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Unlocking the full potential of artificial intelligence requires these stakeholders to ensure their data are accessible and secure. 

How Medical Writing and Regulatory Affairs Professionals Can Embrace and Deploy Generative AI at Scale

Informed consent is a process, not just a form signed by prospective study subjects. Documents such as the Code of Federal Regulations describe the elements of informed consent, but lack substantive direction on the process of obtaining consent.

 The purpose of this article is to provide guidelines for obtaining informed consent. This guide can be useful to anyone involved in clinical research, particularly newcomers to the industry. 	

The process of obtaining informed consent from subjects is a critical point of entry for research participants. Although the basic principles of obtaining informed consent transcend therapeutic areas and vulnerable patient populations, significant differences must be considered when research designs include individuals at increased risk. Special attention must be given to meeting the needs of vulnerable populations such as children, the critically ill, or the mentally impaired. The atmosphere for the family of a trauma patient during the first few critical hours of admission is far removed from the unhurried pace of the outpatient clinic. The focus of this article, however, is the process of obtaining consent from a population of patients who are not under duress at the time of consent.	

Typically, the introduction of a potential subject to a clinical trial occurs in one of the following ways:	

The subject may have been identified as part of a recruitment campaign.

The subject may simply be part of a patient population being studied.

The clinical trial may be offered as a treatment option after a patient has been given the facts concerning a diagnosis and prognosis. 

Although there are several ways that patients learn about clinical trial "little is known about the factors that influence decisions to participate in scientific research."

 Kuczewski and Marshall recommend adopting the approach that consent is an interactive and dynamic process and many factors can influence the study participant's willingness to sign the document. These factors include socioeconomic background, cultural traditions, literacy and language ability, and interactions with physicians and other healthcare professionals. 	

Bosk found "what, how, and when information is presented does make a difference to a subject's understanding of research and to subsequent enrollment."

 The investigator should carefully weigh the consequences of trying to obtain consent after the patient has just been diagnosed with a life-threatening illness. A subject's ability to make decisions may also be affected by his/her emotional state.

 Emotional stress can be a cause of failure to consent. It is recommended that the subject be given a week to accept her diagnosis before discussing enrollment in the study. 		

Trechan found that risk levels influence a subject's willingness to participate in clinical research.

 Furthermore, negative media attention, such as Ellen Roche's death at Johns Hopkins, may adversely affect decisions to participate.

 Getz suggests that subjects who successfully complete other clinical trials are more likely to consent again.

The informed consent process presents some major challenges for study participants and research staff. Several papers have addressed problems with the current process. Among them, Brady identifies the following issues:

Subject's hesitation to ask detailed questions

Difficulty verifying the subject's comprehension.

Additionally, a survey of 1600 respondents performed by CenterWatch in 2002 found that 14% of subjects did not read the consent before signing, and a high percentage of volunteers admitted to not fully understanding the risks and not knowing what questions to ask. The concept of "therapeutic misconception" in research is another problem that has received much attention in both legal and bioethics literature. Generally, it is important that potential subjects are aware that research is not the only therapeutic alternative for them.

 Lack of subject understanding and comprehension is possibly compounded by the increasing regulations that govern the performance of study personnel and the cost pressures, meaning that there is ever-decreasing time available for study personnel to spend reviewing the consent with the subject.	

The informed consent process begins when a potential subject is first approached to participate in a clinical trial. Whether informed consent is obtained over the phone (remember-there may be a specific protocol for doing this at your institution), or in a doctor's office or hospital, the setting should be the same. It should be an unhurried, private atmosphere where the subject has time to review the document and ask questions. The subject should be approached in a respectful manner and the person obtaining consent should introduce themselves by name and role, stating the purpose of their communication. As already indicated, the timing of this process is very important.				

The person obtaining consent must have appropriate credentials and be qualified to do so. She/he should have experience in the field of study-otherwise, how will she answer questions posed by the subject? Additionally, this person should be familiar with good clinical practice guidelines for informed consent and with his/her own institutional review board's requirements for the process.	

