Clinical research

Basics of Clinical Research

1. CLINICAL RESEARCH D. DIVYA M. PHARMACY

2. Introduction Clinical Research is a branch of healthcare science that determines the safety and effectiveness of medications, devices, diagnostic products and treatment regimens intended for human use. Research is a laborious and time consuming task that can take several years. Drug development research in particular is long and arduous and bringing a single new drug costs on an average USD 1.7 billion and takes approximately 13.5 years from discovery to the market.

3. Introduction Clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health related interventions to evaluate the effects on health outcome. Clinical trials are conducted to collect the data regarding the safety and efficacy of new drug and device development. Father of clinical trials--- James Lind .

4. Importance of clinical trials Clinical trials are important for discovering new treatments for diseases as well as new ways to detect, diagnose and reduce the chance of developing the disease. Clinical trials can show researchers what does and doesn’t work in humans that cannot be learned in the laboratory or in animals. Clinical trials also help doctors decide if the side effects of a new treatment are acceptable when weighed against the potential benefits

5. Preclinical trials : Investigational drug must be tested on animals to determine the safety to administer humans. This phase lasts from 1 to 5 years. This test provides information about the pharmaceutical composition of the drug, safety and how the drug will be formulated, manufactured and how it will be administered to the human subjects.

6. Types of Clinical Trails There are two main types of clinical trials----observational and interventional Observational Clinical trials : these trials does not involve treatments or drugs. Researchers observe participants by monitoring their health over a period of time. These studies provide researchers with data that advances our understanding of Parkinson’s and how to treat the disease.

7. Types of Clinical Trials Interventional Clinical trials : These trials test the safety and effectiveness of a candidate drug, therapy or experimental treatment. Within these broad categories, trials also can be classified as follows. Treatment trials : Generally involves an intervention such as medication, psychotherapy, new devices or new approaches to surgery or radiation therapy

8. Types of Clinical Trials Prevention trials : looks for better ways to prevent disorders from developing or returning. Different kinds of prevention research may study medicines, vitamins, vaccines, minerals or lifestyle changes. Diagnostic trials : refers to the practice of looking for better ways to identify a particular disorder or condition. Screening trials : aims to find the best ways to detect certain disorders or health conditions

9. Types of Clinical Trials Quality of life trials : explores ways to improve comfort and the quality of life for individuals with a chronic illness. Genetic studies : aims to improve the prediction of disorders by identifying and understanding how genes and illness may be related. Research in this area may explore ways in which a person’s genes make him or her more or less likely to develop a disorder. This may lead to development of tailor made treatments based on a patient’s genetic make up.

10. Who conducts the clinical trial? The clinical trials are conducted by the Principle Investigator in Academic center, Clinical Research Organizations and Hospitals etc called as sites.

11. Sponsors for clinical trial Sponsor is an individual, institution, company or organization that takes the responsibility to initiate, manage or finance the clinical trial. Pharma and Biotechnology companies National Institute of Health National Cancer Institute Department of Defence Medical Institutions and foundations.

12. Regulatory Bodies The Central Drug Standard Control Organization is the National Regulatory Authority in India. Other regulatory bodies are USFDA, Health Canada, European Medicines Agency. CDSCO is an arm of the Ministry of Health and Family Welfare, Government of India. Its mission is to safeguard and enhance public health by assuring the safety, efficacy and quality of drugs, cosmetics and medical devices.

13. Regulatory Bodies The Drugs Controller General of India (DCGI) is an official of the CDSCO who is final regulatory authority for the approval of clinical trials in the country. Indian Council of Medical Research (ICMR) is the apex body that is responsible for the formulation, coordination and promotion of biomedical research. It provides the ethical guidelines for conducting the clinical trials.

14. Trial Master File TMF is a collection of essential documents which are necessary for conducting a clinical trial. TMF is usually maintained by the sponsor or sponsor representative (CRO). The following essential documents are 1) Protocol: It is a document that describes the background, rationale, objectives, design, methodology, statistical considerations and organization of clinical research project.

15. Trial Master File 2) Informed Consent Form : According to ICH-GCP Informed consent is a process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form. If the subject is minor or older, an Assent form is obtained and is also signed by the guardians.

