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Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows: a Phase 1. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.
During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug.
Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling.
Phase 3 studies usually include from several hundred to several thousand subjects. Therefore, although FDA's review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations, FDA's review of Phases 2 and 3 submissions will also include an assessment of the scientific quality of the clinical investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.
Subsequent amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate.
Annual reports to the IND should serve as the focus for reporting the status of studies being conducted under the IND and should update the general investigational plan for the coming year. Sponsors are expected to exercise considerable discretion, however, regarding the content of information submitted in each section, depending upon the kind of drug being studied and the nature of the available information.
Section A sponsor-investigator who uses, as a research tool, an investigational new drug that is already subject to a manufacturer's IND or marketing application should follow the same general format, but ordinarily may, if authorized by the manufacturer, refer to the manufacturer's IND or marketing application in providing the technical information supporting the proposed clinical investigation. A sponsor-investigator who uses an investigational drug not subject to a manufacturer's IND or marketing application is ordinarily required to submit all technical information supporting the IND, unless such information may be referenced from the scientific literature.
A cover sheet for the application containing the following: i The name, address, and telephone number of the sponsor, the date of the application, and the name of the investigational new drug. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer - in lieu of a listing of the specific obligations transferred - may be submitted.
If the person signing the application does not reside or have a place of business within the United States, the IND is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States. The plan should include the following: a The rationale for the drug or the research study; b the indication s to be studied; c the general approach to be followed in evaluating the drug; d the kinds of clinical trials to be conducted in the first year following the submission if plans are not developed for the entire year, the sponsor should so indicate ; e the estimated number of patients to be given the drug in those studies; and f any risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug or related drugs.
Reprints of published articles on such studies may be appended when useful. In general, protocols for Phase 1 studies may be less detailed and more flexible than protocols for Phase 2 and 3 studies. Phase 1 protocols should be directed primarily at providing an outline of the investigation - an estimate of the number of patients to be involved, a description of safety exclusions, and a description of the dosing plan including duration, dose, or method to be used in determining dose - and should specify in detail only those elements of the study that are critical to safety, such as necessary monitoring of vital signs and blood chemistries.
Modifications of the experimental design of Phase 1 studies that do not affect critical safety assessments are required to be reported to FDA only in the annual report. A protocol for a Phase 2 or 3 investigation should be designed in such a way that, if the sponsor anticipates that some deviation from the study design may become necessary as the investigation progresses, alternatives or contingencies to provide for such deviation are built into the protocols at the outset.
For example, a protocol for a controlled short-term study might include a plan for an early crossover of nonresponders to an alternative therapy. Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available.
FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance. Final specifications for the drug substance and drug product are not expected until the end of the investigational process.
For example, although stability data are required in all phases of the IND to demonstrate that the new drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical investigation, if very short-term tests are proposed, the supporting stability data can be correspondingly limited.
A description of the drug substance, including its physical, chemical, or biological characteristics; the name and address of its manufacturer; the general method of preparation of the drug substance; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance; and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies.
Reference to the current edition of the United States Pharmacopeia - National Formulary may satisfy relevant requirements in this paragraph. A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product's stability during the planned clinical studies.
Reference to the current edition of the United States Pharmacopeia - National Formulary may satisfy certain requirements in this paragraph. A copy of all labels and labeling to be provided to each investigator. Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations.
The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations. Guidance documents are available from FDA that describe ways in which these requirements may be met. Such information is required to include the identification and qualifications of the individuals who evaluated the results of such studies and concluded that it is reasonably safe to begin the proposed investigations and a statement of where the investigations were conducted and where the records are available for inspection.
As drug development proceeds, the sponsor is required to submit informational amendments, as appropriate, with additional information pertinent to safety. A section describing the pharmacological effects and mechanism s of action of the drug in animals, and information on the absorption, distribution, metabolism, and excretion of the drug, if known. Depending on the nature of the drug and the phase of the investigation, the description is to include the results of acute, subacute, and chronic toxicity tests; tests of the drug's effects on reproduction and the developing fetus; any special toxicity test related to the drug's particular mode of administration or conditions of use e.
A summary of previous human experience known to the applicant, if any, with the investigational drug. The information is required to include the following: i If the investigational drug has been investigated or marketed previously, either in the United States or other countries, detailed information about such experience that is relevant to the safety of the proposed investigation or to the investigation's rationale. If the drug has been the subject of controlled trials, detailed information on such trials that is relevant to an assessment of the drug's effectiveness for the proposed investigational use s should also be provided.
Any published material that is relevant to the safety of the proposed investigation or to an assessment of the drug's effectiveness for its proposed investigational use should be provided in full. Published material that is less directly relevant may be supplied by a bibliography. However, if any component in such combination is subject to an approved marketing application or is otherwise lawfully marketed in the United States, the sponsor is not required to submit published material concerning that active drug component unless such material relates directly to the proposed investigational use including publications relevant to component-component interaction.
