The Need for an IND: Question 4
Conducting chemical studies in accordance with the set rules and regulations is essential to avoid legal obligations and to promote safety for human subjects. Issues such as unavailability of drugs to prescribe for patients are inevitable. When such cases arise and an investigator requires to initiate studies on drugs on patients, it is essential that one starts by complying with the clinical research rules and regulations. The process involves acquiring legal approval by submitting an IND. The IND helps in ensuring that risks are minimized on study subjects. In our case, to initiate the Bretylium study on manic patients, the investigator will follow various steps including designing clinical trials, starting an investigational new drug process, determining whether study requires an IND, considering general principles for the application, analyzing the required forms for an IND submission, and making the initial IND submission.
After the IND submission, the next step is waiting for IND process and review, response to a clinical hold if any, amendment of the submission, understanding other responsibilities, and after approval, initiation of the study. Based on other investigators from the literature, potential problems in clinical studies such as violation of federal regulations, safety issues, cost, time, and conflict of interest can lead to significant issues such as study rejection, a clinical hold, study delay, and study failure. Complying with clinical research regulations helps investigators to avoid significant issues that can affect the quality of their studies.
Step 1: Designing clinical trials
To initiate studies on manic patients with the chemical, the first step will be to design clinical trials. The trials help in answering study questions in relation to the medical product. The trials follow a protocol, a specific study plan developed by a researcher (Western Institutional Review Board, 2018). Prior information concerning the drug is first reviewed to help in developing study objectives and questions after which clinical trials begin. In this step various issues are addressed including selection criteria on who qualifies to take part in the process, the number of people who are required to take part in the trials, the time the study would last, means of limiting study bias, means of administering the drug to patients and the proper dosage, type of assessments that will take place, data that need to be collected and time to collect that data, and methods of reviewing and analysing the data (Western Institutional Review Board, 2018). Investigators can use various clinical trial designs. First is the non-randomised clinical trial designs where an investigator allocates participants treatment and control arms.
With the design, control groups can be historical controls or concurrent controls. For example, when historical control is used, all participants receive the study drug. The results then compared to a previous study control group or to the history of a patient. Second is randomised control design (Food and Drug Administration, 2010). With this design, participants are assigned to control arms or to treatment randomly, a process known as randomisation. Various tools are used in the randomisation process including random numbers, sequences that are generated by computers, or closed envelops (Vijayananthan & Nawawi, 2008). The process has two components, that is, generation and implementation of the random sequence. The process keeps study participants unaware of the sequence removing potential bias. There are various types of randomised trial designs including factorial design, stratification, parallel group trial design, cluster sampling, cross-over trial design, withdrawal trials, and matched pair trial design.
Cross-over design involves participants receiving a sequence of various treatments. The design presents various advantages such as low variance. However, washout period must be planned for. For example, in cross-over trial design, patient A and B are randomised into varying treatment arms. Patient A receives treatment X in the first period while Patient B receives treatment Y (Food and Drug Administration, 2010). After the first period of the study, a washout period occurs. In the second period of the study, Patient B receives treatment X while patient A receives treatment Y. In the matched-pair design participants are matched in accordance with certain characteristics. Each participant from the pair is assigned to two varying study subgroups (Food and Drug Administration, 2010). For example, after the participants are screened, they are matched into pairs. From each pair, one participant is randomised onto Treatment X and the other onto treatment Y.
For the cluster sampling, appropriate geographical areas are identified such as cities from which a number is randomly selected. For every chosen area, a balanced subsample from the target population is chosen. These subsamples are then joined forming a sample group. In withdrawal trial, participants undergo a test treatment over a certain period after which they are randomised to withdraw from the test or continue with it (Food and Drug Administration, 2010). After the first period of the study, participants are randomised into two sets, one continues with the treatment while the other receives a placebo. For example, after the first study period which is specified, participants are randomised into group X and Y. Group X continues with the treatment while Group Y receives a placebo.
For the parallel group trial design, after every participant is randomised they stick to the assigned treatment arm over a study period. The designs allow simultaneous running experiments in several groups. For instance, after participants are screened, they are randomised into different treatment groups. Patients remain in these groups throughout the trial duration, analysis, and follow-up activities (Croghan et al., 2015). A factorial design is used in testing the effects of several treatments. It supports the assessment of potential interactions of various treatments. Additionally, stratification design involves comparing study participants undergoing varying study procedures.