16. Trial Master File 3) Investigator Brochure : It is a compilation of the clinical and non clinical data on the investigational products that are relevant to the study of the products in human subjects. 4) Financial aspects of the trial : It is essential to document the financial agreement between the investigator/ institution and the sponsor for the trial. 5) Insurance statement : It is essential to document that compensation to subjects for trial related injury will be available.

17. Trial Master File 6) Signed agreement between the involved parties : It is essential to document the agreements between the Investigator/Institution and sponsor, Investigator/Institution and CRO, Sponsor and CRO, Investigator/Institution and authority. 7) IRB/IEC Composition : It is essential to document that the IRB/IEC is constituted in agreement with GCP.

18. Trial Master File 8) Regulatory authority approval document : To document appropriate authorization/ approval /notification by the regulatory authority has been obtained prior to initiation of the trial in compliance with the applicable regulatory requirements. 9) Curriculum Vitae of Investigator, sub investigator : To document qualifications and eligibility to conduct trial and provide medical supervision of subjects.

19. Trial Master File 10) Normal value ranges for medical laboratory/ technical procedures /tests included in the protocol: To document normal values and ranges of the tests. 11) Medical laboratory technical procedures tests : To document competence of facility to perform required tests and support reliability of results.

20. Trial Master File 12) Samples of labels attached to the investigation product containers : To document compliance with applicable labeling regulations and appropriateness of instructions provided to the subjects. 13) Instructions for handling of investigational product and trial related materials : To document instructions needed to ensure proper storage, packaging, dispensing and disposition of investigational product and trial related materials.

21. Trial Master File Shipping records for investigational products and trial related materials : To document shipment dates, batch numbers and method of shipment of investigational product and trial related materials. Certificate of analysis of investigational products shipped : To document identity, purity and strength of the investigational product to be used in the trail.

22. Trial Master File 16) Decoding procedure for the blinded trials : To document how incase of emergency identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects treatment. 17) Master randomization list : To document method for randomization of trial population. 18) Pre trial monitoring report : To document that the site is suitable for the trial.

23. Trial Master File 19) Trial Initiation monitoring report : To document that trail procedures were reviewed with the investigator and the investigator’s trial staff.

24. Eligibility Criteria Each study protocol has guidelines for who can or cannot participate in the study. These guidelines called eligibility criteria. It describe characteristics that must be shared by all participants. This criteria differ from study to study. They may include age, gender, medical history and current health status . Eligibility criteria for treatment studies often require that patients have a particular type and stage of cancer.

25. Randomization Randomization is the process of assigning patients by chance to groups that receive different treatments. In the simplest trial design, the investigational group receives the new treatment and the control group receives standard therapy. Randomization is of 4 types. 1) Simple randomization 2) Randomized block design 3) Stratified randomization 4) Adaptive randomization

26. Randomization Simple Randomization : The most common and basic method of simple randomization is flipping a coin. Computer generated random numbers can also be used for simple randomization of subjects. Randomized Block design : The subjects are divided into 2 blocks based on gender such as male and female. Then within each block, subjects are randomly assigned to treatment group and control group. Then samples are collected analyzed and compare the results.

27. Randomization Stratified Randomization : Stratified randomization refers to the situation in which strata are constructed based on values of prognostic variables and a randomization scheme is performed separately within each stratum. For example, suppose that there are two prognostic variables, age and gender, such that four strata are constructed.

28. Randomization Adaptive Randomization : It refers to any scheme in which the probability of treatment assignment changes according to assigned treatments of patients already in the trial. Parallel study: One group receives only A treatment and other group receives only B treatment. Cross over study: One group receives A and followed by B and other group receives B and followed by A.

29. Bias Bias is the intentional or unintentional adjustment in the design or conduct of clinical trial and analysis and the evaluation of the data may affect the result. Bias can occur during the trial design, data collection, data analysis and publication.

30. Blinding Blinding is a procedure in which one or more parties in a trial are kept unaware of which treatment arms participants have been assigned to that is which treatment was received in order to avoid bias.