In certain applications, as described below, information on special topics may be needed. Such information shall be submitted in this section as follows: i Drug dependence and abuse potential. If the drug is a psychotropic substance or otherwise has abuse potential, a section describing relevant clinical studies and experience and studies in test animals. If the drug is a radioactive drug, sufficient data from animal or human studies to allow a reasonable calculation of radiation-absorbed dose to the whole body and critical organs upon administration to a human subject.
Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetry calculations. Plans for assessing pediatric safety and effectiveness. A brief statement of any other information that would aid evaluation of the proposed clinical investigations with respect to their safety or their design and potential as controlled clinical trials to support marketing of the drug. If requested by FDA, any other relevant information needed for review of the application.
The sponsor ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously must identify the file by name, reference number, volume, and page number where the information can be found.
A reference to information submitted to the agency by a person other than the sponsor is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information. The sponsor shall submit an accurate and complete English translation of each part of the IND that is not in English.
The sponsor shall also submit a copy of each original literature publication for which an English translation is submitted. The sponsor shall submit an original and two copies of all submissions to the IND file, including the original submission and all amendments and reports. Each submission relating to an IND is required to be numbered serially using a single, three-digit serial number. The initial IND is required to be numbered ; each subsequent submission e. Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application.
This section sets forth the provisions under which new protocols may be submitted and changes in previously submitted protocols may be made. Whenever a sponsor intends to conduct a study that is not covered by a protocol already contained in the IND, the sponsor shall submit to FDA a protocol amendment containing the protocol for the study. Such study may begin provided two conditions are met: 1 The sponsor has submitted the protocol to FDA for its review; and 2 the protocol has been approved by the Institutional Review Board IRB with responsibility for review and approval of the study in accordance with the requirements of part The sponsor may comply with these two conditions in either order.
Examples of changes requiring an amendment under this paragraph include: i Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that in the current protocol, or any significant increase in the number of subjects under study. Once the investigator is added to the study, the investigational drug may be shipped to the investigator and the investigator may begin participating in the study. The sponsor shall notify FDA of the new investigator within 30 days of the investigator being added.
A protocol amendment is required to be prominently identified as such i. If the reference is made to supporting information already in the IND, the sponsor shall identify by name, reference number, volume, and page number the location of the information. A sponsor shall submit a protocol amendment for a new protocol or a change in protocol before its implementation. Protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at day intervals.
When several submissions of new protocols or protocol changes are anticipated during a short period, the sponsor is encouraged, to the extent feasible, to include these all in a single submission. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report.
Examples of information requiring an information amendment include: 1 New toxicology, chemistry, or other technical information; or 2 A report regarding the discontinuance of a clinical investigation. An information amendment is required to bear prominent identification of its contents e. Information amendments to the IND should be submitted as necessary but, to the extent feasible, not more than every 30 days.
The following definitions of terms apply to this section: Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Life-threatening adverse event or life-threatening suspected adverse reaction. An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death.
Serious adverse event or serious suspected adverse reaction. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event.
For the purposes of IND safety reporting, "reasonable possibility" means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. Unexpected adverse event or unexpected suspected adverse reaction.
An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis would be unexpected by virtue of greater severity if the investigator brochure referred only to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected by virtue of greater specificity if the investigator brochure listed only cerebral vascular accidents. The sponsor must promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including information derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the United States.
The sponsor must notify FDA and all participating investigators i. In each IND safety report, the sponsor must identify all IND safety reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze the significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information.
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as: A A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure e. The sponsor must report any findings from epidemiological studies, pooled analysis of multiple studies, or clinical studies other than those reported under paragraph c 1 i of this section , whether or not conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug.
Ordinarily, such a finding would result in a safety-related change in the protocol, informed consent, investigator brochure excluding routine updates of these documents , or other aspects of the overall conduct of the clinical investigation. The sponsor must report any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human exposure.
Ordinarily, any such findings would result in a safety-related change in the protocol, informed consent, investigator brochure excluding routine updates of these documents , or other aspects of the overall conduct of the clinical investigation.
The sponsor must report any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. FDA will periodically issue guidance on how to provide the electronic submission e.
Reports of overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies must be submitted in a narrative format. Each notification to FDA must bear prominent identification of its contents, i. Upon request from FDA, the sponsor must submit to FDA any additional data or information that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request.
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the information. FDA may require a sponsor to submit IND safety reports in a format or at a frequency different than that required under this paragraph. The sponsor may also propose and adopt a different reporting format or frequency if the change is agreed to in advance by the director of the FDA review division that has responsibility for review of the IND.
