For randomized, controlled clinical trials, the selection of the control group is one of the key issues in the study design. This is why ICH has a specific guideline (E10) for “CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL TRIALS”. The choice of the control group will decide whether or not the trial is a superiority or non-inferiority study, double-blinded/single-blinded/open label, and will decide the sample size.
It becomes pretty common that the Standard of Care (SOC) may be chosen as the control group. We often run into an issue that for a specific disease (indication), there is no regulatory-approved therapy (existing therapy) and it is not ethical to conduct the Placebo-controlled study, the comparison of experimental therapy versus Standard of Care seems to be the only choice.
What is the Definition of the SOC?
There is no standard definition for SOC from regulatory guidelines. According to Webster’s New World Medical Dictionary, SOC is defined as “the level at which the average, prudent provider in a given situation would managed the patient’s care under the same or similar circumstances.”
From National Cancer Institute: “standard of care” is defined as “treatment that experts agree is appropriate, accepted, and widely used. Also called best practice, standard medical care, and standard therapy.”
There are more definitions, but all similar.
“A standard of care is a formal diagnostic and treatment process a doctor will follow for a patient with a certain set of symptoms or a specific illness. That standard will follow guidelines and protocols that experts would agree with as most appropriate, also called "best practice."
In legal terms, a standard of care is used as the benchmark against a doctor's actual work. For example, in a malpractice lawsuit, the doctor's lawyers would want to prove that the doctor's actions were aligned with the standard of care. The plaintiff's lawyers would want to show how a doctor violated the accepted standard of care and was therefore negligent.”
Standards of care are developed in a number of ways: Sometimes they are simply developed over time, and in other cases, they are the result of clinical findings. In modern era, the SOC are typically based on the evidence-based medicine. The SOC are based on the results of clinical trials, the Meta analysis results if there are multiple clinical trials, and the Cochrane systematic review of evidences. The SOC may come out as suggestions and treatment guidelines issued by the professional societies. There are actually so many treatment guidelines by different professional societies and by different countries. Just to list a couple of treatment guidelines below:
Does A Standard of Care therapy have to be approved by regulatory authority (such as FDA)?
Not necessarily. As a matter of fact, some of the SOCs may not be regulated by FDA at al. For example, the surgery and the plasma exchange are techniques and procedures that may not be part of FDA regulation.
In FDA’s guidance “Expedited Programs for Serious Conditions – Drugs and Biologics”, SOC was discussed as part of the discussions for ‘available therapy’. The guidance states:
“For purposes of this guidance, FDA generally considers available therapy (and the terms existing treatment and existing therapy) as a therapy that:
§ Is approved or licensed in the
United Statesfor the same indication being considered for the new drug and
§ Is relevant to current
U.S.standard of care (SOC) for the indication
FDA’s available therapy determination generally focuses on treatment options that reflect the current SOC for the specific indication (including the disease stage) for which a product is being developed. In evaluating the current SOC, FDA considers recommendations by authoritative scientific bodies (e.g., National Comprehensive Cancer Network,
of Neurology) based on clinical evidence and other reliable information that reflects current clinical practice. When a drug development program targets a subset of a broader disease population (e.g., a subset identified by a genetic mutation), the SOC for the broader population, if there is one, generally is considered available therapy for the subset, unless there is evidence that the SOC is less effective in the subset. American Academy
Over the course of new drug development, it is foreseeable that the SOC for a given condition may evolve (e.g., because of approval of a new therapy or new information about available therapies). FDA will determine what constitutes available therapy at the time of the relevant regulatory decision for each expedited program a sponsor intends to use (e.g., generally early in development for fast track and breakthrough therapy designations, at time of biologics license application (BLA) or new drug application (NDA) submissions for priority review designation, during BLA or NDA review for accelerated approval). FDA encourages sponsors to discuss available therapy considerations with the Agency during interactions with FDA.
As appropriate, FDA may consult with special Government employees or other experts when making an available therapy determination.”
The newly issued FDA Guidance on Available Therapy echoes the similar opinion:
“available therapy (and the terms existing treatments and existing therapy) should be interpreted as therapy that is specified in the approved labeling of regulated products, with only rare exceptions.
FDA recognizes that there are cases where a safe and effective therapy for a disease or condition exists but it is not approved for that particular use by FDA. However, for purposes of the regulations and policy statements described in Section III, which are intended to permit prompt FDA approval of medically important therapies, only in exceptional cases will a treatment that is not FDA-regulated (e.g., surgery) or that is not labeled for use but is supported by compelling literature evidence (e.g., certain established oncologic treatments) be considered available therapy.”
FDA guidance Non-Inferiority Clinical Trials answered the question if the active comparator for a non-inferiority study can be a product without label. The active comparator could be a SOC.
“Can a drug product be used as the active comparator in a study designed to show non-inferiority if its labeling does not have the indication for the disease being studied, and could published reports in the literature be used to support a treatment effect of the active control?
The active control does not have to be labeled for the indication being studied in the NI study, as long as there are adequate data to support the chosen NI margin. FDA does, in some cases, rely on published literature and has done so in carrying out the meta-analyses of the active control used to define NI margins. An FDA guidance for industry on Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products describes the approach to considering the use of literature in providing evidence of effectiveness, and similar considerations would apply here. Among these considerations are the quality of the publications (the level of detail provided), the difficulty of assessing the endpoints used, changes in practice between the present and the time of the studies, whether FDA has reviewed some or all of the studies, and whether FDA and the sponsor have access to the original data. As noted above, the endpoint for the NI study could be different (e.g., death, heart attack, and stroke) from the primary endpoint (cardiovascular death) in the studies if the alternative endpoint is well assessed”
How Standard are the Standards of Care?
