Federal Practitioner

Preventable errors by health care workers are widespread and cause significant morbidity and mortality. Wrong site surgery (WSS) is a preventable error that causes harm through both the direct insult of surgery and propagation of the untreated initial problem. WSS also can cause poor patient outcomes, low morale, malpractice claims, and increased costs to the health care system. The estimated median prevalence of WSS across all specialties is 9 events per 1,000,000 surgical procedures, and an institutional study of 112,500 surgical procedures reported 1 wrong-site event, which involved removing the incorrect skin lesion and not removing the intended lesion.^1,2

Though the prevalence is low when examining all specialties together, dermatology is also susceptible to WSS.³ Watson and colleagues demonstrated that 31% of intervention errors were due to WSS and suggested that prebiopsy photography helps decrease errors.⁴ Thus, the American Academy of Dermatology has emphasized the importance of reducing WSS.⁵ A study by Nijhawan and colleagues found that 25% of patients receiving Mohs surgery at a private single cancer center could not identify their biopsy location because the duration between biopsy and surgery allowed biopsy sites to heal well, which made finding the lesion difficult.⁶

Risk factors for WSS include having multiple health care providers (HCPs) living remote from the surgery location involved in the case, being a traveling veteran, receiving care at multiple facilities inside and outside the US Department of Veterans Affairs (VA) system, mislabeling photographs or specimens, and photographs not taken at time of biopsy and too close with no frame of reference to assist in finding the correct site. The VA electronic health record (EHR) is not integrated with outside facility EHRs, and the Office of Community Care (OCC) at the VA is responsible for obtaining copies of outside records. If unsuccessful, the HCP and/or patient must provide the records. Frequently, records are not received or require multiple attempts to be obtained. This mostly affects veterans receiving care at multiple facilities inside and outside the VA system as the lack of or timely receipt of past health records could increase the risk for WSS.

To combat WSS, some institutions have implemented standardized protocols requiring photographic documentation of lesions before biopsy so that the surgeon can properly identify the correct site prior to operating.⁷ Fortunately, recent advances in technology have made it easier to provide photographic documentation of skin lesions. Highsmith and colleagues highlighted use of smartphones to avoid WSS in dermatology.⁷ Despite these advances, photographic documentation of lesions is not universal. A study by Rossy and colleagues found that less than half of patients referred for Mohs surgery had clear documentation of the biopsy site with photography, diagram, or measurements, and of those documented, only a small fraction used photographs.⁸

Photographic documentation is not currently required by the VA, increasing the risk of WSS. About 20% of the ~150 VA dermatology departments nationwide are associated with a dermatology residency program and have implemented photographic documentation of lesions before biopsy. The other 80% of departments may not be using photographic documentation. The following 3 cases experienced by the authors highlight instances of how quality photographic documentation of lesions prior to biopsy can improve patient care and save lives. Then, we propose a photographic documentation protocol for VA dermatology departments to follow based on the photographic standards outlined by the American Society for Dermatologic Surgery.⁹

Case 1 Presentation

A 36-year-old traveling veteran who relocates frequently and receives care at multiple VA medical centers (VAMCs) presented for excision of a melanoma. The patient had been managed at another VAMC where the lesion was biopsied in September 2016. He presented to the Orlando, Florida, VAMC dermatology clinic 5 months later with the photographs of his biopsy sites along with the biopsy reports. The patient had 6 biopsies labeled A through F. Lesion A at the right mid back was positive for melanoma (Figure 1), whereas lesion C on the mid lower back was not cancerous (Figure 2). On examination of the patient’s back, he had numerous moles and scars. The initial receiving HCP circled and photographed the scar presumed to be the melanoma on the mid lower back (Figure 3).

On the day of surgery, the surgeon routinely checked the biopsy report as well as the photograph from the patient’s most recent HCP visit. The surgeon noted that biopsy A (right mid back) on the pathology report had been identified as the melanoma; however, biopsy C (mid lower back) was circled and presumed to be the melanoma in the recent photograph by the receiving HCP—a nurse practitioner. The surgeon compared the initial photos from the referring VAMC with those from the receiving HCP and subsequently matched biopsy A (melanoma) with the correct location on the right mid back.

This discrepancy was explained to the patient with photographic confirmation, allowing for agreement on the correct site before the surgery. The pathology results of the surgical excision confirmed melanoma in the specimen and clear margins. Thus, the correct site was operated on.

Case 2 Presentation

A veteran aged 86 years with a medical history of a double transplant and long-term immunosuppression leading to numerous skin cancers was referred for surgical excision of a confirmed squamous cell carcinoma (SCC) on the left upper back. On the day of surgery, the biopsy site could not be identified clearly due to numerous preexisting scars (Figure 4). No photograph of the original biopsy site was available. The referring HCP was called to the bedside to assist in identifying the biopsy site but also was unable to clearly identify the site. This was explained to the patient. As 2-person confirmation was unsuccessful, conservative treatment was used with patient consent. The patient has since had subsequent close follow-up to monitor for recurrence, as SCC in transplant patients can display aggressive growth and potential for metastasis.

Case 3 Presentation

A veteran was referred for surgical excision of a nonmelanoma skin cancer. The biopsy was completed well in advance of the anticipated surgery day. On the day of surgery, the site could not be detected as it healed well after the biopsy. Although a clinical photograph was available, it was taken too close-up to find a frame of reference for identifying the location of the biopsy site. The referring HCP was called to the bedside to assist in identification of the biopsy site, but 2-person confirmation was unsuccessful. This was explained to the patient, and with his consent, the HCPs agreed on conservative treatment and close follow-up.

Discussion

To prevent and minimize poor outcomes associated with WSS, the health care team should routinely document the lesion location in detail before the biopsy. Many HCPs believe a preoperative photograph is the best method for documentation. As demonstrated in the third case presentation, photographs must be taken at a distance that includes nearby anatomic landmarks for reference. It is suggested that the providers obtain 2 images, one that is far enough to include landmarks, and one that is close enough to clearly differentiate the targeted lesion from others.¹⁰

Although high-resolution digital cameras are preferred, mobile phones also can be used if they provide quality images. As phones with built-in cameras are ubiquitous, they offer a quick and easy method of photographic documentation. St John and colleagues also presented the possibility of having patients keep pictures of the lesion on their phones, as this removes potential privacy concerns and facilitates easy transportation of information between HCPs.¹⁰ If it is discovered that a photograph was not taken at the time of biopsy, our practice contacts the patient and asks them to photograph and circle the biopsy site using their mobile phone or camera and bring it to the surgery appointment. We propose a VA protocol for photographic documentation of biopsy sites (Table).

Conclusions

The cases described here highlight how the lack of proper photographic documentation can prevent the use of curative surgical treatment. In order to reduce WSS and improve quality care, HCPs must continue to take steps and create safeguards to minimize risk. Proper documentation of lesions prior to biopsy provides an effective route to reduce incidence of WSS. If the biopsy site cannot be found, various strategies to properly identify the site can be employed. If WSS occurs, it is important that HCPs provide full disclosure to patients. With a growing emphasis on patient safety measures and advances in technology, HCPs are becoming increasingly cognizant about the most effective ways to optimize patient care, and it is anticipated that this will result in a decrease in morbidity and mortality.

Preventable errors by health care workers are widespread and cause significant morbidity and mortality. Wrong site surgery (WSS) is a preventable error that causes harm through both the direct insult of surgery and propagation of the untreated initial problem. WSS also can cause poor patient outcomes, low morale, malpractice claims, and increased costs to the health care system. The estimated median prevalence of WSS across all specialties is 9 events per 1,000,000 surgical procedures, and an institutional study of 112,500 surgical procedures reported 1 wrong-site event, which involved removing the incorrect skin lesion and not removing the intended lesion.^1,2

Though the prevalence is low when examining all specialties together, dermatology is also susceptible to WSS.³ Watson and colleagues demonstrated that 31% of intervention errors were due to WSS and suggested that prebiopsy photography helps decrease errors.⁴ Thus, the American Academy of Dermatology has emphasized the importance of reducing WSS.⁵ A study by Nijhawan and colleagues found that 25% of patients receiving Mohs surgery at a private single cancer center could not identify their biopsy location because the duration between biopsy and surgery allowed biopsy sites to heal well, which made finding the lesion difficult.⁶

Risk factors for WSS include having multiple health care providers (HCPs) living remote from the surgery location involved in the case, being a traveling veteran, receiving care at multiple facilities inside and outside the US Department of Veterans Affairs (VA) system, mislabeling photographs or specimens, and photographs not taken at time of biopsy and too close with no frame of reference to assist in finding the correct site. The VA electronic health record (EHR) is not integrated with outside facility EHRs, and the Office of Community Care (OCC) at the VA is responsible for obtaining copies of outside records. If unsuccessful, the HCP and/or patient must provide the records. Frequently, records are not received or require multiple attempts to be obtained. This mostly affects veterans receiving care at multiple facilities inside and outside the VA system as the lack of or timely receipt of past health records could increase the risk for WSS.

To combat WSS, some institutions have implemented standardized protocols requiring photographic documentation of lesions before biopsy so that the surgeon can properly identify the correct site prior to operating.⁷ Fortunately, recent advances in technology have made it easier to provide photographic documentation of skin lesions. Highsmith and colleagues highlighted use of smartphones to avoid WSS in dermatology.⁷ Despite these advances, photographic documentation of lesions is not universal. A study by Rossy and colleagues found that less than half of patients referred for Mohs surgery had clear documentation of the biopsy site with photography, diagram, or measurements, and of those documented, only a small fraction used photographs.⁸

Photographic documentation is not currently required by the VA, increasing the risk of WSS. About 20% of the ~150 VA dermatology departments nationwide are associated with a dermatology residency program and have implemented photographic documentation of lesions before biopsy. The other 80% of departments may not be using photographic documentation. The following 3 cases experienced by the authors highlight instances of how quality photographic documentation of lesions prior to biopsy can improve patient care and save lives. Then, we propose a photographic documentation protocol for VA dermatology departments to follow based on the photographic standards outlined by the American Society for Dermatologic Surgery.⁹

Case 1 Presentation

A 36-year-old traveling veteran who relocates frequently and receives care at multiple VA medical centers (VAMCs) presented for excision of a melanoma. The patient had been managed at another VAMC where the lesion was biopsied in September 2016. He presented to the Orlando, Florida, VAMC dermatology clinic 5 months later with the photographs of his biopsy sites along with the biopsy reports. The patient had 6 biopsies labeled A through F. Lesion A at the right mid back was positive for melanoma (Figure 1), whereas lesion C on the mid lower back was not cancerous (Figure 2). On examination of the patient’s back, he had numerous moles and scars. The initial receiving HCP circled and photographed the scar presumed to be the melanoma on the mid lower back (Figure 3).

On the day of surgery, the surgeon routinely checked the biopsy report as well as the photograph from the patient’s most recent HCP visit. The surgeon noted that biopsy A (right mid back) on the pathology report had been identified as the melanoma; however, biopsy C (mid lower back) was circled and presumed to be the melanoma in the recent photograph by the receiving HCP—a nurse practitioner. The surgeon compared the initial photos from the referring VAMC with those from the receiving HCP and subsequently matched biopsy A (melanoma) with the correct location on the right mid back.

This discrepancy was explained to the patient with photographic confirmation, allowing for agreement on the correct site before the surgery. The pathology results of the surgical excision confirmed melanoma in the specimen and clear margins. Thus, the correct site was operated on.

Case 2 Presentation

A veteran aged 86 years with a medical history of a double transplant and long-term immunosuppression leading to numerous skin cancers was referred for surgical excision of a confirmed squamous cell carcinoma (SCC) on the left upper back. On the day of surgery, the biopsy site could not be identified clearly due to numerous preexisting scars (Figure 4). No photograph of the original biopsy site was available. The referring HCP was called to the bedside to assist in identifying the biopsy site but also was unable to clearly identify the site. This was explained to the patient. As 2-person confirmation was unsuccessful, conservative treatment was used with patient consent. The patient has since had subsequent close follow-up to monitor for recurrence, as SCC in transplant patients can display aggressive growth and potential for metastasis.

Case 3 Presentation

A veteran was referred for surgical excision of a nonmelanoma skin cancer. The biopsy was completed well in advance of the anticipated surgery day. On the day of surgery, the site could not be detected as it healed well after the biopsy. Although a clinical photograph was available, it was taken too close-up to find a frame of reference for identifying the location of the biopsy site. The referring HCP was called to the bedside to assist in identification of the biopsy site, but 2-person confirmation was unsuccessful. This was explained to the patient, and with his consent, the HCPs agreed on conservative treatment and close follow-up.

