Project 2 - Clinical Investigation Plan

During the risk management process, we identify the risks associated with the device and how such risks have been addressed. The clinical evaluation is expected to address the significance of any risks that remain after design risk mitigation strategies that have been employed by the manufacturer during the manufacturing process.

Post Marketing Surveillance reports should also be considered by the manufacturer, whether they are device related or not, which include the details of the device’s regulatory status, actions undertaken during the reporting period and tabulation of incidents, particularly serious adverse events, including deaths.

To demonstrate the extent of the probable risks, the following factors should be addressed

• Intensity of the risk
• Life threatening or not
• Medical necessity

Quantification of Risks:

Risks are quantified by considering the following,

• Recurrence of adverse events
• Any other harmful affects
• Patient Population

Acceptance of Risks:

The following are mainly considered for risk benefit analysis:

• Biocompatibility data and the Benchmark Test Reports
• Clinical data of similar devices
• Post Marketing Surveillance data

Statistics are an important aspect of clinical trials. The breadth of statistical issues span the full spectrum of a trial from design and protocol development, data monitoring and conduct during an ongoing trial, data management, data analyses, and reporting of trial results. Statistical concepts can be difficult for non-statisticians to understand. However it is important that clinicians involved with clinical trials understand fundamental statistical issues in order to uphold the integrity of a trial. Knowledge of basic biostatistics and of study design is also important for reading medical journals.

Studies suggest a marked increase in the complexity of statistical methods in the medical literature. Studies also demonstrate that the current level of medical training in biostatistics is inadequate. In a study by West and Ficalora, more than two-thirds of clinician respondents disagreed or strongly disagreed with the statement that “the current level of medical training in biostatistics in medicine is adequate”. Clinicians often seem willing to draw conclusions unsupported by the data. Wulff et.al reported that statistical knowledge of most doctors is so limited that they cannot be expected to draw the right conclusions from the analyses presented in medical journals. There is evidence that researchers often inappropriately apply statistical methods due to poor understanding of statistical concepts and Glantz suggested that approximately half of the published articles in medical journals that use statistical methods, use them incorrectly.

There are several common statistical concerns in clinical trials including poor p-value interpretation, the need for presenting confidence intervals, adherence to the intent-to-treat principle, missing data, multiplicity, subgroup analyses, association vs. causation, appropriate reporting of trial results, probability and Bayesian statistics, and the clinician-statistician interaction and the importance of effective communication.

Clinical Data Management (CDM) is a critical phase in clinical research, which leads to generation of high-quality, reliable, and statistically sound data from clinical trials. This helps to produce a drastic reduction in time from drug development to marketing. Team members of CDM are actively involved in all stages of clinical trial right from inception to completion. They should have adequate process knowledge that helps maintain the quality standards of CDM processes. Various procedures in CDM including Case Report Form (CRF) designing, CRF annotation, database designing, data-entry, data validation, discrepancy management, medical coding, data extraction, and database locking are assessed for quality at regular intervals during a trial. In the present scenario, there is an increased demand to improve the CDM standards to meet the regulatory requirements and stay ahead of the competition by means of faster commercialization of product. With the implementation of regulatory compliant data management tools, CDM team can meet these demands. Additionally, it is becoming mandatory for companies to submit the data electronically. CDM professionals should meet appropriate expectations and set standards for data quality and also have a drive to adapt to the rapidly changing technology.

Many software tools are available for data management, and these are called Clinical Data Management Systems (CDMS). In multicentric trials, a CDMS has become essential to handle the huge amount of data. Most of the CDMS used in pharmaceutical companies are commercial, but a few open source tools are available as well. Commonly used CDM tools are ORACLE CLINICAL, CLINTRIAL, MACRO, RAVE, and eClinical Suite. In terms of functionality, these software tools are more or less similar and there is no significant advantage of one system over the other. These software tools are expensive and need sophisticated Information Technology infrastructure to function. Additionally, some multinational pharmaceutical giants use custom-made CDMS tools to suit their operational needs and procedures. Among the open source tools, the most prominent ones are OpenClinica, openCDMS, TrialDB, and PhOSCo. These CDM software are available free of cost and are as good as their commercial counterparts in terms of functionality. These open source software can be downloaded from their respective websites.