Step 2: Starting an Investigational new drug process
Drug sponsors or developers are required to submit an application of investigational new drug (IND) prior to studying drugs on humans. Clinical investigators who seek to begin a chemical study are subject to various regulatory requirements. The regulations address the efficacy and safety issues of the study to the subjects (University of Nevada, Reno, n.d). In the US, the Food and Drug Administration (FDA) is mandated to regulate the majority of the drugs. The mandate extends to regulating clinical studies that involve the use of these products. Therefore, to undertake a drug study, one must comply with the set requirements by the FDA (World Medical Association, 2013). Failure to meet the requirements have financial and legal requirements for an investigator and for the institutions associated with the study.
The first step to comply with the regulations is to notify the FDA of a pharmaceutical agent that an investigator plans to use in an experimental manner. The notification is known as the Investigational New Drug (IND) application (Clinical Trials Compliance, 2003). The purpose of IND is to make sure that during study investigation, patients or other subjects do not face unwarranted harm risk. Therefore, to authorize a study of a drug, the FDA seeks satisfactory material concerning the study and the drug to assess safety (National Institute of Health, 2017). Through the IND, investigators provide necessary information with a purpose of obtaining authorization to administer a study drug on humans. If an approved drug is to be used on a new population or for a new indication, an IND is required (U.S. Department of Health and Human Services, 2015). Studies that use drugs that are unapproved for marketing also require an IND. Studies using approved drugs for unapproved indications, new dosages, new formulations, and in new populations exposed to higher risks are required to apply for an IND.
Clinical investigations that involve drugs are initiated by sponsors for regulatory purposes. The sponsors are responsible for the study conduct. Sponsor represents various entities including an organization, a commercial entity, a government agency, or an individual. On the other hand, an investigator according to FDA is a person who really takes up the responsibility of conducting a drug study (Federal Register, 2017). A person who gives direction in drug dispensing or administering to participants. When investigators are to initiate and conduct a study, and at the same time are responsible for directing dispending and administration of the drug to subjects is considered a sponsor-investigator (University of California San Francisco, 2018). After obtaining an IND, the investigator is usually responsible for the regulatory requirements.
Step 3: Determining whether study requires an IND
IND regulations require that studies that involve humans be undertaken under regulations of an IND especially if the succeeding situations are in existence. First if the study involves a drug. According to the Federal, Food, and Cosmetic Act, a drug is a product whose intention is to prevent, diagnose, treat, cure, or mitigate a disease. The drug also is a product that has effects on the function and structure of the human body (U.S Food and Drug Administration, 2018). Biological products such as toxins, blood component, a virus, allergenic products, antitoxin, and therapeutic serum that are applied to prevent, cure, or, treat a disease in humans also qualify to be drugs under the definition. In this case, Bretylium is a drug because it is intended to be used in treating severe manic patients. The second condition is that the study is a clinical investigation (Robert, 2008).
According to the IND regulations, clinical investigation is an experiment that involves dispensing or administering a drug to humans. It involves the use of the approved or unapproved drug. For instance, a randomised trial that involves evaluating an unapproved use of a drug that is lawfully marketed qualifies to be a clinical study requiring an IND. However, if a study involves the use of a drug that is lawfully marketed for unapproved use during a medical exercise is not a clinical investigation and there is no need for an IND considering that the drug is used in a patient with an intention of treatment (Rick, 2008). In our case, Bretylium is intended to be administered to humans and therefore requires an IND. This will ensure that the subjects are safe in reducing any potential harm (Chidambaram, 2014). Additionally, a study requires an IND if it is not otherwise exempted from the requirements.
Some drug studies are exempted by regulations from the requirements of IND. For instance, some studies that involve marketed drugs. The risk degree associated with the investigation drug and the intent of the study determines if a study of a marketed drug requires an IND or not (Vishal et al., 2014). If the following criteria are met then a study does not require an IND. First if the drug is marketed lawfully in the US. Second if the intention of the study is not to support an important change in drug labelling. Third, if the study complies with IRB requirements for review and in requirements for informed consent (Ferguson, 2003). Fourth, if the study does not involve patient population, administration route, dose, or other factors that may increase the risk associated with the use of the investigational drug (University of Virginia School of Medicine, 2018). Fifth, if the intention of the study is not to commercialize or promote the product. It is the role of the investigator to determine of the study meets the exemption criteria or not. In case of uncertainty, FDA offers advice. After determining that a drug study requires an IND, an investigator seeks to acquire relevant information to submit to FDA for the application of IND.
