Badrul A. Chowdhury, MD, PhD; Eugene J Sullivan, MD*
Division of Pulmonary and Allergy Drug Products
US Food and Drug Administration
*This document is written by the authors in their private capacity and not in their capacity as employees of the US Food and Drug Administration (FDA). The opinions expressed are not intended to convey official FDA policy and are not binding on the regulated industry or the FDA. No support or endorsement by the FDA is intended or should be inferred
A bronchoprovocation study usually involves the administration of a drug to study subjects either by inhalation or by direct instillation of the drug into the airways via a bronchoscope. Currently, no agents are approved for direct instillation into the airway in the US. Methacholine (Provocholine®, Methapharm, Coral Springs, FL) is approved for airway provocation, but only by nebulizer. Thus, drugs that investigators may wish to use in bronchoprovocation studies are either not approved for direct delivery into the lung or not approved for human use at all. In such a circumstance, the use of the provocative agent in research would require the approval of an investigational new drug (IND) application by the US Food and Drug Administration (FDA). In the following sections, we discuss the regulatory framework of the IND process and the elements necessary to support a successful IND application.
Investigators planning to initiate bronchoprovocation studies using either unapproved agents, or drugs approved for other routes of administration (e.g., histamine, allergens), would generally need to file an IND with the FDA. In addition, they must also satisfy the Institutional Review Board (IRB) requirements of the institution at which the study will be conducted. IND and IRB review are complementary but independent processes that have been put into place to enhance the safety of subjects enrolled in clinical studies. Investigators should be familiar with the IND regulations in order to assure compliance with Federal law (21 CFR 312).
In certain circumstances, an investigator may be able to conduct a bronchoprovocation research study using an approved drug product without an IND. FDA regulations (see 21 CFR 312.2(b)(1)) provide that a study is exempt from IND requirement if all the following apply:
An IND application consists of several required forms, a clinical protocol, and other documentation to support the proposed human study. The bulk of the required scientific information is in the areas of chemistry, manufacturing and controls (CMC) information on the drug product, and any preclinical (animal) toxicology data to support the proposed human study. The investigator should also submit any previous human data that may support the proposed clinical study. Depending on the extent and quality of these prior human data as they pertain to safety, animal data may be unnecessary. The FDA uses scientific judgment to decide on the extent of the animal data that will be required. In certain circumstances, depending on the drug product under consideration and the scope of the clinical investigation, the FDA has the discretion to exempt the requirement of an IND. When an IND is submitted, the FDA will review the submitted data within 30 days and will either allow the proposed human study to proceed or place the study on a hold. A clinical investigation that is subject to an IND may not be initiated within this 30-day period (see http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/ucm071073.htmexternal link for helpful information on IND submissions and necessary forms ).
Chemistry, Manufacturing, and Controls (CMC) Considerations
CMC attributes ensure that the purity and performance characteristics of the drug product are such that it is safe for use in bronchoprovocation studies. Included are adequate information on the amount and nature of any contaminants, impurities, and/or degradation products, the stability of the drug product over the intended duration of use, and the sterility of the drug product. Information should be submitted on the drug substance (the active moiety itself), the drug product components (the drug substance and all other ingredients in the formulation), the manufacturing process, and associated controls for each of these areas. The CMC requirements for investigational drugs for bronchoprovocation generally follow the requirements for new drug applications (1, 2), but for an investigational IND would be much less detailed. A specific requirement (21 CFR 200.51) is that all drug products intended for delivery into the lung, including drug products for bronchoprovocations studies, must be sterile.
Detailed information on the manufacturer and the supplier should be provided. Complete information regarding the source (manufacturer) and comprehensive characterization of the physical and chemical properties for the drug substance should be included in the IND application. This often will require obtaining permission from the supplier or manufacturer to refer to data that they may have previously supplied to the FDA in a Drug Master File. The purity of the drug substance and impurity profile should be characterized.
Use of excipients in a drug product for a bronchoprovocaton study should be limited as much as possible, because lung is sensitive to many foreign materials. Any excipient that has not been previously approved in inhalation products may need to be characterized as described above for drug substance.