The researcher should determine the ability of the potential subject to understand the information and give consent before proceeding further. If the subject does not read or speak English adequately, an assessment should be performed to determine the subject's needs. The researcher should then make the decision to call in an interpreter. Kuczewski and Marshall suggest that misunderstandings are more likely to occur when investigators (or coordinators) and participants speak different languages, especially when "there are no equivalent expressions for particular biomedical concepts or when the notion of informed consent is unfamiliar." They offer strategies to help minimize language barriers:	

Use an effective process of translation and back-translation

 when an informed consent document must be translated from one language to another. This process must include adequate pretesting of the consent document to determine that it is comprehensible to individuals who will be recruited for a research project.	

Enlist the help of individuals who can act as "cultural experts"

 on ways in which to communicate difficult scientific concepts for study populations who may be unfamiliar with the biomedical problem being investigated.	

Keep the consent document as short as possible,

 using simple language and a format that is clear and understandable for potential research participants.	

The issue of using family members when there is a language barrier is a gray area. Most subjects feel more comfortable if one or more family members are available to help them with decision-making, though this is not always the case. Additionally, excluding family or friends from the discussion may eliminate bias for or against participation; however, this must be balanced with the subject's wishes. Tailor the discussion to the subject's needs. 	

The informed consent process is based on complete disclosure of the facts. During this process, the study coordinator or principal investigator should endeavor to establish a rapport and trusting relationship with the potential subject. 				

The coordinator or investigator should thoroughly review each section of the informed consent with the study subject. The consent form is, in essence, a teaching tool-a nontechnical, understandable document, written at an eighth-grade reading level. It is imperative that subjects understand the nature of the research study, the risks and the benefits, alternatives to research, and their rights as study subjects. Study subjects need to read (or have read to them) and comprehend the informed consent document. Ensure that they understand the nature of the study, that is, why the research is being done and why they are being asked to participate. The coordinator of the study should use whatever resources are available to promote subject understanding of the study such as, graphics, video, or even the device to be used, if possible. Care must be taken to avoid medical jargon that subjects could not possibly understand. Avoid presenting an overly positive (or negative) picture of the clinical trial for which consent is being obtained. 	

There is a growing body of data showing that research subjects have an unrealistic view of what their participation entails. Emphasis must be placed on the risks as well as the benefits. As has already been mentioned, subjects should understand the distinction between what is research and what is routine medical therapy.

 The idea is not to coerce but to provide the subject with the facts. 	

Finally, subjects should be allowed-and encouraged-to ask questions about the study. They should be able to take the document home with them if time permits. 	

Consent should be obtained when the investigator is available to answer questions or address concerns. The principal investigator is ultimately responsible for all aspects of conducting the research.	

It is incumbent upon the study team to understand how Health Insurance Portability and Accountability Act (HIPAA) regulations affect research and the informed consent process. However, with regard to HIPAA regulations, institutional practices and policies may vary significantly. HIPAA mandates "Standards for Privacy of Individually Identifiable Health Information." HIPAA applies to health information created or maintained by healthcare providers who engage in certain electronic transactions. Due to this and HIPAA's strong emphasis on confidentiality, HIPAA impacts many facets of the work we do in clinical research-specifically with the informed consent process. HIPAA requires subjects to sign an authorization. This authorization is like a consent form for HIPAA and may be a stand-alone document or may be integrated into the study consent form.				

HIPAA requires that the following information be included in the authorization or consent form:

the information that is provided or disclosed

each purpose of the use or disclosure of the information

expiration date or event of the consent and authorization

the subject's right to revoke authorization

the subject's right to refuse to sign authorization

the fact that subsequent disclosures by the recipient may not be protected under HIPAA.

Greg Koski, former director of the Office for Human Research Protections, recently said, "We must move beyond the culture of compliance, to move to a culture of conscience and responsibility." These are challenging times in clinical research. The coordinator has an ever-increasing load of regulations to deal with in an environment of severe time constraints. While there are many regulations governing the content of consent forms, there is very little to guide the process. With the emphasis on the patient as subject, it is easy to overlook the patient as human. 				