Step 4: Considering General Principles for the Application
The IND application is required to have information on manufacturing information, clinical protocols and information of the investigator, and animal pharmacology and toxicology studies. The information is useful in helping the FDA to review the study by making sure that the subjects are safe (Center for Biologics Evaluation and Research Organization, 2009). In pharmacology of animals and studies of toxicology, the pre-clinical information is given to authorize an assessment useful in determining whether the investigational drug is safe. The data on the previous use of the drug in humans is also provided (European Medicines Agency, 2006). Manufacturing information comprises information about product composition, stability, manufacture, and controls that were taken in the manufacture of the product.
The information goes through an assessment to confirm that an enterprise can supply the product sufficiently. In our case, this information will involve the manufacturer of Bretylium to assess whether Sigma Aldridge can supply the drug adequately and consistently. On protocols and information of the investigator, thorough information is provided on study protocols. This helps in assessing whether a preliminary trial can expose participants to avoidable risks (Western Institutional Review Board, 2018). The information on qualifications of the investigator is also provided including information on all professionals involved in the study.
The information helps in assessing whether they meet qualifications to perform the clinical duties. Additionally, information on a commitment to acquire informed consent from study participants, to acquire review from IRB, and to adhere to IND regulations is provided. This information is commonly required from a commercial sponsor. Sponsor-investigators may be exempted from this extensive information particularly information on manufacturing information or preclinical studies. This is because, the investigators usually use pharmaceuticals that are sanctioned by the FDA (U.S Food and Drug Administration, 2018). However, the information is necessary as it helps the FDA to effectively assess the safety of the study on the human subjects.
Step 5: Analyzing Required forms for an IND submission
FDA Form 1571
Investigators must produce FDA Form 1571 while submitting initial IND. The form documents the agreement of an investigator of refraining from initiating a clinical trial before 30 days after the actual date that FDA gets the submission. Other information in the form include the agreement of an investigator to refrain from initiating a clinical study when an IND is on clinical hold, to undertake the study according to the applicable regulations, and to make sure that IRB in compliance with regulations of FDA is responsible for reviewing and approving the proposed trial (Center for Drug Evaluation and Research Organization, 2009). The form serves as a road map for an investigator, and a cover sheet for primary submission considering that it is understandable and comprises of check boxes that list and describe the application contents (U.S Food and Drug Administration, 2017). As per the form, the investigator takes responsibility for conducting, reviewing, and evaluating the study safety. Investigators must provide consistent and complete contact information including an effective daytime contact number.
Form FDA 1572
The form contains investigator’s statement. Signing the form means that the investigator has agreed to comply with regulation requirements in relation to conducting clinical studies, undertake the study according to the established protocol, and to make sure that they meet the requirements of acquiring informed consent from participants and from IRB among others (U.S Food and Drug Administration, 2012). Informed consent involves a subject confirming voluntarily the willingness to take part in a specific study (U.S. Department of Health and Human Services, 2013). The subject makes such decisions after they are fully informed of all the aspects relevant to that particular study. Studies that involve various risks requires informed consent be sought from the subjects.
The information on the aspects relevant to the study should be presented in an understandable manner. The subjects must be educated on their right to withdraw consent from the study or even refuse to take part at any given time and this should not have effects on the relation between the subject and the physician (Grady et al., 2017). In case of special populations that are incapable of giving informed consent such as children or people who are intellectually impaired, the consent is sought from representatives who are legally authorized such as parents, spouse, or appointed guardian. Signing form FDA 1572 shows obligation to gain a consent of IRB before starting a study.
Form FDA 3674
According to the regulations, an IND application should be submitted along with a certificate that indicates that the Public Health Act requirements are met. The 2007 FDA Amendments Act, which is part of the US Public Law requires that valid clinical trials be registered. The purpose of the regulations that require the studies to go through registration process is to make sure that the public can have access to the study information and their results (Food and Drug Administration, 2010). FDA provides direction to register the trials for the certification.
Step 6: Initial IND Submission (21 CFR 312)
After the acquisition of necessary information, the IND is ready to be submitted. The submission should be accompanied by a cover letter. The identity of the investigator and a clear indication of the initial submission is required. The contact information should be complete and clear. The title of the study should be indicated (Brown-Tuttle, 2009). The contact information should match that in the required forms to avoid communication delay which is associated with significant concerns (Norman, 2006). Other components of the submission include a table of contents, an introductory statement, investigational plan in general which is provided in summary and helps FDA to anticipate the needs of the applicant, brochure which helps in understanding the foundation of the protocol’s key features, protocols, and previous experience (Clinical Trials Compliance, 2003). The submission can be done electronically or in papers. The submission should be in triplicate, the original documents and two copies.