Drug Product Manufacturing and Use:
The drug product should be made under aseptic techniques, and a sterile and pyrogen-free diluent should be used. The final drug product should be terminally sterilized by an appropriate method (such as filtration using a sterile 0.2 micron filter). The investigators should develop appropriate specifications and test methods to ensure the purity and reproducibility of the drug product. Bronchoprovocation agents would often be made and used immediately in a research study. However, if the investigator plans to store the drug product for later use, additional specifications parameters should be developed to ensure the purity and stability of the drug product over the duration of storage, and to check for impurities and degradation products that can accumulate over time. In addition the investigator should provide complete information on the container system to ensure that the drug product is compatible with the container and closure system. For instance, a latex stopper in a storage container could lead to the presence of latex antigens in the drug solution. This could have untoward affects in latex allergic individuals.
For biologic products some additional considerations apply. Biologic products often contain unique contaminants and impurities depending on the source material for manufacturing. Allergenic extracts sometimes also have a high content of endotoxin. These contaminants and impurities will need to be characterized and controlled as appropriate. Also for a biologic product, some form of bioassay is recommended to ensure that the final product to be used in a bronchoprovocation study is biologically active.
Biologic products and products in a suspension are often difficult to sterilize. The investigator should develop methods to terminally sterilize the drug product. If that is absolutely not possible, then all the components of the drug product should be manufactured under sterile conditions and the components should be mixed under aseptic conditions.
The goals of the preclinical safety evaluation include the identification of safe starting doses for humans, the characterization of toxic effects with respect to target organs, and the reversibility of these toxic effects. In addition, the mutagenic potential of the drug needs to be documented (3-6). The need for animal data to support a research IND for a bronchoprovocation study would be dependent on the circumstances of use and the particulars of the provocative agent proposed. Wholly new drugs that have never been approved by any route and for which there is little or no human data in the literature would require the most preclinical data. On the other hand, drugs already approved by another route of administration with extensively documented use in the literature, particularly with good documentation of human safety data, may require no additional animal testing.
When required, preclinical toxicology studies should be conducted in at least two animal species, of which one must be a non-rodent species. A range of doses should be studied in both animal species. This will allow identification of a so-called “no observed adverse effect level” that will guide selection of the starting human dose, and also will identify toxic effects that can be monitored in human studies. The duration of exposure for the animals should be equal to or longer than that proposed in humans. The number of groups and the size of the groups should be sufficient to allow meaningful scientific interpretation of the data. Appropriate control groups should be included in the experimental design. The route of drug administration should be the inhalation route to match the human route, and the formulation should be representative of the drug product that will be administered to human subjects.
Prior to any human administration of a drug product, genotoxicity data (e.g., Ames mutagenicity assays and chromosomal aberration assays) for the evaluation of mutations and chromosomal damage would be needed. This may have been previously done (i.e., in approved drug products) or might need to be supplied by the investigator in the IND. If the genotoxicity results are positive, then the investigator must justify why the drug product should be allowed to be used in humans, and must disclose the potential carcinogenicity risk in the informed consent document and in the investigator brochure. Many bronchoprovocation studies utilize drugs approved for other routes of administration and/or other uses (e.g., allergenic extracts). The preclinical requirement for such approved agents would generally be less than for new molecular entities because the systemic toxicity profile of the drug product would have already been studied. If preclinical data were needed, these data should include a so-called “bridging study” to link to the existing preclinical safety data on the drug product to that obtained by inhalation exposure, with the safety study limited to the examination of the airway.
All IND applications must contain an adequately detailed clinical protocol. The focus of the protocol for an investigational IND would be on patient safety. The patient population that will be studied should be specified clearly in the protocol. Generally, subjects enrolled in bronchoprovocation studies would be limited to those with mild or moderate asthma or other airway disease of a severity that will not jeopardize patient safety in the study. Under certain circumstances, subjects with more severe airway disease may be studied, but the use of these subjects would need to be scientifically and ethically justified. In addition, the study design would need to incorporate additional safety measures to protect this more severe population.
