Ind by pankaj
- 1. PHARMACOLOGICAL AND TOXICOLOGICAL SCREENING 2019 INVESTIGATIONAL NEW DRUG SUBMITTED BY: PANKAJ KUMAR MAURYA M.PHARM (PHARMACOLOGY) ROLL NO. 1888024002 SUBMITTED TO: MS. HARJEET KAUR ASSISTANT PROFESSOR DEPARTMENT OF PHARMACOLOGY CT UNIVERSITY, PUNJAB D E P A R T M E N T O F P H A R M A C O L O G Y
- 2. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 2 1.1 INTRODUCTION Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA. During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies. FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system. 1.2 THERE ARE THREE IND TYPES An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population. Emergency use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21CFR, Sec. 312.23 or Sec. 312.20. It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.
- 3. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 3 1.3 THERE ARE TWO IND CATEGORIES Commercial Research (non-commercial) 1.4 THE IND APPLICATION MUST CONTAIN INFORMATION IN THREE BROAD AREA Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experiences with the drug in humans Family histories of febrile convulsions, epilepsy or sudden death. Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug. Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations. Note - Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk. 2.1 THE REGULATORY ENVIRONMENT AND FDA ROLE The FDA is an agency in the US Department of Health and Human Services charged with assuring the safety, efficacy, and security of human as well as veterinary drugs in addition to other areas of regulatory authority. The agency is also responsible for
- 4. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 4 facilitating advances in medications. The FDA is a large and rather complex federal agency with a number of centers, divisions, and offices located both centrally in the Washington Metropolitan Area as well as numerous regional offices in the United States. For the purposes of regulatory supervision of investigational drugs in human clinical trials, the centers primarily involved are the Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health, and the Center for Biologics Evaluation and Research (CBER). Within these centers are offices with regulatory, functional, or therapeutic focus. Most pharmaceutical drug products, both synthetic and biologic, fall under the regulatory supervision of CDER, including most drug studies. The CBER regulates biological and related products including blood, vaccines, allergenic, tissues, and cellular and gene therapies, so only a small number of specialized drug studies would come under CBER jurisdiction. The primary set of federal laws establishing FDA authority as well as codification of the regulations is the Federal Food, Drug, and Cosmetic Act. The specific section of these laws covering an IND is in Part 312 of the Code of Federal Regulations (CFR). There are also other parts of the CFR that impact the conduct of clinical studies using pharmaceutical products Finally, Federal law dictates that in order for a drug to be transported or distributed across state lines, it must have an approved marketing application. Because drugs to be used in most clinical trials will be shipped across state lines, the sponsor must seek an exemption from that legal requirement. The name, “Notice of Claimed Investigational Exemption for a New Drug” refers to this exemption. The more commonly used name is an “IND”.
- 5. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 5 Lists the more important sections relevant to individual investigator
- 6. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 6 Flowchart for a clinical drug study that may require an IND application for an investigator-sponsor
- 7. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 7 3.1 WHEN IS AN IND NOT NEEDED FOR STUDIES INVOLVING MARKETED DRUGS? The use of a placebo does not require an IND if the investigation does not otherwise require submission of an IND. Clinical trials that use an FDA-approved drug within the approved labeling do not need an IND. The FDA has a mechanism to bypass filing an IND if specific exemption criteria are met, which address the safety of the proposed study as well as stated limits on the noncommercial intent of the study. The exemption criteria only apply to studies using marketed pharmaceuticals commercially available in the United States. These criteria are listed in CFR 312.2 (b). 4.1 GENERAL PRINCIPLES The general scheme for an IND includes providing information in general areas: animal pharmacology and toxicology studies, manufacturing information, and clinical protocols and investigator information. The intent is to provide the FDA information to allow a review that assures the safety of participants. For sponsor-investigators, typically, the IND will not require the same extensive information including preclinical studies or manufacturing and process information as would be required for a commercial sponsor applying for an IND for a yet unapproved drug, especially early in its development. To an extent, this is because the studies conducted by sponsor- investigators usually use FDA-approved pharmaceuticals. Note that a sponsor- investigator has responsibilities as both a sponsor and an investigator, and investigations conducted under this designation are frequently single-site studies 5.1 INVESTIGATIONAL NEW DRUG GUIDANCE AND PLANNING For commercial sponsors, the drug development is a far more complex and involved process compared with sponsor-investigator. Analogously, the pre-IND process is more formalized and often entails scheduled meetings or a teleconference. For sponsor-investigator, most questions are typically less complicated. Nonetheless, individual investigators can and should make use of the agency resources. The FDA Web site has downloadable forms, descriptions of the IND application process, and listings of guidance on the completion of the forms and clerical requirements. The
