Guidance Letter - Phase 1 Clinical Trial Requirements and Safety Study Design for Prospective Applicants
MONTANA, September 29, 2026
Purpose
The Montana Experimental Treatment Review Board (ETRB) received a set of questions from a prospective applicant planning a clinical safety study outside the United States with the intention of later qualifying the treatment for use in Montana. Because the questions concern issues likely to arise for other applicants, the ETRB is publishing its responses as general guidance.
This guidance describes how the ETRB expects to apply the statutory Phase 1 requirement and what supporting evidence it expects to review. It is not a determination on any particular treatment or study. The ETRB cannot prospectively determine that a study will satisfy the statutory requirements before reviewing the completed evidence.
MONTANA, September 29, 2026
Purpose
The Montana Experimental Treatment Review Board (ETRB) received a set of questions from a prospective applicant planning a clinical safety study outside the United States with the intention of later qualifying the treatment for use in Montana. Because the questions concern issues likely to arise for other applicants, the ETRB is publishing its responses as general guidance.
This guidance describes how the ETRB expects to apply the statutory Phase 1 requirement and what supporting evidence it expects to review. It is not a determination on any particular treatment or study. The ETRB cannot prospectively determine that a study will satisfy the statutory requirements before reviewing the completed evidence.
Statutory Background
Under Montana law, an "experimental treatment" means the provision of a medical intervention by a health care provider involving an investigational drug, biological product, device, or other treatment that "has successfully completed phase 1 of a clinical trial but has not yet been approved for general use by the United States food and drug administration" and that either "remains under investigation in a clinical trial approved by the United States food and drug administration" or "has a demonstrated safety record through documented clinical evidence from a qualified medical institution as defined by department rule." Mont. Code Ann. § 50-12-102(1), as amended by Senate Bill 535 (2025).
Frequently Asked Questions
1. If an applicant conducts its study on an exploratory basis rather than as a formally designated Phase 1 study, what further material would the ETRB expect to review? In particular, would preclinical data, or manufacturing and quality control information, be required?
The Montana statute requires that an experimental treatment have "successfully completed phase 1 of a clinical trial." The Qualified Medical Institution pathway does not replace this requirement; rather, it provides one of the two additional pathways by which a treatment that has completed Phase 1 may qualify.
The ETRB recognizes that clinical studies conducted outside the United States may operate under different regulatory frameworks and may not necessarily use the same phase terminology as the FDA. The ETRB will therefore focus on whether the study can reasonably be considered a Phase 1 clinical trial based on its purpose, design, conduct, oversight, and resulting evidence, rather than solely on how the study is labeled. The ETRB expects the study to be prospectively designed to evaluate the safety and tolerability of the specific intervention, with a defined study population, treatment protocol, appropriate safety assessments, systematic adverse-event collection, appropriate monitoring and patient protections, and documentation sufficient to support a conclusion that the study was successfully completed.
Accordingly, describing a study as "exploratory" rather than "Phase 1" would not necessarily be determinative, but the ETRB cannot prospectively determine that a study will satisfy the statutory Phase 1 requirement before reviewing the completed evidence.
The ETRB will also expect supporting information sufficient to evaluate the safety of the treatment proposed for use in Montana. This would ordinarily include relevant preclinical and toxicology information where available, as well as manufacturing and quality information sufficient to establish the identity, consistency, purity, and appropriate handling of the clinical product and its comparability to the product evaluated in the supporting clinical study. The extent of this information will depend on the nature of the intervention and its reasonably foreseeable risks.
If a study is being designed specifically to establish eligibility under the Montana framework, the ETRB recommends designing and documenting it from the outset to meet generally recognized Phase 1 safety standards, even if the regulatory framework of the jurisdiction in which the study is conducted does not formally require the study to be designated as "Phase 1."
2. Where the study is conducted on an allogeneic basis, would the ETRB's determination permit the applicant to provide an autologous version of the same product under the same protocol?
Not automatically. The ETRB's determination applies to the specific experimental treatment and protocol supported by the evidence submitted for review. If the clinical evidence is generated using an allogeneic product but the product proposed for administration in Montana is autologous, the applicant would need to identify that difference and provide sufficient information for the ETRB to determine whether the autologous product is adequately supported by the clinical evidence and whether the proposed use maintains a reasonable safety profile.
The ETRB would consider the scientific and clinical significance of the differences between the allogeneic and autologous products, including, as applicable, differences in source material, manufacturing process and controls, product characteristics and release specifications, immunologic or other biological risks, and any resulting differences in administration, monitoring, or patient eligibility.
The fact that one product is allogeneic and the other autologous would not necessarily require entirely separate submissions or studies. However, the ETRB could not assume that safety evidence generated with the allogeneic product establishes the safety of the autologous product without an adequate scientific basis for that conclusion. If the differences are material to safety, additional clinical evidence may be required.
