Draft guidance document on the collection and analysis of disaggregated data in clinical trials: Disaggregated data best practices

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• About disaggregated data best practices
• Considerations in protocol design
• Heterogeneity assessment
• Disaggregated data plan

About disaggregated data best practices

Recruiting diverse clinical trial participants and conducting relevant subgroup analyses remains critically important to ensure the possibility of determining:

• whether differences between subgroups exist based on all of the clinical evidence
• if further monitoring after the drug reaches the market is necessary (where feasible and applicable)
• whether the clinical trial population mirrors the full diversity of the population that will use the drug product being tested

The collection and analysis of disaggregated data is a key aspect in all phases of a health product’s life cycle:

• study design
• dose selection
• testing and evaluation
• clinical validation
• risk analysis and management
• transparency and reporting
• post-market safety monitoring

Considerations in protocol design

This section outlines information to consider in clinical trial protocol design for drugs for human use, especially Phase 3 and 4 trials. Such information will help sponsors recruit diverse clinical trial participants and plan for appropriate subgroup analyses.

As a standard practice, the diversity of clinical trial participants should reflect the population that will use the drug. Before an application is submitted for market authorization in Canada, drugs should be evaluated in participants who represent the full range of persons likely to receive the product, whenever possible.

For example:

• Considerations for inclusion of women in clinical trials and analysis of sex differences

It is also important that clinical trial results are applicable to the populations likely to use the product. Evidence that can help evaluate benefit-risk profiles of specific subgroups is generated by collecting:

• disaggregated data on the age, sex and race/ethnicity of participants
• other clinically relevant baseline characteristics

As mentioned, differences in age, sex and race/ethnicity may contribute to different efficacy and safety profiles for drug products, for example:

• sex differences in pharmacokinetics and pharmacodynamics may impact drug safety and effectiveness in some contexts

Similarly, data from diverse racial/ethnic groups may necessitate different treatment parameters, for example:

• different dosing recommendations for therapeutics, such as:
  • lower initial starting dose of statins in Asian patients or
  • higher doses of tacrolimus in Black patients

It is understood that racial/ethnic differences in drug metabolism are largely attributable to genetic and genomic differences. These differences can directly influence drug absorption, distribution, metabolism and excretion.

Genetic and genomic factors influence the overall enzyme make-up of an individual, and certain mutations or gene variants are more common in specific ethnic groups. This contributes to pharmacokinetic variability in these subgroups. For example, gene variants affecting transporter proteins impact the safety and efficacy of statins. Similarly, gene variants also affect expression of enzymes, which influence the bioavailability and clearance of tacrolimus.

For more information:

• The pharmacogenomics of statins
• Safety and efficacy of statins in Asians
• Sex differences in pharmacokinetics and pharmacodynamics
• Genotype-guided tacrolimus dosing in African American kidney transplant recipients
• Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin, and simvastatin acid in Caucasian and Asian subjects: A class effect?
• African-American race modifies the influence of tacrolimus concentrations on acute rejection and toxicity in kidney transplant recipients

Heterogeneity assessment

A heterogeneity assessment (HA) is an evaluation examining whether differences in treatment efficacy or safety are anticipated between subgroups of the overall study population. The HA should describe the measures taken to establish whether there are, or could be, clinically important age, sex and racial/ethnic differences in response to the drug product being tested.

The U.S. Food and Drug Administration (FDA) outlines a similar approach in the following:

• Diversity plans to improve enrollment of participants from underrepresented racial and ethnic populations in clinical trials: Draft guidance for industry

To ensure diverse subgroups are meaningfully considered in a drug product's development and testing, an overarching HA should be performed at the start of the clinical development program. This HA will determine how best to approach clinical development and trial design.

Sponsors should update the HA as needed throughout the development process as more information on sources of heterogeneity is learned from early phase trials. These additional sources of heterogeneity may require further supporting data.

If the HA indicates that treatment differences are not anticipated among subgroups, enrollment should still be broad and reflect disease epidemiology. Broad enrollment of representative populations:

• permits subgroup analyses
• may enable the assessment of effect consistency across trials, where appropriate

Learn more:

• ICH E9: Statistical principles for clinical trials

Alternatively, if the HA or evidence from previous or ongoing studies indicates meaningful differences in any of the subgroups studied, sponsors should consider such differences when planning, designing and analyzing individual studies within the clinical development program. This includes plans to recruit enough representative patients to be able to analyze the benefit-risk profile in the relevant subgroups, where possible.

