, it is still high and is a problem that universities and public institutions cannot overcome alone.

Intellectual Property

Partnership with industry may be necessary to develop early research in universities, and intellectual property licensing should be viewed as a requirement to attract industry partners. However, researchers must pay attention to patent systems before concluding agreements with pharmaceutical companies (who want a patent system that will protect their investments for as long as possible) and be careful, clearly stating on contracts who has ownership of the data collected, of publications or abstracts arising from study results, and of information obtained based on new data analyses.

Encouragement and Structure

In some developing countries, in addition to other research barriers, such as lack of diagnostic, treatment, and monitoring capacity, there is lack of academic staff (oncology and hematology expertise, specialized cancer nurses, pharmacists), qualified monitors, lack of encouragement to conduct and publish research, as well as lack of a research publishing infrastructure. Training personnel abroad, in other research centers, or in-house training before starting a project may be needed.

Planning and Accrual

Researchers may have problems with proper calculation for accrual, as most cancer registries in low- and middle-income countries have shortcomings and screening programs are largely absent. This can lead to erroneous assumptions regarding the relative frequencies of the varying levels of different cancers based on global trends, which can be misleading. These issues are major challenges for the future, but setting up an institutional cancer registry could be a good start in research planning.

In order to properly choose the study population, the researcher should take into consideration the contrasts in patient’s disease profiles: most cancer patients in developing countries have advanced or incurable cancers at the time their initial presentation, a different profile from that seen in developed countries. The prevalence and incidence can be also markedly different in comparison to developed countries for each disease site.

Developed countries often have relatively high rates of lung, colorectal, breast, and prostate cancer because of the earlier onset of the tobacco epidemic, the earlier exposure to occupational carcinogens, and the Western diet and lifestyle. In contrast, up to a fourth of cancers in developing countries are associated with chronic infections. Liver cancer is often causally associated with infection by the hepatitis B virus (HBV), cervical cancer is associated with infection by certain types of human papillomavirus (HPV), and stomach cancer is associated with Helicobacter pylori infection.

Weak referral systems can also make the accrual slow. This should be anticipated and should encourage creative solutions to strengthen it by the researchers. In some countries there are few cancer services. This can be helpful in the sense that it aggregates most of the cases in a few centers. However, if the health system is a mix of public and private, this dilutes the number of cases, increasing the numbers of institutions necessary for the accrual, and increasing the budget.

Issues During the Trial and for Follow-Up

There is sometimes a lack of awareness of the signs and symptoms of cancer and side effects from treatments, a lack of money to travel to a hospital, which could result in sub-notification of important events or delays in the notification and treatment of important side effects.

As health systems in developing countries are not set up for chronic disease management, chronic diseases such as cancer are often lost to follow-up. Therefore, organizing proper follow-up for patients enrolled in the trials could be a problem.

Need for Palliative Care Research

In some developing countries, there is lack of trained personnel to administer palliative care or pain killers such as morphine. This is particularly startling given that approximately 70 % of the patients seen at these hospitals are at such an advanced stage of cancer upon arrival that they are beyond cure and palliative care and pain management is the only benefit they can still receive. Studies in the palliative setting, which should be relatively easy to accrue, could have a major impact in the quality of life of patients and in the training of local health workers.

Ethics Barriers

The ethics principles in clinical research were established in order to avoid previous abuses/misconducts, such as the Tuskegee Study of Untreated Syphilis (TSUS).

Based on the influential codes of ethics and regulations that guide ethical clinical research (Nuremberg Code¹; Declaration of Helsinki¹, Belmont Report¹, CIOMS¹, U.S. Common Rule¹), seven main principles have been described as guiding the conduct of ethical research¹: social and clinical value; scientific validity; fair subject selection; favorable risk-benefit ratio; independent review; informed consent; and respect for potential and enrolled subjects.

The trial should follow the ethics rules from the country where it was originally written and in the other countries where the research will be developed. Some areas of ethics controversy in developing countries are: the standard of care to be used (as the local standard of care could mean no treatment or less than the “worldwide best”) and the quality of informed consent (due to lack of knowledge, language/cultural barriers, high workload, and time constraints). The discussion about valid science, social benefits, and favorable risk:benefit ratio to justify less than the worldwide best care has to take place early on in the protocol design to avoid an unethical and/or unfeasible trial. Efforts should be taken to improve the quality of informed consent, such as researchers training and observance to the GCP.

Not all the population in developing countries is vulnerable, but a great deal of them is at increased risk of exploitation due to poverty, limited healthcare services, illiteracy, cultural and linguistic differences, and limited understanding of the nature of scientific research. To make things worse, regulatory infrastructures, which could minimize this risk, may lack effectiveness or be nonexistent. As suggested by Emanuael et al. [4], “collaborative partnerships between researchers and sponsors in developed countries and researchers, policy makers, and communities in developing countries help to minimize the possibility of exploitation by ensuring that a developing country determines for itself whether the research is acceptable and responsive to the community’s health problems.”

Lastly, the many differences between developed and developing countries, in addition to the various sociocultural groups existing in a country, must be taken into consideration during the research protocol conception and execution. Specifically, issues to keep private information confidential, to find the person responsible for giving consent, and how best to explain the clinical trial purpose, benefits, risks, and involved procedures could arise due to local peculiarities.