Discussion

To prevent and minimize poor outcomes associated with WSS, the health care team should routinely document the lesion location in detail before the biopsy. Many HCPs believe a preoperative photograph is the best method for documentation. As demonstrated in the third case presentation, photographs must be taken at a distance that includes nearby anatomic landmarks for reference. It is suggested that the providers obtain 2 images, one that is far enough to include landmarks, and one that is close enough to clearly differentiate the targeted lesion from others.¹⁰

Although high-resolution digital cameras are preferred, mobile phones also can be used if they provide quality images. As phones with built-in cameras are ubiquitous, they offer a quick and easy method of photographic documentation. St John and colleagues also presented the possibility of having patients keep pictures of the lesion on their phones, as this removes potential privacy concerns and facilitates easy transportation of information between HCPs.¹⁰ If it is discovered that a photograph was not taken at the time of biopsy, our practice contacts the patient and asks them to photograph and circle the biopsy site using their mobile phone or camera and bring it to the surgery appointment. We propose a VA protocol for photographic documentation of biopsy sites (Table).

Conclusions

The cases described here highlight how the lack of proper photographic documentation can prevent the use of curative surgical treatment. In order to reduce WSS and improve quality care, HCPs must continue to take steps and create safeguards to minimize risk. Proper documentation of lesions prior to biopsy provides an effective route to reduce incidence of WSS. If the biopsy site cannot be found, various strategies to properly identify the site can be employed. If WSS occurs, it is important that HCPs provide full disclosure to patients. With a growing emphasis on patient safety measures and advances in technology, HCPs are becoming increasingly cognizant about the most effective ways to optimize patient care, and it is anticipated that this will result in a decrease in morbidity and mortality.

Preventable errors by health care workers are widespread and cause significant morbidity and mortality. Wrong site surgery (WSS) is a preventable error that causes harm through both the direct insult of surgery and propagation of the untreated initial problem. WSS also can cause poor patient outcomes, low morale, malpractice claims, and increased costs to the health care system. The estimated median prevalence of WSS across all specialties is 9 events per 1,000,000 surgical procedures, and an institutional study of 112,500 surgical procedures reported 1 wrong-site event, which involved removing the incorrect skin lesion and not removing the intended lesion.^1,2

Though the prevalence is low when examining all specialties together, dermatology is also susceptible to WSS.³ Watson and colleagues demonstrated that 31% of intervention errors were due to WSS and suggested that prebiopsy photography helps decrease errors.⁴ Thus, the American Academy of Dermatology has emphasized the importance of reducing WSS.⁵ A study by Nijhawan and colleagues found that 25% of patients receiving Mohs surgery at a private single cancer center could not identify their biopsy location because the duration between biopsy and surgery allowed biopsy sites to heal well, which made finding the lesion difficult.⁶

Risk factors for WSS include having multiple health care providers (HCPs) living remote from the surgery location involved in the case, being a traveling veteran, receiving care at multiple facilities inside and outside the US Department of Veterans Affairs (VA) system, mislabeling photographs or specimens, and photographs not taken at time of biopsy and too close with no frame of reference to assist in finding the correct site. The VA electronic health record (EHR) is not integrated with outside facility EHRs, and the Office of Community Care (OCC) at the VA is responsible for obtaining copies of outside records. If unsuccessful, the HCP and/or patient must provide the records. Frequently, records are not received or require multiple attempts to be obtained. This mostly affects veterans receiving care at multiple facilities inside and outside the VA system as the lack of or timely receipt of past health records could increase the risk for WSS.

To combat WSS, some institutions have implemented standardized protocols requiring photographic documentation of lesions before biopsy so that the surgeon can properly identify the correct site prior to operating.⁷ Fortunately, recent advances in technology have made it easier to provide photographic documentation of skin lesions. Highsmith and colleagues highlighted use of smartphones to avoid WSS in dermatology.⁷ Despite these advances, photographic documentation of lesions is not universal. A study by Rossy and colleagues found that less than half of patients referred for Mohs surgery had clear documentation of the biopsy site with photography, diagram, or measurements, and of those documented, only a small fraction used photographs.⁸

Photographic documentation is not currently required by the VA, increasing the risk of WSS. About 20% of the ~150 VA dermatology departments nationwide are associated with a dermatology residency program and have implemented photographic documentation of lesions before biopsy. The other 80% of departments may not be using photographic documentation. The following 3 cases experienced by the authors highlight instances of how quality photographic documentation of lesions prior to biopsy can improve patient care and save lives. Then, we propose a photographic documentation protocol for VA dermatology departments to follow based on the photographic standards outlined by the American Society for Dermatologic Surgery.⁹

Case 1 Presentation

A 36-year-old traveling veteran who relocates frequently and receives care at multiple VA medical centers (VAMCs) presented for excision of a melanoma. The patient had been managed at another VAMC where the lesion was biopsied in September 2016. He presented to the Orlando, Florida, VAMC dermatology clinic 5 months later with the photographs of his biopsy sites along with the biopsy reports. The patient had 6 biopsies labeled A through F. Lesion A at the right mid back was positive for melanoma (Figure 1), whereas lesion C on the mid lower back was not cancerous (Figure 2). On examination of the patient’s back, he had numerous moles and scars. The initial receiving HCP circled and photographed the scar presumed to be the melanoma on the mid lower back (Figure 3).

On the day of surgery, the surgeon routinely checked the biopsy report as well as the photograph from the patient’s most recent HCP visit. The surgeon noted that biopsy A (right mid back) on the pathology report had been identified as the melanoma; however, biopsy C (mid lower back) was circled and presumed to be the melanoma in the recent photograph by the receiving HCP—a nurse practitioner. The surgeon compared the initial photos from the referring VAMC with those from the receiving HCP and subsequently matched biopsy A (melanoma) with the correct location on the right mid back.

This discrepancy was explained to the patient with photographic confirmation, allowing for agreement on the correct site before the surgery. The pathology results of the surgical excision confirmed melanoma in the specimen and clear margins. Thus, the correct site was operated on.

Case 2 Presentation

A veteran aged 86 years with a medical history of a double transplant and long-term immunosuppression leading to numerous skin cancers was referred for surgical excision of a confirmed squamous cell carcinoma (SCC) on the left upper back. On the day of surgery, the biopsy site could not be identified clearly due to numerous preexisting scars (Figure 4). No photograph of the original biopsy site was available. The referring HCP was called to the bedside to assist in identifying the biopsy site but also was unable to clearly identify the site. This was explained to the patient. As 2-person confirmation was unsuccessful, conservative treatment was used with patient consent. The patient has since had subsequent close follow-up to monitor for recurrence, as SCC in transplant patients can display aggressive growth and potential for metastasis.

Case 3 Presentation

A veteran was referred for surgical excision of a nonmelanoma skin cancer. The biopsy was completed well in advance of the anticipated surgery day. On the day of surgery, the site could not be detected as it healed well after the biopsy. Although a clinical photograph was available, it was taken too close-up to find a frame of reference for identifying the location of the biopsy site. The referring HCP was called to the bedside to assist in identification of the biopsy site, but 2-person confirmation was unsuccessful. This was explained to the patient, and with his consent, the HCPs agreed on conservative treatment and close follow-up.

Discussion

To prevent and minimize poor outcomes associated with WSS, the health care team should routinely document the lesion location in detail before the biopsy. Many HCPs believe a preoperative photograph is the best method for documentation. As demonstrated in the third case presentation, photographs must be taken at a distance that includes nearby anatomic landmarks for reference. It is suggested that the providers obtain 2 images, one that is far enough to include landmarks, and one that is close enough to clearly differentiate the targeted lesion from others.¹⁰

Although high-resolution digital cameras are preferred, mobile phones also can be used if they provide quality images. As phones with built-in cameras are ubiquitous, they offer a quick and easy method of photographic documentation. St John and colleagues also presented the possibility of having patients keep pictures of the lesion on their phones, as this removes potential privacy concerns and facilitates easy transportation of information between HCPs.¹⁰ If it is discovered that a photograph was not taken at the time of biopsy, our practice contacts the patient and asks them to photograph and circle the biopsy site using their mobile phone or camera and bring it to the surgery appointment. We propose a VA protocol for photographic documentation of biopsy sites (Table).

Conclusions

The cases described here highlight how the lack of proper photographic documentation can prevent the use of curative surgical treatment. In order to reduce WSS and improve quality care, HCPs must continue to take steps and create safeguards to minimize risk. Proper documentation of lesions prior to biopsy provides an effective route to reduce incidence of WSS. If the biopsy site cannot be found, various strategies to properly identify the site can be employed. If WSS occurs, it is important that HCPs provide full disclosure to patients. With a growing emphasis on patient safety measures and advances in technology, HCPs are becoming increasingly cognizant about the most effective ways to optimize patient care, and it is anticipated that this will result in a decrease in morbidity and mortality.

Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.¹ While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.² Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.³ With a rapidly growing older population, there will be increasing demand for cancer care.

Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.⁴ Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.⁵

Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.

What Is Geriatric Assessment? 

Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.⁶ CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.⁷ Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.⁶ In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.

Components of CGA 

Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.⁸

Comorbidity

The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.⁹ Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.¹⁰ In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.¹¹ Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.¹²

The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.¹³ It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.¹⁴ The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.¹⁵

Polypharmacy

Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”¹⁶ The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.¹⁷

Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.¹⁸ While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.¹⁸

Functional Status

Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.¹⁹ IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.¹¹

Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.²⁰ Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.¹² Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.²¹ Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.¹¹ Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.

Cognition

Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.¹¹

Psychological and Social Status

A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.²² In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.²³ All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.²⁴ A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.

Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.²³ Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.

Nutrition

Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.²⁵ The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.¹¹ This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.

Effectiveness of CGA

Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.²⁶ Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).²⁷

In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.²⁸ A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.²⁹ Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.

Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).^30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.

Geriatric Assessment Screening Tools

A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.³² The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.¹² The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.³³

Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.³⁴ However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.

CARG Chemotoxicity Calculator

Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.³⁵ They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.¹² This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).³¹

Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.³¹ An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.

CRASH Score

The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.³⁰ A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).³⁰

Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.¹² Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.³⁰ Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.

Conclusions 

In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.³⁶ Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.³⁵ Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.^37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.⁵ In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.³⁹

Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.

Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.

Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.¹ While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.² Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.³ With a rapidly growing older population, there will be increasing demand for cancer care.

Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.⁴ Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.⁵

Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.

What Is Geriatric Assessment? 

Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.⁶ CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.⁷ Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.⁶ In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.

Components of CGA 

Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.⁸

Comorbidity

The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.⁹ Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.¹⁰ In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.¹¹ Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.¹²

The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.¹³ It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.¹⁴ The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.¹⁵

Polypharmacy

Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”¹⁶ The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.¹⁷

Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.¹⁸ While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.¹⁸

Functional Status

Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.¹⁹ IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.¹¹

Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.²⁰ Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.¹² Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.²¹ Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.¹¹ Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.

Cognition

Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.¹¹

Psychological and Social Status

A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.²² In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.²³ All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.²⁴ A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.

Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.²³ Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.

Nutrition

Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.²⁵ The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.¹¹ This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.

Effectiveness of CGA

Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.²⁶ Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).²⁷

In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.²⁸ A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.²⁹ Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.

Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).^30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.

Geriatric Assessment Screening Tools

A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.³² The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.¹² The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.³³

Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.³⁴ However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.

CARG Chemotoxicity Calculator

Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.³⁵ They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.¹² This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).³¹

Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.³¹ An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.

CRASH Score

The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.³⁰ A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).³⁰

Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.¹² Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.³⁰ Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.

Conclusions 

In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.³⁶ Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.³⁵ Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.^37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.⁵ In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.³⁹

Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.

Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.

Age is a well recognized risk factor for cancer development. The population of older Americans is growing, and by 2030, 20% of the US population will be aged ≥ 65 years.¹ While 25% of all new cancer cases are diagnosed in people aged 65 to 74 years, more than half of cancers occur in individuals aged ≥ 70 years, with even higher rates in those aged ≥ 75 years.² Although cancer rates have declined slightly overall among people aged ≥ 65 years, this population still has an 11-fold increased incidence of cancer compared with that of younger individuals.³ With a rapidly growing older population, there will be increasing demand for cancer care.

Treatment of cancer in older individuals often is complicated by medical comorbidities, frailty, and poor functional status. Distinguishing patients who can tolerate aggressive therapy from those who require less intensive therapy can be challenging. Age-related physiologic changes predispose older adults to an increased risk of therapy-related toxicities, resulting in suboptimal therapeutic benefit and substantial morbidity. For example, cardiovascular changes can lead to reduction of the cardiac functional reserve, which can increase the risk of congestive heart failure. Similarly, decline in renal function leads to an increased potential for nephrotoxicity.⁴ Although patients may be of the same chronologic age, their performance, functional, and biologic status may be quite variable; thus, tolerance to aggressive treatment is not easily predicted. The comprehensive geriatric assessment (CGA) may be used as a global assessment tool to risk stratify older patients prior to oncologic treatment decisions.⁵

Health care providers (HCPs), including physician assistants, nurse practitioners, clinical nurse specialists, nurses, and physicians, routinely participate in every aspect of cancer care by ordering and interpreting diagnostic tests, addressing comorbidities, managing symptoms, and discussing cancer treatment recommendations. HCPs in oncology will continue to play a vital role in the coordination and management of older patients with cancer. However, in general, CGA has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools.