A sponsor of a clinical study of a drug marketed or approved in the United States that is conducted under an IND is required to submit IND safety reports for suspected adverse reactions that are observed in the clinical study, at domestic or foreign study sites.
The sponsor must also submit safety information from the clinical study as prescribed by the postmarketing safety reporting requirements e. Study endpoints e. However, if a serious and unexpected adverse event occurs for which there is evidence suggesting a causal relationship between the drug and the event e.
A safety report or other information submitted by a sponsor under this part and any release by FDA of that report or information does not necessarily reflect a conclusion by the sponsor or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse event. A sponsor need not admit, and may deny, that the report or information submitted by the sponsor constitutes an admission that the drug caused or contributed to an adverse event.
A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation that includes: a Individual study information. A brief summary of the status of each study in progress and each study completed during the previous year. The summary is required to include the following information for each study: 1 The title of the study with any appropriate study identifiers such as protocol number , its purpose, a brief statement identifying the patient population, and a statement as to whether the study is completed.
Information obtained during the previous year's clinical and nonclinical investigations, including: 1 A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system. Examples of such advice may include advice on the adequacy of technical data to support an investigational plan, on the design of a clinical trial, and on whether proposed investigations are likely to produce the data and information that is needed to meet requirements for a marketing application.
A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not be given the investigational drug.
When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed on the investigational drug; patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety. The phrase "women with reproductive potential" does not include pregnant women. For purposes of this paragraph, "life-threatening illnesses or diseases" are defined as "diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted.
FDA may place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it finds that: i Any of the conditions in paragraphs b 1 i through b 1 v of this section apply; or ii The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.
FDA may place an expanded access IND or expanded access protocol on clinical hold under the following conditions: i Final use. FDA may place a proposed expanded access IND or treatment use protocol on clinical hold if it is determined that: A The pertinent criteria in subpart I of this part for permitting the expanded access use to begin are not satisfied; or B The expanded access IND or expanded access protocol does not comply with the requirements for expanded access submissions in subpart I of this part.
FDA may place an ongoing expanded access IND or expanded access protocol on clinical hold if it is determined that the pertinent criteria in subpart I of this part for permitting the expanded access are no longer satisfied. FDA ordinarily intends that clinical holds under paragraphs b 4 ii , b 4 iii and b 4 v of this section would only apply to additional enrollment in nonconcurrently controlled trials rather than eliminating continued access to individuals already receiving the investigational drug.
Whenever FDA concludes that a deficiency exists in a clinical investigation that may be grounds for the imposition of clinical hold FDA will, unless patients are exposed to immediate and serious risk, attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the clinical hold order.
The clinical hold order may be made by telephone or other means of rapid communication or in writing. The clinical hold order will identify the studies under the IND to which the hold applies, and will briefly explain the basis for the action. The clinical hold order will be made by or on behalf of the Division Director with responsibility for review of the IND. As soon as possible, and no more than 30 days after imposition of the clinical hold, the Division Director will provide the sponsor a written explanation of the basis for the hold.
An investigation may only resume after FDA usually the Division Director, or the Director's designee, with responsibility for review of the IND has notified the sponsor that the investigation may proceed. Resumption of the affected investigation s will be authorized when the sponsor corrects the deficiency ies previously cited or otherwise satisfies the agency that the investigation s can proceed.
FDA may notify a sponsor of its determination regarding the clinical hold by telephone or other means of rapid communication. If a sponsor of an IND that has been placed on clinical hold requests in writing that the clinical hold be removed and submits a complete response to the issue s identified in the clinical hold order, FDA shall respond in writing to the sponsor within calendar days of receipt of the request and the complete response.
FDA's response will either remove or maintain the clinical hold, and will state the reasons for such determination. Notwithstanding the calendar day response time, a sponsor may not proceed with a clinical trial on which a clinical hold has been imposed until the sponsor has been notified by FDA that the hold has been lifted.
If an IND is terminated, the sponsor shall end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. Except as provided in paragraph d of this section, a termination shall be preceded by a proposal to terminate by FDA and an opportunity for the sponsor to respond.
FDA may propose to terminate an IND during Phase 1 if it finds that: i Human subjects would be exposed to an unreasonable and significant risk of illness or injury. FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that: i Any of the conditions in paragraphs b 1 i through b 1 xi of this section apply; or ii The investigational plan or protocol s is not reasonable as a bona fide scientific plan to determine whether or not the drug is safe and effective for use; or iii There is convincing evidence that the drug is not effective for the purpose for which it is being investigated.
If the sponsor does not respond to the notification within the allocated time, the IND shall be terminated. The sponsor's request for a regulatory hearing must be made within 10 days of the sponsor's receipt of FDA's notification of nonacceptance.
Notwithstanding paragraphs a through c of this section, if at any time FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the agency shall immediately, by written notice to the sponsor from the Director of the Center for Drug Evaluation and Research or the Director of the Center for Biologics Evaluation and Research, terminate the IND.