In regulatory submission studies, maintaining an audit trail of data management activities is of paramount importance. These CDM tools ensure the audit trail and help in the management of discrepancies. According to the roles and responsibilities (explained later), multiple user IDs can be created with access limitation to data entry, medical coding, database designing, or quality check. This ensures that each user can access only the respective functionalities allotted to that user ID and cannot make any other change in the database. For responsibilities where changes are permitted to be made in the data, the software will record the change made, the user ID that made the change and the time and date of change, for audit purposes (audit trail). During a regulatory audit, the auditors can verify the discrepancy management process; the changes made and can confirm that no unauthorized or false changes were made.

The CDM process, like a clinical trial, begins with the end in mind. This means that the whole process is designed keeping the deliverable in view. As a clinical trial is designed to answer the research question, the CDM process is designed to deliver an error-free, valid, and statistically sound database. To meet this objective, the CDM process starts early, even before the finalization of the study protocol.

In a CDM team, different roles and responsibilities are attributed to the team members. The minimum educational requirement for a team member in CDM should be graduation in life science and knowledge of computer applications. Ideally, medical coders should be medical graduates. However, in the industry, paramedical graduates are also recruited as medical coders. Some key roles are essential to all CDM teams. The list of roles given below can be considered as minimum requirements for a CDM team:

• Data Manager
• Database Programmer/Designer
• Medical Coder
• Clinical Data Coordinator
• Quality Control Associate
• Data Entry Associate

The data manager is responsible for supervising the entire CDM process. The data manager prepares the DMP, approves the CDM procedures and all internal documents related to CDM activities. Controlling and allocating the database access to team members is also the responsibility of the data manager. The database programmer/designer performs the CRF annotation, creates the study database, and programs the edit checks for data validation. He/she is also responsible for designing of data entry screens in the database and validating the edit checks with dummy data. The medical coder will do the coding for adverse events, medical history, co-illnesses, and concomitant medication administered during the study. The clinical data coordinator designs the CRF, prepares the CRF filling instructions, and is responsible for developing the DVP and discrepancy management. All other CDM-related documents, checklists, and guideline documents are prepared by the clinical data coordinator. The quality control associate checks the accuracy of data entry and conducts data audits. Sometimes, there is a separate quality assurance person to conduct the audit on the data entered. Additionally, the quality control associate verifies the documentation pertaining to the procedures being followed. The data entry personnel will be tracking the receipt of CRF pages and performs the data entry into the database.

To many, the term informed consent is mistakenly viewed as synonymous with obtaining a subject's signature on the consent form. FDA believes that obtaining a subject's oral or written informed consent is only part of the consent process. Informed consent involves providing a potential subject with adequate information to allow for an informed decision about participation in the clinical investigation, facilitating the potential subject's comprehension of the information, providing adequate opportunity for the potential subject to ask questions and to consider whether to participate, obtaining the potential subject's voluntary agreement to participate, and continuing to provide information as the clinical investigation progresses or as the subject or situation requires. To be effective, the process must provide sufficient opportunity for the subject to consider whether to participate. (21 CFR 50.20.) FDA considers this to include allowing sufficient time for subjects to consider the information and providing time and opportunity for the subjects to ask questions and have those questions answered. The investigator (or other study staff who are conducting the informed consent interview) and the subject should exchange information and discuss the contents of the informed consent document. This process must occur under circumstances that minimize the possibility of coercion or undue influence.

The consent process begins with subject recruitment, and it includes advertising used to recruit subjects into the clinical trial. Once a potential subject is identified, a person knowledgeable about the clinical investigation and capable of answering questions raised by the potential subject should conduct a consent interview.