Step 7: IND Process and Review
After the IND is submitted and received by the FDA, a letter of IND Acknowledgement is sent to the investigator. The letter contains information on IND number, date of receipt, assigned review division, and division contact (Office of the Inspector General, 2003). The trial may not be initiated until after 30 days a period taken by review team made of chemists, project managers, clinical reviewers, and toxicologists to review the materials of the proposed clinical study. For example, review of the toxicity, toxicology, formulation, non-clinical pharmacology, and previous experiences of humans of the proposed investigational chemical.
Each member plays a significant role in the review process. For example, project manager plays the role of coordinating the activities of the team. Pharmacologist plays the role of reviewing preclinical studies. The role of the chemist is analysing the chemical compounds of a drug. Additionally, a chemist analyses manufacturing and stability of the drug, presence of impurities, and quality control. The investigator may be contacted or not by the FDA after the 30-day period of reviewing the chemical study (U.S Food and Drug Administration, 2013). Of IRB has been obtained, the trial can proceed if not notified of a clinical hold. If a determination has been made on putting a clinical trial on hold is made, an investigator is put on hold soonest. The following figure shows the IND review process.
Step 8: Response to a clinical hold
In case of any concerns by FDA, a study is put on hold. The concerns are raised and conveyed to the investigator who applied for an IND through a call and a detailed letter. Some of the issues that can lead to clinical hold are human participants being exposed to unreasonable risks, incomplete application, insufficient information, and lack of expertise in conducting a trial (University of Hong Kong, 2012). Upon receiving the concerns, the investor requires to respond to the issues clearly. The response with a clear headline indicating that it is a complete response to a clinical hold should accompany the response.
Form FDA 1571 should also indicate through a checkbox and a serial number that it is a clinical hold response. The FDA is required to respond to the hold response in 30 days. Three likely outcomes exists; one, the FDA can respond by putting the study on hold again pending resolution of the concerns, two, the agency can put the trial on partial hold where precise constraints are put, or the agency can lift the hold and the study can initiate (Western Institutional Review Board, 2018). To avoid being put on hold, it is essential that an investigator familiarizes with the provisions of putting studies on clinical hold. The study can only proceed if the FDA lifts a hold.
Step 9: Amendments of IND
After the initial IND submission is made and is effected, changes are required on IND to ensure that the investigations are done in accordance with the protocols in the application. Other information provided in on safety and annual report. The FDA reviews the amendments. If the investigator requires the FDA to respond to a submission, an FDA reply request is done. The investigator can also reach out directly the division responsible for review for more information on a submission (U.S. Food and Drug Administration, 2018). When an investigator is unclear on what information to communicate to the review division, it is important that one seeks guidance from the relevant agency to reduce the chances of being put on clinical hold.
Step 10: Understanding other responsibilities
Before initiating a study, it is important that an investigator reads all the regulations and familiarize with the responsibilities to observe during the study. Undertaking the responsibilities is in accordance with the IND regulations which helps in avoiding unexpected clinical hold (U.S. Food and Drug Administration, 2018). First, the investigator must undertake the study in agreement with the good clinical conduct. The practice involves scientific and ethical quality standards. The standards are adhered to when humans are the subjects. The standards protect human subjects. Investigators are required to observe the FDA regulations concerning the safety of the subjects and the study be studied and ratified by IRB (University of California, 2015). The second responsibility is monitoring the ongoing studies. Investigators are required to properly monitor the study. This ensures that the subjects are well protected, and data reporting is complete and accurate. To show that there is adequate monitoring, brief summaries are submitted to the IND ensuring that the study is led in accordance with the set regulatory requirements.
The third responsibility is avoiding promoting the drug under investigation. Such a conduct is prohibited. Additionally, charging for such drugs is only allowed in rare circumstances with the FDA approval. The fourth responsibility that an investigator should familiarize with is maintaining records and reports. These include maintaining supporting data such as informed consent forms that are dated and signed, and case report forms. Enough records showing receiving of drug and disposition are required (Kalantri, 2004). Drug disposition records require administration dates and quantity used. Periodically, the FDA inspects trial sites to assess storing and capturing of the critical data. The fifth responsibility is maintaining IND safety reports. In case of any threats with the investigational drug, the investigator notifies the FDA.