An IND so terminated is subject to reinstatement by the Director on the basis of additional submissions that eliminate such danger. If an IND is terminated under this paragraph, the agency will afford the sponsor an opportunity for a regulatory hearing under part 16 on the question of whether the IND should be reinstated.
If FDA seeks to act on its own initiative under this section, it shall first notify the sponsor in writing of the proposed inactive status. Upon receipt of such notification, the sponsor shall have 30 days to respond as to why the IND should continue to remain active. If the protocol amendment relies on information previously submitted, the plan shall reference such information. Additional information supporting the proposed investigation, if any, shall be submitted in an information amendment.
Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the extent that FDA's resources permit.
The general principle underlying the conduct of such meetings is that there should be free, full, and open communication about any scientific or medical question that may arise during the clinical investigation. These meetings shall be conducted and documented in accordance with part At specific times during the drug investigation process, meetings between FDA and a sponsor can be especially helpful in minimizing wasteful expenditures of time and money and thus in speeding the drug development and evaluation process.
In particular, FDA has found that meetings at the end of Phase 2 of an investigation end-of-Phase 2 meetings are of considerable assistance in planning later studies and that meetings held near completion of Phase 3 and before submission of a marketing application "pre-NDA" meetings are helpful in developing methods of presentation and submission of data in the marketing application that facilitate review and allow timely FDA response.
The purpose of an end-of-phase 2 meeting is to determine the safety of proceeding to Phase 3, to evaluate the Phase 3 plan and protocols and the adequacy of current studies and plans to assess pediatric safety and effectiveness, and to identify any additional information necessary to support a marketing application for the uses under investigation. While the end-of-Phase 2 meeting is designed primarily for IND's involving new molecular entities or major new uses of marketed drugs, a sponsor of any IND may request and obtain an end-of-Phase 2 meeting.
To be most useful to the sponsor, end-of-Phase 2 meetings should be held before major commitments of effort and resources to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2 meeting is not, however, intended to delay the transition of an investigation from Phase 2 to Phase 3.
At least 1 month in advance of an end-of-Phase 2 meeting, the sponsor should submit background information on the sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, plans for pediatric studies, including a time line for protocol finalization, enrollment, completion, and data analysis, or information to support any planned request for waiver or deferral of pediatric studies, and, if available, tentative labeling for the drug.
Both the sponsor and FDA may bring consultants to the meeting. Presence and public availability of CU regulations, population size, gross domestic product, and clinical trial activity were independently associated with the CU request activity in multivariable analysis. Conclusions and Relevance In this cohort study analyzing Novartis CU requests over a 3-year period, existence and public availability of CU regulations and local clinical trial activity were positively associated with higher CU request rates.
The analysis also identified an association between macroeconomic factors and CU request activity, despite the generally free provision of unlicensed therapeutic products. Similar analyses of other comparable experiences are needed to supplement these initial observations.
Ultimately, better understanding of factors associated with CU request activity would translate into improved early access to novel lifesaving products for patients with unmet medical needs around the world. Introduction Clinical trials are the preferred channel for access to unlicensed therapeutic products. However, there are patients with serious or life-threatening diseases for whom enrollment in a clinical trial is not possible and all available treatment options have been exhausted. Owing to the nature of the regulatory approval process, there is typically a gap of several months to years between generation of robust efficacy and safety data in clinical trials, local marketing authorization, and subsequently local patient access.
For many patients with serious or life-threatening medical conditions, waiting for months or years until licensing of the drug in their country means unnecessary suffering or even death. The purpose of CU is to close this gap and facilitate early access. With multiple local approval processes ongoing, Novartis established global access to Zolgensma via a CU program, which has been providing the therapy to patients free of charge in countries where it is yet to be licensed.
There are substantial differences in the CU regulatory landscape across countries, with some introducing or updating their regulations as the landscape evolves. This study examines this further and explores factors that might be associated with the disparity observed in CU access globally. The numbers of requests were evaluated and stratified by country.
Written patient informed consent was obtained by the treating physician for every patient treated via CU included in this study. Study Design This study examined country-specific request counts and rates against selected factors that could be associated with CU request activity: Presence of CU regulations in the country and their public availability: Data were obtained from the Cortellis database 22 and HA websites when available.
In-country clinical trial activity: Information was obtained from the ClinicalTrials. Macroeconomic factors and population: Country gross domestic product GDP and gross national income GNI per capita categorized as low-income, lower-middle-income, upper-middle-income, and high-income economies and population size data were retrieved from the World Bank Open Data, 24 based on the information if not available, data were retrieved from Statista.