The consent form must contain information to allow the subject to make an informed decision about participation in a clinical investigation. The consent form serves several purposes, including helping to ensure that the subject receives the required information, providing a "take home" reminder of the elements of the clinical investigation, providing contact information in case additional questions or concerns arise, and documenting the subject's voluntary agreement to participate.

The informed consent process often continues after the consent form is signed. Depending on the clinical investigation, additional information may need to be given to the subject, and the subject may need additional opportunities to ask questions and receive answers throughout the clinical investigation.

Except as provided in §§ 50.23 and 50.24, no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence. (21 CFR 50.20.)

Informed consent is required for participation in FDA-regulated clinical investigations except under limited circumstances as described in 21 CFR 50.23 (involving certain life-threatening situations, military operations, or public health emergencies) and 21 CFR 50.24 (involving emergency research). See 21 CFR 50.20. Nothing in FDA's informed consent regulations is intended to limit the authority of a physician to provide emergency medical care to the extent the physician is permitted to do so under applicable Federal, State, or local law (21 CFR 50.25(d)).

Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject: (21 CFR 50.25(a).

Description of Clinical Investigation:

A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental. (21 CFR 50.25(a)(1).)

A clear statement that the clinical investigation involves research is important so prospective subjects are aware that, although preliminary data (bench, animal, pilot studies, literature) may exist, the purpose of their participation is primarily to contribute to research (for example, to evaluate the safety and effectiveness of the test article, to evaluate a different dose or route of administration of an approved drug, etc.) rather than to their own medical treatment.

FDA recommends that potential subjects first be informed of the care a patient would likely receive if not part of the research and then be provided with information about the research. This sequence allows potential subjects to understand how the research differs from the care they might otherwise receive. The description should identify tests or procedures that would be part of usual care that will not be performed as well as those required by the protocol that would not be part of their care outside of the research, for example, drawing blood samples for a pharmacokinetic study. The information provided should also inform prospective subjects about the potential consequences of these differences in care. Note that all experimental procedures must be identified as such. (21 CFR 50.25(a)(1).) Procedures related solely to research (for example, protocol-driven versus individualized dosing, randomized assignment to treatment, blinding of subject and investigator, and receipt of placebo if the study is placebo-controlled) must be explained.

The description of the clinical investigation must describe the test article and the control. The description should include relevant information of what is known about both the test article and the control. For example, the description should indicate whether the test article is approved/cleared for marketing and describe that use. Clarification may be provided that a marketed product may be prescribed by a health care practitioner for the labeled indication as well as other conditions/diseases he/she determines are reasonable. The description should also provide relevant information about any control used in the study. For example, whether the control is a medically recognized standard of careor is a placebo (including an explanation of what a placebo is). The information provided about the test article and control should include appropriate and reliable information about the benefits and risks of each, to the extent such information is available.

The consent process should outline what the subject's participation will involve in order to comply with the protocol, for example, the number of clinic visits, maintenance of diaries, and medical or dietary restrictions (including the need to avoid specific medications or activities, such as participation in other clinical investigations. If describing every procedure would make the consent form too lengthy or detailed, FDA recommends providing the general procedures in the consent form with an addendum describing all study procedures. It may be helpful to provide a chart outlining what happens at each visit to simplify the consent form and assist the subject in understanding what participation in the clinical investigation will involve. FDA believes that removing procedural details from the consent form will reduce its length, enhance its readability, and allow its focus to be on more important content, such as the risks and anticipated benefits, if any.

The informed consent process must clearly describe the expected duration of the subject's participation in the clinical investigation (see 21 CFR 50.25(a)(1)), which includes their active participation as well as long-term follow-up, if appropriate. The subject must be informed of the procedures that will occur during such follow-up, which may be provided in a chart as described above. (21 CFR 50.25(a)(1).)

Risks and Discomforts:

A description of any reasonably foreseeable risks or discomforts to the subject. (21 CFR 50.25(a)(2).)