In case of potential risks during a trial, FDA requires immediate reporting. If similar safety reports have previously been submitted, the investigator has a responsibility of locating the reports and analysing the significance of the current findings in light of these reports. Additionally, an investigator has a responsibility of informing the IRB in case of potential risks to human subjects. The sixth responsibility is to maintain IND annual reports. 60 days after an IND goes into effect, an investigator is required to submit a summary annual report on trial progress (U.S. Food and Drug Administration, 2018). The report informs the review division of the relevant trial developments. Some of the information that it contains include trial progress in terms of enrolment and dropout, a summary of IND safety reports, and any new information in relation to the study either in toxicology, technical information, or pharmacology. In case the trial is complete, the FDA requires a final report (U.S. Food and Drug Administration, 2018).
Step 11: Inactivation, termination and withdrawal of an IND
An investigator can withdraw, terminate, inactivate, or reactivate an IND. For instance, one can withdraw an IND after completing a trial by sending a notification to the review division. In case of a withdrawal, all trials conducted under the IND comes to an ending. If the withdrawal is done for welfare motives, then IRB and the FDA must be informed quickly. Sometimes, the FDA can decide to terminate in an IND. In such a case, an investigator must end the studies that are under an IND (Yin, 2012). One of the reasons that can drive the FDA to terminate an IND is deficiencies in the conduct of a study under an IND. However, before the termination, the issues are attempted to be resolved informally. In inactivation, an investigator can request that an IND is inactivated is clinical hold takes more than one year. With this status, the investor is free from submitting annual reports. Sometimes an investigator can decide to reactivate an IND (U.S. Food and Drug Administration, 2018). This process entails that a submission is sent to request for an IND reactivation.
Step 12: Initiating the study
After the IND has been approved and the investigator understands all the responsibilities that rules and regulations require him or her to fulfil while conducting a study, one can now initiate the study on human subjects (Holbein, 2009). Part 312 of the IND regulations require that a study that involves human subjects be undertaken under an IND especially when the study involves a drug like in our study, Bretylium and when the subjects are human like in our case, where manic patients will be used in studying the chemical. Therefore, it is necessary that the regulatory requirements are met before conducting the study. The process of filing and maintaining an IND is essential because, it ensures that subjects are safe from unreasonable risks, and the process reduces delay in proceeding with the chemical study (Holbein, 2009). Once the FDA is satisfied that the study meets the federal standards, the investigator is free to proceed with the study. It is important that the investigator continues to inform the review team of the development of the study for continuous monitoring useful in detecting potential problems. The process ends when the investigator ends the trial.
Violation of federal regulations
Applying for an IND ensures that the FDA supports a clinical trial after ensuring that an investigator follows set rules and regulations when humans are used as subjects in a study. However, some investigators have failed to adhere to the regulations leading to rejection of their studies. For example, after visiting Semler Research Center, an Indian research organization, the FDA warned about the clinical trials conducted by the center (Silverman, 2016). After inspection, the FDA found that the research organization faces issues of violations and misconduct of federal regulations. This includes manipulation and substitution of the samples of the study subject.
The inspection found the manipulation of the study samples over a period indicating that the practice could be common. Several other studies conducted in the research center has also faced rejection proposals due to the concerns of misconduct and failure to comply with the clinical study regulations. Every investigator wishes to get a go ahead with the studies to help patients who really need treatment with the investigational drug. However, failure to adhere to relevant rules and regulations can lead to rejection of a study. If the study is rejected then it will be challenging to provide treatment to the manic patients in our case (Silverman, 2016). It is thus necessary to comply with the FDA regulations to avoid study regulations that can delay achievement of set objectives. Application for an IND will help in avoiding the potential problem.
The FDA has put various trial studies on hold due to safety issues causing delay. For example, upon submission of an IND, the CRISPR Therapeutics received a clinical hold on their trial. The proposed study was to involve human patients by investigating patients suffering from sickle cell disease. The study was to involve isolation of stem cells from the blood of a subject and then use CRISPR to generate a particular genetic change that is intended to increase fetal haemoglobin in red blood cells (Haridy, 2018). The investigator however, revealed that the trial study was put on hold by the FDA. Being put on hold delays a study trial that is purposed to improve life quality for the patients.
Bellicum is another company that has experienced a clinical hold after safety issues have been raised on the subjects. After learning of the risky practices that the lead cell therapy has had including the damaging brain of the subjects, the FDA placed the study on hold. The clinical study is aimed at fighting infections, preventing disease relapse, and aiding engraftment (Taylor, 2018). However, the FDA whose concerns about subject safety put the clinical study on hold to have a clear understanding of the safety concerns. This delayed the study as the company had to wait for the lifting of the hold by the FDA.