The study also examined these factors for the countries from which Novartis did not receive any requests during the study period. Distributions of request rates were summarized with means, SDs, medians, and IQRs and examined with stratification on the following variables: existence and public availability of CU regulations; number of phase 1 to 3 trials conducted in the country January 1, , through December 31, ; and population size, GDP, and GNI per capita.
In the stratified analysis, numerical variables of population size, GDP, and number of trials were grouped in quartiles. Association of the country-specific attributes with the request activity was examined in multivariable analysis based on a log-linear negative binomial regression model. Details of model specification are provided in the eMethods in the Supplement. Briefly, the outcome variable was defined as the request count per country during the analysis period.
Covariates included existence and public availability of CU regulations, population size, GDP, and number of trials. Continuous covariates were log-transformed because of their strongly right-skewed distributions. Because GDP and population size jointly determine the GNI, the GNI categories were not included in the model separately, to avoid multicollinearity and model overfitting.
Request counts predicted by the model were tabulated along with the observed request counts and prediction errors observed minus predicted for each country to assess model fit and evaluate variability in the request activity not explained by the model. Mean, median, and IQR of the absolute prediction error were calculated.
Countries with the prediction error of greater than 30 requests and more than 3-fold in either direction both conditions satisfied were flagged as outliers. Results Analysis of CU Requests Over the month period, 31 CU requests were processed from countries requests in , 13 in , and 11 in The top 30 countries with the highest request rates per million population are shown in Table 1 full distribution is provided in the eTable 1 in the Supplement.
Table 2 shows the number of CU requests and countries in relation to existence and public availability of regulations, clinical trial activity, population, GDP, and GNI per capita. Clinical Trial Activity A positive association between in-country clinical trial activity and CU request activity was observed in stratified analysis Table 2.
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Nitazoxanide, a nitro-thiazolide, exhibits broad spectrum activity against anaerobic bacteria and against anaerobic intestinal parasites. Nitazoxanide brand name Alinia, Romark Laboratories Ltd, Tampa Florida is FDA approved for the treatment of intestinal infections caused by Giardia intestinalis and Cryptosporidium parvum in adults and children This drug is increasingly being used off-label to treat infections caused by Clostridium difficile based on demonstration of clinical efficacy In these studies, nitazoxanide was shown to be equivalent to comparator drugs metronidazole and vancomycin.
The drug also exhibits some antiviral activity against rotavirus and hepatitis C , The wide spectrum has raised concerns of safety, but the drug is of low toxicity to humans, with few side effects, probably due to its high affinity for serum proteins. The concerns of safety arise because at different doses used to treat diseases caused by a variety of organisms, the drug will also inhibit other organisms eg.
Other targets for this drug include nitroreductases in Giardia sp. Most microorganisms, systemic parasites and humans oxidize pyruvate via pyruvate dehydrogenase, which is not a target for the drug. Recent studies on mechanism have provided evidence to suggest that nitazoxanide inhibits an early step in the PFOR reaction by a non- competitive inhibition of the interaction of pyruvate with the thiamine pyrophosphate TPP cofactor In this study it was determined that nitazoxanide is biologically active as an anion which becomes protonated by abstraction of a proton from the TPP-pyruvate intermediate resulting in no substrate catabolism and inactivation of the drug via protonation.
Inhibition of PFOR by nitazoxanide stops the conversion of pyruvate to acetate, a key component of fatty acid biosynthesis, amino acid biosynthesis and energy production. This novel mode of action by nitazoxanide illustrates several fundamental points that might be of value in the design of future therapeutics. First, nitazoxanide interacts with the TPP vitamin cofactor and not with the PFOR enzyme, thus diminishing mutation based drug resistance mechanisms and second, PFOR is unique in mechanism to the target group of pathogens and not present in humans.
In over 10 years of clinical use there has been no reported drug resistance and attempts to produce drug resistance under laboratory conditions have generally not met with much success. Nitazoxanide may be the first antimicrobial drug for which the mechanism of action against a small vitamin cofactor precludes development of drug resistance, a model that might hold promise with enzyme targets containing other classes of vitamin cofactors.
Fidaxomicin OPT is a novel macrocycle which is non-absorbed systemically and has potency against anaerobes such as C. Sulopenem is an orally active penem in current clinical development and is potent against multi-drug resistant pathogens including penicillin-resistant S. It has in vitro activity against carbapenem-resistant strains of P. BAL is a new siderophore monobactam that bypasses porin mutations and inhibits PBPs and has broad spectrum Gram-negative activity including multidrug resistant Acinetobacter, Burkholderia, Pseudomonas and Stenotrophomonas spp.
It is in clinical trials in combination with ceftazidime in patients with complicated urinary tract infections It is 8-fold more potent than moxifloxacin against Gram-positive pathogens, Expert Opin Investig Drugs. It also has Gram-negative activity against H.