The informed consent process must describe the reasonably foreseeable risks or discomforts to the subject. This includes risks or discomforts of tests, interventions and procedures required by the protocol (including standard medical procedures, exams and tests), especially those that carry significant risk of morbidity or mortality. Possible risks or discomforts due to changes to a subject's medical care (e.g., by changing the subject's stable medication regimen or by randomizing to placebo) should also be addressed. The explanation of potential risks of the test article and control, if any, and an assessment of the likelihood of these risks occurring should be based on information presented in the protocol, investigator's brochure, package labeling, and previous research reports.

Reasonably foreseeable discomforts to the subject must also be described. (21 CFR 50.25(a)(2).) For example, the consent form should disclose the severity and duration of pain from a surgical procedure or the discomfort of prolonged immobilization for MRI.

All possible risks do not need to be described in detail in the informed consent form, especially if it could be overwhelming for subjects to read. Information on risks that are more likely to occur and those that are serious should be included. The discussion may include information on whether a risk is reversible and the probability of the risk based on existing data. Information on what may be done to mitigate the most likely to occur and serious risks and discomforts should also be considered for inclusion.

The description should not understate the probability and magnitude of the reasonably foreseeable risks and discomforts. If applicable, the consent document should include a description of the reasonably foreseeable risks not only to the subject, but also to "others" (for example, radiation therapy where close proximity to subjects post procedure may be of some risk to others). When appropriate, a statement must be included that the clinical investigation may involve currently unforeseeable risks to the subject (or to the subject's embryo or fetus, if the subject is or may become pregnant). (21 CFR 50.25(b)(1).)

Benefits:

A description of any benefits to the subject or to others which may reasonably be expected from the research. (21 CFR 50.25(a)(3).)

The description of potential benefits should be clear, balanced, and based on reliable information to the extent such information is available. This element requires a description of the potential benefits not only to the subject (for example, "This product is intended to decrease XXX; however, we cannot guarantee that you will benefit"), but also to "others" (for example, "your participation in this research may not benefit you but may benefit future patients with your disease or condition"). Overly optimistic representations of the clinical investigation may be misleading and may violate FDA regulations that prohibit promotion of investigational drugs and devices (see 21 CFR 312.7 and 21 CFR 812.7). Because the purpose of the study is to determine the safety and/or effectiveness of the test article compared to the control, it is not yet known whether the test article may or may not provide a benefit.

FDA considers payment to subjects for participation in clinical investigations to be compensation for expenses and inconveniences, not a benefit of participation in research. If payments are provided, the consent process should not identify them as benefits.

Alternative Procedures or Treatments:

A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject. (21 CFR 50.25(a)(4).)

To enable an informed decision about taking part in a clinical investigation, consent forms must disclose appropriate alternatives to entering the clinical investigation, if any, that might be advantageous to the subject. (21 CFR 50.25(a)(4).) Prospective subjects must be informed of the care they would likely receive if they choose not to participate in the research. This includes alternatives such as approved therapies for the patient's condition, other forms of therapy (e.g., surgical), and when appropriate, supportive care with no disease-directed therapy. This disclosure must include a description of the current medically recognized standard of care, particularly in studies of serious illness. Standard of care may include uses or treatment regimens that are not included in a product's approved labeling (or, in the case of a medical device cleared under the 510(k) process, in the product's statement of intended uses). FDA believes that treatment options lacking evidence of therapeutic value do not need to be discussed.

When disclosing appropriate alternative procedures or courses of treatment, FDA believes a description of any reasonably foreseeable risks or discomforts and potential benefits associated with these alternatives must be disclosed. Where such descriptions or disclosures can contain quantified comparative estimates of risks and benefits (e.g., from the clinical literature), they should do so. The agency does not believe that imposing such a strict requirement for every case would be realistic or appropriate. Where such well-defined estimates are not possible, the agency believes that a description of the risks and benefits will be sufficient.