31. Types of Blinding Un blinded or Open labeled study : In which both the participant and investigator knows about medication details. Single blinded study : The participant don’t know about the medication but the investigator knows about medication. Double blinded study : The participant and investigator both don’t know about the medication. Triple blinded study : The participant, investigator and statician also don’t know about the medication

32. Phase 0 Phase 0 (Micro dosing studies): Duration—1 week Participants—10 to 15 Dose of drug---≤100 µg Use---Determination of preliminary PK parameters. If the medication acts differently than expected, the investigators will likely to do some additional preclinical research before deciding whether to continue the trial.

33. Phase I Phase 1 (Human Pharmacology studies): Duration---one month to several months Participants---20 to 80 Healthy volunteers Use---Determination of safety, tolerability, Pharmacokinetics and pharmacodynamics . The main aim of this phase is to determination of highest dose that human can take without serious side effects.

34. Phase I Finding best ways to administer the drug such as orally, intravenously and topically etc. Investigators monitor participants very closely to see how their bodies react to the medication during this phase. While preclinical research usually provides some general information about dosing, the effects of medication on the human body can be un predicatble . According to FDA approximately 70% of medications move on to phase 2.

35. Phase I There are 3 methods to conduct phase 1 studies: Single ascending dose(SAD) or phase I A : A single dose of the drug is given to small group (3 members) of people. If they are safe then we will increase the dose to another 3 members. Multiple ascending dose (MAD) or Phase IIA : Multiple doses of the drug is given at different time points. Samples are collected and analyzed.

36. Phase I Food effect : Designed to investigate any differences in absorption of the drug by the body caused by eating before the drug is given. These studies are run as cross over studies. Reasons to select healthy volunteers: Large number of people available and greater compliance Risks are considerably reduced More homogenous group and rapid recruitment rate. Incase of ADR’s chances of speedy and complete recovery will be more.

37. Phase II Phase II (Therapeutic Exploratory studies): Duration---several months to 2 years. Participants---20 to 300 patients. Use ---Determination of efficacy of drug. Dose ---there’s is usually given the same dose that was found to be safe in the previous phase. According FDA approximately 33% medications move on to phase 3.

38. Phase II Phase II trials are of 2 types Phase II A : These studies are also called as early phase, pilot clinical trails. Require 20 to 200 patients. Single blinded and single center trials To assess safe dose of the drug Test drug compares with the placebo.

39. Phase II Phase II B : These studies are also called as late phase, pivotal clinical trials Require 50 to 300 patients. Double blinded and multicentric trials. We should know about therapeutic dosage regimen, frequency of administration and duration of therapy. Test drug compares with the placebo or standard drug.

40. Phase III Phase III (Therapeutic confirmatory studies): Duration---≤5 years Participants---300 to 3000 patients. Main objective is proving or confirming the clinical efficacy with no unacceptable safety concerns. To do this the investigators use a process called randomization According to FDA approximately 25 to 30% of medications move on to phase 4.

41. Phase III Phase III studies are 2 types: Phase IIIA or prior NDA studies: With the efficacy and safety data obtained from the phase II trials, phase III a trials are initiated. Most of the phase III studies are conducted in phase III a trials like non inferiority trials, long term safety studies.

42. Phase III Most of the studies producing the information supporting the patient information leaflet/ label along with post marketing commitments. Some studies may also conducted in special population depend upon the drug/disease. Most of the times drug candidate compared with an active comparator. If there is a lack of standard treatment for target disease, drug candidate compared with the placebo. This phase done before getting the first indication approval.

43. Phase III Phase IIIB or After NDA studies : This phase starts after getting first approved indication from regulatory authority and before getting the marketing approval/ launch of the drug. These are additional studies which gather additional information like long term safety and drug effect on quality of life etc. The intention of these studies is to produce the data supporting the publications and marketing claims.

44. Phase IV Phase IV ( Pharmacovigilance studies): The phase 4 trials also referred to as post marketing surveillance and as the name suggests, it is conducted after the drug is already marketed and available to the public. The main objective of this phase is to check the drug performance in real life scenarios, to study the long term risks and benefits of using the drug to discover any rare side effects. If any rare adverse event observed in larger population the drug must be withdrawn from the market.