Bacterial cell division inhibition is an unexploited antibacterial target. PC, identified by structure based molecular docking, binds to FtsZ analogous to anti-cancer drug Taxol binding to tubulin , inhibiting septum production during cell division and has activity against S. Structure based design has also led to the discovery of novel pyrimidine-based compounds Rx with Gram positive antibacterial activity that target methionyl-tRNA synthetase MetRS Components of membrane biogenesis in bacteria such as FabI involved in fatty acid biosynthesis have several identified inhibitors Novel aryloxy-phenol Fab I inhibitors derivatized from triclosan eg.
Antimicrobial peptides eg. Omiganan with direct killing action or a host modulatory effect during innate immunity hold promise as an entirely new class of antibacterial drugs which would mitigate the growing problem of drug resistance.
Several peptides and peptidomimetics are in commercial development and resolving their issues of poor pharmacokinetics and toxicity could be in sight Some other attractive antibacterial compounds include quorum-sensing blockers such as LED, read below , lipid II binding compounds, bacterial efflux pump inhibitors and bacterial 2- component signal transduction inhibitors New Targets for the Next Generation of Antimicrobial drugs While most antimicrobial drugs in current clinical use inhibit essential processes such as protein or cell wall biosynthesis, many of these drugs are also bacteriostatic, which may contribute to development of resistance.
One way of developing novel antibacterial drugs with minimal potential for resistance development could be to target bactericidal functions of bacterial proteins eg. Targeting of essential proteins must take into consideration the structural constraints within substrate binding and catalytic domains and the mitigating effects of mutations on enzyme function.
Alternatively, targeting virulence factors or host-microbial response pathways might lead to rapid clearance of infecting organisms. An example of virulence factor based therapy arises by the recent discovery of a cholesterol reducing agent BPH, a phosphonosulphonate which is an inhibitor of MRSA CrtM from S.
Fungi possess a nuclear receptor-like pathway that activates multi-drug resistant efflux pumps and could be a new therapeutic target against multidrug resistant pathogenic fungi These examples illustrate the analogies of mammalian pathways to microbial pathways which can be targeted for therapeutic purposes. However, the drugs must be stringently designed to specifically inhibit only the bacterial target to prevent toxicity eg.
Precedent exists in the design of antibacterial drugs against targets also found in humans, eg. Page 11 evading the host innate immune response. These small molecules were originally identified in a bacterial reporter assay as inhibitors of expression of Yop effector proteins in Yersinia Another interesting example of antivirulence targeting is to target bacterial defences that render it vulnerable to the host innate immune response In Gram-negative organisms, the outer bacterial membrane composed of LPS is required for resistance to complement and cationic peptides.
Inhibitors of RfaE have been identified that inhibit synthesis of LPS but do not affect bacterial growth. Antivirulence drugs can have an in vivo antibacterial effect as demonstrated by inhibitors of DltA, an enzyme which causes D-alanylation of lipotechoic acid in Gram-positive pathogens. This D-alanylation is correlated to survival of bacteria against cationic peptides, cell killing and cell invasion. Inhibitors of Streptococcus agalactiae and S. In an experimental model of systemic infection of mice by S.
The in vivo antibacterial effects of the compounds were at doses that are comparable to the effective doses of classic antibacterial drugs Inhibition of signaling is another proposed strategy; a bacterial adrenergic receptor QseC histidine kinase is a target for antibacterial compound LED which blocks QseC-dependent virulence gene activation in S. Bacterial infections such as tuberculosis are difficult to treat due to dormant bacteria that are fold resistant to antibacterial drugs that target growth and division.
Mycobacterium tuberculosis is 8-fold more sensitive to ATP synthesis inhibitors than standard anti-TB drugs, since they reduce ATP synthesis while adjusting to the hypoxic conditions while establishing an infection. Disruption of the PMF proton motive force , by specific inhibitors, which is necessary for ATP generation, is also bactericidal TMC is a novel anti-mycobacterial drug belonging to the diarylquinoline class of compounds and is an ATP synthase inhibitor A growing trend in antimicrobial drug targets has been the host response pathways; modulating them could reduce the persistence and severity of infectious disease.
The TLR Toll-like receptor family of proteins is activated during innate immune response and leads to production of antimicrobial peptides and activates the adaptive immune response to combat infection TLR activators and modulators could potentially have an antimicrobial role. Along the same line, macrolides such as clarithromycin have immunomodulatory properties in sepsis in experimental models and clinical trials.
In a rabbit model of sepsis and acute pyelonephritis caused by multi-drug resistant P. In a clinical trial conducted in patients with sepsis due to Ventilator-associated pneumonia VAP , intravenous clarithromycin was beneficial as it hastened resolution of VAP and prolonged life Intracellular pathogens such as S.