It may be appropriate to refer the subject to a healthcare professional who can more fully discuss the alternatives, for example, when alternatives include various combinations of treatments such as radiation, surgery and chemotherapy for some cancers. This referral should be completed prior to the subject signing and dating the consent form.

FDA recognizes that, while an individual subject may be eligible for more than one clinical investigation, that determination and the decision as to which trial would be most appropriate for a particular subject would need to be made on a case-by-case basis. FDA believes that the discussion of other trials for which the subject may be eligible is best left to the informed consent discussion rather than the informed consent document and may need to include the subject's primary care provider.

As applicable, the informed consent process should advise that participation in one clinical investigation may preclude an individual's eligibility to participate in other clinical investigations for the same or other indications. When there are multiple clinical investigations for evaluating the treatment of a particular disease, the sequence in which a subject may participate in the protocols may be important and should be discussed with the subject and the subject's primary care provider, if appropriate.

Confidentiality:

A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records. (21 CFR 50.25(a)(5).)

The consent process must describe the extent to which confidentiality of records identifying subjects will be maintained (21 CFR 50.25(a)(5)) and should identify all entities, for example, the study sponsor, who may gain access to the records relating to the clinical investigation. The consent process must also note the possibility that FDA may inspect records (21 CFR 50.25(a)(5)), and should not state or imply that FDA needs permission from the subject for access to the records. Please note that under the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule, FDA does not need permission to inspect records containing health information (45 CFR 164.512). FDA may inspect study records, for example, to assess investigator compliance with the study protocol and the validity of the data reported by the sponsor.

Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), FDA may inspect and copy all records relating to the clinical investigation. 21 U.S.C. § 374(a)(1). See also 21 CFR 312.58(a), 312.68, and 812.145(b). FDA generally will not copy records that include the subject's name unless there is reason to believe the records do not represent the actual cases studied or results obtained. When FDA requires subject names, FDA will generally treat such information as confidential, but on rare occasions, FDA may be required to disclose this information to third parties, for example, to a court of law. See 21 CFR 20.63(a) and 20.83(a)-(b). Therefore, the consent process should not promise or imply absolute confidentiality by FDA.

Compensation and Medical Treatment in Event of Injury:

For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained. (21 CFR 50.25(a)(6).)

For clinical investigations involving more than minimal risk, the informed consent process must describe any compensation and medical treatments available to subjects if injury occurs. (21 CFR 50.25(a)(6).) Because available compensation and medical treatments may vary depending on the medical circumstances of the individual subject or the policies of the institution, the consent process should include an explanation to subjects of where they may obtain further information. An example of an adequate statement is, "the sponsor has made plans to pay for medical costs related to research-related injuries" followed by an explanation of how to obtain further information. If no compensation is available, the consent process should include statements such as:

• Because of hospital policy, the hospital is not able to offer financial compensation should you be injured as a result of participating in this research. However, you are not precluded from seeking to collect compensation for injury related to malpractice, fault, or blame on the part of those involved in the research, including the hospital.
• Because of hospital policy, the hospital makes no commitment to provide free medical care or payment for any unfavorable outcomes resulting from participation in this research. Medical services will be offered at the usual charge. However, you are not precluded from seeking to collect compensation for injury related to malpractice, fault, or blame on the part of those involved in the research, including the hospital.

Contacts:

An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject. (21 CFR 50.25(a)(7).)

The consent process must provide information on how to contact an appropriate individual for pertinent questions about the clinical investigation and the subjects' rights, and whom to contact in the event that a research-related injury to the subject occurs. (21 CFR 50.25(a)(7).) This information should include contact names (or offices) and their telephone numbers. FDA recommends that the individual or office named for questions about subjects' rights not be part of the investigational team. Subjects may be hesitant to report specific concerns or identify possible problems to someone who is part of the investigational team. In addition, the consent process should include information on whom to contact and what to do in the event of an emergency, including 24-hour contact information, if appropriate.

If contact information changes during the clinical investigation, then the new contact information must be provided to the subject. (21 CFR 50.25(a)(7).) This may be done through a variety of ways, for example, a card providing the relevant contact information for the clinical investigation.