- 8. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 8 FDA has issued a Guidance that addresses the IND submission process specifically for sponsor-investigators. An extensive information for sponsors to guide preclinical and phase 1 studies and pre-IND consultations is also listed. The FDA makes contact information for both CDER and CBER officials available on the FDA Web site. Questions about the IND process can be directed to the appropriate office or division, generally by telephone or email. 5.2 FDA FORM 1571 The IND application, FDA Form 1571, provides the structure to present the information about the proposed research. By definition, the sponsor is the single individual initiating and taking responsibility for the study. Hence, an individual investigator who initiates (e.g., designs, obtains funding) and conducts the trial meets the criteria of a sponsor-investigator. Note especially, even if a pharmaceutical company will supply drugs or placebos, the individual investigator is still the named sponsor. For sponsor-investigators, parts of the information required on the 1571 overlap and are covered by the FDA Form 1572. Form 1571 is used by all applicants, commercial or research investigators, and there are several sections that do not apply to a sponsor-investigator. 5.3 FDA FORM 1572 This form comprises the “Statement of Investigator”. The information requested regarding the investigator’s qualifications and contact information can often be met by an academic curriculum vitae, noting on the form that the information is contained in the attachment. Note also that sponsor-investigator sections of the FDA Form 1572 satisfy the information requirements for specific sections of the FDA Form 1571. 5.4 FDA FORM 3674 The IND application must be accompanied by a certification that the requirements of section 402(j) of the Public Health Service Act have been met. United States Public Law 110-85 (FDA Amendments Act of 2007), Title VIII, Section 801, requires registration of “applicable clinical trials”. All controlled clinical investigations that use a drug regulated by the FDA must be registered with the exception of phase 1 studies. The intent of the legislation requiring that applicable clinical studies be registered is to ensure that the public has access to information about certain clinical
- 9. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 9 trials that are being conducted, including access and results. This registration process is done via filing trial information with the Protocol Registration System of clinical trials run by the US National Library of Medicine at the National Institutes of Health. Form 3674 certification requires the appropriate ClinicalTrials.gov identifiers (NCT numbers) that are obtained from registration. The FDA has issued draft guidance on the certification process. For a sponsor-investigator filing an IND, the responsibility for registration rests with the investigator. For most sponsor-investigators, the institution with the regulatory oversight for the conduct of the study is probably already a registered research entity with a registration account, and the investigator will not need to create a separate registration account. 6.1 SUBMITTING AN IND A cover letter should accompany the IND submission. Include identification of the sponsor-investigator, a clear indication that this is an initial IND submission, and ensure that the contact information is clear and complete. Because this is the initial IND submission, there is no IND number. Each sequential correspondence regarding an IND should carry a sequential identifying serial number, which, in this initial submission, would be “0000”. Clearly indicate the title of the study. Take care that the contact information exactly matches that in 1571 and 1572 to avoid any delays in communications. Because this process is time-sensitive, delays due to communications errors can have significant consequences. Send the submission to the attention of the division that oversees the therapeutic area for the study drug. If there has been a discussion with an individual at CDER or CBER, they may direct the submission to a specific recipient. The IND should be submitted in triplicate, namely, 1 original and 2 copies. No special binders or packaging is required.
- 10. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 10 7.1 FOLLOWING RECEIPT OF IND BY THE FDA The IND will be routed to the appropriate division for review. A letter of acknowledgment will be sent to the sponsor-investigator. This letter provides the assigned IND number, date received, and the name and telephone number of the FDA project manager to whom questions about the application and further correspondence should be directed. The IND becomes effective 30 days after the stated FDA receipt date unless the FDA sends notification otherwise. The FDA generally does not send a letter notifying the sponsor-investigator of approval. Studies may begin after the 30- day interval, if the FDA does not notify the investigator otherwise. If the FDA requests further information or clarification, the 30-day window is not affected unless the FDA gives an indication that the study is placed on a complete or partial clinical hold. A partial hold will allow a specific part of the study to begin while the other part cannot be started. A clinical hold explicitly means that the study may not begin. 8.1 RESPONDING TO A CLINICAL HOLD A clinical hold occurs when the FDA contacts the sponsor-investigator and indicates that the study cannot start pending resolution of questions or concerns. The specific questions that the agency has are conveyed to the investigator, typically by telephone followed by a detailed letter. Upon receipt of the list of FDA concerns, the sponsor- investigator should respond to the issues cited in the letter in their entirety. The cover letter that accompanies the response should clearly indicate the response with a heading, “Clinical Hold Complete Response’. Likewise, the accompanying FDA Form 1571 should indicate by serial number and checkbox that it is a response to a clinical hold. The “clock” on the review process does not begin until all issues have been addressed and the responses have been received and acknowledged by the FDA. The FDA should reply within 30 days of the receipt of the complete response from the sponsor-investigator. The agency will issue a letter that lifts the clinical hold (the study may proceed), places the study on partial hold (specific restrictions), or that the study continues to be on hold pending resolution of continuing questions. Until the FDA indicates that a hold has been removed, a study must not proceed. 9.1 REGULATORY REQUIREMENTS FOR AN IND DURING STUDY AND AT COMPLETION