45. Best practices for clinical trial operations To conduct clinical trials efficiently and effectively from start to finish, there are number of factors to consider. These factors in trials can have impact on outcome the clinical trial. The following are a few best practices for clinical operations. Pre Trial Due Diligence: Protocol: Before starting the trial, the most important factor is understanding the protocol and what it requires from a logistical standpoint.

46. Best practices for clinical trial operations This understanding must come from a comprehensive assessment, considering the protocol from the perspective of the site, investigator, coordinator and patient. Evaluating the protocol from the perspective is particularly important, as understanding the logistical requirements from their point of view will help with the recruitment of patients willing and able to commit to participating in the trial from start to finish.

47. Best practices for clinical trial operations Site Selection: Once understanding the protocol is complete, it will be easier to begin the site selection process and start considering what type of sites you will need for the trial such as private practices, specialized clinics, hospitals, group practices etc. Site distribution should also be considered. It is beneficial for sites to be geographically diverse so the trial is accessible to more patients. Consider how each region might affect the study. For example does the population of an area fluctuate throughout the year or does it remain steady? How might the whether within the region impact your trial?

48. Best practices for clinical trial operations Pre feasibility assessments can help provide a critical snapshot of the current landscape for your trial before the trial begins. Are there sites interested and available to participate in your trial? The information received from pre feasibility assessments can provide the baseline for developing initial assumptions regarding recruitment and enrollment.

49. Best practices for clinical trial operations In the pre feasibility assessments, a site’s proposed recruitment methods can be collected. This information can be used to determine which methods of recruitment would be ideal. Should social media be considered or would the trial be better suited for more traditional methods, such as print, TV or radio advertising

50. Best practices for clinical trial operations Risk assessment : An initial risk assessment should also be conducted during the pretrial phase. Risks can affect each stage of the trial. By identifying and categorizing risks from the beginning, sponsors can be aware of potential risks to begin determining whether to accept, avoid, mitigate or transfer these risks. Consider non protocol risks. For example, have the sponsor and CRO ever worked together? If the sponsor and CRO do not have an established working relationship, risk mitigation may be needed for each party to have a clear understanding one another’s responsibilities, expectations, needs and treatment.

51. Best practices for clinical trial operations Risk mitigation may also be necessary if the CRO and/or Sponsor have never worked with the vendors selected for the trial. Clarifying pathways of communication is key to managing these relationships---knowing from the start who to contact and how to communicate across project team members from the sponsor, CRO and vendors can help avoid future confusion, delays and unnecessary back and forth.

52. Best practices for clinical trial operations Training -Finally during the pre trial phase training should be considered both training of site personnel and project team members. Again, understanding the protocol is key in determining how much training is needed and the best way to deliver that training. Recording trainings is best practice. By recording live trainings, site personnel and project team members can complete initial or refresher self paced training by reviewing the recordings independently.

53. Best practices for clinical trial operations CRA : During the pre trial phase consideration should be given to whether Clinical Research Associates will be involved in the study start up activities. Involving CRA’s in study start up activities early on is beneficial for training purposes.

54. Best practices for clinical trial operations Trial Maintenance and Close out: The two key factors to consider during trail maintenance are enrollment and data: ensuring each site is enrolling patients that meet all eligibility criteria and ensuring accurate data is being collected. Enrollment : The actual enrollment of subjects is slower than the projected enrollment data. Study level material should be developed and made available to sites from study start to facilitate enrollment for your trial.

55. Best practices for clinical trial operations Bringing site personnel together to discuss enrollment and share successes, failures, challenges and best practices can help identify enrollment trends and challenges. Conducting site recruitment calls/ visit to collect detailed information regarding sites recruitment and enrollment activities provides valuable information regarding enrollment activity.

56. Best practices for clinical trial operations Enrollment should be monitored frequently at both the site and study level. Actual enrollment should be compared to the projected enrollment data regularly. If your trial is not meeting the projected enrollment goal, the projected enrollment may need to be re evaluated and updated.