For specific tips from the Office for Protection from Research Risks go to 		

http://ohrp.osophs.dhhs.gov/humansubjects/guidance/ictips.htm

	1.	Code of Federal Regulations, Title 21, Part 50, (U.S. Government Printing Office, Washington, DC).				

	2.	Code of Federal Regulations, Title 45, Part 46, (U.S. Government Printing Office, Washington, DC).	

	3.	M.G. Kuczewski, P. Marshall, "The Decision Dynamics of Clinical Research: The Context and Process of Informed Consent," 

	4.	C.L. Bosk, "Obtaining Voluntary Consent for Research in Desperately Ill Patients," 

	5.	E. Wager, P.J. Tooley, M.B. Emanuel, S.F. Wood, "How To Do It. Get Patients' Consent to Enter Clinical Trials," 

	6.	T.A. Treschan, T. Scheck, A. Kober, E. Fleischmann, B. Birkenberg, B. Petschnigg, O. Akca, F.X. Lackner, E. Jandl-Jager, D.I. Sessler, "The Influence of Protocol Pain and Risk on Patients' Willingness to Consent for Clinical Studies: A Randomized Trial," 

Informed consent is a process, not just a form signed by prospective study subjects. Documents such as the Code of Federal Regulations describe the elements of informed consent, but lack substantive direction on the process of obtaining consent.1-2 The purpose of this article is to provide guidelines for obtaining informed consent. This guide can be useful to anyone involved in clinical research, particularly newcomers to the industry.

Guidelines for Obtaining Informed Consent for Clinical Research

Project managers considering EDC deployment for a clinical trial might well worry about security. A network security breach can make frightening headlines. Although no system can be made completely impervious to intrusion, some key decisions can help you move forward with confidence.

Trial data inevitably winds up in the data managers computer system, so all trials share certain risks. A crashed hard drive, a corrupt employee, or a faulty program can damage your central data regardless of how it was collected at the front end. This article focuses on mitigating security risks in front-end systems, and on capitalizing upon ways that careful EDC implementation can provide better data security than conventional methods.

Here are a few terms and concepts from the world of computer security. Information security rests largely on three factors: confidentiality, integrity, and availability.

 requires keeping data accessible to only those authorized to use it in only authorized ways. Preventing competitors or saboteurs from accessing confidential data is the most obvious aspect of this, but clinical trials often need additional layers of confidentialitysuch as internally securing information that might compromise a double-blind study.

 requires ensuring that your data is authentic and complete. Risks to integrity range from typographical errors to hardware failures to paid saboteurs.

 Your computing systems and the data they handle must be available to those who need them.

The pursuit of these three goals goes far beyond guarding against professional hackers. In fact, the confidentiality, integrity, and availability of your data is far more often impaired by mundane threats. Natural disaster, hardware failure, computer viruses, power outages, and simple human error are often larger risks than the skilled intruders who inspire such fear. Accordingly, a good security plan focuses first on such everyday items as spare equipment, rigorous backups, off-site storage of backup media, regular reviews of phyiscal security, routine antivirus updates, and redundant network connections. These steps are the foundation upon which one builds the fortress of security. Only when such measures are in place is there any point to considering costly anti-intrusion measures.

Atop the foundation, securitys ground floor consists of regular maintenance and system updates. Most attacks exploit software errors to gain illicit access to a system. A system that has been updated to correct known errors is largely safe from these attacks.

Because no useful system can be made completely impervious to attack, anti-intrusion measures generally anticipate the most likely threats and invest as much in each area as is cost-effective. Between regulatory requirements, privacy laws, and the demands of the increasingly fast-paced clinical trials climate, trial managers should take security concerns very seriously. Because all security is relative, managers need to set priorities rather than expect absolute certainty.

To defend against professional intruders, some economic analysis comes further into play. The idea is to figure out the rough cost of the financial loss an intruder could imposeor the financial return an intruder might gain. Then make intrusion more costly than that. Most of the analysis involved is fairly straightforward, and there are well-established ways to increase the cost of attack.