What Is Geriatric Assessment? 

Geriatric assessment is a multidisciplinary, multidimensional process aimed at detecting medical, psychosocial, and functional issues of older adults that are not identified by traditional performance status measures alone. It provides guidance for management of identified problems and improvement in quality of life.⁶ CGA was developed by geriatricians and multidisciplinary care teams to evaluate the domains of functional, nutritional, cognitive, psychosocial, and economic status; comorbidities; geriatric syndromes; and mood, and it has been tested in both clinics and hospitals.⁷ Although such assessment requires additional time and resources, its goals are to identify areas of vulnerability, assist in clinical decisions of treatable health problems, and guide therapeutic interventions.⁶ In oncology practice, the assessment not only addresses these global issues, but also is critical in predicting toxicity and survival outcomes in older oncology patients.

Components of CGA 

Advancing age brings many physiologic, psychosocial, and functional challenges, and a cancer diagnosis only adds to these issues. CGA provides a system of assessing older and/or frail patients with cancer through specific domains to identify issues that are not apparent on routine evaluation in a clinic setting before and during chemotherapy treatments. These domains include comorbidity, polypharmacy, functional status, cognition, psychological and social status, and nutrition.⁸

Comorbidity

The prevalence of multiple medical problems and comorbidities, including cancer, among people aged > 65 years is increasing.⁹ Studies have shown that two-thirds of patients with cancer had ≥ 2 medical conditions, and nearly one quarter had ≥ 4 medical conditions.¹⁰ In older adults, common comorbidities include cardiovascular disease, hypertension, diabetes mellitus, and dementia. These comorbidities can impact treatment decisions, increase the risk of disease, impact treatment-related complications, and affect a patient’s life expectancy.¹¹ Assessing comorbidities is essential to CGA and is done using the Charlson Comorbidity Index and/or the Cumulative Illness Rating Scale.¹²

The Charlson Comorbidity Index was originally designed to predict 1-year mortality on the basis of a weighted composite score for the following categories: cardiovascular, endocrine, pulmonary, neurologic, renal, hepatic, gastrointestinal, and neoplastic disease.¹³ It is now the most widely used comorbidity index and has been adapted and verified as applicable and valid for predicting the outcomes and risk of death from many comorbid diseases.¹⁴ The Cumulative Illness Rating Scale has been validated as a predictor for readmission for hospitalized older adults, hospitalization within 1 year in a residential setting, and long-term mortality when assessed in inpatient and residential settings.¹⁵

Polypharmacy

Polypharmacy (use of ≥ 5 medications) is common in older patients regardless of cancer diagnosis and is often instead defined as “the use of multiple drugs or more than are medically necessary.”¹⁶ The use of multiple medications, including those not indicated for existing medical conditions (such as over‐the‐counter, herbal, and complementary/alternative medicines, which patients often fail to declare to their specialist, doctor, or pharmacist) adds to the potential negative aspects of polypharmacy that affect older patients.¹⁷

Patients with cancer usually are prescribed an extensive number of medicines, both for the disease and for supportive care, which can increase the chance of drug-drug interactions and adverse reactions.¹⁸ While these issues certainly affect quality of life, they also may influence chemotherapy treatment and potentially impact survival. Studies have shown that the presence of polypharmacy has been associated with higher numbers of comorbidities, increased use of inappropriate medications, poor performance status, decline in functional status, and poor survival.¹⁸

Functional Status

Although Eastern Cooperative Oncology Group (ECOG) performance status and Karnofsky Performance Status are commonly used by oncologists, these guidelines are limited in focus and do not reliably measure functional status in older patients. Functional status is determined by the ability to perform daily acts of self-care, which includes assessment of activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs refer to such tasks as bathing, dressing, eating, mobility, balance, and toileting.¹⁹ IADLs include the ability to perform activities required to live within a community and include shopping, transportation, managing finances, medication management, cooking, and cleaning.¹¹

Physical functionality also can be assessed by measures such as gait speed, grip strength, balance, and lower extremity strength. These are more sensitive and shown to be associated with worse clinical outcomes.²⁰ Grip strength and gait speed, as assessed by the Timed Up and Go test or the Short Physical Performance Battery measure strength and balance.¹² Reduction in gait speed and/or grip strength are associated with adverse clinical outcomes and increased risk of mortality.²¹ Patients with cancer who have difficulty with ADLs are at increased risk for falls, which can limit their functional independence, compromise cancer therapy, and increase the risk of chemotherapy toxicities.¹¹ Impaired hearing and poor vision are added factors that can be barriers to cancer treatment.

Cognition

Cognitive impairment in patients with cancer is becoming more of an issue for oncology HCPs as both cancer and cognitive decline are more common with advancing age. Cognition in cancer patients is important for understanding their diagnosis, prognosis, treatment options, and adherence. Impaired cognition can affect decision making regarding treatment options and administration. Cognition can be assessed through validated screening tools such as the Mini-Mental State Examination and Mini-Cog.¹¹

Psychological and Social Status

A cancer diagnosis has a major impact on the mental and emotional state of patients and family members. Clinically significant anxiety has been reported in approximately 21% of older patients with cancer, and the incidence of depression ranges from 17 to 26%.²² In older patients with, psychologic distress can impact cancer treatment, resulting in less definitive therapy and poorer outcomes.²³ All patients with cancer should be screened for psychologic distress using standardized methods, such as the Geriatric Depression Scale or the General Anxiety Disorder-7 scale.²⁴ A positive screen should lead to additional assessments that evaluate the severity of depression and other comorbid psychological problems and medical conditions.

Social isolation and loneliness are factors that can affect both depression and anxiety. Older patients with cancer are at risk for decreased social activities and are already challenged with issues related to home care, comorbidities, functional status, and caregiver support.²³ Therefore, it is important to assess the social interactions of an older and/or frail patient with cancer and use social work assistance to address needs for supportive services.

Nutrition

Nutrition is important in any patient with cancer undergoing chemotherapy treatment. However, it is of greater importance in older adults, as malnutrition and weight loss are negative prognostic factors that correlate with poor tolerance to chemotherapy treatment, decline in quality of life, and increased mortality.²⁵ The Mini-Nutritional Assessment is a widely used validated tool to assess nutritional status and risk of malnutrition.¹¹ This tool can help identify those older and/or frail patients with cancer with impaired nutritional status and aid in instituting corrective measures to treat or prevent malnutrition.

Effectiveness of CGA

Multiple randomized controlled clinical trials assessing the effectiveness of CGA have been conducted over the past 3 decades with overall positive outcomes related to its value.²⁶ Benefits of CGA can include overall improved medical care, avoidance of hospitalization or nursing home placement, identification of cognitive impairment, and prevention of geriatric syndrome (a range of conditions representing multiple organ impairment in older adults).²⁷

In oncology, CGA is particularly beneficial, as it can identify issues in nearly 70% of patients that may not be apparent through traditional oncology assessment.²⁸ A systematic review of 36 studies assessing the prognostic value of CGA in elderly patients with cancer receiving chemotherapy concluded that impaired performance and functional status as well as a frail and vulnerable profile are important predictors of severe chemotherapy-related toxicity and are associated with a higher risk of mortality.²⁹ Therefore, CGA should be an integral part of the evaluation of older and/or frail patients with cancer prior to chemotherapy consideration.

Several screening tools have been developed using information from CGA to assess the risk of severe toxicities. The most commonly used tools for predicting toxicity include the Cancer and Aging Research Group (CARG) chemotoxicity calculator and the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH).^30,31 Although these tools are readily available to facilitate CGA, and despite their proven beneficial outcome and recommended usage by national guidelines, implementation of these tools in routine oncology practice has been challenging and slow to spread. Unless these recommended interventions are effectively implemented, the benefits of CGA cannot be realized. With the expected surge in the number of older patients with cancer, hopefully this will change.

Geriatric Assessment Screening Tools

A screening tool recommended for use in older and/or frail patients with cancer allows for a brief assessment to help clinicians identify patients in need of further evaluation by CGA and to provides information on treatment-related toxicities, functional decline, and survival.³² The predictive value and utility of geriatric assessment screening tools have been repeatedly proven to identify older and/or frail adults at risk for treatment-related toxicities.¹² The CARG and the CRASH are validated screening tools used in identifying patients at higher risk for chemotherapy toxicity. These screening tools are intended to provide guidance to the clinical oncology practitioner on risk stratification of chemotherapy toxicity in older patients with cancer.³³

Both of these screening tools provide similar predictive performance for chemotherapy toxicity in older patients with cancer.³⁴ However, the CARG tool seems to have the advantage of using more data that had already been obtained during regular office visits and is clear and easy to use clinically. The CRASH tool is slightly more involved, as it uses multiple geriatric instruments to determine the predictive risk of both hematologic and nonhematologic toxicities of chemotherapy.

CARG Chemotoxicity Calculator

Hurria and colleagues originally developed the CARG tool from data obtained through a prospective multicenter study involving 500 patients with cancer aged ≥ 65 years.³⁵ They concluded that chemotherapy-related toxicity is common in older adults, with 53% of patients sustaining grade 3 or 4 treatment-related toxicities and 2% treatment-related mortality.¹² This predictive model for chemotherapy-related toxicity used 11 variables, both objective (obtained during a regular clinical encounter: age, tumor type, chemotherapy dosing, number of drugs, creatinine, and hemoglobin) and subjective (completed by patient: number of falls, social support, the ability to take medications, hearing impairment, and physical performance), to determine at-risk patients (Table 1).³¹

Compared with standard performance status measures in oncology practice, the CARG model was better able to predict chemotherapy-related toxicities. In 2016, Hurria and colleagues published the results of an updated external validation study with a cohort of 250 older patients with cancer receiving chemotherapy that confirmed the prediction of chemotherapy toxicity using the CARG screening tool in this population.³¹ An appealing feature of this tool is the free online accessibility and the expedited manner in which screening can be conducted.

CRASH Score

The CRASH score was derived from the results of a prospective, multicenter study of 518 patients aged ≥ 70 years who were assessed on 24 parameters prior to starting chemotherapy.³⁰ A total of 64% of patients experienced significant toxicities, including 32% with grade 4 hematologic toxicity and 56% with grade 3 or 4 nonhematologic toxicity. The hematologic and nonhematologic toxicity risks are the 2 categories that comprise the CRASH score. Both baseline patient variables and chemotherapy regimen are incorporated into an 8-item assessment profile that determines the risk categories (Table 2).³⁰

Increased risk of hematologic toxicities was associated with increased diastolic blood pressure, increased lactate dehydrogenase, need for assistance with IADL, and increased toxicity potential of the chemotherapy regimen. Nonhematologic toxicities were associated with ECOG performance score, Mini Mental Status Examination and Mini-Nutritional Assessment, and increased toxicity of the chemotherapy regimen.¹² Patient scores are stratified into 4 risk categories: low, medium-low, medium-high, and high.³⁰ Like the CARG tool, the CRASH screening tool also is available as a free online resource and can be used in everyday clinical practice to assess older and/or frail adults with cancer.

Conclusions 

In older adults, cancer may significantly impact the natural course of concurrent comorbidities due to physiologic and functional changes. These vulnerabilities predispose older patients with cancer to an increased risk of adverse outcomes, including treatment-related toxicities.³⁶ Given the rapidly aging population, it is critical for oncology clinical teams to be prepared to assess for, prevent, and manage issues for older adults that could impact outcomes, including complications and toxicities from chemotherapy.³⁵ Studies have reported that 78 to 93% of older oncology patients have at least 1 geriatric impairment that could potentially impact oncology treatment plans.^37,38 This supports the utility of CGA as a global assessment tool to risk stratify older and/or frail patients prior to deciding on subsequent oncologic treatment approaches.⁵ In fact, major cooperative groups sponsored by the National Cancer Institute, such as the Alliance for Clinical Trials in Oncology, are including CGA as part of some of their treatment trials. CGA was conducted as part of a multicenter cooperative group study in older patients with acute myeloid leukemia prior to inpatient intensive induction chemotherapy and was determined to be feasible and useful in clinical trials and practice.³⁹

Despite the increasing evidence for benefits of CGA, it has not been a consistent part of oncology practices, and few HCPs are familiar with the benefits of CGA screening tools. Although oncology providers routinely participate in every aspect of cancer care and play a vital role in the coordination and management of older patients with cancer, CGA implementation into routine clinical practice has been slow in part due to lack of knowledge and training regarding the use of GA tools.

Oncology providers can easily incorporate CGA screening tools into the history and physical examination process for older patients with cancer, which will add an important dimension to these patient evaluations. Oncology providers are not only well positioned to administer these screening tools, but also can lead the field in developing innovative ways for effective implementation in busy routine oncology clinics. However, to be successful, oncology providers must be knowledgeable about these tools and understand their utility in guiding treatment decisions and improving quality of care in older patients with cancer.