Voluntary Participation:

A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (21 CFR 50.25(a)(8).)

This element requires that subjects be informed that they may decline to take part in the clinical investigation or may stop participation at any time without penalty or loss of benefits to which subjects are entitled. (21 CFR 50.25(a)(8).) Language that limits the subject's right to decline to participate or withdraw from the clinical investigation must not be used. If special procedures should be followed for the subject to withdraw from the clinical investigation, the consent process must outline and explain the procedures (21 CFR 50.25(b)(4). Also note that subjects may not withdraw data that was collected about them prior to their withdrawal.

Eligibility criteria are a critical component of clinical trials, as they define the patient population under investigation. These criteria are often tailored to allow assessments of the effectiveness of a treatment in a well-defined population. Inclusion criteria specify the characteristics required for study entry, such as stage of disease or specific pathophysiological characteristics. They typically identify a population in which it is expected that the effect of the drug can be shown. An obvious example is identifying patients with a specific mutation that is targeted by the treatment, where the drug is likely to be effective only in those patients with the disease who have the mutation. More broadly, it is usual to not only include patients who have the disease to be treated, but those who also have a threshold severity of disease and do not have certain other conditions, or who are not using medications that could mask the effect. Exclusion criteria specify characteristics that disqualify patients from participation and often include factors such as comorbidities or concomitant treatment or factors that could mask the effect of the intervention. However, if these criteria exclude a subgroup that will eventually receive the drug once approved (e.g., people with comorbidities), relevant effects of the drug on that subgroup will not be detected. Broader inclusion criteria and less-restrictive exclusion criteria will lead to a study that provides more information about the product’s effects in the population most likely to use the product if it is approved.

When designing clinical trials, there is tension between balancing the desire to minimize heterogeneity (“noise”), which can mask a finding of the effect, and the desire to generate data that are generalizable to a broader patient population that is likely to be treated. Narrow eligibility criteria can result in (1) a homogenous sample of subjects, limiting the variability in a study population, and (2) controlling for confounding factors, maximizing the probability of detecting a treatment effect if one exists. On the other hand, narrow eligibility criteria can diminish the understanding of the risk benefit of the study treatment relevant to the patient population likely to take the drug if the drug is approved. Sponsors must balance the need to generate evidence of effectiveness to support a regulatory decision while obtaining evidence in the population most likely to utilize the treatment.

Balancing these scientific considerations and designing clinical trials that both generate substantial evidence of effectiveness for regulatory approval and inform the safe and effective use of medical products in patient populations that will be exposed to them after approval will continue to be a challenge for stakeholders across the full spectrum of drug development, regulation, and use.

Whether the benefits of enrolling in a study outweigh the potential risks is also a primary consideration for determining eligibility criteria. Older adults and patients with organ dysfunction or multiple chronic conditions may be excluded from clinical trials because of concerns about potential adverse impacts arising from comorbidities and concomitant medications. Ethical considerations may lead to the exclusion of children, adolescents, and pregnant and lactating women in clinical trials. On the other hand, exclusion of such patients provides no information about a drug’s benefits and risks in such patients, but they may use the drug if it is approved. Therefore, it is important to consider on a caseby-case basis whether such exclusions are truly necessary.

There may be longstanding eligibility criteria practices that unnecessarily limit eligibility for certain patient populations. In designing eligibility criteria, sponsors, investigators, and regulators should avoid assumptions and revise criteria lacking clear scientific justification. Exclusions based on age alone are rarely appropriate. For example, heart failure is more prevalent in older adults. In a trial for heart failure, excluding patients over 70 years old would lead to a lack of data for an important component of the heart failure population and would lead to a failure to evaluate appropriate dosages and needed monitoring in a significant portion of the U.S. population.

To design inclusive trials, sponsors can engage expert clinicians to ensure that the needs and priorities of specific populations are addressed. For example, it may be useful for sponsors to engage gerontologists when designing clinical trials that anticipate enrolling primarily older adults.