Roche is another investigator whose study was put on partial hold by the FDA due to safety concerns. According to the investigator, the FDA put on partial hold some studies on Tecentriq due to deaths in combo trials of Keytruda with Celgene medications. The hold was to help in assessing the situation (Sagonowsky, 2017). The information of the deaths drove the FDA to stop Roche from enrolling other patients in the studies. The hold caused study delay for Roche.
The high cost is a potential problem in clinical trials. Research shows that clinical trials are costly depending on the number of participants involved, and the complexity of a trial. According to a senior investigator at Thrombolysis, Christopher Cannon, two clinical trials cost him $600 million (Corneli et al., 2017). According to the investigator, these exorbitant costs requires that investigators focus in moving towards large trials that are simpler which involve studying a larger population, and the inclusion of less data reducing the overall cost.
According to the investigator, keeping trials large and simple would help in answering study concerns at a reduced cost. The high cost of conducting a chemical study would definitely be an issue. For example, investigators are required ti collect data from all participants for regulatory compliance. They use the case report form to collect this information. Data safety monitoring boards are used in checking the data. Monitoring costs in linked to the complexity of the form (Corneli et al., 2017). If a study develops a complex form characterized by many data points, the cost of monitoring is higher. If the cost is too high, then it would be impossible to conduct the study which means that patients will not be cared for. The investigator would not also be able to achieve the set objectives for the study.
Time is a potential problem in a clinical trial. Various investigators have recorded facing challenges with the significant amount of time required in conducting a chemical study. For example, some investigators have expressed concerns about the amount of time they spent in gaining informed consent from participants. A significant amount of time is spent in obtaining informed consent from every human subject (Institute of Medicine, 2010). The process is lengthy considering it involves the development of a worded consent document, discussion of the documents, discussing the study, obtaining signatures, and keeping track of the generated paperwork. For example, according to one investigator, Greenbaum, during her diabetes clinical study, the process of gaining informed consent took too long stressing her. A total of 6 members of a family decided to participate in the study. The informed consent required 6 consent forms that were separate, each form required 6 pages, 12 signatures, and five forms from Health Information Portability and Accountability (Institute of Medicine, 2010). The additional monitoring and compliance work was also required. A lot of time and effort was required for this process alone (Fagerlin et al, 2011). Such a problem can lead to spending so much time on the other process instead of focusing on the study.
Additionally the process of recruiting subjects can take time and more effort slowing down the study process. Finding subjects who fit a study determines its success. According to Greenbaum, an investigator, the socioeconomic status of potential subjects determines whether they agree to be subjects or not (Institute of Medicine, 2010). Patient education also determines of patients agree to take part in a study or not. Majority patients who are not very educated or aware of study trials have issues in playing role in clinical trials. In such a case, recruiting patients can be time consuming and sometimes unfruitful. For example, one study with 14 cancer centers had more than half of the study sites failing to recruit any patient. Such failures mean that the studies are not conducted (Institute of Medicine, 2010). Failure to conduct the study in our case means that the manic patients will not have medications affecting their quality of life. It is clear that patient recruitment and enrolment have direct effects in a drug study.
Conflict of interest
Conflict of interests has led to various scandals such as the WorldCom and Enron scandals. The topic has also been raised in clinical research. The current laws require financial disclosure from clinical investigators under FDA. In case an investigator has a conflict of interest in a study, the subjects are likely to be subjected to unreasonable risks. This calls for managing if such conflicts before conducting a study (Portier & Dunne, 2006). According to the Code of Federal Regulations, the IRB is forbidden from participating in study review when there exists a conflict of interest (Gillis, 2003). Various studies have been conducted when investigators have a conflict of interest putting subjects under increased risk. For example, a cancer center enrolled 195 human subjects but failed to inform that the president of the institution had a financial interest in the product that had a potential of earning him millions (Portier & Dunne, 2006). To avoid harming people or facing legal obligations, it is essential that investigators address any conflict of interest prior to conducting any clinical study.