The composition of street drugs like heroin and cocaine are changing. According to a new analysis, almost all contain at least one toxic adulterant, and many contain a plethora. Most adulterants have pharmacologic activities and toxicities. Their presence has added impact in the context of the COVID-19 pandemic, since some may cause a drastic drop in white blood cells that could leave drug users more vulnerable to infection.

“It’s remarkable that we just forgot to notice, in the horrendous transition from prescription opioid epidemic to the illicit opioid and psychostimulant epidemics, that we would have to pay special attention to what the medications are in the drugs that the person was exposed to – and for how long,” said Mark S. Gold, MD, a coauthor of the review.

The analysis showed that adulterants include new psychoactive substances, industrial compounds, fungicides, veterinary medications, and various impurities. In addition, other various medications are being found in street drugs, such as antipsychotics, antidepressants, anxiolytics, antihistamines, anthelmintics, anesthetics, anti-inflammatory agents, antipyretics, analgesics, antispasmodics, antiarrhythmics, antimalarials, bronchodilators, decongestants, expectorants, muscle relaxers, natural/synthetic hallucinogens, and sedatives.

Illicit drugs are by nature manufactured without Food and Drug Administration oversight, and it is becoming increasingly common that substances like leftover medicines and other active drugs are added to illicit drug batches to add weight, said Dr. Gold, a professor at Washington University,St. Louis. The study appeared in Current Psychopharmacology.
 

Effects of adulterants ‘terrifying’

The findings of adulterants and their consequences are concerning, according to Jean Lud Cadet, MD, who was asked to comment on the findings. “The blood dysplasia, the pulmonary problems that some of those adulterants can cause – it’s actually terrifying, to put it bluntly,” said Dr. Cadet, who is a senior investigator and chief of the Molecular Neuropsychiatry Research Branch at the National Institute on Drug Abuse.

Before 2000, street drugs were generally diluted with comparatively benign substances such as caffeine, sugars, or lidocaine. Drugs like phenacetin, levamisole, acetaminophen, and diltiazem began to appear in heroin and cocaine in the late 1990s, and by 2010, more powerful adulterants like fentanyl, ketamine, and quetiapine became common. Adulterants can lead to a range of clinical effects, including renal and liver problems, blood disorders, infections, respiratory depression, and cardiac arrest.

In 2015, the U.S. Department of State partnered with the Colombo Plan, an international organization based in Sri Lanka, to use field spectroscopy to detect toxins directly in cocaine and heroin samples found in Argentina, Brazil, Ecuador, Peru, Sri Lanka, Thailand, Honduras, Guatemala, Mexico, Colombia, and South Africa. They found a range of adulterants such as aminopyrine, diltiazem, metamizole, levamisole, and phenacetin.

A similar project with 431 heroin and cocaine samples from Vermont and Kentucky found that 69% of samples had five or more controlled drugs, toxic adulterants, or impurities. About 15% had nine or more, and 95% of samples had at least one toxic adulterant.

In the midst of the COVID-19 pandemic, these adulterants take on even greater significance. Individuals with substance use disorders often have other health conditions that can make them more vulnerable to viral infections, and this could be exacerbated by the effects of adulterants on white blood cells or other systems. The pandemic has also had an indirect effect by causing a shortage of street drugs. During production shortages, traffickers might boost potency by adding more cutting agents and adulterants. As a result, COVID-19 and opioid addiction tend to reinforce each other.

“The clinical message would be that our [substance use] patients will contract infectious disease and need to be prioritized for [COVID-19] vaccination,” said Dr. Gold.

The findings came as a surprise to Dr. Cadet, and that illustrates a need to publicize the presence of adulterants in street drugs.

“If I wasn’t aware of many of these, then the general public is also not going to be aware of them,” Dr. Cadet said. “Scientists, including myself, and government agencies need to do a better job [of communicating this issue].”

The study references individuals with substance use disorder, but Dr. Cadet cautioned that anyone who uses street drugs, even once or twice, could be a victim of adulterants. “You don’t need to have met criteria for diagnosis in order to suffer the consequences.”

The study had no funding. Dr. Gold and Dr. Cadet have no relevant financial disclosures.

The composition of street drugs like heroin and cocaine are changing. According to a new analysis, almost all contain at least one toxic adulterant, and many contain a plethora. Most adulterants have pharmacologic activities and toxicities. Their presence has added impact in the context of the COVID-19 pandemic, since some may cause a drastic drop in white blood cells that could leave drug users more vulnerable to infection.

“It’s remarkable that we just forgot to notice, in the horrendous transition from prescription opioid epidemic to the illicit opioid and psychostimulant epidemics, that we would have to pay special attention to what the medications are in the drugs that the person was exposed to – and for how long,” said Mark S. Gold, MD, a coauthor of the review.

The analysis showed that adulterants include new psychoactive substances, industrial compounds, fungicides, veterinary medications, and various impurities. In addition, other various medications are being found in street drugs, such as antipsychotics, antidepressants, anxiolytics, antihistamines, anthelmintics, anesthetics, anti-inflammatory agents, antipyretics, analgesics, antispasmodics, antiarrhythmics, antimalarials, bronchodilators, decongestants, expectorants, muscle relaxers, natural/synthetic hallucinogens, and sedatives.

Illicit drugs are by nature manufactured without Food and Drug Administration oversight, and it is becoming increasingly common that substances like leftover medicines and other active drugs are added to illicit drug batches to add weight, said Dr. Gold, a professor at Washington University,St. Louis. The study appeared in Current Psychopharmacology.
 

Effects of adulterants ‘terrifying’

The findings of adulterants and their consequences are concerning, according to Jean Lud Cadet, MD, who was asked to comment on the findings. “The blood dysplasia, the pulmonary problems that some of those adulterants can cause – it’s actually terrifying, to put it bluntly,” said Dr. Cadet, who is a senior investigator and chief of the Molecular Neuropsychiatry Research Branch at the National Institute on Drug Abuse.

Before 2000, street drugs were generally diluted with comparatively benign substances such as caffeine, sugars, or lidocaine. Drugs like phenacetin, levamisole, acetaminophen, and diltiazem began to appear in heroin and cocaine in the late 1990s, and by 2010, more powerful adulterants like fentanyl, ketamine, and quetiapine became common. Adulterants can lead to a range of clinical effects, including renal and liver problems, blood disorders, infections, respiratory depression, and cardiac arrest.

In 2015, the U.S. Department of State partnered with the Colombo Plan, an international organization based in Sri Lanka, to use field spectroscopy to detect toxins directly in cocaine and heroin samples found in Argentina, Brazil, Ecuador, Peru, Sri Lanka, Thailand, Honduras, Guatemala, Mexico, Colombia, and South Africa. They found a range of adulterants such as aminopyrine, diltiazem, metamizole, levamisole, and phenacetin.

A similar project with 431 heroin and cocaine samples from Vermont and Kentucky found that 69% of samples had five or more controlled drugs, toxic adulterants, or impurities. About 15% had nine or more, and 95% of samples had at least one toxic adulterant.

In the midst of the COVID-19 pandemic, these adulterants take on even greater significance. Individuals with substance use disorders often have other health conditions that can make them more vulnerable to viral infections, and this could be exacerbated by the effects of adulterants on white blood cells or other systems. The pandemic has also had an indirect effect by causing a shortage of street drugs. During production shortages, traffickers might boost potency by adding more cutting agents and adulterants. As a result, COVID-19 and opioid addiction tend to reinforce each other.

“The clinical message would be that our [substance use] patients will contract infectious disease and need to be prioritized for [COVID-19] vaccination,” said Dr. Gold.

The findings came as a surprise to Dr. Cadet, and that illustrates a need to publicize the presence of adulterants in street drugs.

“If I wasn’t aware of many of these, then the general public is also not going to be aware of them,” Dr. Cadet said. “Scientists, including myself, and government agencies need to do a better job [of communicating this issue].”

The study references individuals with substance use disorder, but Dr. Cadet cautioned that anyone who uses street drugs, even once or twice, could be a victim of adulterants. “You don’t need to have met criteria for diagnosis in order to suffer the consequences.”

The study had no funding. Dr. Gold and Dr. Cadet have no relevant financial disclosures.

The composition of street drugs like heroin and cocaine are changing. According to a new analysis, almost all contain at least one toxic adulterant, and many contain a plethora. Most adulterants have pharmacologic activities and toxicities. Their presence has added impact in the context of the COVID-19 pandemic, since some may cause a drastic drop in white blood cells that could leave drug users more vulnerable to infection.

“It’s remarkable that we just forgot to notice, in the horrendous transition from prescription opioid epidemic to the illicit opioid and psychostimulant epidemics, that we would have to pay special attention to what the medications are in the drugs that the person was exposed to – and for how long,” said Mark S. Gold, MD, a coauthor of the review.

The analysis showed that adulterants include new psychoactive substances, industrial compounds, fungicides, veterinary medications, and various impurities. In addition, other various medications are being found in street drugs, such as antipsychotics, antidepressants, anxiolytics, antihistamines, anthelmintics, anesthetics, anti-inflammatory agents, antipyretics, analgesics, antispasmodics, antiarrhythmics, antimalarials, bronchodilators, decongestants, expectorants, muscle relaxers, natural/synthetic hallucinogens, and sedatives.

Illicit drugs are by nature manufactured without Food and Drug Administration oversight, and it is becoming increasingly common that substances like leftover medicines and other active drugs are added to illicit drug batches to add weight, said Dr. Gold, a professor at Washington University,St. Louis. The study appeared in Current Psychopharmacology.
 

Effects of adulterants ‘terrifying’

The findings of adulterants and their consequences are concerning, according to Jean Lud Cadet, MD, who was asked to comment on the findings. “The blood dysplasia, the pulmonary problems that some of those adulterants can cause – it’s actually terrifying, to put it bluntly,” said Dr. Cadet, who is a senior investigator and chief of the Molecular Neuropsychiatry Research Branch at the National Institute on Drug Abuse.

Before 2000, street drugs were generally diluted with comparatively benign substances such as caffeine, sugars, or lidocaine. Drugs like phenacetin, levamisole, acetaminophen, and diltiazem began to appear in heroin and cocaine in the late 1990s, and by 2010, more powerful adulterants like fentanyl, ketamine, and quetiapine became common. Adulterants can lead to a range of clinical effects, including renal and liver problems, blood disorders, infections, respiratory depression, and cardiac arrest.

In 2015, the U.S. Department of State partnered with the Colombo Plan, an international organization based in Sri Lanka, to use field spectroscopy to detect toxins directly in cocaine and heroin samples found in Argentina, Brazil, Ecuador, Peru, Sri Lanka, Thailand, Honduras, Guatemala, Mexico, Colombia, and South Africa. They found a range of adulterants such as aminopyrine, diltiazem, metamizole, levamisole, and phenacetin.

A similar project with 431 heroin and cocaine samples from Vermont and Kentucky found that 69% of samples had five or more controlled drugs, toxic adulterants, or impurities. About 15% had nine or more, and 95% of samples had at least one toxic adulterant.

In the midst of the COVID-19 pandemic, these adulterants take on even greater significance. Individuals with substance use disorders often have other health conditions that can make them more vulnerable to viral infections, and this could be exacerbated by the effects of adulterants on white blood cells or other systems. The pandemic has also had an indirect effect by causing a shortage of street drugs. During production shortages, traffickers might boost potency by adding more cutting agents and adulterants. As a result, COVID-19 and opioid addiction tend to reinforce each other.

“The clinical message would be that our [substance use] patients will contract infectious disease and need to be prioritized for [COVID-19] vaccination,” said Dr. Gold.

The findings came as a surprise to Dr. Cadet, and that illustrates a need to publicize the presence of adulterants in street drugs.

“If I wasn’t aware of many of these, then the general public is also not going to be aware of them,” Dr. Cadet said. “Scientists, including myself, and government agencies need to do a better job [of communicating this issue].”

The study references individuals with substance use disorder, but Dr. Cadet cautioned that anyone who uses street drugs, even once or twice, could be a victim of adulterants. “You don’t need to have met criteria for diagnosis in order to suffer the consequences.”

The study had no funding. Dr. Gold and Dr. Cadet have no relevant financial disclosures.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

Changing the continuous antibiotic prophylactic agent had no significant effect on the risk of a second infection in children with breakthrough urinary tract infections (UTIs), based on data from 62 children treated at a single center.

Continuous antibiotic prophylaxis (CAP) is often used for UTI prevention in children with febrile UTIs or anomalies that predispose them to UTIs, such as vesicoureteral reflux (VUR) or bladder and bowel dysfunction, said Lane M. Shish, MPH, of the University of Washington, Bothell, and colleagues in a poster (#1245) presented at the Pediatric Academic Societies annual meeting.