It depends on the specific disease area and the available treatment. A standard of care in one country, one hospital may not necessarily be the same standard in another. Further, one doctor's standard can vary from another doctor's. In many cases, even though the same therapy is considered as the standard of care, the usage of the therapy may be quite different. For example, the tPA is considered as a standard of care in US to treat the leg attack (peripheral arterial occlusion). However, different medical centers and different doctors may give tPA therapy differently – the differences are reflected in the total amount of the tPA dose, bolus versus continuous infusion, infusion rate, total length of the tPA treatment.
The article below also discussed the heterogeneity of the SOC: How standard is standard care? Exploring control group outcomes in behaviour change interventions for young people with type 1 diabetes.
The heterogeneity of the standard of care presents great challenges in conducting clinical trials using the standard of care as the control group. This issue was extensively discussed in FDA’s guidance on Chronic Cutaneous Ulcer and Burn Wounds — Developing Products for Treatment. If we think about doing a multi-national clinical trial with the standard of care as the control group, the challenges will be even greater or the trial is not entirely feasible because of the difficulties in defining the SOC for a specific disease treatment. Here are the paragraphs from FDA’s guidance concerning about using the Standard of Care as the control group.
“Standard care refers to generally accepted wound care procedures, other than the investigational product, that will be used in the clinical trial. Good standard care procedures in a wound-treatment product trial are a prerequisite for assessing safety and efficacy of a product. Since varying standard care procedures can confound the outcome of a clinical trial, it is generally advisable that all participating centers agree to use the same procedures and these procedures are described within the clinical protocol. If it is not practical to apply uniform standard care procedures across study centers, randomization stratified by study center should be considered. It is also important that the sample size within study centers and wound care records be adequate to assess the effect of wound care variation.
A number of standard procedures for ulcer and burn care are widely accepted. Several professional groups have initiated development of care guidelines for ulcers and burns. The Agency does not require adherence to any specific guidelines, the basic principle being that standard care regimens in wound-treatment product trials should optimize conditions for healing and be prospectively defined in the protocol. The rationale for the standard care chosen should be included in the protocol, and the study plan should be of sufficient detail for consistent and uniform application across study centers. Case report forms (CRFs) should be designed such that, at each visit, investigators describe the type of ulcer or burn care actually delivered (e.g., extent of debridement, use of concomitant medications). For outpatients, the CRF should also capture compliance with standard care measures, including wound dressing, off-loading, and appropriate supportive factors, such as dietary intake.The value of study site consistency in standard care regimens within a trial cannot be over-emphasized because of the profound effects these procedures have on clinical outcome for burns and chronic wounds. Consistency in standard care regimens is important for minimizing variability and allowing assessment of treatment effect. It may be reasonable to evaluate a single standard care regimen in early trials to minimize this variability. If comparison of an investigational product to more than one commonly used standard care option is desired, the overall development plan should include specific assessment of the effect of these standard care options on the experimental treatment. These common options should be identified and addressed prospectively in clinical trial design including being clearly described in the clinical protocol and compliance captured via the CRFs; criteria for data poolability should be defined prospectively. Every attempt should be made to minimize deviations from the procedures described in the protocol and subject compliance recorded in CRFs. If more than one standard care regimen is used in the same clinical trial, then randomized treatment allocation within strata defined by these options in standard care is important.”
To minimize the heterogeneity of the standard of care, cluster randomization may also be emplyed. As stated in FDA’s guidance “Antibacterial Therapies for Patients With Unmet Medical Need for the Treatment of Serious Bacterial Diseases”, with cluster randomization, “Patients enrolled at sites randomized to the standard-of-care arm would be treated no differently than is usual practice at that site, while patients enrolled at sites randomized to the investigational drug arm would be treated with the investigational drug.”
When a clinical trial uses standard of case as control group, should the study be designed as superiority or non-inferiority?
It depends on whether or not the experimental treatment group is a stand alone (without standard of case) or add-on (on top of the standard of care) therapy.
If the experimental treatment group is an add-on therapy and the experimental treatment is given on top of the existing standard of case, the trial design must be a superiority study to demonstrate that the add-on therapy is superior to the existing standard of case.
If the experimental treatment group is a stand alone therapy and can be given without the standard of care, the trial design can be either non-inferiority or superiority depending on the effect size of the experimental therapy.
In FDA’s guidance “Non-Inferiority Clinical Trials”, the ‘Add-on study’ was suggested as an alternative to the non-inferiority study design. In the guidance, ‘treatment that are already available’ can include the standards of care. The combo therapy of the novel treatment plus the existing treatment must be shown to be superior to the existing treatment (standard of care alone) or the existing treatment + Placebo.
In many cases, for a pharmacologically novel treatment, the most interesting question is not whether it is effective alone but whether the new drug can add to the effectiveness of treatments that are already available. The most pertinent study would therefore be a comparison of the new agent and placebo, each added to established therapy. Thus, new treatments for heart failure have added new agents (e.g., ACE inhibitors, beta blockers, and spironolactone) to diuretics and digoxin. As each new agent became established, it became part of the background therapy to which any new agent and placebo would be added. This approach is also typical in oncology, in the treatment of seizure disorders, and, in many cases, in the treatment of AIDS. “
Here is a real example of an add-on study: Influence of early goal-directed therapy using arterial waveform analysis on major complications after high-risk abdominal surgery: study protocol for a multicenter randomized controlled superiority trial.
“In this multicenter, randomized, controlled superiority trial, 542 patients scheduled for elective, high-risk abdominal surgery will be included. Patients are allocated to standard care (control group) or early goal-directed therapy (intervention group) using a randomization procedure stratified by center and type of surgery. In the control group, standard perioperative hemodynamic monitoring is applied. In the intervention group, early goal-directed therapy is added to standard care, based on continuous monitoring of cardiac output with arterial waveform analysis.”