It is clear that for investigators to be successful with their clinical studies, they must comply with the relevant regulations. To initiate Bretylium studies on manic patients, the investigator will undergo a regulatory process and the study can only be initiated after a legal approval. To acquire the legal approval, an IND submission process is undergone which involves various steps. The steps have been discussed in detail in this paper including designing clinical trials, starting an Investigational new drug process, determining whether study requires an IND, considering general principles for the application, analyzing the required forms for an IND submission, making initial IND submission, waiting for IND process and review, response to a clinical hold if any, amendment of the submission, understanding other responsibilities, and after approval, initiating the study. The paper has also discussed problems that can cause significant issues such as violation of federal regulations, safety issues, cost, time, and conflict of interest can lead to significant issues such as study rejection, a clinical hold, study delay, and study failure. It is thus essential that investigators comply with relevant regulations to have successful clinical studies.
Brown-Tuttle, M. (2009). IND Submissions: A Primer. Needham, MA: Barnett International.
Center for Biologics Evaluation and Research Organization (2009). About FDA. Retrieved on July 2, 2018 from http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm135943.htm
Center for Drug Evaluation and Research Organization (2009). About FDA. Retrieved on July 2, 2018 from http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm135674.htm.
Chidambaram, N. (2014). CDER Regulatory Applications – Investigational New Drug and New Drug Applications. U.S Food and Drug Administration, pp.1-70.
Clinical Trials Compliance (2003). FDA warning letter signals move to tighten oversight. June 2003 Strategies for Medicare Billing, FDA, and Research Compliance, Vol. 2, pp.1–12.
Clinical Trials Compliance (2003). Sidestepping the five most common FDA compliance pitfalls, Vol. 2, No.9, pp.1–3.
Corneli, A., Pierre, C., Hinkley, T., Hamre, G. & Roe, M. (2017). One and done: Reasons principal investigators conduct only one FDA-regulated drug trial. Contemporary Clinical Trials Communications, Vol. 6, pp. 31-38.
Croghan, I., Viker, S., Limper, A., Evans, T. & Gertz, M. (2015). Developing a clinical trial unit to advance research in an academic institution. Contemporary Clinical Trials, Vol. 45, Part B, pp. 270-276.
European Medicines Agency (2006). General Considerations for Clinical Trials, pp. 1-14.
Fagerlin, A., Zikmund-Fisher, B. J., Ubel, P. A. (2011). Helping patients decide: Ten steps to better risk communication. Journal of the National Cancer Institute, Vol.103, pp.1436–1443.
Federal Register (2017). Federal policy for the protection of human subjects (82 FR 7149, Effective on January 19, 2018). Retrieved from https://www.federalregister.gov/documents/2017/01/19/2017-01058/federal-policy- for-the-protection-of-human-subjects
Ferguson, P. (2003). Information giving in clinical trials: The views of medical researchers. Bioethics, Vol.17, pp.101–111.
Food and Drug Administration (2010). Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics.
Gillis, J. (2003). A hospital’s conflict of interest – Patients weren’t told of stake in cancer drug. Retrieved on July 2, 2018 from http://www.commondreams.org/headlines02/0630-03.htm.
Grady, C., Cummings, S., McConnell, M., Kang, G. Informed Consent (2017). The New England Journal of Medicine: Article Review. Clinical Trial Series, pp.856-866.
Haridy, R. (2018). FDA hits pause on one of the first US human clinical trials to use CRISPR. New Atlas. Retrieved on June 30, 2018 from https://newatlas.com/us-crispr- human-trial-hold-fda/54862/
Holbein, B. (2009). Understanding FDA Regulatory Requirements for Investigational New Drug Applications for Sponsor-Investigators. Journal of Investigative Medicine, Vol. 57, No. 6, pp. 689-695.
Institute of Medicine (2010). Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, DC: The National Academies Press.
Kalantri, S. (2004). Informed Consent and Clinical Trials. Indian J. Anaesthesia, Vol. 48, No. 3, pp.192-195.
National Institute of Health (2017). Timeline of Laws Related To the Protection of Human Subjects. Retrieved on July 2, 2018 from https://history.nih.gov/about/timelines_laws_human.html
Norman, G. (2006). Drugs, Devices, and the FDA: Part 1: An Overview of Approval Processes for Drugs. JACC: Basic to Translational Science Vol. 1, No. 3, pp.170-179
Office of the Inspector General (2003). Work Plan. Retrieved July 2, 2018 from http://oig.hhs.gov/publications/workplan.html.
Portier, W. & Dunne, C. (2006). Current Challenges and Opportunities in Clinical Research Compliance. The Ochsner Journal, Vol. 1, pp.21-24.
Protocol Registration System Information. Retrieved on July 2, 2018 from https://register.clinicaltrials.gov/.