3. If it would not, may the autologous product be included within the same study as the allogeneic product?
Yes, potentially. The Montana statute and rules do not require the clinical evidence supporting different configurations of an experimental treatment to be generated in separate clinical trials. An autologous and an allogeneic version could therefore potentially be evaluated within the same Phase 1 study.
Ultimately, the ETRB would need to determine that the completed Phase 1 evidence adequately supports each version proposed for use in Montana. Inclusion of both products within the same study would not by itself establish that both satisfy the requirements; that determination would depend on the design and results of the completed study and the supporting manufacturing and safety information.
4. For the purpose of demonstrating safety, would observational reporting by the treating physician of any adverse effect or health concern be sufficient? If not, what specific measurements or tests does the ETRB expect to see performed?
Observational reporting by the treating physician would be an important component of safety monitoring, but would generally not, by itself, be sufficient for a study intended to establish successful completion of Phase 1 and provide the clinical safety evidence supporting ETRB review.
The study should include a prospective and systematic approach to safety assessment appropriate to the nature and reasonably foreseeable risks of the intervention. This would generally include predefined adverse-event and serious-adverse-event assessment and reporting; defined periods of observation and follow-up; appropriate baseline and follow-up clinical assessments; and predefined criteria for holding or stopping treatment or escalating care where applicable. Adverse events should be captured in a manner that allows their type, severity, frequency, timing, and outcome to be evaluated.
The ETRB does not prescribe a universal set of laboratory tests, imaging studies, or other measurements applicable to all experimental treatments. The appropriate assessments will depend on the biological characteristics of the product, its route and method of administration, available preclinical and clinical evidence, known or reasonably foreseeable risks, and the characteristics of the study population. The applicant should identify these risks and select clinical measurements and monitoring procedures sufficient to detect and characterize them.
The completed study should ultimately provide sufficient structured clinical evidence for the ETRB to evaluate the treatment's safety profile and determine whether the applicable Phase 1 and Qualified Medical Institution standards have been satisfied.
5. Is there anything further the ETRB would expect an applicant to include in a planned safety study?
In addition to the considerations described above, the ETRB recommends designing the study so that the completed evidence provides a clear and interpretable characterization of the safety of each experimental treatment proposed for use in Montana.
The study should clearly define the intervention and study population; dose, route, schedule, and duration; relevant inclusion and exclusion criteria; prospective safety assessments and follow-up; adverse-event and serious-adverse-event capture; and appropriate stopping, holding, or escalation criteria. The duration and nature of follow-up should be appropriate to the known and reasonably foreseeable risks of the intervention.
The applicant should also maintain sufficient manufacturing and quality information to establish the identity and consistency of the products studied and their comparability to the products ultimately proposed for administration in Montana.
The ETRB does not prescribe a universal Phase 1 study design or minimum set of laboratory or other measurements. The applicant should determine the appropriate study design and safety assessments based on the characteristics and reasonably foreseeable risks of the intervention. Ultimately, the completed study and supporting documentation should be sufficient for the ETRB to determine that the treatment has successfully completed Phase 1 and that the proposed Montana treatment protocol meets the applicable safety standards and has a reasonable safety profile.
Because a planned study has not yet been designed or completed, the ETRB cannot guarantee that a particular study design will satisfy these requirements. Applicants may, however, use the ETRB Submission Guide as a framework for the categories of evidence and documentation that will be expected at the time of submission.
What Is a Phase 1 Clinical Trial?
For purposes of ETRB review, a "Phase 1 clinical trial" is a prospective, protocol-defined clinical investigation in human participants whose primary purpose includes the systematic evaluation of the safety and tolerability of a defined medical intervention.
The ETRB does not interpret this requirement as necessarily turning on whether the relevant study was formally labeled “Phase 1” by the jurisdiction in which it was conducted. Where different clinical-development terminology is used, the applicant must demonstrate that the intervention has in substance undergone and successfully completed the stage of clinical evaluation corresponding to Phase 1, based on the study's design, conduct, regulatory or ethics oversight, safety objectives, and resulting evidence. The applicant bears responsibility for demonstrating and certifying that the statutory requirement has been satisfied.
At a minimum, the study should:
Under Montana law, an "experimental treatment" means the provision of a medical intervention by a health care provider involving an investigational drug, biological product, device, or other treatment that "has successfully completed phase 1 of a clinical trial but has not yet been approved for general use by the United States food and drug administration" and that either "remains under investigation in a clinical trial approved by the United States food and drug administration" or "has a demonstrated safety record through documented clinical evidence from a qualified medical institution as defined by department rule." Mont. Code Ann. § 50-12-102(1), as amended by Senate Bill 535 (2025).