Exclusion of pregnant or lactating women in clinical trials is complex and multifactorial. Uncertainty regarding the risk of adverse events in pregnant or lactating women and their fetuses or newborns has historically led to their exclusion from research. There are concerns on the part of sponsors and researchers regarding potential liability from adverse outcomes. In addition, HHS regulations (45 CFR part 46, subpart B) outline additional protections for pregnant women and include language that identifies pregnant women as a vulnerable population.14 The protections afforded in subpart B to pregnant women are in place not because pregnant women are vulnerable to coercion or undue influence or are incapable of protecting their own interests, but rather because of the potential for injury to the fetus. There are, however, good reasons to seek data in the pregnant population. Physiologic changes resulting from pregnancy, for example, can alter the pharmacokinetics and pharmacodynamics of an investigational therapy, potentially affecting its safety and efficacy. Failure to include these patients results in knowledge gaps regarding the safe and effective use of medicines during pregnancy and lactation. Increasing the enrollment of pregnant and lactating women in clinical trials is therefore an important public health issue that raises specific ethical concerns.

To address these concerns, the 21st Century Cures Act required that a Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) be formed.15 This group will ultimately produce a report that includes (1)a plan to identify and address gaps in knowledge and research regarding safe and effective drugs for pregnant and lactating women, (2) ethical issues surrounding their inclusion in clinical research, and (3) recommendations to improve the development of safe and effective therapies for these populations. FDA has also recently issued draft guidance on the scientific and ethical considerations for inclusion of pregnant women in clinical trials. These efforts are important steps toward enhancing the inclusion of pregnant and lactating women in clinical research, while recognizing the complexity associated with these populations.

Premature termination is when a study ends sooner than scheduled, as in the following examples:

• Determination that a study product’s efficacy is better or worse than anticipated.
• Occurrence of unforeseen study drug safety issues or if data from preclinical studies indicate a presence of unanticipated toxicity risks that cannot be adequately quantified.
• Futility: Determination that a demonstrable difference in relevant therapy/treatment proves unlikely.
• Operational futility: the protocol is determined to no longer be able to meet study objectives (e.g., fails to enroll participants within a requisite time period, study drug
  no longer available or usable), and is ended.

Other situations may require suspension of some or all clinical trial activities for the study or at a specific CRS. Often during a suspension, the clinical trial and/or the CRS may not enroll new participants or receive additional study product. CRSs may, however, be required to continue follow up of previously enrolled participants for safety or other assessments.

When conducting a study, there are often different communication and process requirements for suspension or termination, and these are typically defined by the protocol itself, the Study-Specific Procedures (SSP) and/or the Network’s Manual of Operations/Procedures (MOP).

Reasons for early terminating of a clinical trial:

• Loss of the strategic interest because the market potential is insufficient, new drugs have been approved for the same indication, or because a positioning for other indications is being pursued.
• Logistics issues for being unable to recruit the expected number of subjects. It is important to publish this type of trials indicating problems observed and the causes leading to early termination, since they can help other investigators avoid the same problems and repeat the same mistakes.
• The benefit of the drug is proven early, which would mean that it is unethical to continue the trial with control patients, especially those treated with placebo. The main issue with early termination is that of considering that some results are sound when they are not. This may reduce the scientific validity of the trial and increase the chance of obtaining false results, increasing differences with other treatments. In addition, prompt disclosure of results may influence the clinical practice and result in therapeutic strategies persisting over time when they are not the most appropriate ones.
• The drug's lack of efficacy is proven early for failure to obtain the expected benefit. Treatment does not lead to an equal or better result than the treatment against which it is compared.
• Be shown prematurely (in an interim analysis) that the drug is harmful, resulting in a risk for patients enrolled in the trial.