Rick, N. (2008). Drugs from discovery to approval. 2nd ed. John Wiley & Sons, Inc., pp. 201-202.
Robert, P. (2008). The Pharmaceutical Regulatory Process. 2nd ed. Informa healthcare, p. 45.
Sagonowsky, E. (2017). FDA slaps enrollment hold on 2 Tecentriq studies after Keytruda myeloma trial deaths. Fierce Pharma. Retrieved on June 30, 2018 from https://www.fiercepharma.com/pharma/roche-halts-enrollment-tecentriq-studies-at- fda-s-request
Silverman, E. (2016). FDA and WHO warn about clinical trials run by an Indian company. STAT News. Retrieved on June 30, 2018 from https://www.statnews.com/pharmalot/2016/04/25/fda-warn-clinical-trials-run-indian- company/
Taylor, N. (2018). FDA hits Bellicum with clinical hold after brain damage cases in T-cell therapy trial. Fierce Biotech. Retrieved on June 30, 2018 from https://www.fiercebiotech.com/biotech/fda-hits-bellicum-clinical-hold-after-brain- damage-cases-t-cell-therapy-trial
U.S Food and Drug Administration (2012). Informed Consent and Ethical Considerations in clinical trials, pp.1-58.
U.S Food and Drug Administration (2013). Good Review Practice: Clinical Review of Investigational New Drug Applications, pp. 1-113.
U.S Food and Drug Administration (2017). Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs). Retrieved on June 30, 2018 from https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandap proved/approvalapplications/investigationalnewdrugindapplication/ucm071098.htm
U.S Food and Drug Administration (2018). Investigational New Drug (IND) Application. Retrieved on June 30, 2018 from https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandap proved/approvalapplications/investigationalnewdrugindapplication/default.htm
U.S Food and Drug Administration (2018). Regulations: Good Clinical Practice and Clinical Trials. Retrieved on June 30, 2018 from https://www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/ucm155713.ht
U.S Food and Drug Administration (2018). Step 3: Clinical Research. Retrieved on June 30, 2018 from https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm#Clinical_Researc h_Phase_Studies
U.S. Department of Health and Human Services (2013). Guidance for Clinical Investigators, Sponsors, and IRBs, pp. 1-23.
U.S. Department of Health and Human Services (2015). Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators Guidance for Industry, pp. 1-28.
U.S. Food and Drug Administration (2018). FDA Policy for the Protection of Human Subjects. Retrieved on July 2, 2018 from https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm1188 93.htm
U.S. Food and Drug Administration (2018). Regulations: Good Clinical Practice and Clinical Trials. Retrieved on July 2, 2018 from https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm1557 13.htm
University of California (2015). Ethical Guidelines, Federal Regulations and State Statutes. Available at https://research.uci.edu/compliance/human-research- protections/researchers/ethical-guidelines-fed-regs-and-state-statutes.html
University of California San Francisco (2018). IND Development Process. The Regents of the University of California. Retrieved on June 30, 2018 from https://hub.ucsf.edu/file-ind
University of Hong Kong (2012). Book Reviews. Drug Information Journal, Vol. 46, No.6, pp. 746-747.
University of Nevada, Reno. (n.d). 101. FDA Regulations for the Protection of Human Subjects. Available at https://www.unr.edu/research-integrity/human-research/human- research-protection-policy-manual/101-fda-fda-regulations-for-the-protection-of- human-subjects
University of Virginia School of Medicine (2018). Getting Started in Clinical Research. Retrieved on June 30, 2018 from https://med.virginia.edu/office-for- research/resources-and-collaborators/getting-started-in-clinical-research/
US Public Law 110-85 (Food and Drug Administration Amendments Act of 2007), Title VIII, Section 801.
Vijayananthan, A. & Nawawi, O. (2008). The importance of Good Clinical Practice guidelines and its role in clinical trials. Biomedical Imaging and Intervention Journal, Vol. 4, No. 1, e5.
Vishal, P., Rahulgiri, G., Pratik, M., Kumar, B. & Ahmedabad, H. (2014). A Review on Drug Approval Process for US, Europe and India. International Journal of Drug Regulatory Affairs, Vol. 2, No.1, pp.1- 11.
Western Institutional Review Board (2018). A Guide for Researchers, pp. 1-85.
World Medical Association (2013). World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, pp.2191–4
Yin, G. (2012).Clinical Trial Design: Bayesian and Frequentist Adaptive Methods. Hoboken, NY: John Wiley & Sons.