 The principal added risk of any EDC project is the flow of trial data across a large network. The network may be the global Internet, the corporate network of a large pharmaceutical company or contract research organization, or the public telephone network. Any large network increases the risk that data could be monitored, or that an unauthorized party might be able to stage an attack from elsewhere on the network.

Another risk to any system on a public network (such as the Internet) is that it may be more vulnerable to a denial of service (DoS) attack than its private-network counterparts. Some DoS attacks exploit system weaknesses to crash servers, but these are a very small risk for an organization that maintains its systems well. Other DoS attacks simply overload networks and servers with massive numbers of requestsa less preventable but far less common attack.


Fortunately, we now live in an age of robust encryption and authentication technologies. Todays cryptosystems, properly implemented, can keep trial data transmissions private from any known attack. Todays authentication systems can ensure a users identity with great certainty; and digital signature technology can verify the integrity of a document and the identity of its creator.

 A well-implemented EDC system can provide some security benefits difficult to achieve by traditional means, particularly in the area of integrity. For example, digital signatures on electronically submitted forms can ensure the identity of a forms submitter more securely than entry from paper forms. Digital signatures can likewise ensure that records are unchanged from when they were entered. Standard commercial-grade web security can secure traffic against monitoring of trial data while it is being transmitted.

Any EDC vendor whose tools are placed directly in the hands of subjects will tell you that data passed directly from the subject to the central collection site provides obvious advantages to integrity of data. Each item transcribed by trial staff carries with it the possibility of typographical error, so protocols that require considerable detailed data create an added incentive to consider these kinds of tools.

Some advanced database systems can perform real-time backups even as data is being submitted. While this kind of redundancy is costly, real-time backups to write-once media may be worth the investment for trials with particularly great data integrity needs.

Above all, trial data stored on a computer system can be backed up, stored in multiple places for safety, and audited in its electronic form. If only clinical data is stored on the system, it may be necessary to check paper forms to verify the integrity of a piece of data, but an all-electronic system can store signatures, countersignatures, audit histories, and other pertinent facts about the clinical data. Paper forms can be destroyed by time, disaster, or clerical error, but anything stored electronically can be made much more durable.

Not all EDC programs provide all these benefits. In fact, I know of none that performs all these functions today, but every technique discussed here is well within reach of todays technology. Any crypto-enabled integrity feature not now offered is surely on the horizon.


Sponsors considering a move to EDC can take several steps to make the best decisions.


	Involve your technology staff from the very earliest stages. Even if you have no in-house security expert, one or two hands-on technology implementers should be included at every step in your EDC evaluation.

	Bring in an outside security consultant to help in specifying your requirements and priorities, and to help your team evaluate the security of specific EDC products. A professional outside perspective is always a good double-check, and sometimes an outsider can offer uniquely powerful suggestions for simplifying systems or streamlining work processes.

	Consider a number of EDC products. Many are out there, with widely varying features and security characteristics. Tying yourself to a single vendor without a clear idea of how its products will fit into your business environment can be a costly mistake.

Evaluating EDC systems and vendors is an extensive process beyond the scope of this article. For evaluating the security of each system, however, here are a few points to consider.


	Find out what operating systems and database platforms each product supports.

	A product that runs on multiple server platforms is likely to be more carefully engineered, and a multiplatform product can free you to make other technical decisions independently.

	In general, its a good idea to deploy more of what you already have. If your data center is full of Sun servers, for example, your team will be most able to support additional similar systems.

	All things being equal, Windows is somewhat harder to secure than other platforms, but dont let this factor stop you from choosing what your staff is most able to support.


Network protocols should generally be common and simple rather than special-purpose and proprietary. It is easier to find technologists who can support common protocols properlyand because simple network protocols are less prone to bugs, they offer greater security. 

Encryption protocols (including authentication and digital signature protocols) should generally be common and newer, but the important point here is that any encryption protocol is only as strong as the way it is used. Careful analysis of how crypto technologies are used is more important than which technologies.