CAP, once initiated, is used until a planned endpoint or a breakthrough UTI, at which point alternative treatments usually include surgical intervention or a CAP agent change, the researchers said. However, changing the CAP agent is based on consensus without evidence of benefit, they noted.

To evaluate the potential effect of switching or maintaining CAP in cases of breakthrough UTIs, the researchers conducted a retrospective cohort study of all patients younger than 18 years on CAP for UTI prevention enrolled in a pediatric urology registry between January 2013 and August 2020.

All patients experienced a breakthrough UTI while on CAP; CAP was changed for 24 patients and left unchanged for 38 patients.

The primary outcome of second-breakthrough infections occurred in 12 of the changed CAP group and 22 of the unchanged group, with a relative risk of 0.86. The percentage of second breakthrough UTIs resistant to the current CAP was not significantly different between the changed and unchanged CAP groups (75% vs. 77%; P = 0.88).

The researchers also identified a rate ratio of 0.67 for a second breakthrough UTI in the changed CAP group, and found that approximately one-third of these patients (33.3%) developed antibiotic resistance to their initial antibiotic agent and the changed antibiotic agent.

The study findings were limited by several factors, including the retrospective design and small sample size, the researchers noted.

However, the results suggest that changing the CAP after an initial breakthrough UTI in children did not increase the risk of a second breakthrough UTI, and that CAP changing did introduce a risk of developing a second UTI with increased CAP resistance, the researchers noted. The results support leaving a child’s CAP unchanged after an initial breakthrough UTI, although additional research is needed to verify the findings, including studies involving a larger cohort with a multi-institutional prospective evaluation, they concluded.

Manage UTIs to reduce recurrence and resistance

“As we know, avoiding recurrent UTIs is important in preserving renal function in pediatric patients,” said Tim Joos, MD, a Seattle-based clinician with a combination internal medicine/pediatrics practice, in an interview.

“Avoiding recurrent UTIs is also important to avoid the development and spread of multidrug-resistant organisms,” he said.

Dr. Joos said he was surprised by some of the study findings. “I was surprised that, over the course of this 7-year retrospective review, overall only approximately 50% of patients with a first breakthrough UTI on CAP developed a second breakthrough UTI,” he noted. “Also, the relative risk of a second UTI was not significantly affected by whether the CAP antibiotic was changed after the first infection,” he said. “It would be interesting to see whether these results hold up in a randomized, prospective study,” he added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Joos had no financial conflicts to disclose, but serves as a member of the Pediatric News Editorial Advisory Board.

The U.S. Food and Drug Administration has cleared the Bigfoot Unity Diabetes Management System, a cap device that connects to insulin pens and translates continuous glucose data into dosing recommendations, for use in individuals aged 12 and older.

The Bigfoot Unity System has three primary components – proprietary smart pen caps for both rapid- and long-acting insulin, a mobile app, and an integrated FreeStyle Libre 2 continuous glucose monitor (iCGM) sensor, which was FDA-cleared in June 2020 – that fit into the person’s dose-decision process when they need it throughout the day.

It allows the user to scan the FreeStyle Libre 2 sensor, displaying the user’s current glucose value, trend arrow, and recommended correction dose. The smart pen cap also directly displays the health care provider’s suggested meal insulin doses with the correction dose. In just a few steps the system gives the person with diabetes support to make real-time treatment decisions.

It also includes hypoglycemia alerts and is compatible with all major U.S. brands of rapid- and long-acting disposable insulin pens.  

Health care providers can monitor the patient’s data through a secure web portal called the Bigfoot Clinic Hub.

JDRF said in a statement it “applauds the U.S. FDA on its decision to provide clearance for the Bigfoot Unity Diabetes Management by Bigfoot Biomedical.”

The new system “fills a critical gap and brings benefits of automation and device interconnectedness to people with diabetes who rely on multiple daily injections to manage their blood sugar levels.” It is a “win for both the type 1 and type 2 diabetes communities as it broadens the options of treatment to alleviate daily burdens.”
 

Growing market for smart insulin pens

The device is the latest advance in the “smart pen” field of semiautomated insulin delivery in which pen and compatible devices, software, and platforms are teamed up in various combinations to provide easier insulin dosing for patients with diabetes who require multiple daily injections but don’t wear insulin pumps.

On May 6, 2021, Eli Lilly announced it had signed “strategic international agreements” with Dexcom, Glooko, MyDiabby Healthcare, and Roche to provide platforms or devices compatible with Lilly’s prefilled Tempo Pen, which is already available in several global markets, and the Tempo Smart Button, currently in late-stage development and pending CE mark.  

And in November 2020, Medtronic launched a new version of its smart insulin pen with integrated CGM called the InPen. The reusable insulin injector pen uses a smartphone app to calculate dosing of short-acting insulin based on CGM readings and allows users to view glucose readings and insulin dose information. It was originally launched in 2017 by Companion Medical, and the company was acquired by Medtronic in September 2020.

Novo Nordisk and Sanofi are also developing products in the smart pen space.

More information about the Bigfoot Unity Program is available here.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has cleared the Bigfoot Unity Diabetes Management System, a cap device that connects to insulin pens and translates continuous glucose data into dosing recommendations, for use in individuals aged 12 and older.

The Bigfoot Unity System has three primary components – proprietary smart pen caps for both rapid- and long-acting insulin, a mobile app, and an integrated FreeStyle Libre 2 continuous glucose monitor (iCGM) sensor, which was FDA-cleared in June 2020 – that fit into the person’s dose-decision process when they need it throughout the day.

It allows the user to scan the FreeStyle Libre 2 sensor, displaying the user’s current glucose value, trend arrow, and recommended correction dose. The smart pen cap also directly displays the health care provider’s suggested meal insulin doses with the correction dose. In just a few steps the system gives the person with diabetes support to make real-time treatment decisions.

It also includes hypoglycemia alerts and is compatible with all major U.S. brands of rapid- and long-acting disposable insulin pens.  

Health care providers can monitor the patient’s data through a secure web portal called the Bigfoot Clinic Hub.

JDRF said in a statement it “applauds the U.S. FDA on its decision to provide clearance for the Bigfoot Unity Diabetes Management by Bigfoot Biomedical.”

The new system “fills a critical gap and brings benefits of automation and device interconnectedness to people with diabetes who rely on multiple daily injections to manage their blood sugar levels.” It is a “win for both the type 1 and type 2 diabetes communities as it broadens the options of treatment to alleviate daily burdens.”
 

Growing market for smart insulin pens

The device is the latest advance in the “smart pen” field of semiautomated insulin delivery in which pen and compatible devices, software, and platforms are teamed up in various combinations to provide easier insulin dosing for patients with diabetes who require multiple daily injections but don’t wear insulin pumps.

On May 6, 2021, Eli Lilly announced it had signed “strategic international agreements” with Dexcom, Glooko, MyDiabby Healthcare, and Roche to provide platforms or devices compatible with Lilly’s prefilled Tempo Pen, which is already available in several global markets, and the Tempo Smart Button, currently in late-stage development and pending CE mark.  

And in November 2020, Medtronic launched a new version of its smart insulin pen with integrated CGM called the InPen. The reusable insulin injector pen uses a smartphone app to calculate dosing of short-acting insulin based on CGM readings and allows users to view glucose readings and insulin dose information. It was originally launched in 2017 by Companion Medical, and the company was acquired by Medtronic in September 2020.

Novo Nordisk and Sanofi are also developing products in the smart pen space.

More information about the Bigfoot Unity Program is available here.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has cleared the Bigfoot Unity Diabetes Management System, a cap device that connects to insulin pens and translates continuous glucose data into dosing recommendations, for use in individuals aged 12 and older.

The Bigfoot Unity System has three primary components – proprietary smart pen caps for both rapid- and long-acting insulin, a mobile app, and an integrated FreeStyle Libre 2 continuous glucose monitor (iCGM) sensor, which was FDA-cleared in June 2020 – that fit into the person’s dose-decision process when they need it throughout the day.

It allows the user to scan the FreeStyle Libre 2 sensor, displaying the user’s current glucose value, trend arrow, and recommended correction dose. The smart pen cap also directly displays the health care provider’s suggested meal insulin doses with the correction dose. In just a few steps the system gives the person with diabetes support to make real-time treatment decisions.

It also includes hypoglycemia alerts and is compatible with all major U.S. brands of rapid- and long-acting disposable insulin pens.  

Health care providers can monitor the patient’s data through a secure web portal called the Bigfoot Clinic Hub.

JDRF said in a statement it “applauds the U.S. FDA on its decision to provide clearance for the Bigfoot Unity Diabetes Management by Bigfoot Biomedical.”

The new system “fills a critical gap and brings benefits of automation and device interconnectedness to people with diabetes who rely on multiple daily injections to manage their blood sugar levels.” It is a “win for both the type 1 and type 2 diabetes communities as it broadens the options of treatment to alleviate daily burdens.”
 

Growing market for smart insulin pens

The device is the latest advance in the “smart pen” field of semiautomated insulin delivery in which pen and compatible devices, software, and platforms are teamed up in various combinations to provide easier insulin dosing for patients with diabetes who require multiple daily injections but don’t wear insulin pumps.

On May 6, 2021, Eli Lilly announced it had signed “strategic international agreements” with Dexcom, Glooko, MyDiabby Healthcare, and Roche to provide platforms or devices compatible with Lilly’s prefilled Tempo Pen, which is already available in several global markets, and the Tempo Smart Button, currently in late-stage development and pending CE mark.  

And in November 2020, Medtronic launched a new version of its smart insulin pen with integrated CGM called the InPen. The reusable insulin injector pen uses a smartphone app to calculate dosing of short-acting insulin based on CGM readings and allows users to view glucose readings and insulin dose information. It was originally launched in 2017 by Companion Medical, and the company was acquired by Medtronic in September 2020.

Novo Nordisk and Sanofi are also developing products in the smart pen space.

More information about the Bigfoot Unity Program is available here.

A version of this article first appeared on Medscape.com.

Restrictions due to COVID-19 created new challenges for maintaining the values of palliative care and educating medical students about it during the pandemic, Clarissa Johnston, MD, said during a virtual presentation at the annual meeting of the Society of General Internal Medicine.

Dr. Johnston, of the University of Texas at Austin, and colleagues experienced an extreme COVID-19 surge when they reopened after initial closure in the first weeks of the pandemic.

“Our hospital and clinics are the health care safety net in Austin, and we serve a predominantly uninsured and Hispanic population that experienced a greater burden of COVID-19 than other populations in our area,” she said in the presentation.

The rapid onset and spread of COVID-19 locally required physicians and staff to innovate quickly, and “we developed and implemented collaborative and novel partnerships between generalists and palliative care specialists to help ensure that our core humanizing values were not lost in the pandemic,” Dr. Johnston emphasized.

Collaboration between internal medicine and palliative care involved developing relationship-centered communication for families and health care workers, as well as engaging medical students in a Transitions of Care elective, Dr. Johnston said.

The early weeks of the pandemic impacted families with the no visitor policy and the loss of death rituals, she said. Health care providers suffered, too, as nurses experienced an overload of work, fears for their own health and safety, and feelings of disconnect from their patients. Physicians dealt with the challenges of a unique illness, and their own fears and uncertainty, Dr. Johnston said.
 

Meeting communication challenges

One of the strategies used to bridge the communication gap caused by the lack of visitors and family contact was the adoption of the Meet My Loved One program, adapted from a similar program at the University of Alabama, said Dr. Johnston. Meet My Loved One was a collaborative effort focused on ICU patients, Dr. Johnston said. Members of the primary care team, including medical students in the Transitions of Care elective, called family members of ICU patients to collect personal details and humanizing information about the patient, such as preferred name, favorite foods, favorite activities, and some personal history (i.e. played basketball when he was young), and this information was collated, summarized, and posted on the door of the patient’s room.

Advanced care conversations

Advanced care planning (ACP) benefits include not only the promotion of patient-centered care, but also decreases in ICU admissions, length of stay, and cost. Dr. Johnston and colleagues developed a multipronged curriculum that trainees could use to have ACP conversations with clinic patients who would be considered high risk if they developed COVID-19 infections, Dr. Johnston explained. As part of the elective, medical students were trained to have ACP conversations with patients via telehealth; students practiced role-playing conversations with each other via Zoom and met virtually as a group to review the conversations, she said.

Maintaining Humanity

“COVID-19 has changed the way we interact with patients and families,” Dr. Johnston said in an interview. The inability to rely on face-to-face discussions means that “we really need to think carefully how we maintain humanity and the human touch,” she said.

Challenges in providing palliative care during the pandemic include “maintaining humanity, remembering that there is a person behind the prone, paralyzed patient, with family members who love them, and are desperate to be with them but unable,” Dr. Johnston said.

“The Meet My Loved One program helped, as well as multidisciplinary rounds, chaplain services, and frequent check ins with the bedside nurses,” she said.