SopB Some Akt kinase inhibitors have antibacterial properties, while other inhibitors are currently in clinical trials as anticancer drugs. Kinase inhibitors are being developed as anticancer drugs because of aberrant kinase signaling in cancerous cells, however due to the importance of certain host kinases in Expert Opin Investig Drugs.
Page 12 intracellular infection, host kinase inhibitors that specifically inhibit intracellular bacterial growth but not host cell proliferation during anticancer drug discovery will also be found. Moreover, chronic infections sometimes lead to development of cancers eg. Salmonella typhi infections cause gallbladder cancer , H.
New Strategies for Antibacterial Drug Discovery Most of the current antibacterial drugs were discovered between and by traditional approaches which are now saturated, and the emergence of drug resistance as well as the emergence of new pathogens calls for new strategies in antibacterial drug discovery due to the inadequacies of screening libraries for novel antibacterial compounds as described in this section Antibacterial drugs have unique physicochemical properties which are dependent on their spectrum of activity Natural products are proposed to be an optimal antibacterial drug screening library as they have optimal cellular penetration and privileged structures to interact with finite structural spaces in protein folds Identifying feasible drug targets given the vast microbial genomics information by comparing different pathogen genomes and narrowing the targets based on essentiality, novelty of target or mechanism, absence of human homolog and low likelihood of resistance development is a failed strategy, and requires a chemically diverse compound collection Improving the quality of synthetic libraries by using core scaffolds to introduce natural product like characteristics could be a way to generate a chemically diverse compound collection.
Comparative bacterial genomics has yielded knowledge of previously unknown biosynthetic pathways absent in humans which can be specifically targeted to discover antibacterial drugs for a specific microbe New microbial species from marine sediments or associated with plants are an untapped source of novel antibacterial drugs One such example is the increasing use of colistin , a polymyxin antibiotic , as a last-line therapeutic option in critically ill patients despite nephrotoxicity, because of its efficacy against multi-drug resistant P.
However, modern clinical trials would provide insight into the dosing regimen and the extent of adverse effects. Discovery of lytic phages specific to pathogenic bacteria especially MRSA has potential as natural and ecological treatment against pathogens Systemic administration of bacteriophage therapy is efficacious in a mouse Burkholderia cepacia lung infection model Inactivation of antibacterial drugs by enzymatic hydrolysis or formation of inactive derivatives causes widespread drug resistance Another strategy would be if antibacterial drugs were engineered prodrug or anti-antibacterial drug such that a highly potent drug would result upon enzymatic action within a microbe, then common resistance mechanisms could be bypassed.
Page 13 Antibacterial drugs could also be engineered to introduce two pharmacophores for high potency against two targets. CBR is a rifamycin-quinolone hybrid which is a RNA polymerase inhibitor and also a DNA gyrase and topoisomerase IV inhibitor and demonstrates potency against gram positive cocci , Improved formulations of alternative drug delivery methods such as inhaled anti-infectives Amikacin nanoscale liposome formulation show potential for treatment of chronic P.
MP is a new formulation of levofloxacin for inhalation and is effective in mouse models of acute and chronic lung infections caused by P. The high concentrations of drug delivered to the lung tissue causes increased bacterial clearance than inhaled tobramycin or aztreonam leading to increased mice survival Passive immunization is a strategy which activates the host immune response leading to pathogen clearance by attacking the organism directly, enhancing phagocytosis or altering the immune system, but this strategy is yet to encounter success in clinical trials Conclusion The number of new antibacterial medicines entering the clinic has been declining for years, while the emergence of drug resistance and especially multi-drug resistance continues to rise at an alarming rate 1.
The more traditional approaches of generating new derivatives of old drugs or finding new ecosystems to mine for natural products are giving way to more innovative non-traditional strategies to develop next generation drugs , , The future does not seem bleak as several promising antibacterial drugs with novel mechanisms of action are in development and new types of targets Type III secretion systems have emerged Expert Opinion Finally, since anti-infective research over the past 15 years has underperformed other therapeutic areas, there is little incentive to throw good money after bad.
In the absence of the pharmaceutical industry, it is now left to government sponsored research in universities and small biotech companies to produce next generation therapeutics. However, the pace of discovery in these venues will be slow when compared with the resource rich pharmaceutical industry. If society regards new life saving medicines as beneficial, then should society contribute to such discovery efforts?
In an attempt to bridge this issue, as an incentive, the U. Congress proposed a 2-year wild card patent extension on existing blockbuster drugs to increase protected sales; and, under the US Bioshield II legislation, a drug company would qualify for a wildcard patent if the antimicrobial is licensed for military or antiterrorism use 5.
The revenue from such sales would support an antimicrobial development program. Senate and addresses management and monitoring of antimicrobial resistance, prevention and control and increasing federal funding for research Expert Opin Investig Drugs. Page 14 and development of new antibacterial drugs In view of the fact that new compounds for multi-drug resistant Gram-negative bacilli MDRGNB will unlikely be available for more than 10 years, infection control measures to limit spread of these organisms within institutions, and potentially into the community, are paramount.