57. Best practices for clinical trial operations Data : Gathering clean data is among the most important steps to a successful clinical trial. Sites can be found, patients can be recruited, but if the data is inaccurate, it will not be of use to the sponsor. Data is also a key factor to consider during trial close out. However the primary focus from a clinical operations perspective is data cleaning to meet the database lock milestone.

58. Best practices for clinical trial operations CRA’s should collaborate directly with data management to ensure data is monitored and cleaned on an ongoing basis. Data management should provide status trackers or reports routinely that outline the current status of CRF data review---what queries are open, what data has been SDVed , what data has been frozen etc.

59. Nuremberg Trials Nuremberg trials were a series of 13 trials carried out in Nuremberg, Germany, between 1945 and 1949. The defendants, who included Nazi party officials and high ranking military officers along with German industrialists, lawyers and doctors were indicted on such charges as crimes against peace and crimes against humanity. In these trials involuntary subjects are involved most of whom were imprisoned Jews, Poles, Russians and Roma. The verdict included a section entitled “Permissible Medical Experiments” now called the Nuremberg Code that addressed fundamental issues on the use of human subjects in medical research

60. Tuskegee Syphilis Study In 1932 the public health service working with Tuskegee Institute began a study to record the natural history of Syphilis in hopes of justifying treatment programs for blacks. It was called the “Tuskegee study of Untreated Syphilis in the Negro male. The study was conducted without the benefit of patient’s informed consent. Researchers told the men they were being treated for bad blood, a local term used to describe several ailments, including Syphilis, anaemia and fatigue. In truth they did not receive the proper treatment needed to cure their illness.

61. Tuskegee Syphilis Study The subjects undergone free medical examinations and they provide free meals, transportation and burial insurance. On July 1972, the public learned that, over the course of the previous 40 years experiment had allowed hundreds of African American men with Syphilis to go untreated even after Penicillin was discovered as a cure for Syphilis.

62. Nuremberg Code The Nuremberg code was introduced in August 1947, after Nuremberg trials. It attempted to give clear rules about what was legal and what was not when conducting human experiments. The code consists of ten points. 1) The voluntary consent of the human subject is absolutely essential. 2 ) The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study and not random and unnecessary in nature.

63. Nuremberg Code 3 ) The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under the study, that the anticipated results will justify the performance of the experiment. 4 ) The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

64. Nuremberg Code 5 ) No experiment should be conducted, where there is an priori reason to believe that death or disabling injury will occur, except perhaps, in those experiments where the experimental physicians also serve as subjects. 6) The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.

65. Nuremberg Code 7 ) Proper preparation should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death. 8 ) The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

66. Nuremberg Code 9 ) During the course of the experiment, the human subject should be at liberty to bring the experiment to an end, if he has reached the physical or mental state, where continuation of the experiment seemed to him to be impossible 10) During the course of the experiment, the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgement required of him, that a continuation of the experiment is likely to result in injury, disability or death to the experimental subject.

67. Belmont Report Belmont report was published in 1979, in this the basic guidelines are intended to prevent ethical problems related to research. It is commissioned by the US Government in response to ethical failures in medical research, such as the Tuskegee Syphilis Study. The Belmont report was written by a panel of experts and proposes following three principles. Respect for persons Beneficence Justice

68. Belmont Report Respect for persons consists of two distinct principles –individuals should be treated as autonomous and individuals with diminished autonomy should be entitled to additional protections. The principle of respect for persons is interpreted to mean that researchers should, if possible, received informed consent from participants and the Belmont report identifies 3 elements of informed consent such as information, comprehension and voluntariness.

69. Belmont Report The principle of Beneficence is behind efforts by researchers to minimize risks to participants and maximize benefits to participants and society. The principle of justice addresses the distribution of the burdens and benefits of research. That is it should not be the case that one group in society bears the costs of research while another group reaps its benefits. Issues of justice arise most strongly around questions about the selection of participants.

70. Declaration of Helsinki The world medical association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects . The Declaration was the first document to require that biomedical research involving humans conform to generally accepted scientific principles 

71. Declaration of Helsinki The Declaration specifies information that must be given to the subject before consent is obtained, including all foreseeable risks and discomforts, the fact that he or she may withdraw at any time, and a complete description of the study protocol.