Frequently Asked Questions
1. If an applicant conducts its study on an exploratory basis rather than as a formally designated Phase 1 study, what further material would the ETRB expect to review? In particular, would preclinical data, or manufacturing and quality control information, be required?
The Montana statute requires that an experimental treatment have "successfully completed phase 1 of a clinical trial." The Qualified Medical Institution pathway does not replace this requirement; rather, it provides one of the two additional pathways by which a treatment that has completed Phase 1 may qualify.
The ETRB recognizes that clinical studies conducted outside the United States may operate under different regulatory frameworks and may not necessarily use the same phase terminology as the FDA. The ETRB will therefore focus on whether the study can reasonably be considered a Phase 1 clinical trial based on its purpose, design, conduct, oversight, and resulting evidence, rather than solely on how the study is labeled. The ETRB expects the study to be prospectively designed to evaluate the safety and tolerability of the specific intervention, with a defined study population, treatment protocol, appropriate safety assessments, systematic adverse-event collection, appropriate monitoring and patient protections, and documentation sufficient to support a conclusion that the study was successfully completed.
Accordingly, describing a study as "exploratory" rather than "Phase 1" would not necessarily be determinative, but the ETRB cannot prospectively determine that a study will satisfy the statutory Phase 1 requirement before reviewing the completed evidence.
The ETRB will also expect supporting information sufficient to evaluate the safety of the treatment proposed for use in Montana. This would ordinarily include relevant preclinical and toxicology information where available, as well as manufacturing and quality information sufficient to establish the identity, consistency, purity, and appropriate handling of the clinical product and its comparability to the product evaluated in the supporting clinical study. The extent of this information will depend on the nature of the intervention and its reasonably foreseeable risks.
If a study is being designed specifically to establish eligibility under the Montana framework, the ETRB recommends designing and documenting it from the outset to meet generally recognized Phase 1 safety standards, even if the regulatory framework of the jurisdiction in which the study is conducted does not formally require the study to be designated as "Phase 1."
2. Where the study is conducted on an allogeneic basis, would the ETRB's determination permit the applicant to provide an autologous version of the same product under the same protocol?
Not automatically. The ETRB's determination applies to the specific experimental treatment and protocol supported by the evidence submitted for review. If the clinical evidence is generated using an allogeneic product but the product proposed for administration in Montana is autologous, the applicant would need to identify that difference and provide sufficient information for the ETRB to determine whether the autologous product is adequately supported by the clinical evidence and whether the proposed use maintains a reasonable safety profile.
The ETRB would consider the scientific and clinical significance of the differences between the allogeneic and autologous products, including, as applicable, differences in source material, manufacturing process and controls, product characteristics and release specifications, immunologic or other biological risks, and any resulting differences in administration, monitoring, or patient eligibility.
The fact that one product is allogeneic and the other autologous would not necessarily require entirely separate submissions or studies. However, the ETRB could not assume that safety evidence generated with the allogeneic product establishes the safety of the autologous product without an adequate scientific basis for that conclusion. If the differences are material to safety, additional clinical evidence may be required.
3. If it would not, may the autologous product be included within the same study as the allogeneic product?
Yes, potentially. The Montana statute and rules do not require the clinical evidence supporting different configurations of an experimental treatment to be generated in separate clinical trials. An autologous and an allogeneic version could therefore potentially be evaluated within the same Phase 1 study.
Ultimately, the ETRB would need to determine that the completed Phase 1 evidence adequately supports each version proposed for use in Montana. Inclusion of both products within the same study would not by itself establish that both satisfy the requirements; that determination would depend on the design and results of the completed study and the supporting manufacturing and safety information.
4. For the purpose of demonstrating safety, would observational reporting by the treating physician of any adverse effect or health concern be sufficient? If not, what specific measurements or tests does the ETRB expect to see performed?
Observational reporting by the treating physician would be an important component of safety monitoring, but would generally not, by itself, be sufficient for a study intended to establish successful completion of Phase 1 and provide the clinical safety evidence supporting ETRB review.
The study should include a prospective and systematic approach to safety assessment appropriate to the nature and reasonably foreseeable risks of the intervention. This would generally include predefined adverse-event and serious-adverse-event assessment and reporting; defined periods of observation and follow-up; appropriate baseline and follow-up clinical assessments; and predefined criteria for holding or stopping treatment or escalating care where applicable. Adverse events should be captured in a manner that allows their type, severity, frequency, timing, and outcome to be evaluated.
The ETRB does not prescribe a universal set of laboratory tests, imaging studies, or other measurements applicable to all experimental treatments. The appropriate assessments will depend on the biological characteristics of the product, its route and method of administration, available preclinical and clinical evidence, known or reasonably foreseeable risks, and the characteristics of the study population. The applicant should identify these risks and select clinical measurements and monitoring procedures sufficient to detect and characterize them.