Learn more in the following EMA guidance document:

• Guideline on the investigation of subgroups in confirmatory clinical trials

If there is a possibility that there could be differing treatment responses between subgroups, sponsors should explore the potential reasons for the heterogeneity and describe this in the trial(s) design(s) stage. Analyses should consider these potential differences. Note: In some cases, this type of analysis may only be feasible when analyzing all of the clinical evidence and/or in post-market monitoring.

Known factors that may affect the safety and efficacy of the drug product between subgroups should inform the HA. Sponsors should consider disease pathophysiology, previously identified predictive or prognostic factors, biological plausibility, epidemiology of the condition and/or therapeutic drug class.

Information for certain diseases may be limited, making it difficult to assess potential subgroup-specific heterogeneity. To supplement their HA, sponsors should find relevant data sources in academic literature and/or seek out real world evidence (RWE).

Sponsors may use non-clinical studies to provide supportive data. For example, pharmacology and toxicology studies conducted in male and female animals can indicate potential sex-related differences in concentration response, safety or efficacy.

To understand how non-clinical studies can support and inform clinical trial evidence, consult ICH harmonized guidelines for clinical trials, such as:

• ICH E8 : General considerations for clinical studies
• ICH S9 : Nonclinical evaluation for anticancer pharmaceuticals
• ICH S11 : Nonclinical safety testing in support of development of paediatric pharmaceuticals
• ICH M3(R2) : Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals

As the HA informs the study design and enrollment plan, sponsors should include it in their submission material for clinical trial applications and/or market authorization.

Of note, the contents of the current guidance apply to preceding documents such as:

• Guidance document for clinical trial sponsors: Clinical trial applications

Disaggregated data plan

A disaggregated data plan (DDP) is used to determine the parameters for disaggregated data collection and subsequent analyses. By supporting the collection and assessment of disaggregated data by age, sex, racial/ethnic groups and other associated covariates, the DDP helps sponsors establish if and how a treatment may affect the benefit-risk profile of specific subgroups.

The content of the DDP should be based on the findings of the HA. To support subgroup analysis, sponsors should aim to enroll representative proportions of age, sex and racial/ethnic subgroups that are consistent with those who will use the drug product or as indicated by the HA.

Otherwise, sponsors should either:

• justify how the enrollment criteria provide acceptable representation for the intended population or
• explain if a factor other than age, sex or race/ethnicity is a primary driver of heterogeneity upon which the disaggregated data plan should be based

These recommendations generally apply to all trials, but more feasibly, are targeted to phase 3 and 4 studies, as these trials tend to enroll more patients than earlier trials.

The DDP and data submission should describe:

• the number of participants planned for each study
  • outline how the sponsor will collect subgroup data throughout the product life cycle in the description
• how age, sex and race/ethnicity, as well as other related covariates, will be assessed
• how potential differences will be taken into account
  • for example, by enriched or restricted enrollment (by selecting for or limiting certain patient characteristics), confirmatory trials and so on, as applicable

This description will maximize early discussions of subgroups and establish a strategy for considering diverse subgroups before the trials begin, if required. For example:

• if it is known early on that the treatment is only effective in certain subgroups, then trial enrollment could be restricted to those populations
• if a factor affecting subgroups is known to be prognostic in value, then treatment groups may be balanced for this factor at the randomization stage through stratification

Sponsors should capture the details of both the HA and DDP, including enrollment strategies, in the appropriate sections of the clinical study protocol and statistical analysis plan (SAP). Include applicable results, analyses and discussion in the clinical study report (CSR).

For data submitted in the CSR, sponsors should:

• capture disaggregated data for enrolled and completed participants
  • population pharmacokinetic analyses often include age and sex as co-variates
  • race/ethnicity should also be included as it may affect the interpretation of drug product efficacy and/or safety in subgroups as well as clinical parameters of use
  • pharmacometric modelling and analyses are encouraged
• present key efficacy and safety data by age, sex and race/ethnicity and describe whether any treatment modifications (for example, of dose or dosing regimen) are needed for subgroups
  • clinically relevant findings may be reflected in the product labelling as per Health Canada's guidance on the product monograph

We encourage sponsors to engage in discussions with the relevant Health Canada directorate early on in the process. Sponsors may also ask for feedback during pre-clinical trial application meetings and/or in pre-submission meetings for a new drug submission (NDS) or supplement to a new drug submission (SNDS).

More details on pre-submission meetings for NDS or SNDS are included in the following guidance document:

• Management of drug submissions and applications