Safety parameters, and the intervals at which they will be determined, should be clearly delineated in the protocol. Safety monitoring should include, as a minimum, physical examination, clinical chemistry, and serial spirometry. All study subjects should be monitored for excessive bronchospasm, including late-phase reactions (particularly for whole lung allergen challenge), and the protocol should have appropriate safety measures in place to handle excessive bronchospasm. The protocol should also indicate the outcome measures of clinical interest and state how that data will be gathered.
Conflict of Interest Statement
Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Robert J. Levine, M.D. (1), Robert M. Nelson, M.D. PhD (2), Alan R. Fleischman, M.D. (3), Jeremy Sugarman, M.D., M.P.H., M.A (4)
Research involving bronchoprovocation and bronchoscopy is of substantial scientific importance. The ethical obligation to conduct research involving human subjects was articulated well by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in its Belmont Report:
“The principle of beneficence often occupies a well-defined justifying role in many areas of research involving human subjects. An example is found in research involving children. Effective ways of treating childhood diseases and fostering healthy development are benefits that serve to justify research involving children -- even when individual research subjects are not direct beneficiaries. Research also makes it possible to avoid the harm that may result from the application of previously accepted routine practices that on closer investigation turn out to be dangerous.” (1)
Nevertheless, the conduct of research involving human subjects, including research protocols in which bronchoprovocation and bronchoscopy are used, is governed by policies requiring that all such research conform to scientific and ethical standards. Of special relevance to such research is that the risks and discomforts to which research subjects are exposed must be justified by either the importance of the knowledge to be gained or the potential for direct benefit to the research subjects themselves. Such a determination is prerequisite to obtaining informed consent for participation in a particular research protocol, managing conflicts of interests and obligations, determining the appropriate use of financial incentives and selection of subjects as well as other ethical requirements for research with human subjects. Indeed, the two reported unfortunate deaths of volunteers in this type of research seem related primarily to issues regarding the assessment and minimization of risk.
N. W. died in 1996 from a fatal overdose of lidocaine one to two hours after the completion of a bronchoscopy done for research purposes. Subsequent investigation revealed the lack of guidelines for the maximum dose of lidocaine, inadequate monitoring during the procedure, and lack of adequate IRB oversight (2). E. R. died in 2001 after inhaling the chemical hexamethonium as part of a study designed to test the physiology of airway narrowing in asthma. Although the chemical was not licensed for human use, the investigator did not obtain approval from the Food and Drug Administration (FDA). In a warning letter, the FDA cited the investigator for (among other things): (a) failing to seek FDA approval for the investigational use of the chemical; (b) not submitting animal toxicity data to support safety; and (c) not obtaining adequate informed consent (3).
Limits to justifiable risk
The level of risk is an important attribute of research that determines the substantive and procedural protections that are necessary for the ethical justification of either a category of research or of an individual research protocol. Consideration must be directed not only at the actual risk but also to the perception of risk. For research involving adults, the risks of an intervention that does not offer the prospect of direct benefit must be justified by the importance of the knowledge that reasonably can be expected to result from the research. When children are involved (as discussed below), the allowable risks of such interventions are restricted regardless of the importance of the anticipated knowledge.
The risks of procedures performed only for research may be over- or under-estimated because the data used to estimate such risks are usually derived from clinical experience. Adverse event data from routine clinical procedures may not be systematically and prospectively collected, leading to inaccuracies in estimates of their probabilities. In estimating the risks of performing procedures for research purposes, it is necessary to account for the full range of risks that accompany a procedure, such as those related to the sedation and/or anesthesia that might be used for bronchoscopy. Standards for performance of research procedures such as bronchoscopy and BAL should be developed and these should be based on prospective data collection. The obligation to minimize research risks entails that these standards meet or exceed those that are, or ought to be, in place for the clinical performance of these same procedures. In addition, the risks of performing procedures vary inversely with the experience of the individual who performs them (4, 5). There should also be a mechanism for credentialing individual physician-researchers as competent to perform bronchoscopy, BAL and related procedures for research purposes. Such a mechanism should include the training of fellows in research bronchoscopy only after they have obtained competency and certification with clinical bronchoscopy.