“I tried hard to call families every day to start to build that trust and rapport that was lost by all the distancing and lack of visits. I didn’t realize how much the day in and day out care of ICU patients is witnessed by families when they are in the room,” she noted. “During COVID-19, it was so much harder to build trust, especially when you add in the inequities and structural racism problems in our health care system,” she said.

“Why would a family member believe and trust some random doctor calling them on the phone? Were we really trying our hardest? Families didn’t have a way to assess that, at least not like they do when they are at bedside and see how hard everyone works,” Dr. Johnston said. “Video visits helped but were not the same.”

Some key lessons about palliative care Dr. Johnson said she learned from the pandemic were how important it is to remember the patient and family, “how we need to work to build trust,” and that clinicians should be mindful that video visits don’t work for everyone, and to “ask, ask, ask about what you don’t know, including death rituals.”

Additional research needs in palliative care in the wake of COVID-19 include more information on what works and what doesn’t work, from the patient and family perspective, said Dr. Johnston. Communication strategies are important, and “we need to address how we can better communicate around serious illness and end-of-life issues with Black and Brown communities,” she said.
 

Challenges of COVID care

One of the main challenges to providing palliative care in the early days of the pandemic was navigating the constantly evolving science of COVID-19, Aziz Ansari, DO, of Loyola University Chicago, Maywood, Ill., said in an interview.

“It was, and remains, very hard to prognosticate on how a patient will do having respiratory failure with COVID,” said Dr. Ansari, who was the leader of the Palliative Care interest group at the SGIM meeting.

“So, the challenge was how to have a conversation on goals, values, and preferences when we really did not know the disease entity,” Dr. Ansari noted.

“We were surprised many times [when patients with COVID-19] recovered though it took a long time, so we could not really say that in the acute phase of COVID, it was a terminal illness,” he noted.

“Regardless, it still behooves us to have conversations with our patients and families about what are they willing to go through, and how they define a quality of life,” he said.

Strategies such as those used at the University of Texas show the importance of primary care palliative skill development, said Dr. Ansari. “Every physician should have the skill set of having conversations with patients and families on goals, values, and preferences even in unknown situations,” he said. That lifelong skill set development begins in medical school, he added.

Dr. Johnston and Dr. Ansari had no financial conflicts to disclose.

Restrictions due to COVID-19 created new challenges for maintaining the values of palliative care and educating medical students about it during the pandemic, Clarissa Johnston, MD, said during a virtual presentation at the annual meeting of the Society of General Internal Medicine.

Dr. Johnston, of the University of Texas at Austin, and colleagues experienced an extreme COVID-19 surge when they reopened after initial closure in the first weeks of the pandemic.

“Our hospital and clinics are the health care safety net in Austin, and we serve a predominantly uninsured and Hispanic population that experienced a greater burden of COVID-19 than other populations in our area,” she said in the presentation.

The rapid onset and spread of COVID-19 locally required physicians and staff to innovate quickly, and “we developed and implemented collaborative and novel partnerships between generalists and palliative care specialists to help ensure that our core humanizing values were not lost in the pandemic,” Dr. Johnston emphasized.

Collaboration between internal medicine and palliative care involved developing relationship-centered communication for families and health care workers, as well as engaging medical students in a Transitions of Care elective, Dr. Johnston said.

The early weeks of the pandemic impacted families with the no visitor policy and the loss of death rituals, she said. Health care providers suffered, too, as nurses experienced an overload of work, fears for their own health and safety, and feelings of disconnect from their patients. Physicians dealt with the challenges of a unique illness, and their own fears and uncertainty, Dr. Johnston said.
 

Meeting communication challenges

One of the strategies used to bridge the communication gap caused by the lack of visitors and family contact was the adoption of the Meet My Loved One program, adapted from a similar program at the University of Alabama, said Dr. Johnston. Meet My Loved One was a collaborative effort focused on ICU patients, Dr. Johnston said. Members of the primary care team, including medical students in the Transitions of Care elective, called family members of ICU patients to collect personal details and humanizing information about the patient, such as preferred name, favorite foods, favorite activities, and some personal history (i.e. played basketball when he was young), and this information was collated, summarized, and posted on the door of the patient’s room.

Advanced care conversations

Advanced care planning (ACP) benefits include not only the promotion of patient-centered care, but also decreases in ICU admissions, length of stay, and cost. Dr. Johnston and colleagues developed a multipronged curriculum that trainees could use to have ACP conversations with clinic patients who would be considered high risk if they developed COVID-19 infections, Dr. Johnston explained. As part of the elective, medical students were trained to have ACP conversations with patients via telehealth; students practiced role-playing conversations with each other via Zoom and met virtually as a group to review the conversations, she said.

Maintaining Humanity

“COVID-19 has changed the way we interact with patients and families,” Dr. Johnston said in an interview. The inability to rely on face-to-face discussions means that “we really need to think carefully how we maintain humanity and the human touch,” she said.

Challenges in providing palliative care during the pandemic include “maintaining humanity, remembering that there is a person behind the prone, paralyzed patient, with family members who love them, and are desperate to be with them but unable,” Dr. Johnston said.

“The Meet My Loved One program helped, as well as multidisciplinary rounds, chaplain services, and frequent check ins with the bedside nurses,” she said.

“I tried hard to call families every day to start to build that trust and rapport that was lost by all the distancing and lack of visits. I didn’t realize how much the day in and day out care of ICU patients is witnessed by families when they are in the room,” she noted. “During COVID-19, it was so much harder to build trust, especially when you add in the inequities and structural racism problems in our health care system,” she said.

“Why would a family member believe and trust some random doctor calling them on the phone? Were we really trying our hardest? Families didn’t have a way to assess that, at least not like they do when they are at bedside and see how hard everyone works,” Dr. Johnston said. “Video visits helped but were not the same.”

Some key lessons about palliative care Dr. Johnson said she learned from the pandemic were how important it is to remember the patient and family, “how we need to work to build trust,” and that clinicians should be mindful that video visits don’t work for everyone, and to “ask, ask, ask about what you don’t know, including death rituals.”

Additional research needs in palliative care in the wake of COVID-19 include more information on what works and what doesn’t work, from the patient and family perspective, said Dr. Johnston. Communication strategies are important, and “we need to address how we can better communicate around serious illness and end-of-life issues with Black and Brown communities,” she said.
 

Challenges of COVID care

One of the main challenges to providing palliative care in the early days of the pandemic was navigating the constantly evolving science of COVID-19, Aziz Ansari, DO, of Loyola University Chicago, Maywood, Ill., said in an interview.

“It was, and remains, very hard to prognosticate on how a patient will do having respiratory failure with COVID,” said Dr. Ansari, who was the leader of the Palliative Care interest group at the SGIM meeting.

“So, the challenge was how to have a conversation on goals, values, and preferences when we really did not know the disease entity,” Dr. Ansari noted.

“We were surprised many times [when patients with COVID-19] recovered though it took a long time, so we could not really say that in the acute phase of COVID, it was a terminal illness,” he noted.

“Regardless, it still behooves us to have conversations with our patients and families about what are they willing to go through, and how they define a quality of life,” he said.

Strategies such as those used at the University of Texas show the importance of primary care palliative skill development, said Dr. Ansari. “Every physician should have the skill set of having conversations with patients and families on goals, values, and preferences even in unknown situations,” he said. That lifelong skill set development begins in medical school, he added.

Dr. Johnston and Dr. Ansari had no financial conflicts to disclose.

Restrictions due to COVID-19 created new challenges for maintaining the values of palliative care and educating medical students about it during the pandemic, Clarissa Johnston, MD, said during a virtual presentation at the annual meeting of the Society of General Internal Medicine.

Dr. Johnston, of the University of Texas at Austin, and colleagues experienced an extreme COVID-19 surge when they reopened after initial closure in the first weeks of the pandemic.

“Our hospital and clinics are the health care safety net in Austin, and we serve a predominantly uninsured and Hispanic population that experienced a greater burden of COVID-19 than other populations in our area,” she said in the presentation.

The rapid onset and spread of COVID-19 locally required physicians and staff to innovate quickly, and “we developed and implemented collaborative and novel partnerships between generalists and palliative care specialists to help ensure that our core humanizing values were not lost in the pandemic,” Dr. Johnston emphasized.

Collaboration between internal medicine and palliative care involved developing relationship-centered communication for families and health care workers, as well as engaging medical students in a Transitions of Care elective, Dr. Johnston said.

The early weeks of the pandemic impacted families with the no visitor policy and the loss of death rituals, she said. Health care providers suffered, too, as nurses experienced an overload of work, fears for their own health and safety, and feelings of disconnect from their patients. Physicians dealt with the challenges of a unique illness, and their own fears and uncertainty, Dr. Johnston said.
 

Meeting communication challenges

One of the strategies used to bridge the communication gap caused by the lack of visitors and family contact was the adoption of the Meet My Loved One program, adapted from a similar program at the University of Alabama, said Dr. Johnston. Meet My Loved One was a collaborative effort focused on ICU patients, Dr. Johnston said. Members of the primary care team, including medical students in the Transitions of Care elective, called family members of ICU patients to collect personal details and humanizing information about the patient, such as preferred name, favorite foods, favorite activities, and some personal history (i.e. played basketball when he was young), and this information was collated, summarized, and posted on the door of the patient’s room.

Advanced care conversations

Advanced care planning (ACP) benefits include not only the promotion of patient-centered care, but also decreases in ICU admissions, length of stay, and cost. Dr. Johnston and colleagues developed a multipronged curriculum that trainees could use to have ACP conversations with clinic patients who would be considered high risk if they developed COVID-19 infections, Dr. Johnston explained. As part of the elective, medical students were trained to have ACP conversations with patients via telehealth; students practiced role-playing conversations with each other via Zoom and met virtually as a group to review the conversations, she said.

Maintaining Humanity

“COVID-19 has changed the way we interact with patients and families,” Dr. Johnston said in an interview. The inability to rely on face-to-face discussions means that “we really need to think carefully how we maintain humanity and the human touch,” she said.

Challenges in providing palliative care during the pandemic include “maintaining humanity, remembering that there is a person behind the prone, paralyzed patient, with family members who love them, and are desperate to be with them but unable,” Dr. Johnston said.

“The Meet My Loved One program helped, as well as multidisciplinary rounds, chaplain services, and frequent check ins with the bedside nurses,” she said.

“I tried hard to call families every day to start to build that trust and rapport that was lost by all the distancing and lack of visits. I didn’t realize how much the day in and day out care of ICU patients is witnessed by families when they are in the room,” she noted. “During COVID-19, it was so much harder to build trust, especially when you add in the inequities and structural racism problems in our health care system,” she said.

“Why would a family member believe and trust some random doctor calling them on the phone? Were we really trying our hardest? Families didn’t have a way to assess that, at least not like they do when they are at bedside and see how hard everyone works,” Dr. Johnston said. “Video visits helped but were not the same.”

Some key lessons about palliative care Dr. Johnson said she learned from the pandemic were how important it is to remember the patient and family, “how we need to work to build trust,” and that clinicians should be mindful that video visits don’t work for everyone, and to “ask, ask, ask about what you don’t know, including death rituals.”

Additional research needs in palliative care in the wake of COVID-19 include more information on what works and what doesn’t work, from the patient and family perspective, said Dr. Johnston. Communication strategies are important, and “we need to address how we can better communicate around serious illness and end-of-life issues with Black and Brown communities,” she said.
 

Challenges of COVID care

One of the main challenges to providing palliative care in the early days of the pandemic was navigating the constantly evolving science of COVID-19, Aziz Ansari, DO, of Loyola University Chicago, Maywood, Ill., said in an interview.

“It was, and remains, very hard to prognosticate on how a patient will do having respiratory failure with COVID,” said Dr. Ansari, who was the leader of the Palliative Care interest group at the SGIM meeting.

“So, the challenge was how to have a conversation on goals, values, and preferences when we really did not know the disease entity,” Dr. Ansari noted.

“We were surprised many times [when patients with COVID-19] recovered though it took a long time, so we could not really say that in the acute phase of COVID, it was a terminal illness,” he noted.

“Regardless, it still behooves us to have conversations with our patients and families about what are they willing to go through, and how they define a quality of life,” he said.

Strategies such as those used at the University of Texas show the importance of primary care palliative skill development, said Dr. Ansari. “Every physician should have the skill set of having conversations with patients and families on goals, values, and preferences even in unknown situations,” he said. That lifelong skill set development begins in medical school, he added.

Dr. Johnston and Dr. Ansari had no financial conflicts to disclose.

In 2016, results from the LEADER trial of liraglutide in patients with type 2 diabetes helped jump-start awareness of the potential role of this new class of drugs, the glucagonlike peptide–1 receptor agonists, for reducing cardiovascular events. The randomized, placebo-controlled trial enrolled more than 9000 patients at more than 400 sites in over 30 countries, and took nearly 6 years from the start of patient enrollment to publication of the landmark results.