The completed study should ultimately provide sufficient structured clinical evidence for the ETRB to evaluate the treatment's safety profile and determine whether the applicable Phase 1 and Qualified Medical Institution standards have been satisfied.
5. Is there anything further the ETRB would expect an applicant to include in a planned safety study?
In addition to the considerations described above, the ETRB recommends designing the study so that the completed evidence provides a clear and interpretable characterization of the safety of each experimental treatment proposed for use in Montana.
The study should clearly define the intervention and study population; dose, route, schedule, and duration; relevant inclusion and exclusion criteria; prospective safety assessments and follow-up; adverse-event and serious-adverse-event capture; and appropriate stopping, holding, or escalation criteria. The duration and nature of follow-up should be appropriate to the known and reasonably foreseeable risks of the intervention.
The applicant should also maintain sufficient manufacturing and quality information to establish the identity and consistency of the products studied and their comparability to the products ultimately proposed for administration in Montana.
The ETRB does not prescribe a universal Phase 1 study design or minimum set of laboratory or other measurements. The applicant should determine the appropriate study design and safety assessments based on the characteristics and reasonably foreseeable risks of the intervention. Ultimately, the completed study and supporting documentation should be sufficient for the ETRB to determine that the treatment has successfully completed Phase 1 and that the proposed Montana treatment protocol meets the applicable safety standards and has a reasonable safety profile.
Because a planned study has not yet been designed or completed, the ETRB cannot guarantee that a particular study design will satisfy these requirements. Applicants may, however, use the ETRB Submission Guide as a framework for the categories of evidence and documentation that will be expected at the time of submission.
What Is a Phase 1 Clinical Trial?
For purposes of ETRB review, a "Phase 1 clinical trial" is a prospective, protocol-defined clinical investigation in human participants whose primary purpose includes the systematic evaluation of the safety and tolerability of a defined medical intervention.
The ETRB does not interpret this requirement as necessarily turning on whether the relevant study was formally labeled “Phase 1” by the jurisdiction in which it was conducted. Where different clinical-development terminology is used, the applicant must demonstrate that the intervention has in substance undergone and successfully completed the stage of clinical evaluation corresponding to Phase 1, based on the study's design, conduct, regulatory or ethics oversight, safety objectives, and resulting evidence. The applicant bears responsibility for demonstrating and certifying that the statutory requirement has been satisfied.
At a minimum, the study should:
• Prospectively define the intervention, including the product or treatment, route of administration, dose or exposure where applicable, schedule, and duration;
• Prospectively define the study population, including relevant eligibility criteria;
• Include systematic safety assessment, with predefined methods for identifying and documenting adverse events and serious adverse events and appropriate clinical, laboratory, or other safety measurements based on the known or reasonably foreseeable risks of the intervention;
• Provide defined observation and follow-up periods appropriate to the nature and reasonably foreseeable risks of the intervention;
• Include appropriate patient protections and independent ethical or regulatory oversight consistent with the jurisdiction in which the study is conducted;
• Generate an interpretable clinical safety dataset sufficient to characterize the nature, frequency, severity, timing, and outcomes of observed adverse events and other relevant safety findings; and
• Reach a documented conclusion regarding safety and tolerability sufficient to support a determination that the study was successfully completed.
• Prospectively define the study population, including relevant eligibility criteria;
• Include systematic safety assessment, with predefined methods for identifying and documenting adverse events and serious adverse events and appropriate clinical, laboratory, or other safety measurements based on the known or reasonably foreseeable risks of the intervention;
• Provide defined observation and follow-up periods appropriate to the nature and reasonably foreseeable risks of the intervention;
• Include appropriate patient protections and independent ethical or regulatory oversight consistent with the jurisdiction in which the study is conducted;
• Generate an interpretable clinical safety dataset sufficient to characterize the nature, frequency, severity, timing, and outcomes of observed adverse events and other relevant safety findings; and
• Reach a documented conclusion regarding safety and tolerability sufficient to support a determination that the study was successfully completed.
A Phase 1 clinical trial need not be randomized or placebo-controlled, demonstrate efficacy, enroll a predetermined minimum number of participants, or employ a universal set of laboratory or diagnostic tests. The specific design, sample size, safety assessments, and monitoring should be scientifically appropriate to the intervention and its reasonably foreseeable risks. Routine clinical use, case reports, retrospective chart review, or passive adverse-event reporting do not by themselves constitute a Phase 1 clinical trial, although such evidence may provide additional support for the treatment's safety profile.
Contact
Questions regarding this guidance may be directed to the ETRB at contact@montanaetrb.org.
This guidance may be revised as the ETRB gains further experience with submissions.