In addition, antimicrobial stewardship programs should be put in place to preserve the few remaining compounds with some activity against MDRGNB, e. Acknowledgments The authors are grateful to the reviewers of this manuscript for useful suggestions. References 1. Clinical and economic impact of common multidrug- resistant gram-negative bacilli. Antimicrob Agents Chemother Mar;52 3 — Market Analysis and Competitive Landscape. An update from the Infectious Diseases Society of America.
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Antimicrob Agents Chemother Mar;51 3 — Oxazolidinone resistance mutations in 23S rRNA of Escherichia coli reveal the central region of domain V as the primary site of drug action. J Bacteriol Oct; 19 — In vitro activity of TR, the antibacterial moiety of the prodrug TR, against linezolid-resistant strains. Antimicrob Agents Chemother Dec;52 12 — Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance.
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Ketolides: the future of the macrolides? Curr Opin Pharmacol Oct;2 5 — Structural basis for the antibiotic activity of ketolides and azalides. Structure Mar;11 3 — Studies of the novel ketolide ABT transport, binding to ribosomes, and inhibition of protein synthesis in Streptococcus pneumoniae. Antimicrob Agents Chemother Jun;44 6 — Champney WS, Pelt J.
The ketolide antibiotic ABT is a specific inhibitor of translation and 50S ribosomal subunit formation in Streptococcus pneumoniae cells. Curr Microbiol Sep;45 3 : — Page 18 Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA.
J Bacteriol Dec; 23 — Antipneumococcal activity of ABT compared to those of 10 other agents. Antimicrob Agents Chemother Jul; 44 7 — Comparison of in vitro activities of ABT and telithromycin against macrolide-susceptible and -resistant streptococci and staphylococci.
Antimicrob Agents Chemother Mar;46 3 — Telithromycin and the FDA: implications for the future. Lancet Infect Dis Feb;8 2 — Milanesio, NA. Ketolides lack inducibility properties of MLS B resistance phenotype. J Antimicrob Chemother Jul;40 1 — Ketolide resistance in Streptococcus pyogenes correlates with the degree of rRNA dimethylation by Erm. Mol Microbiol Oct;58 2 — Streptococcus pneumoniae isolates resistant to telithromycin. Antimicrob Agents Chemother May;50 5 : — Telithromycin resistance in Streptococcus pneumoniae is conferred by a deletion in the leader sequence of erm B that increases rRNA methylation.
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Synthesis and structure-activity relationship of novel glycylcycline derivatives leading to the discovery of GAR Bioorg Med Chem Lett May 17;9 10 — Functional, biophysical, and structural bases for antibacterial activity of tigecycline.
Antimicrob Agents Chemother Jun;50 6 — Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade Tet M - and Tet O -mediated ribosomal protection. Antimicrob Agents Chemother Sep;40 9 — Inhibition of protein synthesis occurring on tetracycline- resistant, TetM-protected ribosomes by a novel class of tetracyclines, the glycylcyclines.
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Antimicrob Agents Chemother Sep;45 9 : — Antimicrobial activity and spectrum of the new glycylcycline, GAR tested against 1, recent clinical bacterial isolates. Diagn Microbiol Infect Dis Jan;36 1 — In vitro activities of the glycylcycline GAR against gram-positive bacteria. Antimicrob Agents Chemother Aug;44 8 — Tafur, JD. Activity and diffusion of tigecycline GAR in experimental enterococcal endocarditis.
Antimicrob Agents Chemother Jan;47 1 — The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam.
Safety and efficacy of intravenous tigecycline in treatment of community-acquired pneumonia: results from a double-blind randomized phase 3 comparison study with levofloxacin. Diagn Microbiol Infect Dis Jan;63 1 — Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a Phase 3, multicentre, double-blind, randomized study. A Phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae.
J Antimicrob Chemother Sep;i29—i Arbeit, RD. AcrAB efflux pump plays a role in decreased susceptibility to tigecycline in Morganella morganii. Lipoprotein-associated phospholipase A 2 Lp-PLA 2 seems to play a major role in the development of such high-risk lesions, in both the coronary and carotid arteries. Darapladib is a selective inhibitor of Lp-PLA 2. Areas covered in this review: An overview of darapladib by reviewing the studies - that have provided the rationale for the development of darapladib; and a discussion of its potential merit as a new therapeutic drug to target high-risk atherosclerosis.
What the reader will gain: The reader should gain an understanding of the importance of inflammation during atherogenesis as well as of the biology of Lp-PLA 2 and its proatherogenic role. Additional insights will be gained into the role of selective inhibitors of Lp-PLA 2 as new therapeutic agents.
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