For research protocols that employ bronchoprovocation, there may be a tendency for IRBs to regard “natural” provocations (such as cold air) as less dangerous than the use of drugs (such as methacholine). However, the use of a drug that permits the administration of a specific dose under controlled conditions may be justified as the effects are generally more predictable.
The requirements for informed consent and its documentation when the prospective subjects are legally competent and have the capacity to give informed consent are widely understood and generally non-controversial with regard to protocols involving bronchoprovocation and bronchoscopy (45 CFR 46.116 & 117) (6,7). Much more controversial are the circumstances, if any, in which prospective subjects, having limited capacities to consent, such as children, may authorize their own involvement in research (8, 9). This issue is discussed in further detail below.
Conflicts of interest and obligation
Many investigators have a conflict of interest (COI) or conflict of obligation. A financial COI is easiest to detect; psychological and professional COI and conflicts of obligation can be subtler and therefore more difficult to detect and manage. Nevertheless, managing these conflicts is critical since they may be detrimental to the integrity of the research and may undermine the informed consent process. Institutions, sponsors, and IRBs are responsible for having specific procedures in place to identify conflicts of interest and assure that subjects of research are not compromised by these conflicts. The researcher may consciously or unconsciously engage in behaviors that encourage the subject to acquiesce to the researcher’s requests, and discourage the exercise of the right to withdraw without prejudice. A clinician-researcher’s conflict of obligation may also reinforce the ‘therapeutic misconception’ as subjects have a tendency to believe falsely that all interventions and procedures performed by a clinician-researcher are, at least in part, designed to contribute directly to the health needs of the subject.
In the United States, it is widely agreed that it is ethically appropriate to reimburse subjects for their ‘out-of-pocket’ expenses and to provide modest stipends for their service as research subjects. The amount of the stipend should not be so much that it would overpower the prospective subject’s capability to exercise ‘free power of choice.’ Excessive stipends, as well as the provision without charge to subjects of otherwise costly goods and services can be ethically problematic and may be ‘undue inducements’ to research participation.
One particularly controversial aspect of financial incentives is whether it is appropriate to increase the level of incentive according to the amount of risk. Ideally, all research subjects should receive modest stipends and reimbursement for out-of-pocket expenses. This would work well if there were in place a comprehensive plan to provide no-fault compensation for researchinduced injury. Although such compensation plans have been strongly recommended by multiple national advisory commissions, federal regulations now require only that prospective subjects be informed as to whether there is a plan for compensation for injury and provision of medical treatment for research-induced injury. There is no requirement that either be provided.
Selection of subjects
The selection of subjects for participation in research should be responsive to the demands of scientific merit, subject safety and equitability in the distribution of the burdens and benefits of research. Inclusion and exclusion criteria should be established to assure that the subjects will have the biological, behavioral and social attributes necessary to accurately test the hypothesis of the research and to exclude those individuals especially likely to be harmed by the research. Historically, the concern for equitability was focused primarily on protecting vulnerable persons from bearing more than their fair share of the burdens of research participation. More recently, another primary concern has developed, that there will be no unjust exclusion of groups from the benefits of research participation (10, 11).