Finally, consider each product in light of your security foundations. An EDC system that fits into your existing data backup operation and works over your existing network connections may offer a cost advantage over one that requires special solutions in those areas. If your disaster recovery plan calls for maintaining spare equipment off-site, hardware costs may be a bigger factor than is obvious. Remember from the start that your new EDC system will not operate in a vacuum.

The security issues involved in connecting your trial data to a larger world may seem daunting, but you can address each piece of the challenge by gathering the right professionals and evaluating carefully before moving forward. The task is not small, but anyone running multicenter trials can surely justify the investmentand the benefits for some smaller operations are still compelling.            

Security issues for electronic data capture may seem daunting, but they can become manageable with the right professionals and careful evaluation.

EDC Network Security Basics

Clinical trials sponsors seek quick subject enrollment and high data quality, expressed by both strict adherence to good clinical practice (GCP) requirements and completeness and correctness of the data collected from investigative sites. However, the most informative sources of detailed information on data quality such as site monitoring visit reports, sponsor, and CRO audit reports are maintained as strictly confidential documents and are not publicly disseminated. Therefore, a substantial proportion of the information on data quality in clinical research that is available to the general public is based on anecdotal reports rather than well-referenced and organized observations. The U.S. Food and Drug Administration found no evidence of poor GCP compliance during inspections in the emerging clinical research countries, including Eastern Europe and the former Soviet Union.

Figure 1. Worldwide recruitment by region. The numbers in the segments indicate actual number of patients recruited in the region.	

The query generation rate (QGR), the number of case report form (CRF) data queries generated per subject, is one index of overall quality and performance. Minimizing QGR should reduce data management workload, costs, and time to database lock.	

There has been a great deal of discussion about the comparative quality of data from countries/regions participating in multinational trials.

 However, there is little debate that the recruitment rate per country is a direct indicator of workload that could influence data quality either positively or negatively. In general, a higher regional recruitment rate increases recall and retention of conventions for CRF completion due to more frequent training. A lower recruitment rate may diminish quality due to less frequent training. 	

Applying similar logic, one would also expect to observe higher quality data from sites coming on board later in the trial than from those that started earlier. Survival of the initial "trial and error" period during which the majority of potential ambiguities in protocol wording and CRF instructions are consistently resolved is important.	

The aim of this study was to evaluate query generation rate as an indicator of data quality using data from a recently completed Phase 3 GCP trial to identify major factors influencing quality. Recruitment rate, duration of participation in the trial, English language fluency, and the region where the data came from were all considered as covariates in this study.	

We assessed the number of queries on a per investigator basis from a recently completed Phase 3 GCP trial performed by 118 investigators from 15 countries. We grouped the trial sites into three regions: 				

Group WST, 45 sites-the United States, Canada, Australia, and New Zealand 

Group EU, 25 sites-Ireland, Greece, Italy, Spain, United Kingdom, and Israel 

Group EE, 48 sites-Czech Republic, Georgia, Poland, Romania, and Russia. 

All WST countries, the United Kingdom, and Ireland were considered as countries with English as a native/official language.	

Of the 824 subjects recruited, 520 (63%) were enrolled in EE, 85 (10%) in EU, and 219 (27%) in WST (Figure 1). 	

Our analysis was not designed to provide solid statistical comparisons, but was rather an illustration of trends and a description of factors that could presumably influence quality. Numerical values are presented as means Â± standard deviations. 	

Duration of participation in the study and recruitment rate.

 Mean duration of participation in the study was longest for WST investigators (18Â±5 months), while EU and EE investigators participated in the trial for shorter periods (12Â±7 and 11Â±6 months, respectively). Recruitment rate in EE (1.3Â±1.6 subjects/month) was markedly higher than in other regions (0.4Â±0.4 and 0.3Â±0.5 subjects/month for EU and WST, respectively). Twenty-six sites (22%) enrolled only one subject each during the course of their participation in the study. Of those, two were from the EE region, 12 from EU, and 12 from WST.				