In December 2020, an independent team of researchers published results from a study with a design identical to LEADER, but used data that came not from a massive, global, years-long trial but from already-existing numbers culled from three large U.S. insurance claim databases. The result of this emulation using real-world data was virtually identical to what the actual trial showed, replicating both the direction and statistical significance of the original finding of the randomized, controlled trial (RCT).

What if research proved that this sort of RCT emulation could reliably be done on a regular basis? What might it mean for regulatory decisions on drugs and devices that historically have been based entirely on efficacy evidence from RCTs?
 

Making the most of a sea of observational data

Medicine in the United States has become increasingly awash in a sea of observational data collected from sources that include electronic health records, insurance claims, and increasingly, personal-health monitoring devices.

The Food and Drug Administration is now in the process of trying to figure out how it can legitimately harness this tsunami of real-world data to make efficacy decisions, essentially creating a new category of evidence to complement traditional data from randomized trials. It’s an opportunity that agency staff and their outside advisors have been keen to seize, especially given the soaring cost of prospective, randomized trials.

Recognition of this untapped resource in part led to a key initiative, among many others, included in the 21st Century Cures Act, passed in December 2016. Among the Act’s mandates was that, by the end of 2021, the FDA would issue guidance on when drug sponsors could use real-world evidence (RWE) to either help support a new indication for an already approved drug or help satisfy postapproval study requirements.

The initiative recognizes that this approach is not appropriate for initial drug approvals, which remain exclusively reliant on evidence from RCTs. Instead, it seems best suited to support expanding indications for already approved drugs.

Although FDA staff have made progress in identifying the challenges and broadening their understanding of how to best handle real-world data that come from observing patients in routine practice, agency leaders stress that this complex issue will likely not be fully resolved by their guidance to be published later this year. The FDA released a draft of the guidance in May 2019.
 

Can RWE be ‘credible and reliable?’

“Whether observational, nonrandomized data can become credible enough to use is what we’re talking about. These are possibilities that need to be explained and better understood,” said Robert Temple, MD, deputy director for clinical science of the FDA Center for Drug Evaluation and Research.

“Since the 1970s, the FDA has recognized historical controls as legitimate, so it’s possible [for RWE] to be credible. The big test is when is it credible and reliable enough [to assess efficacy]?” wondered Dr. Temple during a 2-day workshop on the topic held mid-February and organized by Duke University’s Margolis Center for Health Policy.

“We’re approaching an inflection point regarding how observational studies are generated and used, but our evidentiary standards will not lower, and it will be a case-by-case decision” by the agency as they review future RWE submissions, said John Concato, MD, the FDA’s associate director for real-world evidence, during the workshop.

“We are working toward guidance development, but also looking down the road to what we need to do to enable this,” said Dr. Concato. “It’s a complicated issue. If it was easy, it would have already been fixed.” He added that the agency will likely release a “portfolio” of guidance for submitting real-world data and RWE. Real-world data are raw information that, when analyzed, become RWE.

In short, the FDA seems headed toward guidance that won’t spell out a pathway that guarantees success using RWE but will at least open the door to consideration of this unprecedented application.
 

Not like flipping a switch

The guidance will not activate acceptance of RWE all at once. “It’s not like a light switch,” cautioned Adam Kroetsch, MPP, research director for biomedical innovation and regulatory policy at Duke-Margolis in Washington, D.C. “It’s an evolutionary process,” and the upcoming guidance will provide “just a little more clarity” on what sorts of best practices using RWE the FDA will find persuasive. “It’s hard for the FDA to clearly say what it’s looking for until they see some good examples,” Dr. Kroetsch said in an interview.

What will change is that drug sponsors can submit using RWE, and the FDA “will have a more open-minded view,” predicted Sebastian Schneeweiss, MD, ScD, a workshop participant and chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston. “For the first time, a law required [the FDA] to take a serious look” at observational data for efficacy assessment.

“The FDA has had a bias against using RWE for evidence of efficacy but has long used it to understand drug safety. Now the FDA is trying to wrap its arms around how to best use RWE” for efficacy decisions, said Joseph S. Ross, MD, another workshop participant and professor of medicine and public health at Yale University, New Haven, Conn.

The agency’s cautious approach is reassuring, Dr. Ross noted in an interview. “There was worry that the 21st Century Cures Act would open the door to allowing real-world data to be used in ways that weren’t very reliable. Very quickly, the FDA started trying to figure out the best ways to use these data in reasonable ways.”
 

Duplicating RCTs with RWE

To help better understand the potential use of RWE, the FDA sponsored several demonstration projects. Researchers presented results from three of these projects during the workshop in February. All three examined whether RWE, plugged into the design of an actual RCT, can produce roughly similar results when similar patients are used.

A generally consistent finding from the three demonstration projects was that “when the data are fit for purpose” the emulated or duplicated analyses with RWE “can come to similar conclusions” as the actual RCTs, said Dr. Schneeweiss, who leads one of the demonstration projects, RCT DUPLICATE.

At the workshop he reported results from RWE duplications of 20 different RCTs using insurance claims data from U.S. patients. The findings came from 10 duplications already reported in Circulation in December 2020 (including a duplication of the LEADER trial), and an additional 10 as yet unpublished RCT duplications. In the next few months, the researchers intend to assess a final group of 10 more RCT duplications.

Workshop participants also presented results from two other FDA demonstration projects: the OPERAND program run by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard; and the CERSI program based at Yale and the Mayo Clinic in Rochester, Minn. Both are smaller in scale than RCT DUPLICATE, incorporate lab data in addition to claims data, and in some cases test how well RWE can emulate RCTs that are not yet completed.

Collectively, results from these demonstration projects suggest that RWE can successfully emulate the results of an RCT, said Dr. Ross, a coinvestigator on the CERSI study. But the CERSI findings also highlighted how an RCT can fall short of clinical relevance.

“One of our most important findings was that RCTs don’t always represent real-world practice,” he said. His group attempted to replicate the 5,000-patient GRADE trial of four different drug options added to metformin in patients with type 2 diabetes. One of the four options included insulin glargine (Lantus), and the attempt to emulate the study with RWE hit the bump that no relevant real-world patients in their US claims database actually received the formulation.

That means the GRADE trial “is almost meaningless. It doesn’t reflect real-world practice,” Dr. Ross noted.

Results from the three demonstration projects “highlight the gaps we still have,” summed up Dr. Kroetsch. “They show where we need better data” from observational sources that function as well as data from RCTs.

Still, the demonstration project results are “an important step forward in establishing the validity of real-world evidence,” commented David Kerr, MBChB, an endocrinologist and director of research and innovation at the Sansum Diabetes Research Institute in Santa Barbara, Calif.
 

‘Target trials’ tether RWE

The target trial approach to designing an observational study is a key tool for boosting reliability and applicability of the results. The idea is to create a well-designed trial that could be the basis for a conventional RCT, and then use observational data to flesh out the target trial instead of collecting data from prospectively enrolled patients.

Designing observational studies that emulate target trials allows causal inferences, said Miguel A. Hernán, MD, DrPH, a professor of biostatistics and epidemiology at the Harvard School of Public Health, Boston. Plugging real-world data into the framework of an appropriately designed target trial substantially cuts the risk of a biased analysis, he explained during the workshop.

However, the approach has limitations. The target trial must be a pragmatic trial, and the approach does not work for placebo-controlled trials, although it can accommodate a usual-care control arm. It also usually precludes patient blinding, testing treatments not used in routine practice, and close monitoring of patients in ways that are uncommon in usual care.

The target trial approach received broad endorsement during the workshop as the future for observational studies destined for efficacy consideration by the FDA.

“The idea of prespecifying a target trial is a really fantastic place to start,” commented Robert Ball, MD, deputy director of the FDA Office of Surveillance and Epidemiology. “There is still a whole set of questions once the trial is prespecified, but prespecification would be a fantastic step forward,” he said during the workshop.

Participants also endorsed other important steps to boost the value of observational studies for regulatory reviews, including preregistering the study on a site such as clinicaltrials.gov; being fully transparent about the origins of observational data; using data that match the needs of the target trial; not reviewing the data in advance to avoid cherry picking and gaming the analysis; and reporting neutral or negative results when they occur, something often not currently done for observational analyses.

But although there was clear progress and much agreement among thought leaders at the workshop, FDA representatives stressed caution in moving forward.
 

“No easy answer”

“With more experience, we can learn what works and what doesn’t work in generating valid results from observational studies,” said Dr. Concato. “Although the observational results have upside potential, we need to learn more. There is no easy answer, no checklist for fit-for-use data, no off-the-shelf study design, and no ideal analytic method.”

Dr. Concato acknowledged that the FDA’s goal is clear given the 2016 legislation. “The FDA is embracing our obligations under the 21st Century Cures Act to evaluate use of real-world data and real-world evidence.”

He also suggested that researchers “shy away from a false dichotomy of RCTs or observational studies and instead think about how and when RCTs and observational studies can be designed and conducted to yield trustworthy results.” Dr. Concato’s solution: “a taxonomy of interventional or noninterventional studies.”

“The FDA is under enormous pressure to embrace real-world evidence, both because of the economics of running RCTs and because of the availability of new observational data from electronic health records, wearable devices, claims, etc.,” said Dr. Kerr, who did not participate in the workshop but coauthored an editorial that calls for using real-world data in regulatory decisions for drugs and devices for diabetes. These factors create an “irresistible force” spurring the FDA to consider observational, noninterventional data.

“I think the FDA really wants this to go forward,” Dr. Kerr added in an interview. “The FDA keeps telling us that clinical trials do not have enough women or patients from minority groups. Real-world data is a way to address that. This will not be the death of RCTs, but this work shines a light on the deficiencies of RCTs and how the deficiencies can be dealt with.”

Dr. Kroetsch has reported no relevant financial relationships. Dr. Schneeweiss has reported being a consultant to and holding equity in Aetion and receiving research funding from the FDA. Dr. Ross has reported receiving research funding from the FDA, Johnson & Johnson, and Medtronic. Dr. Hernán has reported being a consultant for Cytel. Dr. Kerr has reported being a consultant for Ascensia, EOFlow, Lifecare, Merck, Novo Nordisk, Roche Diagnostics, and Voluntis. Dr. Temple, Dr. Concato, and Dr. Ball are FDA employees.

A version of this article first appeared on Medscape.com.

In 2016, results from the LEADER trial of liraglutide in patients with type 2 diabetes helped jump-start awareness of the potential role of this new class of drugs, the glucagonlike peptide–1 receptor agonists, for reducing cardiovascular events. The randomized, placebo-controlled trial enrolled more than 9000 patients at more than 400 sites in over 30 countries, and took nearly 6 years from the start of patient enrollment to publication of the landmark results.

In December 2020, an independent team of researchers published results from a study with a design identical to LEADER, but used data that came not from a massive, global, years-long trial but from already-existing numbers culled from three large U.S. insurance claim databases. The result of this emulation using real-world data was virtually identical to what the actual trial showed, replicating both the direction and statistical significance of the original finding of the randomized, controlled trial (RCT).

What if research proved that this sort of RCT emulation could reliably be done on a regular basis? What might it mean for regulatory decisions on drugs and devices that historically have been based entirely on efficacy evidence from RCTs?
 

Making the most of a sea of observational data

Medicine in the United States has become increasingly awash in a sea of observational data collected from sources that include electronic health records, insurance claims, and increasingly, personal-health monitoring devices.

The Food and Drug Administration is now in the process of trying to figure out how it can legitimately harness this tsunami of real-world data to make efficacy decisions, essentially creating a new category of evidence to complement traditional data from randomized trials. It’s an opportunity that agency staff and their outside advisors have been keen to seize, especially given the soaring cost of prospective, randomized trials.

Recognition of this untapped resource in part led to a key initiative, among many others, included in the 21st Century Cures Act, passed in December 2016. Among the Act’s mandates was that, by the end of 2021, the FDA would issue guidance on when drug sponsors could use real-world evidence (RWE) to either help support a new indication for an already approved drug or help satisfy postapproval study requirements.

The initiative recognizes that this approach is not appropriate for initial drug approvals, which remain exclusively reliant on evidence from RCTs. Instead, it seems best suited to support expanding indications for already approved drugs.

Although FDA staff have made progress in identifying the challenges and broadening their understanding of how to best handle real-world data that come from observing patients in routine practice, agency leaders stress that this complex issue will likely not be fully resolved by their guidance to be published later this year. The FDA released a draft of the guidance in May 2019.
 

Can RWE be ‘credible and reliable?’

“Whether observational, nonrandomized data can become credible enough to use is what we’re talking about. These are possibilities that need to be explained and better understood,” said Robert Temple, MD, deputy director for clinical science of the FDA Center for Drug Evaluation and Research.