Additional Protections for Research Involving Children
Although research involving children as subjects was not the main focus of discussion at this conference, it is evident that bronchoprovocation and bronchosopy are increasingly being employed or considered for younger subjects. This raises several concerns that are mentioned below. This topic will require further discussion by other groups in the future. Meanwhile we offer a general and necessarily limited overview of some of the major issues. Federal regulations for the protection of children as research subjects contain criteria for ethical justification which vary according to the degree of risk and by whether or not the intervention or procedure that presents the risk “holds out the prospect of direct benefit for the individual subject [beneficial procedures]….” Research involving children as subjects requires generally the child’s assent and the permission of the parent(s) or guardian. Research that presents no more than minimal risk may be carried out without additional substantive or procedural protections. Research in which more than minimal risk is presented by a beneficial intervention or procedure is permitted if the risks are minimized and are justified by the anticipated benefit and the relationship of anticipated benefit to the risk is at least as favorable as that presented by available alternatives. Research in which more than minimal risk is presented by a non-beneficial intervention or procedure is permitted only if the level of risk is a minor increase over minimal, the intervention or procedure presents experiences to subjects that are commensurate with actual or expected medical, dental, psychological, social, or educational situations and the research is likely to yield generalizable information of vital importance about the subjects’ disorder or condition. Research that is not otherwise approvable under the first three categories but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children, may be permitted by the Secretary of Health and Human Services after expert consultation and opportunity for public review. This regulatory framework imposes a significant limit on the discretion of investigators and parents to permit the participation of children in research that entails more than minimal risk but at the same time permits much research of vital importance to the health and well being of children now and in the future.
The key to understanding these categories is the definition of ‘minimal risk’ set forth in the regulations: “Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical examinations or tests.” 45 CFR 46.102(i). However, the definition of minimal risk is difficult to apply because it is not clear; there is wide disagreement on the probability and magnitude of risk ordinarily encountered. Consistent with The National Commission’s original intent, a recent Institute of Medicine report recommends that minimal risk be interpreted in relation to “the normal experiences of average, healthy, normal children”(12,13). A ‘minor increase over minimal risk’ is then a “slight increase” over this level of risk (13).
Bronchoscopy presents children with more than a ‘minor increase over minimal risk’ and thus could only be approved by a local IRB for research purposes when the procedure also offered the prospect of direct benefit. The addition of a research objective to an otherwise clinically indicated bronchoscopy may present no more than a ‘minor increase over minimal risk’ depending on the necessary changes in the procedure, such as duration, anesthetic approach and so forth. In this context, the incremental risk to the child by adding the research objective to the clinical procedure becomes the determining factor in assessing the research risks of the bronchoscopy. In some but not all circumstances bronchoprovocation may present only a ‘minor increase over minimal risk’. Factors that must be considered would include subject population (i.e., risk for severe bronchospasm), agent (including dose and duration), ease of reversibility, the setting of the research including monitoring equipment, professional availability, competence to respond rapidly to an untoward event, and so forth. Researchers must have adequate pediatricspecific expertise and experience to perform the research in order to minimize risks (13).
Recently a federal panel reviewed a request to perform bronchoscopy for research purposes on infants with cystic fibrosis. Of the six panelists, four assessed the risks of bronchoscopy as more than a ‘minor increase over minimal risk.’ All six panelists recommended to the Office of Human Research Protection that the research be approved by the Secretary of HHS, pending certain modifications (14). The Secretary of HHS has not yet made a final determination. The process of federal review of research involving children that cannot be approved by a local IRB has come under scrutiny (15). In principle, there should be broad public discussion whenever research involving children moves beyond the standard categories of risks and potential benefits that IRBs are permitted to approve.
Public Discussion of the Ethics of Research
The foregoing discussion of the ethics of research involving bronchoscopy, bronchoprovocation and related procedures is offered as an overview and interpretation of contemporary standards. These standards and their interpretation will require further elaboration and revision particularly as new information becomes available about such matters as the risks of the procedures when they are performed for research purposes by suitably qualified experts and as we develop better consensus about the meaning of such terms as ‘minor increase over minimal risk’. We recommend that in the future, such discussions should include as full members, representatives of other groups such as patients, patient advocates and community members with health care interests. Further, an effort should be made to make such proceedings suitably transparent. Such an approach promises to enhance the protection of the rights and interests of participants in important research endeavors.
Conflict of Interest Statement
R.J.L. is a member of the Bioethics Committee of Eli Lilly Corporation, for this he received $5,000 in 2004, $0 in 2003, $8,194 in 2002 and $4,475 in 2001. R.M.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.R.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.