- 11. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 11 Submission of an IND begins the regulatory process under which a study progresses. There are ongoing obligations that the sponsor-investigator agrees to with the signature of the FDA Form 1571. In brief, the sponsor-investigator agrees to keep the IND current, to notify the FDA about any safety issues, to file annual reports, and to notify the FDA when the study ends for any reason. Any amendment to the IND must be filed with the FDA. 9.2 PROTOCOL AMENDMENTS (21 CFR 312.30) Provisions in this section allow for the filing of a new protocol, changes to protocol, or the addition of a new investigator. Changes can include any increase or decrease in drug exposure by way of dose or duration, a change in the subject population’s inclusion or exclusion, or a change in monitoring for safety. The IRB with oversight responsibility must likewise be notified and give approval. The amended protocols must be submitted before implementation with the exception of a protocol change intended to eliminate an apparent immediate hazard to subjects. In this case, the IRB is notified in accordance to regulations and the FDA subsequently notified. 9.3 INFORMATION AMENDMENTS (21 CFR 312.31) Similar to amendments in the research protocol, changes in the essential information regarding the IND that are not within other reports are added via an “information amendment”. This can include changes in toxicology, chemistry, or other technical information. All amendments should be clearly labeled as to the contents (e.g., “Information Amendment: Pharmacology-Toxicology”). These amendments should not be issued more frequently than 30-day intervals. 9.4 SAFETY REPORTS (21 CFR 312.32) Sponsor-investigators are responsible for investigating all safety concerns brought to their attention. They must notify the FDA, all participating investigators, and the local IRB of any adverse experience associated with the use of the drug that is both serious and unexpected in a written IND safety report. This equally applies to any finding that suggests a significant risk for human subjects. The time frame for reporting is no later than 15 calendar days after the sponsor’s initial receipt of the information. The report should be made via FDA Form 3500A (MedWatch) or in a narrative format. The
- 12. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 12 report should be clearly labeled “IND Safety Report”. The sponsor-investigator is responsible for analyzing the significance of the report in context of other safety reports. In the case of either death or life-threatening experience associated with the study drug, notification of the FDA must be made no later than 7 calendar days after the sponsor-investigator’s initial receipt of the information. This should be done either by telephone report or by facsimile transmission. The local IRB should likewise be informed. 9.5 ANNUAL REPORTS (21 CFR 312.33) Annual reports must be filed by the sponsor-investigator. The filing deadline is within 60 days of annual date of the IND. If there are multiple protocols under a single IND, each should be identified by title and have a summary report. The investigator should include the status of each study still in progress and each study completed during the previous year. The progress of enrollment should be tallied including total number of subjects planned, number entered to date (by age, sex, and race), the number of subjects whose participation in the study was completed as planned; and the number who dropped out of the study for any reason. If the study has been completed, or if interim results are known, a brief report of results should be included. A summary of all IND safety reports submitted during the past year should be included. A summary of any significant changes in the pharmacology, toxicology, or technical information should be included. Lastly, the plan for the coming year should be stated. 10.1 WITHDRAWAL, TERMINATION, AND INACTIVATION A sponsor may withdraw an IND at any time. The FDA and all investigators should be notified and all drug stocks accounted for. If the withdrawal is for safety reasons, the notification must provide a report of the reasons. In this case, the reviewing IRB must also receive notification. When a study ends, the sponsor-investigator must notify the FDA. The FDA may terminate an IND. This is usually done in cooperation with the sponsor but may be unilateral. The sponsor is allowed a response to an FDA- initiated termination, but the time frame is quite limited. A study may be placed on “inactive status” by the sponsor or the FDA. This may be due to a number of reasons such as delays in implementation, insufficient enrollment, failure to file annual
- 13. INVESTIGATIONAL NEW DRUG 2019 CT UNIVERSITY,LUDHIANA Page 13 reports, or failure to respond to FDA inquiries. An IND that remains in inactive status for 5 or more years may be terminated. 11.1 MONITORING RESPONSIBILITIES FOR SPONSOR-INVESTIGATORS Monitoring of the study is an ongoing responsibility. The regulations explicitly charge the sponsor-investigator with accountability. Sponsors must monitor and assure that human subjects are adequately protected, that all reported clinical data are accurate and complete, and that the conduct of the trial is in compliance with the protocol and regulations. Unique to drug studies is the added responsibility for drug accountability. Investigators must also correct any problems that occur during the study or terminate the study and notify their IRB, the FDA, and other investigators 12.1 REFERENCE https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelop edandapproved/approvalapplications/investigationalnewdrugindapplication/de fault.htm Holbein, ME Blair. "Understanding FDA regulatory requirements for investigational new drug applications for sponsor-investigators." Journal of investigative medicine 57.6 (2009): 688-694