 QGR was plotted against the recruitment rate and stratified by region and English language nativity (Figure 2). While a review of the general data shows that there is an inverse relationship between the recruitment rate and QGR (a higher recruitment rate is associated with somewhat lower QGR, Figure 2A), no such correlation could be noted in the EE sites, which showed low QGR regardless of the actual recruitment rate (4Â±1 query/subject vs. 12Â±5 query/subject for WST and 8Â±2 query/subject for the EU sites, Figure 2B). Similar observations refer to the comparisons of native English-speaking versus non-native English-speaking investigators (Figure 2C).		

Figure 2. Relationship between the query generation (QGR) and the subject recruitment rates shown for all investigators (A) as well as split by region (B) and by English language nativity (C). Each filled circle corresponds to one investigator. Extremely low recruiters (average recruitment rate per month approaching zero) generally showed poor data quality expressed in QGR (number of queries per subject).	

Plotting QGR against the length of the investigator's recruitment period showed no clear correlation between when sites joined the trial and QGR (Figure 3). 	

Our study was a descriptive attempt aimed at identifying factors affecting quality of data. To the best of our knowledge, no similar analysis of QGR as a combined indicator of quality and performance has been published. However, observations of fewer queries per CRF in Eastern Europe have been published.

Our study showed that clear differences in data quality exist between regions revealed in an unbiased comparison using a simple index-QGR. Our study does not provide enough information to make statements concerning all reasons for that finding. Moreover, while an inverse correlation between recruitment rate and QGR was observed in the study, this was not the case for Eastern European investigators who recruited well and, on average, showed a low rate of mistakes. The quality of the EE group's performance showed little correlation with workload as expressed by subject recruitment rate. One may associate this with cultural differences that have been extensively discussed elsewhere.

We believe, however, that one myth of clinical research in a multinational arena has been debunked as a result of our analysis. Previous theories have suggested that the language barrier existing outside the English speaking regions, in Eastern Europe in particular, negatively influences the quality and integrity of data collected in multinational studies. Our findings support the opposite hypothesis, which itself raises interesting questions. 			

Figure 3. Correlation between the query generation rate (QGR) and the duration of the recruitment period (months). The shorter recruitment period indicates that the sites joined the trial at its later stage.	

Why should such a marked difference in QGR exist between native English investigators and others, whose knowledge of the English language may vary from excellent to very elementary? Among possible (mainly speculative) explanations is that English as native language may create nuances in the interpretation of what the CRF is requesting for certain data fields, resulting in site data recording errors and, ultimately, more queries.	

We analyzed the data from only one trial, limiting our ability to generalize our findings. We also understand that the majority of sites that contributed data to the trial were previously unfamiliar with the sponsor's CRFs. Therefore, they may provide a more pure index of expected data quality than if we were to compare the QGR data obtained from a series of similar trials using the same sites and the same or similar CRFs across studies. Nonetheless, performing QGR or similar comparisons on a large database from recently performed or currently running multinational Phase 3 mega-trials would substantially improve our understanding of the factors affecting quality of data, and could potentially affect data management plans and investigator selection. 	

We invite all those who are interested in the topic for further discussion and cooperation.	

1.	P. Platonov, "Clinical Trials in Russia and Eastern Europe: Recruitment and Quality," 

Clinical trials sponsors seek quick subject enrollment and high data quality, expressed by both strict adherence to good clinical practice (GCP) requirements and completeness and correctness of the data collected from investigative sites. However, the most informative sources of detailed information on data quality such as site monitoring visit reports, sponsor, and CRO audit reports are maintained as strictly confidential documents and are not publicly disseminated. Therefore, a substantial proportion of the information on data quality in clinical research that is available to the general public is based on anecdotal reports rather than well-referenced and organized observations. The U.S. Food and Drug Administration found no evidence of poor GCP compliance during inspections in the emerging clinical research countries, including Eastern Europe and the former Soviet Union.1-2

Inger Ødum Nielsen, Vanessa de Langsdorff, and John April

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