To conclude, criteria to discontinue a clinical trial early must be very strict at the time of determining the scope of the effect. This situation can only be found with a cumulative number of events higher than 200. On the other hand, it should also be considered that both the adjustment and the accuracy of the estimate —based on the number of interim data analyses— may lead to an understanding of the true effect of treatment in clinical trials that are terminated early.

Steps to Write an Effective Case Report:

A Case Report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of a patient. Case Reports may contain a demographic profile of the patient but usually describes an unusual or novel occurrence.

Step 1: Identify the Category of Your Case Report

• An unexpected association between diseases or symptoms
• An unexpected event in the course of observing or treating a patient
• Findings that shed new light on the possible pathogenesis of a disease or an adverse effect
• Unique or rare features of a disease
• Unique therapeutic approaches
• A positional or quantitative variation of the anatomical structures

Step 2: Select an Appropriate Journal

Example, unusual injury presentations are more likely to be accepted in journals such as Trauma, rather than more mainstream, general-interest journals such as British Medical Journal; this does not publish Case Reports but only Lesson of the Week.

Another important point with respect to journal selection is that it is extremely important to follow the basic format required by the journal. Your Case Report may be rejected because it does not conform to the standard format, no matter how good the content is. Therefore, formatting such as margins, spacing, figure numbering, and style of references (Vancouver, Harvard, etc.), all are important aspects.

Step 3: Structure Your Case Report According to the Journal Format

Example; A suggested outline of sections for a Case Report is listed below.

• Abstract/Summary
  – The abstract (also know as summary) is concise and directly addresses your research topic.
• Introduction
  – The introduction is a more detailed explanation stating the purpose of the study, uniqueness of the case, and how it contributes to the existing literature.
• Case Presentation
  – Correctly elaborate the medical condition and medical history of the patient in chronological order as stated below:
  
  • Patient’s Examination/Identification
  • Medical History
  • Analysis of test results
  • Appropriate plan and analysis
• Differential Diagnosis
  • Support for conditions considered
  • Support for additional investigations
• Pathophysiology
  – State the physiological processes associated with the diagnosed disease or injury.
• Treatment/Patient Management
  – Describe the treatment plan, follow-up, and final diagnosis.
• Discussion
  – Summarize the key features of the study and discuss the experiences learnt. Write the discussion in the flow stated below:
  • Etiology
  • Epidemiology
  • Prevalence
  • Complications
  • Prognosis
  • Ethical Dilemmas (if any)
• Conclusion
  – Conclude the case report with summary points, depending on the journal’s specified format. You could give suggestions and recommendations to practitioners, researchers, etc. in this section.
• References
  – Relevant to your case report and must be cited appropriately throughout the paper following citation guidelines of the journal.

Step 4: Start Writing

A Case Report is a way of communicating information to the medical world about a rare or unreported feature, condition, complication, or intervention by publishing it in a medical journal. Decide whether your Case Report is publishable. This can be decided based on the following criteria:

Does your Case Report,

• Describe rare, perplexing, or novel diagnostic features of a diseased state?
• Report therapeutic challenges, controversies, or dilemmas?
• Describe a new surgical procedure?
• Report how a drug can enhance a surgical procedure?
• Report new medical errors or medication errors?
• Describe rare or novel adverse drug reactions?
• Describe a therapeutic failure or a lack of therapeutic efficacy?

You should also ensure that you adhere to the following points:

• Do an extensive literature search—PubMed, Medline, Ovid, Embase, and even search engines like Google will give you a vast amount of information related to your topic.
• Narrow down the search to your actual topic
• If this comes up with very few search results, it means (assuming your search method is correct) that the case is rare, and the report is therefore more likely to be published.

Step 5: Collect Information Related to the Case

• Use the patient’s notes to record the details of all the events in the patient’s care—that is, history, examination findings, results of investigations with dates, and operative findings, if any, together with the details of the actual interventions and follow-ups.
• Use copies—do not take the originals of radiographs, photographs, etc (they are the patient’s only records for future reference).
• Verify all patient data such as history and dates of examination with the patient again and make sure you have got the facts right.