“Since the 1970s, the FDA has recognized historical controls as legitimate, so it’s possible [for RWE] to be credible. The big test is when is it credible and reliable enough [to assess efficacy]?” wondered Dr. Temple during a 2-day workshop on the topic held mid-February and organized by Duke University’s Margolis Center for Health Policy.

“We’re approaching an inflection point regarding how observational studies are generated and used, but our evidentiary standards will not lower, and it will be a case-by-case decision” by the agency as they review future RWE submissions, said John Concato, MD, the FDA’s associate director for real-world evidence, during the workshop.

“We are working toward guidance development, but also looking down the road to what we need to do to enable this,” said Dr. Concato. “It’s a complicated issue. If it was easy, it would have already been fixed.” He added that the agency will likely release a “portfolio” of guidance for submitting real-world data and RWE. Real-world data are raw information that, when analyzed, become RWE.

In short, the FDA seems headed toward guidance that won’t spell out a pathway that guarantees success using RWE but will at least open the door to consideration of this unprecedented application.
 

Not like flipping a switch

The guidance will not activate acceptance of RWE all at once. “It’s not like a light switch,” cautioned Adam Kroetsch, MPP, research director for biomedical innovation and regulatory policy at Duke-Margolis in Washington, D.C. “It’s an evolutionary process,” and the upcoming guidance will provide “just a little more clarity” on what sorts of best practices using RWE the FDA will find persuasive. “It’s hard for the FDA to clearly say what it’s looking for until they see some good examples,” Dr. Kroetsch said in an interview.

What will change is that drug sponsors can submit using RWE, and the FDA “will have a more open-minded view,” predicted Sebastian Schneeweiss, MD, ScD, a workshop participant and chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston. “For the first time, a law required [the FDA] to take a serious look” at observational data for efficacy assessment.

“The FDA has had a bias against using RWE for evidence of efficacy but has long used it to understand drug safety. Now the FDA is trying to wrap its arms around how to best use RWE” for efficacy decisions, said Joseph S. Ross, MD, another workshop participant and professor of medicine and public health at Yale University, New Haven, Conn.

The agency’s cautious approach is reassuring, Dr. Ross noted in an interview. “There was worry that the 21st Century Cures Act would open the door to allowing real-world data to be used in ways that weren’t very reliable. Very quickly, the FDA started trying to figure out the best ways to use these data in reasonable ways.”
 

Duplicating RCTs with RWE

To help better understand the potential use of RWE, the FDA sponsored several demonstration projects. Researchers presented results from three of these projects during the workshop in February. All three examined whether RWE, plugged into the design of an actual RCT, can produce roughly similar results when similar patients are used.

A generally consistent finding from the three demonstration projects was that “when the data are fit for purpose” the emulated or duplicated analyses with RWE “can come to similar conclusions” as the actual RCTs, said Dr. Schneeweiss, who leads one of the demonstration projects, RCT DUPLICATE.

At the workshop he reported results from RWE duplications of 20 different RCTs using insurance claims data from U.S. patients. The findings came from 10 duplications already reported in Circulation in December 2020 (including a duplication of the LEADER trial), and an additional 10 as yet unpublished RCT duplications. In the next few months, the researchers intend to assess a final group of 10 more RCT duplications.

Workshop participants also presented results from two other FDA demonstration projects: the OPERAND program run by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard; and the CERSI program based at Yale and the Mayo Clinic in Rochester, Minn. Both are smaller in scale than RCT DUPLICATE, incorporate lab data in addition to claims data, and in some cases test how well RWE can emulate RCTs that are not yet completed.

Collectively, results from these demonstration projects suggest that RWE can successfully emulate the results of an RCT, said Dr. Ross, a coinvestigator on the CERSI study. But the CERSI findings also highlighted how an RCT can fall short of clinical relevance.

“One of our most important findings was that RCTs don’t always represent real-world practice,” he said. His group attempted to replicate the 5,000-patient GRADE trial of four different drug options added to metformin in patients with type 2 diabetes. One of the four options included insulin glargine (Lantus), and the attempt to emulate the study with RWE hit the bump that no relevant real-world patients in their US claims database actually received the formulation.

That means the GRADE trial “is almost meaningless. It doesn’t reflect real-world practice,” Dr. Ross noted.

Results from the three demonstration projects “highlight the gaps we still have,” summed up Dr. Kroetsch. “They show where we need better data” from observational sources that function as well as data from RCTs.

Still, the demonstration project results are “an important step forward in establishing the validity of real-world evidence,” commented David Kerr, MBChB, an endocrinologist and director of research and innovation at the Sansum Diabetes Research Institute in Santa Barbara, Calif.
 

‘Target trials’ tether RWE

The target trial approach to designing an observational study is a key tool for boosting reliability and applicability of the results. The idea is to create a well-designed trial that could be the basis for a conventional RCT, and then use observational data to flesh out the target trial instead of collecting data from prospectively enrolled patients.

Designing observational studies that emulate target trials allows causal inferences, said Miguel A. Hernán, MD, DrPH, a professor of biostatistics and epidemiology at the Harvard School of Public Health, Boston. Plugging real-world data into the framework of an appropriately designed target trial substantially cuts the risk of a biased analysis, he explained during the workshop.

However, the approach has limitations. The target trial must be a pragmatic trial, and the approach does not work for placebo-controlled trials, although it can accommodate a usual-care control arm. It also usually precludes patient blinding, testing treatments not used in routine practice, and close monitoring of patients in ways that are uncommon in usual care.

The target trial approach received broad endorsement during the workshop as the future for observational studies destined for efficacy consideration by the FDA.

“The idea of prespecifying a target trial is a really fantastic place to start,” commented Robert Ball, MD, deputy director of the FDA Office of Surveillance and Epidemiology. “There is still a whole set of questions once the trial is prespecified, but prespecification would be a fantastic step forward,” he said during the workshop.

Participants also endorsed other important steps to boost the value of observational studies for regulatory reviews, including preregistering the study on a site such as clinicaltrials.gov; being fully transparent about the origins of observational data; using data that match the needs of the target trial; not reviewing the data in advance to avoid cherry picking and gaming the analysis; and reporting neutral or negative results when they occur, something often not currently done for observational analyses.

But although there was clear progress and much agreement among thought leaders at the workshop, FDA representatives stressed caution in moving forward.
 

“No easy answer”

“With more experience, we can learn what works and what doesn’t work in generating valid results from observational studies,” said Dr. Concato. “Although the observational results have upside potential, we need to learn more. There is no easy answer, no checklist for fit-for-use data, no off-the-shelf study design, and no ideal analytic method.”

Dr. Concato acknowledged that the FDA’s goal is clear given the 2016 legislation. “The FDA is embracing our obligations under the 21st Century Cures Act to evaluate use of real-world data and real-world evidence.”

He also suggested that researchers “shy away from a false dichotomy of RCTs or observational studies and instead think about how and when RCTs and observational studies can be designed and conducted to yield trustworthy results.” Dr. Concato’s solution: “a taxonomy of interventional or noninterventional studies.”

“The FDA is under enormous pressure to embrace real-world evidence, both because of the economics of running RCTs and because of the availability of new observational data from electronic health records, wearable devices, claims, etc.,” said Dr. Kerr, who did not participate in the workshop but coauthored an editorial that calls for using real-world data in regulatory decisions for drugs and devices for diabetes. These factors create an “irresistible force” spurring the FDA to consider observational, noninterventional data.

“I think the FDA really wants this to go forward,” Dr. Kerr added in an interview. “The FDA keeps telling us that clinical trials do not have enough women or patients from minority groups. Real-world data is a way to address that. This will not be the death of RCTs, but this work shines a light on the deficiencies of RCTs and how the deficiencies can be dealt with.”

Dr. Kroetsch has reported no relevant financial relationships. Dr. Schneeweiss has reported being a consultant to and holding equity in Aetion and receiving research funding from the FDA. Dr. Ross has reported receiving research funding from the FDA, Johnson & Johnson, and Medtronic. Dr. Hernán has reported being a consultant for Cytel. Dr. Kerr has reported being a consultant for Ascensia, EOFlow, Lifecare, Merck, Novo Nordisk, Roche Diagnostics, and Voluntis. Dr. Temple, Dr. Concato, and Dr. Ball are FDA employees.

A version of this article first appeared on Medscape.com.

In 2016, results from the LEADER trial of liraglutide in patients with type 2 diabetes helped jump-start awareness of the potential role of this new class of drugs, the glucagonlike peptide–1 receptor agonists, for reducing cardiovascular events. The randomized, placebo-controlled trial enrolled more than 9000 patients at more than 400 sites in over 30 countries, and took nearly 6 years from the start of patient enrollment to publication of the landmark results.

In December 2020, an independent team of researchers published results from a study with a design identical to LEADER, but used data that came not from a massive, global, years-long trial but from already-existing numbers culled from three large U.S. insurance claim databases. The result of this emulation using real-world data was virtually identical to what the actual trial showed, replicating both the direction and statistical significance of the original finding of the randomized, controlled trial (RCT).

What if research proved that this sort of RCT emulation could reliably be done on a regular basis? What might it mean for regulatory decisions on drugs and devices that historically have been based entirely on efficacy evidence from RCTs?
 

Making the most of a sea of observational data

Medicine in the United States has become increasingly awash in a sea of observational data collected from sources that include electronic health records, insurance claims, and increasingly, personal-health monitoring devices.

The Food and Drug Administration is now in the process of trying to figure out how it can legitimately harness this tsunami of real-world data to make efficacy decisions, essentially creating a new category of evidence to complement traditional data from randomized trials. It’s an opportunity that agency staff and their outside advisors have been keen to seize, especially given the soaring cost of prospective, randomized trials.

Recognition of this untapped resource in part led to a key initiative, among many others, included in the 21st Century Cures Act, passed in December 2016. Among the Act’s mandates was that, by the end of 2021, the FDA would issue guidance on when drug sponsors could use real-world evidence (RWE) to either help support a new indication for an already approved drug or help satisfy postapproval study requirements.

The initiative recognizes that this approach is not appropriate for initial drug approvals, which remain exclusively reliant on evidence from RCTs. Instead, it seems best suited to support expanding indications for already approved drugs.

Although FDA staff have made progress in identifying the challenges and broadening their understanding of how to best handle real-world data that come from observing patients in routine practice, agency leaders stress that this complex issue will likely not be fully resolved by their guidance to be published later this year. The FDA released a draft of the guidance in May 2019.
 

Can RWE be ‘credible and reliable?’

“Whether observational, nonrandomized data can become credible enough to use is what we’re talking about. These are possibilities that need to be explained and better understood,” said Robert Temple, MD, deputy director for clinical science of the FDA Center for Drug Evaluation and Research.

“Since the 1970s, the FDA has recognized historical controls as legitimate, so it’s possible [for RWE] to be credible. The big test is when is it credible and reliable enough [to assess efficacy]?” wondered Dr. Temple during a 2-day workshop on the topic held mid-February and organized by Duke University’s Margolis Center for Health Policy.

“We’re approaching an inflection point regarding how observational studies are generated and used, but our evidentiary standards will not lower, and it will be a case-by-case decision” by the agency as they review future RWE submissions, said John Concato, MD, the FDA’s associate director for real-world evidence, during the workshop.

“We are working toward guidance development, but also looking down the road to what we need to do to enable this,” said Dr. Concato. “It’s a complicated issue. If it was easy, it would have already been fixed.” He added that the agency will likely release a “portfolio” of guidance for submitting real-world data and RWE. Real-world data are raw information that, when analyzed, become RWE.

In short, the FDA seems headed toward guidance that won’t spell out a pathway that guarantees success using RWE but will at least open the door to consideration of this unprecedented application.
 

Not like flipping a switch

The guidance will not activate acceptance of RWE all at once. “It’s not like a light switch,” cautioned Adam Kroetsch, MPP, research director for biomedical innovation and regulatory policy at Duke-Margolis in Washington, D.C. “It’s an evolutionary process,” and the upcoming guidance will provide “just a little more clarity” on what sorts of best practices using RWE the FDA will find persuasive. “It’s hard for the FDA to clearly say what it’s looking for until they see some good examples,” Dr. Kroetsch said in an interview.

What will change is that drug sponsors can submit using RWE, and the FDA “will have a more open-minded view,” predicted Sebastian Schneeweiss, MD, ScD, a workshop participant and chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston. “For the first time, a law required [the FDA] to take a serious look” at observational data for efficacy assessment.

“The FDA has had a bias against using RWE for evidence of efficacy but has long used it to understand drug safety. Now the FDA is trying to wrap its arms around how to best use RWE” for efficacy decisions, said Joseph S. Ross, MD, another workshop participant and professor of medicine and public health at Yale University, New Haven, Conn.

The agency’s cautious approach is reassuring, Dr. Ross noted in an interview. “There was worry that the 21st Century Cures Act would open the door to allowing real-world data to be used in ways that weren’t very reliable. Very quickly, the FDA started trying to figure out the best ways to use these data in reasonable ways.”